Pbl Exam 6 Case 5

Front 1

1. Innate immunity

Back 1

The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner.

This means that the cells of the innate system recognize, and respond to, pathogens in a generic way, but unlike the acquired immune system, it does not confer long-lasting or protective immunity to the host.

Front 2

2. Examples of innate immunity

Back 2

1. Phagocytosis of bacteria and other invaders by white blood cells
2. Destruction of swallowed organisms by the acid secretions of the stomach and the digestive enzymes
3. Resistance of the skin to invasion by organisms
4. Presence in the blood of certain chemical compounds that attach to foreign organisms and destroys them (lysozymes, basic polypeptides, complement complexes, natural killer cells)

Front 3

3. Acquired immunity

Back 3

AKA adaptive immunity

The body has the ability to develop extremely powerful specific immunity against individual invading agents such as lethal bacteria, viruses, toxins, and even foreign tissues from other animals

Caused by a special immune system that forms antibodies and/or activated lymphocytes that attack and destroy the specific invading organism or toxin.

Front 4

4. Two basic types of acquired immunity

Back 4

1. Humoral immunity (B-cell immunity)

2. Cell mediated immunity (T-cell immunity)

Front 5

5. Importance of antigens

Back 5

Each toxin or each type of organism almost always contains one or more specific chemical compounds in its makeup that are different from all other compounds.

These are proteins or large polysaccharides and it is they that initiate the acquired immunity.

Front 6

6. What is the importance of lymphocytes?

Back 6

They are responsible for acquired immunity

They include the T lymphocytes which form the activated lymphocytes that provide "cell mediated immunity"

and the B lymphocytes which form the antibodies that provide "humoral immunity"

Both types of cells derived from pluripotent hematopoietic stem cells.

Front 7

7. Where are T lymphocytes preprocessed?

Back 7

In the thymus gland

They migrate to the thymus from the bone marrow and divide rapidly and at the same time develop extreme diversity for reacting against different specific antigens.

Front 8

8. Selective processing of the thymus

Back 8

It's thymic education, baby.

The thymus makes certain that any T lymphocytes leaving will not react against proteins or other antigens that are present in the body's own tissue.

It selects which ones will be released by first mixing them with all the specific "self-antigens" from the body's own tissues. If it reacts, it is destroyed and phagocytized instead of being released.

Front 9

9. Where are B lymphocytes preprocessed?

Back 9

In the liver and bone marrow

Instead of the whole cell developing reactivity against an antigen, the B lymphocytes actively secrete antibodies that are the reactive agents.

B lymphocytes also have a greater diversity than T lymphocytes.

Front 10

10. Origin of the many clones of lymphocytes

Back 10

The whole gene for forming each type of T cell or B cell is never present in the original stem cells from which the functional immune cells are formed. Instead, there are only "gene segments"-actually, hundreds of such segments-but not whole genes. During preprocessing of the respective T- and B-cell lymphocytes, these gene segments become mixed with one another in random combinations, in this way finally forming whole genes.

For each functional T or B lymphocyte that is finally formed, the gene structure codes for only a single antigen specificity. These mature cells then become the highly specific T and B cells that spread to and populate the lymphoid tissue.

Front 11

11. Activating clones of B lymphocytes

Back 11

Each B lymphocyte has on the surface of its cell membranes about 100,000 antibody molecules that will react highly specifically w/only one specific type of antigen.

When the appropriate antigen comes along, it immediately attaches to the antibody in the cell membrane; this leads to the activation process.

Front 12

12. Activating clones of T lymphocytes

Back 12

Molecules similar to antibodies, called surface receptor proteins (or T-cell markers), are on the surface of the T-cell membrane, and these, too, are highly specific for one specified activating antigen.

Front 13

13. Role of macrophages in the activation process

Back 13

Most invading organism are first phagocytized and partially digested by the macrophages and the antigenic products are liberated into the macrophage cytosol.

The macrophages then pass these antigens by cell-to-cell contact directly to the lymphocytes, thus leading to activation of lymphocytic clones.

They also secrete IL-1 which also promotes growth of lymphocytes.

Front 14

14. Role of T cells in the activation of the B lymphocytes

Back 14

Some of the T cells that are formed, called "helper cells", secrete specific substances (lymphokines) that activate the specific B lymphocytes.

Front 15

15. Formation of antibodies by plasma cells

Back 15

On entry of a foreign antigens, macrophages in the lymphoid tissue phagocytize the antigen and then present it to adjacent B lymphocytes.

In addition, the antigen is presented to T cells at the same time, and activated helper T cells are formed.

Front 16

16. Formation of memory cells

Back 16

The B-cell population of the specifically activated clone becomes greatly enhanced, and the new B lymphocytes are added to the original lymphocytes of the same clone.

They spread throughout the body and remain dormant until activated once again by a new quantity of the same antigen.

Subsequent exposure will cause a much more rapid and potent antibody response the second time around.

Front 17

17. Differences between primary and secondary responses

Back 17

The primary responses usually have a 1-week delay, weak potency, and a short life.

The secondary response begins rapidly after exposure to the antigen, is far more potent, and forms antibodies for many months rather than only a few weeks.

Front 18

18. What are antibodies?

Back 18

They are gamma globulins called immunoglobulins; they are composed of light and heavy polypeptide chains.

They have a variable portion (for antibodies) and a constant portion (determines properties of antibody).

Front 19

19. Specificity of antibodies

Back 19

Each antibody is specific for a particular antigen; when the antibody is highly specific, there are so many bonding sites that the antibody-antigen coupling is exceedingly strong and is held together by:

1. Hydrophobic bonding
2. Hydrogen boding
3. Ionic attractions
4. van der Waals forces

Front 20

20. Ka (affinity constant)

Back 20

A measure of how tightly the antibody binds with the antigen

Ka= [Bound antibody-antigen]/([antibody]*[antigen])

Front 21

21. Classes of antibodies (five)

Back 21

1. IgM - primary response
2. IgG - 75% of antibodies
3. IgA
4. IgD
5. IgE - involved in allergies

Front 22

22. Two mechanisms of action of antibodies

Back 22

1. Direct attack
2. Activation of the "complement system"

Front 23

23. Direct action of antibodies

Back 23

1. Agglutination (clumping)
2. Precipitation
3. Neutralization
4. Lysis

Front 24

24. Complement system for antibody action

Back 24

"Complement" is a collective term that describes a system of about 20 proteins, many of which are enzyme precursors.

All these are present normally among the plasma proteins in the blood as well as among the proteins that leak out of the capillaries into the tissue spaces. The enzyme precursors are normally inactive, but they can be activated mainly by the so-called classic pathway.

Front 25

25. Classic pathway

Back 25

Initiated by an antigen-antibody reaction

when an antibody binds with an antigen, a specific reactive site on the "constant" portion of the antibody becomes uncovered, or "activated," and this in turn binds directly with the C1 molecule of the complement system, setting into motion a "cascade" of sequential reactions, beginning with activation of the proenzyme C1 itself.

The C1 enzymes that are formed then activates successively increasing quantities of enzymes, so that from a small beginning, an extremely large amplified reaction occurs.

Front 26

26. Important effects of the classic pathway

Back 26

1. Opsonization and phagocytosis
2. Lysis
3. Agglutination
4. Neutralization of viruses
5. Chemotaxis
6. Activation of mast cells and basophils
7. Inflammatory effects

Front 27

27. Release of activated T cells

Back 27

Principal difference from B cells is that instead of releasing antibodies, whole activated T cells are formed and released into the lymph, circulating again and again throughout the body.

Front 28

28. T-lymphocyte memory cells

Back 28

Formed in the same way that B memory cells are formed in the antibody system.

When a clone of T lymphocytes is activated by an antigen, many of the newly formed lymphocytes are preserved in the lymphoid tissue to become additional T lymphocytes of that specific clone.

These memory cells spread throughout the body and are more rapidly released upon second exposure.

Front 29

29. How do T lymphocytes respond to antigens?

Back 29

They respond only when they are bound to specific molecules called MHC proteins on the surface of antigen-presenting cells in the lymphoid tissues.

Front 30

30. Three major types of antigen presenting cells

Back 30

1. Macrophages
2. B lymphocytes
3. Dentritic cells.

Front 31

31. MHC proteins

Back 31

The MHC proteins are encoded by a large group of genes called the major histocompatibility complex (MHC). The MHC proteins bind peptide fragments of antigen proteins that are degraded inside antigen-presenting cells and then transport them to the cell surface.

There are two types of MHC proteins: (1) MHC I proteins, which present antigens to cytotoxic T cells, and (2) MHC II proteins, which present antigens to T helper cells.

Front 32

32. Three major groups of T cells

Back 32

1. Helper T cells
2. Cytotoxic T cells
3. Suppressor T cells

Front 33

33. Helper T cells

Back 33

Most numerous of the T cells; major regulators of all immune functions

Form a series of protein mediators called lymphokines that act on other cells of the immune system as well as on bone marrow cells; without lymphokines the immune system would be paralyzed

Front 34

34. Lymphokines formed by helper T cells

Back 34

1. IL-2
2. IL-3
3. IL-4
4. IL-5
5. IL-5
6. Granulocyte-monocyte colony-stimulating factor
7. Interferon-γ

Front 35

35. Interleukin-2

Back 35

The lymphokine interleukin-2 has an especially strong stimulatory effect in causing growth and proliferation of both cytotoxic and suppressor T cells.

Front 36

36. B-cell stimulating factors

Back 36

Almost all the interleukins participate in the B-cell response, but especially:

1. IL-4
2. IL-5
3. IL-6

Front 37

37. Activation of the macrophage system by T-cells

Back 37

1. They slow or stop the macrophages after they migrate via chemotaxis causing great accumulation

2. They activate the macrophages to cause far more efficient phagocytosis

Front 38

38. Feedback Stimulatory Effect on the Helper Cells

Back 38

Some of the lymphokines, especially interleukin-2, have a direct positive feedback effect in stimulating activation of the helper T cells themselves. This acts as an amplifier by further enhancing the helper cell response as well as the entire immune response to an invading antigen.

Front 39

39. Cytotoxic T cells

Back 39

A direct attack cell that is capable of killing micro-organisms an at times, even some of the body's own cells.

The receptor proteins on the surfaces of the cytotoxic cells cause them to bind tightly to those organisms or cells that contain the appropriate binding-specific antigen. Then, they kill the attacked cell.

After binding, the cytotoxic T cell secretes hole-forming proteins, called perforins, that literally punch round holes in the membrane of the attacked cell. Then fluid flows rapidly into the cell from the interstitial space. In addition, the cytotoxic T cell releases cytotoxic substances directly into the attacked cell. Almost immediately, the attacked cell becomes greatly swollen, and it usually dissolves shortly thereafter.

Front 40

40. Suppressor T cells

Back 40

They are capable of suppressing the functions of both cytotoxic and helper T cells.

It is believed that these suppressor functions serve the purpose of preventing the cytotoxic cells from causing excessive immune reactions that might be damaging to the body's own tissues.

Front 41

41. Examples of autoimmune diseases caused by the failure of the tolerance mechanism

Back 41

1. Rheumatic fever
2. Glomerulonephritis
3. Mayastenia gravis
4. Lupus erythematosus

Front 42

42. Immunization

Back 42

Immunity can be achieved against toxins that have been treated with chemicals so that their toxic nature has been destroyed even though their antigens for causing immunity are still intact. This procedure is used in immunizing against tetanus, botulism, and other similar toxic diseases

And, finally, a person can be immunized by being infected with live organisms that have been "attenuated." That is, these organisms either have been grown in special culture media or have been passed through a series of animals until they have mutated enough that they will not cause disease but do still carry specific antigens required for immunization. This procedure is used to protect against poliomyelitis, yellow fever, measles, smallpox, and many other viral diseases.

Front 43

43. Passive immunity

Back 43

Temporary immunity can be achieved in a person without injecting any antigen.

This is done by infusing antibodies, activated T cells, or both obtained from the blood of someone else or from some other animal that has been actively immunized against the antigen.

Front 44

44. Delayed reaction allergy

Back 44

Caused by activated T cells and not by antibodies.

Usually results in serious tissue damage

Example: poison ivy

Front 45

45. Allergic tendency

Back 45

Called atopic allergies b/c they are caused b a nonordinary response of the immune system.

Usually passed from parent to child.

Characterized by the presence of large quantities of IgE antibodies in the blood. These antibodies are called reagins or sensitizing antibodies to distinguish them from the more common IgG antibodies.

When an allergen (defined as an antigen that reacts specifically with a specific type of IgE reagin antibody) enters the body, an allergen-reagin reaction lakes place, and a subsequent allergic reaction occurs.

Front 46

46. Special characteristic of IgE antibodies

Back 46

IgE has a strong propensity to attach to mast cells and basophils.

Indeed, a single mast cell or basophil can bind as many as half a million molecules of IgE antibodies.

Front 47

47. Anaphylaxis

Back 47

When a specific allergen is injected directly into the circulation, the allergen can react with basophils of the blood and mast cells in the tissues located immediately outside the small blood vessels if the basophils and mast cells have been sensitized by attachment of IgE reagins.

Therefore, a widespread allergic reaction occurs throughout the vascular system

Front 48

48. Urticaria

Back 48

Urticaria results from antigen entering specific skin areas and causing localized anaphylactoid reactions.

Histamine released locally causes (1) vasodilation that induces an immediate red flare and (2) increased local permeability of the capillaries that leads to local circumscribed areas of swelling of the skin within another few minutes. The swellings are commonly called hives.

Front 49

49. Hay Fever

Back 49

In hay fever, the allergen-reagin reaction occurs in the nose. Histamine released in response to the reaction causes local intranasal vascular dilation, with resultant increased capillary pressure as well as increased capillary permeability.

Both these effects cause rapid fluid leakage into the nasal cavities and into associated deeper tissues of the nose; and the nasal linings become swollen and secretory.

Front 50

50. Asthma

Back 50

Asthma often occurs in the "allergic" type of person. In such a person, the allergen-reagin reaction occurs in the bronchioles of the lungs.

Here, an important product released from the mast cells is believed to be the slow-reacting substance of anaphylaxis, which causes spasm of the bronchiolar smooth muscle.

Front 51

51. What are the symptoms of splenomegaly?

Back 51

When sufficiently enlarged, the spleen causes a dragging sensation in the left upper quadrant and, through pressure on the stomach, discomfort after eating. In addition, its enlargement can lead to sequestration of blood elements. This gives rise to hypersplenism.

Front 52

52. What is the clinical triad of hypersplenism?

Back 52

1. Splenomegaly
2. Anemia, leukopenia, thrombocytopenia, or any combo of these, in association w/hyperplasia of the marrow precursors of the deficient cell type
3. Correction of the blood cytopenias by splenectomy

Front 53

53. What is nonspecific acute splenitis?

Back 53

Enlargement of the spleen occurs in any blood-borne infection. The nonspecific splenic reaction in these infections is caused by both the microbiologic agents themselves and by cytokines that are released as part of the immune response.

Front 54

54. What is the morphology of nonspecific acute splenitis?

Back 54

The spleen is enlarged (up to 200-400 g) and soft. The splenic substance is often diffluent and can be so soft that it literally flows out from the cut surface.

Microscopically, the major change is acute congestion of the red pulp, which can encroach on and sometimes virtually efface the lymphoid follicles. Neutrophils, plasma cells, and occasionally eosinophils are usually present throughout the white and red pulp. At times, there is acute necrosis of the centers of the splenic follicles, particularly when the causative agent is a hemolytic streptococcus.

Front 55

55. What is congestive splenomegaly?

When is it encountered?

Back 55

Chronic venous congestion can cause a form of splenic enlargement referred to as congestive splenomegaly. All of these disorders ultimately lead to portal or splenic vein hypertension. Systemic, or central, venous congestion is encountered in cardiac decompensation involving the right side of the heart, or following left-sided heart failure. Systemic passive congestion produces only moderate enlargement of the spleen that rarely exceeds 500 gm in weight.

Front 56

56. What are the only common causes of striking congestive splenomegaly?

Back 56

The various forms of cirrhosis of the liver. The "pipe-stem" hepatic fibrosis of schitosomiasis causes particularly severe congestive splenomegaly, while the diffuse fibrous scarring of alcoholic cirrhosis and pigment cirrhosis also evokes profound enlargements.

Front 57

57. What else can cause congestive splenomegaly?

Back 57

Congestive splenomegaly is also caused by obstruction of the extrahepatic portal vein or splenic vein. This can stem from spontaneous portal vein thrombosis, which is usually associated w/some intrahepatic obstructive disease, or inflammation of the portal vein (pylephlebitis), such as follows intraperitoneal infections.

Front 58

58. What is the morphology of congestive splenomegaly?

Back 58

Long standing congestion produces marked enlargement of the spleen. The organ is firm and becomes increasingly so the longer the congestion lasts. The weight can reach 5 kg. The capsule is usually thickened and fibrous. The cut surface has a meaty appearance and varies from gray-red to deep red, depending on the amt of fibrosis.

Microscopically, the red pulp is congested in early chronic congestion but becomes increasingly more fibrous and cellular w/time.

Foci of recent or old hemorrhage are often present. **Organization of these focal hemorrhages gives rise to Gandy-Gamma nodules: foci of fibrosis containing iron and calcium salts deposited on connective tissue and elastic fibers.

Front 59

59. What causes splenic infarcts?

Back 59

Splenic infarcts are common lesions. Caused by occlusion of the major splenic artery or any of its branches, in normal sized spleens they are most often due to emboli that arise from thrombi in the heart.

The resulting infarcts can be small or large, single or multiple, or can even involve the entire organ.

Front 60

60. What is the morphology of splenic infarcts?

Back 60

Bland infarcts are characteristically pale and wedge-shaped, w/their bases at the periphery, where the overlying capsule is often covered w/fibrin.

In septic infarcts, this appearance is modified by the development of suppurative necrosis.

In the course of healing of splenic infarcts, large, depressed scars often develop.

Front 61

61. Although rare, what are the neoplasms involving the spleen?

Back 61

Neoplastic involvement of the spleen is rare except in tumors of the lymphohematopoietic system. When present, they induce splenomegaly.

Fibromas, osteomas, chrondromas, *lymphangiomas, and *hemangiomas may arise in the spleen.

*Most common and are often cavernous in type.

Front 62

62. Complete absence of the spleen...?

Back 62

Completely absence of the spleen is rare and is usually associated w/other congenital abnormalities such as situs inversus and cardiac malformations.

Hypoplasia is a more common finding.

Front 63

63. What are spleniculi?

Why are they clinically significant?

Back 63

Accessory spleens (spleniculi) are common and have been encountered singly or multiply.

They are small, spherical structures that are histologically and functionally identical to the normal spleen, reacting to various stimuli in the same manner.

They are generally situated in the gastrosplenic ligament or the tail of the pancreas but are sometimes located in the omentum or mesenteries of the small or large intestine.

*They are clinically significant in that accessory spleens may be left in the body by the surgeon when splenectomy is indicated for treatment.

Front 64

64. What causes splenic rupture?

Back 64

Splenic rupture is usually precipitated by a crushing injury or severe blow. Spontaneous ruptures are associated w/infectious mononucleosis, malaria, typhoid fever, and lymphoid neoplasms. These diverse entities can all cause rapid splenic enlargement, producing a thin, tense splenic capsule that is susceptible to rupture.

*Spontaneous rupture of chronically enlarged spleens is less likely b/c of reactive fibrosis that toughens the capsule and pulp.

Front 65

65. What is thymic hypoplasia, and in what condition is it usually seen?

Back 65

Thymic hypoplasia is seen in DiGeorge syndrome, accompanied by PTH developmental failures. This condition is marked by severe deficits in cell-mediated immunity and variable hypoparathyroidism.

DiGeorge syndrome is often associated w/other developmental defects as art of the 22q11 deletion syndrome.

Front 66

66. What are isolated thymic cysts?

Back 66

Isolated thymic cysts are uncommon lesions that are usually discovered incidentally postmortem or during surgery. They rarely exceed 4 cm in diameter, can be spherical or arborizing, and are lined by stratified to columnar epithelium. The fluid contents can be serous or mucinous and are often modified by hemorrhage.

While they are not clinically, significant, neoplastic thymic masses are often associated w/cysts that presumably develop b/c of distortion and compression of adjacent normal thymus.

Front 67

67. What is thymic hyperplasia?

When is it most frequently encountered?

Back 67

AKA thymic follicular hyperplasia.

Although follicular hyperplasia can occur in a number of chronic inflammatory and immunologic states, it is most freq encountered in myasthenia gravis, being present in 65-75% of cases.

Similar thymic changes are sometimes encountered in Graves disease, SLE, scleroderma, and RA as well as other autoimmune disorders.

Front 68

68. What are thymomas?

What are the two main types?

Back 68

This is a tumor of thymic epithelial cells. Thymomas have been classified according to the following categories:
1. Benign or encapsulated thymoma: cytologically and biologically benign
2. Malignant thymoma
a. Type I; also called invasive thymoma: cytologically benign but biologically aggressive and capable of local invasion and, rarely, distant spread
b. Type II, also called "thymic carcinoma"; cytologically malignant with all of the biologic features of cancer

Front 69

69. What is the prevalence of thymomas?

Back 69

All categoies of thymomas are tumors of adults, usually older than 40 years of age, and are rare in children. Males and females are affected equally. Most arise in the anterior superior mediastinum, but sometimes they occur in the neck, thyroid, pulmonary hilus, or elsewhere.

Front 70

70. What is the morphology of a generic thymoma?

Back 70

Macroscopically, thymomas are lobulated, firm, gray-white masses up to 15-20 cm in the longest dimension. They sometimes have areas of cystic necrosis and calcification even in tumors that later prove to be benign. The majority are encapsulated, but 20-25% of the tumors penetrate the capsule and infiltrate perithymic tissues and structures.

*Thymomas typically consist of jigsaw puzzle-type lobules separated by fibrous bands. Microscopically, virtually all are made up of a mixture of epithelial cells and a variable infiltrate of non-neoplastic thymocytes.

Front 71

71. What is the morphology of benign thymomoas?

Back 71

Benign thymomas are most often composed of medullary type epithelial cells or a mixture of medullary and cortical type epithelial cells. In medullary type thymomas, the epithelial cells are elongated or spindle shaped.

In mixed thymomas, there is an admixture of plumper, rounder, cortical type epithelial cells and a denser infiltrate of thymocytes.

*Hassall corpuscles are rarely present w/either pattern and, when found, often are poorly formed.

Front 72

72. What is the morphology of malignant thymoma type I?

Back 72

This refers to a tumor that, although cytologically benign, is locally invasive and has the capaicty for metastasis.

The epithelial cells are most commonly of the cortical variety, w/abundant cytoplasm and rounded vesicular nuclei, and are usually accompanied by immature thymocytes expressing TdT.

Palisading of epithelial cells about blood vessels is sometimes seen.

Front 73

73. What is the critical feature of malignant thymoma type I?

Back 73

The critical feature of malignant thymoma type I is penetration of the capsule and invasion into surrounding structures.

Front 74

74. What is the morphology of malignant thymoma type II?

Back 74

AKA "thymic carcinoma", this represents about 5% of thymomas. In contrast to Type I, these are cytologically malignant, having all the anaplastic features seen in other CAs.

Macroscopically, they are usually fleshy, obviously invasive masses sometimes accompanied by metastases to such sites as the lungs.

*Microscopically, most are squamous cell CAs, either well or poorly differentiated.

Front 75

75. What is lymphoepithleioma-like carcinoma?

Back 75

The next most common thymoma variant is the lymphoepithelioma-like carcinoma, a tumor composed of sheets of cells w/indistinct borders that bears a close histologic resemblance to nasopharyngeal CA.

About 50% of lymphoepithelioma-like carcinomas contain monoclonal EBV genomes, suggesting a role for this virus in their pathogenesis.

Front 76

76. What is the difference between malignant and benign thymic neoplasms?

Back 76

Thymic carcinomas tend to express CD5, a molecule that is normally restricted to T cells and a small subset of B cells, whereas cytologically benign thymomas and other carcinomas do not.

Front 77

77. What is the clinical course of thymomas?

Back 77

About 40% of thymomas present b/c of symptoms stemming from impingement on mediastinal structures, and another 30-50% present due to their association w/myasthenia gravis.

In addition to myasthenia gravis, other paraneoplastic syndromes, such as acquired hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dematomyositis-polymyositis, and Cushing syndrome, can be seen.

Front 78

78. What is the basis for the association of thymomas with autoimmune disorders?

Back 78

The thymocytes that arise within thymomas give rise to long lived CD4+ and CD8+ cells, and cortical thymomas rich in thymocytes are more likely to be associated w/autoimmune disease. Hence, it is possible that abnormalities in the selection or "education" of T cells w/in the disturbed environment of the neoplasm contribute to the development of autoimmune disorders.

Front 79

79. What are two useful generalizations concerning upper and lower respiratory tract infections?

Back 79

1. Although many microorganisms are restricted to the surface epithelium, some spread to other parts of the body before returning to the respiratory tract, oropharynx, salivary glands.

2. Two groups of microbes can be distinguished: 'professional' and 'secondary' invaders.

Front 80

80. What are professional vs. secondary invaders?

Back 80

Professional invaders are those that successfully infect the normally healthy respiratory tract. They generally possess specific properties that enable them to evade local host defenses, such as the attachment mechanisms of respiratory viruses.

Secondary invaders only cause disease when host defenses are already impaired.

Front 81

81. What causes the common cold?

Back 81

Rhinoviruses and coronaviruses together cause more than 50% of colds. Viruses are the most common invaders of the nasopharynx, and a great variety of types are responsible for the common cold. They induce a flow of virus-rich fluid from the nasopharynx, and when the sneezing reflex is triggered, large numbers of virus particles are discharged into the air. Transmission is therefore by aerosol and also by virus-contaminated hands.

After a few days, damage to epithelial cells and the secretion of fluid containing inflammatory mediatiors such as bradykinin lead to common cold-type symptoms.

Front 82

82. How are common cold virus infections diagnosed?

Back 82

Common cold virus infections are Dx by clinincal appearance. Dx becomes important when the lower respiratory tract is involved, as for instance with influenza viruses or in children w/respiratory syncytial virus (RSV) infection.

Treatment of the common cold is symptomatic

Front 83

83. What causes a sore throat?

Back 83

About 70% of acute sore throats are caused by viruses. Common cold and other upper respiratory tract viruses inevitably encounter the submucosal lymphoid tissues that form a defensive ring around the oropharynx. The throat becomes sore either b/c the overlying mucosa is infected or because of inflammatory and immune responses in the lymphoid tissues themselves.

Front 84

84. What are some common causes of sore throat?

Back 84

Adenoviruses are common causes, often infecting the conjunctiva as well as the pharynx to cause pharyngoconjunctival fever.

EBV and CMV multiply locally in the pharynx, and HSV and certain coxsackie A viruses multiply in the oral mucosa to produce a painful local lesion or ulcer.

Certain enteroviruses (e.g. coxsackie A16) can cause additional vesicles on the hands and feet and in the mouth (hand, foot and mouth disease).

Front 85

85. What is CMV?

How is it transmitted?

Back 85

CMV is the largest human herpesvirus and there is only one serotype. CMV refers to the multinucleated cells, which together w/the intranuclear inclusions, are characteristic responses to infection w/this virus. CMV is transmitted by saliva, urine, blood, semen, and cervical secretions.

Front 86

86. What are the symptoms of CMV infection?

Back 86

CMV infection is often asymptomatic, but can reactivate and cause disease when cell-mediated immunity is impaired.

Front 87

87. How does CMV spread in the body?

Back 87

After clinically silent infection in the upper respiratory tract, CMV spreads locally to lymphoid tissues and then sytemically in circulating lymphocytes and monocytes to involve lymph nodes and the spleen. The infection then localizes in epithelial cells in salivary glands and kidney tubules, and in cervix, testes and epididymis, from where the virus is shed to the outside world.

The virus inhibits T-cell responses, and there is a temporary reduction in their immune reactivity to other antigens.

Front 88

88. CMV owes its success as a virus to...

Back 88

Its ability to evade immune defenses. For instance, it presents a poor target for cytotoxic T cells by interfering w/the transport of MCH class I molecules to the cell surface and it induces Fc receptors on infected cells.

Front 89

89. What is CMV infection like?

Back 89

In the natural host, the human infant, or child, CMV causes no illness, and in general it causes a mild illness in adults.

A glandular fever type illness can occur in adolescents which is similar to EBV infection, with fever, lethargy, and abnormal lymphocytes and mononucleosis in blood smears.

Front 90

90. What about pregnancy and CMV?

Back 90

Primary infection during pregnancy allows the spread of virus from the blood to the placenta and then to the fetus, resulting in symptomatic CMV infection at birth in 18%, and detection of other sequelae in 25% by just under five years of age.

Reactivation of infection during pregnancy also occurs, which may be asymptomatic at birth but up to 8% will have symptoms by 5. CMV is second only to Down's syndrome as a cause of mental retardation in babies.

Front 91

91. How does CMV affect immunodeficient pts?

Back 91

In immunodeficient patients such as bone marrow or solid organ transplant recipients, CMV infection causes an interstitial pneumonitis with infiltrating mononuclear cells.

Other sites affected include the CNS, w/focal cerebral 'micronodular' lesions w/infected mononuclear cells.

Also CMV retinitis affects HIV patients and those with AIDS.

Front 92

92. How is CMV diagnosed?

Back 92

Clinical Dx of primary infection is rarely possible b/c it is often asymptomatic. However, in symptomatic immunocompetent individuals, the Dx is made by detected CMV IgM in blood samples. In those w/possible CMV pneumonitis, a bronchoalveolar lavage sample is collected, and CMV antigen or CMV DNA detection methods are used.

CMV IgM and IgG serology is available but it is unlikely to be of help in immunosuppressed patients.

Front 93

93. What is the treatment for CMV?

Back 93

While ganciclovir, foscarnet, or cidofovir are effective treatments, aciclovir is ineffective.

These antivirals reduce viral replication, do not eliminate the virus and can be used as pre-emptive therapy in certain situations.

CMV specific or human normal immunoglobuin is given in addition to the antiviral agents to potentially block the Tc-cell response to pneumocytes expressing the target antigens.

Front 94

94. What is EBV?

What are the major antigens?

Back 94

EBV is structurally and morphologically idential to other herpesviruses, but is antigenically distinct. A major antigen is the viral capsid antigen (VCA) sued in diagnostic tests. Other useful diagnostically are the early antigens (EA) which are produced before viral DNA synthesis, and the EBV associated nuclear antigens (EBNA), which are located in the nucleus of the infected cells.

Front 95

95. How is EBV transmitted?

Back 95

EBV is transmitted by the exchange of saliva, for instance, during kissing, and is a ubiquitous infection.

In resource poor countries, infection probably occurs via close contact in early childhood and is subclinical. Elsewhere, infection occurs in two peaks at 1-6 years and 14-20 years of age, and in most cases causes illness.

Front 96

96. How does the EBV replicate?

Back 96

EBV replicates in B lymphocytes, after making a specific attachment to the C3d receptor (CD21) on these cells, and also in certain epithelial cells.

The pathogenesis for this disease and the clinical features can be accounted for on this basis.

Virus is shed in saliva from infected epithelial cells and possibly lymphocytes in salivary glands, and from the oropharynx, with clinically silent spread to B lymphocytes in local lymphoid tissues and elsewhere in the body (lymph nodes, spleen).

Front 97

97. How do the T lymphocytes respond to the infected B cells in EBV?

Back 97

They respond immunologically and appear in peripheral blood as 'atypical lymphocytes'. Much of the disease is attributable to an immunologic civil war, as specifically activated T cells respond to the infected B cells.

In the naturally infected infant or small child, these immune responses are weak and there is generally no clinical disease. Older children, however, become unwell, and young adults especially develop infectious mononucleosis or glandular fever.

Front 98

98. What are the clinical symptoms in infectious mononucleosis?

Back 98

This is characterized by fever, sore throat, often with petechiae on the hard palate, lymphadenopathy and splenomegaly, w/anorexia and lethargy as prominent features.

Hepatitis may occur, w/mild elevations of hepatic enzymes in 90% of cases and jaundice in 9%. Splenic rupture may occur.

Less than 1% of cases develop neurological complications, including aseptic meningitis and encephalitis, nearly always with complete recovery.

Front 99

99. What causes the symptoms in EBV infectious mononucleosis?

Back 99

The symptoms are presumably due to the action of cytokines released during the intense immunologic activity. The infected B cells are stimulated to differentiate and produce antibodies; this polyclonal activation of B cells is responsible for the production of heterophil antibodies (reacting w/RBCs of sheep or horses) and a variety of autoantibodies.

Spontaneous recovery usually occurs in 2-3 weeks, but the symptoms may persist for a few months. The virus remains as a latent infection in spite of antibody and CMI responses, and saliva often remains infectious for months after clinical recovery.

Front 100

100. What is the 'hairy tongue' condition caused by EBV?

Back 100

A 'hairy tongue' condition caused by EBV replication in squamous epithelial cells in the tongue occurs in immunodeficient patients.

Front 101

101. Does EBV survive indefinitely in ones body?

Back 101

Yes, EBV remains latent in a small proportion of B lymphocytes.

EBV is well equipped to evade immune defenses. It acts against complement and interferon, and produces a fake IL-10 molecules that interferes w/the action of the hosts own IL-10 (an important immunoregulatory cytokine). EBV also prevent apoptosis of infected cells, and the boldness of this strategy has enabled it to take up permanent residence within the immune system.

Front 102

102. How is infectious mononucleosis diagnosed clinically?

Back 102

Infectious mononucleosis is diagnosed clinically by the characteristic syndrome and the appearance of petechiae in the throat.

Front 103

103. What lab tests are used for diagnosing infectious mononucleosis?

Back 103

1. Demonstrating atypical lymphocytes, comprising up to 30% of nucleated cells, in a blood smear
2. Demonstrating heterophil antibodies to horse or sheep RBCs in the monospot test. These are present in 90% of cases, but may not be detected in those under 14 years of age.
3. Demonstrating EBV-specific antibody. Detection of VCA IgM indicates current infection. VCA IgG and EBNA IgG are markers of previous exposure
4. Demonstrating EBV DNA by DNA hybridization or PCR

Front 104

104. What is the treatment of EBV?

Back 104

Antiviral agents are not used to treat EBV infected immunocompetent individuals.

In immunosuppresed people in specific clinical setting there are some data on using specific antivirals to reduce viral replication, but they are only effective in the lytic part of the life cycle.

Front 105

105. What cancers are associated w/EBV?

Back 105

1. Burkitt's lymphoma
2. B-cell lymphomas
3. Nasopharyngeal carcinoma

Front 106

106. What is Burkitt's lymphoma and how is it related to EBV?

Back 106

Burkitt's lymphoma is virtually restricted to parts of Africa and Papua New Guinea, so it is clear that EBV alone is not enough to cause the lymphoma.

The most likely co-carcinogen is malaria, which acts by weakening T-cell control of EBV infection and perhaps by causing polyclonal activation of B cells, the increased turnover rendering them more susceptible to neoplastic transformation.

Front 107

107. How is B-cell lymphoma associated with EBV in immunodeficient patients?

Back 107

For example, B-cell lymphomas occur in 1-10% of solid organ transplant recipients, especially children, when primary EBV infection occurs post-transplantation.

EBV DNA and RNA transcripts are found in the tumors cells, which also show a translocation of the c-myc oncogene on chromosome 8 to the immunoglobulin heavy chain locus on chromosome 14.

Front 108

108. How is EBV infection associated w/nasopharyngeal carcinoma?

Back 108

Nasopharyngeal carcinoma is a very common cancer in China and SE Asia. EBV DNA is detectable in the tumor cells, and a co-carcinogen, possibly ingested nitrosamines from preserved fish, is likely. Host genetic factors controlling HLA antigens and immune responses may confer susceptibility to nasopharyngeal carcinoma.

Front 109

109. What are the five bacteria responsible for pharyngitis?

Which is the most common? Most important?

Back 109

1. **Strep. pyogenes (group A β-hemolytic), the commonest and most important to Dx b/c it can lead to complications**
2. Corynebacterium diphtheriae
3. Haemophilus influenzae (type B), which can occasionally cause severe epiglottis w/obstruction of the airways
4. Borrrelia vincentii together w/certain fusiform bacilli, which can cause throat or gingival ulcers
5. Neisseria gonorrhoeae

Front 110

110. What are the six possible complications of Strep. pyogenes infection?

Back 110

1. Peritonsillar abscess ('quinsy'), an uncommon complication of untreated streptococcal sore throat
2. Otitis media, sinusitis, mastoiditis, caused by local spread of Step. pyogenes
3. Scarlet fever
4. Rheumatic fever
5. Rheumatic heart disease
6. Acute glomerulonephritis

Front 111

111. What is scarlet fever?

What causes it?

Back 111

Certain strains of Strep. pyogenes produce an erythrogenic toxin coded for by a lysogenic phage. The toxin spreads thru the body and localizes in the skin to induce a rash. The tongue is initially furred, but later red. The rash begins as facial erythema and then spreads to involve most of the body except the palms and soles. The face is generally flushed w/circumoral pallor.

The rash fades over the course of 1 weeks and is followed by extensive desquamation.

Front 112

112. What is rheumatic fever?

Back 112

This is an indirect complication...antibodies formed to antigens in the streptococcal cell wall cross react w/the sarcolemma of human heart and with tissues elsewhere. Granulomas are formed in the heart (Aschoff's nodules), and 2-4 weeks after the sore throat the patient develops myocarditis or pericarditis, which may be associated w/chorea.

Chorea is a disease of the CNS resulting from streptococcal antibodies reacting w/neurones.

Front 113

113. What is Rheumatic heart disease?

Back 113

Repeated attacks of Strep. pyogenes w/different M types can lead to damage to the heart valves. Certain children have a genetic predisposition to this immune-mediated disease.

If a primary attack is accompanied by rising or high antistreptolysin O (ASO) antibody levels, future attacks must be prevented via penicillin prophylaxis throughout childhood.

Front 114

114. What is acute glomerulonephritis?

Back 114

Antibodies to streptococcal compoenents combine w/them to form circulating immune complexes which are then deposited in the glomeruli. Here, the complement and coag systems are activated, resulting in local inflammation.

ASO antibodies are usually elevated. Blood appears in the urine, and there are signs of acute nephritis syndrome (edema, hypertension) 1-2 weeks after the sore throat.

Front 115

115. How is pharyngitis and tonsilitis diagnosed?

Back 115

Lab Dx is not generally necessary for pharyngitis and tonsilitis.

Bacteria are identified by culturing throat swabs.

EBV is distinguished from CMV by detecting heterophil antibodies using the monospot test and VCA IgM, wheras CMV Dx is made by dtecting CMV IgM.

HSV is readily isolated on the DNA detected in swabs from lesions sent to the lab.

Front 116

116. What is parotitis?

Back 116

Mumps. There is only one serotyep of this single stranded RNA paramyxovirus. It spreads via air-borne droplets, salivary secretions, and possible urine.

Susceptible adults are at risk of complications of mumps such as orchitis and pancreatitis.

Front 117

117. How does mumps infect?

Back 117

After entering the body, the primary site of replication is the epithelium of the upper respiratory tract or eye. The virus spreads in local lymphoid tissues and reticuloendothelial cells. After approx 7-10 days, a primary viremia localizes in salivary and other glands and the body sides including the CNS, testis, pancreas, and ovary and is excreted in the urine.

Infected cells lining the parotid ducts degenerate, and finally, after an incubation period of 16-18 days, the inflammation results in disease.

Front 118

118. What are the symptoms of parotitis?

Back 118

After a prodromal period of malaise and anorexia lasting 1-2 days, the parotid gland becomes painful, tender and swollen, and is sometimes accompanied by submandibular gland involvement. This is the classic sign of mumps and parotitis and is the most common clinical sign.

Other sites may be invaded, with clinical consequences such as inflammation of the testis and pancreas, resulting respectively in orchitis and pancreatitis.

Front 119

119. How is the Dx of parotitis made?

Back 119

Lab Dx is made:

1. By isolating virus in cell culture or detecting viral RNA in throat swabs, CSF, or urine
2. By detecting mumps-specific IgM antibody.

Front 120

120. What causes acute otitis media?

Back 120

Common causes of acute otitis media are viruses (especially RSV), Strep. pneumoniae, and H. influenzae,

Sometimes Strep. pyogenes or Staph. aeureus can cause it.

This condition is very common in infants and children b/c their eustachian tube is open more widely at this age.

Front 121

121. What causes otitis externa?

Back 121

Causes of otitis extena are Staph. aureus, Candida albicans, and Gram negative opportunists.

In contrast to the middle ear, the extenal canal has a bacterial flora similar to that of the skin.

Ear drops containing polymyxin or other antibiotics are usually an effective treatment.

Front 122

123. What causes acute sinusitis?

Back 122

The etiology and pathogenesis of acute sinusitis are similar to those of otitis media. Clinical features include facial pain and localized tenderness.

It may be possible to identify the causative bacteria via sinus puncture; however, sinus puncture is not often carried out.

Front 123

124. What is acute epiglottis?

What causes it?

Back 123

Acute epiglottis is generally due to H. influenzae capsular type B infection. It is most often seen in young children. H. influenzae capsular type B spreads from the nasopharynx to the epiglottis, causing severe inflammation and edema. There is usually a bacteremia.

*Acute epiglottis is an emergency and necessitates intubation and treatment w/antibiotics.

Front 124

125. What are the symptoms of acute epiglottis?

How is it treated?

Back 124

Acute epiglottis is characterized by difficulty in breathing b/c of respiratory obstruction and until the airway has been secured, extreme care must be taken when examining the throat in case the swollen epiglottis is sucked into the airway and causes total obstruction.

Treatment is begun with antibiotics effective against H. influenzae (cefotaxime, chloramphenicol).

The clinical Dx is confirmed by isolating bacteria from the blood and possibly the epiglottis.

Front 125

126. How does diphtheria cause respiratory obstruction?

Back 125

Respiratory obstruction due to diphtheria is rare in resource-rich countries, but the characteristic false membrane and local swelling can extend from the pharynx to involve the uvula.

Front 126

127. What is oral candidiasis?

Back 126

Changes in the oral flora produced by broad spectrum antibiotics and impaired immunity predispose to thrush. For instance, oral thrush (candidiasis) occurs w/prolonged administration of broad spectrum antibiotics which allows the normally harmless C. albicans to flourish, penetrating the epithelium with its pseudomycelia, and causing thrush.

It also commonly occurs in HIV infection and malignancy, and sometimes in newborns and the elderly.

Front 127

128. How is oral thrush treated?

Back 127

Topical antifungal agents (nystatin or clotrimazole) or oral fluconazole are effective treatments for thrush.

Front 128

129. What are the most common cause of dental caries?

Back 128

In the USA, 80-90% of people are colonized by Streptococcus mutans, which causes dental caries.

These microorganisms are specifically adapted for life on teeth and form a film called dental plaque on the tooth surface.

This is a complex mass of bacteria embedded in a polysaccharide matrix. The bacteria use dietary sugar (sucrose) and form lactic acid, which decalcifies the tooth locally.

Front 129

130. What causes periodontal disease?

Back 129

Actinomyces viscosus, Actinobacillus, and bacteriodes spp. are commonly involved in periodontal disease.

Front 130

131. What are the cells of cell-mediated immunity?

Back 130

T lymphocytes are the cells of cell-mediated immunity, the arm of the adaptive immune system that combats intracellular microbes, which may be microbes that are ingested by phagocytes and live within these cells or microbes that infect nonphagocytic cells.

Front 131

132. What are the phases of T cell responses?

Back 131

1. Antigen recognition by naive T cells
2. Activation
3. Clonal expansion
4. Differentiation
5. Effector functions

Front 132

133. T cells use their antigen receptors to recognize...what?

Back 132

T cells use their antigen reecptors to recognize peptide antigens displayed by MHC molecules on APC (which accounts for the specificity of the ensuing response) and polymorphic residues of the MHC molecules (accounting for the restriction of T cell responses).

Front 133

134. What initiates T cell responses?

Back 133

The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on APCs.

The TCR recognizes MHC associated peptide antigens, CD4 or CD8 co-receptors recognize the MHC molecules, adhesion molecules strengthen the binding of T cells to APCs, and receptors for costimulators recognize second signals provided by the APCs.

Front 134

135. The T cell receptor for antigen (TCR) and the CD4 or CD8 co-receptor together recognize...?

Back 134

The complex of peptide antigens and MHC molecules on APCs, and this recognition provides the first signal for T cell activation.

Front 135

136. Class II MHC molecules are displayed on which type of antigens?

Back 135

Protein antigens are ingested by APCs from the extracellular mileu into vesicles, and these antigens are processed into peptides that are displayed by class II MHC molecules.

Front 136

137. Class I MHC molecules are displayed on which type of antigens?

Back 136

By contrast, protein antigens that are present in the cytoplasm are processed into peptides that are displayed by class I MHC molecules.

Front 137

138. What is the TCR?

Back 137

The TCR expressed on most T cells consists of an α chain and a β chain, both of which participate in antigen recognition.

The TCR of a peptide antigen-specific T cell recognizes the displayed peptide and simultaneously recognizes residues of the MHC molecule that are located around the peptide binding cleft.

Every mature T-cell expresses either CD4 or CD8.

Front 138

139. What are CD4+ T cells?

Back 138

CD4+ T cells function as cytokine-producing helper cells. They recognize microbial antigens that are ingested from the extracellular milieu and are displayed by class II MHC cells

Front 139

139. What are CD8+ T cells?

Back 139

CD8+ T cells function as cytotoxic lymphocytes and recognize peptides derived from cytoplasmic microbes displayed by class I MHC molecules.

Thus, the specificity of CD4 and CD8 for different classes of MHC molecules and the distinct pathways of processing of vesicular and cytosolic antigens ensures that the correct T cells respond to different microbes.

Front 140

140. What are the requirements for the T cell resposne?

Back 140

Two or more TCRs and co-receptors need to be engaged simultaneously, b/c only when they are brought together can appropriate biochemical signaling cascades be activated.

Also, each T cell needs to engage antigen (i.e. MHC-peptide complexes) for a long period.

Front 141

141. What triggers the biochemical signals that lead to T cell activation?

Back 141

Antigen recognition by the TCR triggers signals that are delivered to the interior of the cells by molecules associated with the TCR (the CD3 and ζ chains) and by the co-receptors CD4 and CD8.

Front 142

142. What are the roles of the parts of the TCR complex in T cell activation?

Back 142

In the TCR complex, the function of antigen recognition is performed by the variable TCR α & β chains, whereas the conserved signaling function is performed by the attached CD3 and ζ proteins.

Front 143

143. What are adhesion molecules and why are they important?

Back 143

Adhesion molecules on T cells recognize their ligands on APCs and stabilize the binding of the T cells to the APCs.

The binding is enhanced by integrins, whose affinity for their ligands is increased by chemokines produced in response to microbes and by antigen recognition by the TCR.

Front 144

144. What is the most important family of adhesion molecules on the T cells?

Which is the major member of the family that is involved in binding to APCs?

Back 144

Integrins

The major T cell integrin is the leukocyte function-associated antigen-1 (LFA-1), whose ligand on APCs is called intercellular adhesion molecule-1 (ICAM-1).

Front 145

146. The full activation of T cells is dependent on ....?

Back 145

The full activation of T cells is dependent on the recognition of costimulators on APCs.

The best defined costimulators for T cells are B7-1 and B7-2, both of which are expressed on APCs and whose expression is greatly increased when the APCs encounter microbes.

Front 146

147. What recognizes B7 proteins?

Back 146

These B7 proteins are recognized by a receptor called CD28, which is expressed on virtually all T cells. Signals from CD28 on T cells binding on APCs work together w/signals generated by binding of teh TCR and coreceptor to peptide-MHC complexes on the same APCs.

Front 147

148. Why is CD28-mediated signaling essential for initiating the responses of naive T cells?

Back 147

In the absence of CD28-B7 interactions, engagement of the TCR alone is unable to activate the T cells. The requirement for costimulation ensures that naive T lymphs are activated fully by microbial antigens and not by harmless foreign substances.

Front 148

149. What is another set of molecules that participates in increasing costimulatory signals for T cell responses?

Back 148

CD40L (CD154) on the T cells and CD40 on APCs.

CD40L expressed on an antigen-stimulated T cell binds to CD40 on APCs and activates the APCs to express more B7 costimulators and to secrete cytokines such as IL-12 that enhance T cell differentiation.

Front 149

150. What are adjuvants?

Back 149

Protein antigens, such as those used in vaccines, fail to elicit T cell-dependent immune responses unless these antigens are administered w/substances that activate APCs, including dendritic cells and macrophages.

Such substances are called adjuvants, and they function by inducing the expression of costimulators on APCs and by stimulating APCs to secrete cytokines that activate T cells.

Front 150

151. What other proteins homologous to CD28 are critical for limiting and terminating immune responses?

Why are they important?

Back 150

Different members of the CD28 family are involved in activating and inhibiting T cells.

The prototypes of the inhibitory receptors are CDLA-4, which, like CD28, also recognizes B7 on APCs, and PD-1, which recognizes different but related ligands on many cells types.

Both are induced in activated T cells and genetic deletion of these results in excessive lymphocyte expansion and autoimmune disease.

Front 151

152. How do CD8+ T cells become activated?

Back 151

CD8+ T cells recognize peptides of intracellular (MHC class I) protein antigens and may require help from CD4+ T cells to differentiate into effector cytotoxic lymphocytes.

Front 152

153. How do CD4+ helper T cells help CD8+ T cell activation?

Back 152

In some infections, APCs may ingest infected cells and present microbial antigens to CD8+ T cells and to CD4+ helper T cells. The helper T cells then produce cytokines that stimulate the expansion and differentiation of the CD8+ T cells. It is also thought that helper cells may activate APCs to make them competent at stimulating CD8+ T cells.

Front 153

154. The biochemical signals triggered in T cells by antigen recognition and costimulation result in what?

Back 153

The activation of various transcription factors that stimulate the expression of genes encoding cytokines, cytokine receptors, and other molecules involved in T cell responses.

Front 154

155. What is the immunological synapse?

Back 154

Multiple TCRs and co-receptors are brought together when they bind MHC-peptide complexes that are near APCs. In addition, there is an orderly redistribution of other proteins, such that the TCR complex, CD4/CD8 co-receptors, and CD28 coalesce to the center and the integrins move to form a peripheral ring. This provides an optimal shape for activating signals.

The region of contact between the APC and T cell, including the redistributed membrane proteins, is called the immunologic synapse.

Front 155

156. The clustering of CD4 or CD8 co-receptors activates what protein tyrosine kinase?

Back 155

Lck, which is attached to the tails of these coreceptors.

Front 156

157. What are ITAMS?

Back 156

CD3 and ζ chains contain tyrosine rich motifs called immunoreceptor tyrosine based activation motifs (ITAMS). ITAMS are critical for signaling.

Lck, which is carried near the TCR complex, phosphorylates tyrosine residues containing with the ITAMs of the ζ and CD3 proteins.

Front 157

158. The phosphorylated ITAMs become what...?

Back 157

The phosphorylated ITAMs become docking sites for a tyrosine kinase called ZAP-70, which is also phosphorylated by Lck and thereby made active.

The active ZAP-70 then phosphorylates various proteins and enzymes, which mediate signaling evens.

Front 158

159. What are the three major signaling pathways linked to ζ chain phosphorylation and ZAP-70?

Back 158

1. NFAT pathway
2. Ras/Rac-MAP kinase pathway
3. PKCθ-NF-κB pathway

Front 159

160. What is the NFAT pathway?

Back 159

Nuclear factor of activated T cells (NFAT) is a transcription factor whose activation is dependent on calcium ions.

This pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase C, which catalyzes the hydrolysis of PIP₂ to IP₃.

IP₃ stimulates teh release of clacium into the ER, which opens a plasma membrane calcium channel and allows the cytoplasmic calcium concentration to rise.

The increased cytoplasmic calcium concentration binds to a protein called calmodulin, and the calcium-calmodulin complex activates calcineurin.

Front 160

161. What is calcineurin?

Back 160

Calcineurin removes phosphates from NFAT, which allows NFAT to migrate into the nucleus, where it binds to and activates several genes, including the genes encoding the T cell growth factor IL-2.

Front 161

162. How does cyclosporine work?

Back 161

Cyclosporine binds to and inhibits the activity of calcineurin and thus inhibits the production of cytokines by T cells.

This agent is used as an immunosuppressant.

Front 162

163. What is the Ras-Rac-MAP kinase pathway?

Back 162

This pathway includes the GTP binding Ras and Rac proteins, several adapter proteins, and a cascade of enzymes that eventually activate one of a family of MAP kinases. These pathways are initiated by ZAP-70 phosphorylation.

The terminal MPA kinases promote the expression of a protein called c-Fos and c-Jun, which combine to form the transcription factor AP-1 (activating protein 1), which enhances the transcription of several T cell genes.

Front 163

164. What is the PKCθ-NF-κB pathway?

Back 163

PKCθ is activated by DAG, which, like IP₃, is generated by phospholipase C mediated hydrolysis of membrane inositol lipids.

PKCθ acts via adapter proteins that are recruited to the TCR complex to activate NF-κB. NF-κB exists in the cytoplasm bound to an inhibitor called IκB.

TCR induced signals activate a kinase that phosphorylates IκB and targets its destruction. As a results, NF-κB is released and moves to the nucleus where it promotes the transcription of several genes.

Front 164

165. What is the fourth pathway of signal transduction?

Back 164

A fourth pathway involves a lipid kinase called PI-3 kinase, which phosphorylates membrane PIP₂ to generate PIP₃.

PIP₃ activates another kinase called Akt, which stimulates expression of antiapoptotic proteins and thus promotes survival of antigen-stimulates T cells.

This pathway is triggered not only by the TCR but also by CD28 and IL-2 receptors.

Front 165

166. What is the first cytokine to be produce by CD4+ T cells?

Back 165

IL-2

Front 166

167. Why are there less CD4+ T cells after clonal expansion when compared to CD8+ T cells?

Back 166

CD8+ CTLs are effector cells in which large numbers may be needed to kills infected cells.

By contrast, each CD4+ effector cells secrets cytokines that activate many other effector cells so a relatively small number of cytokine producers may be all that is needed.

Front 167

168. What molecules are involved in the effector functions of CD4+ helper T cells?

Back 167

CD4+ helpter T cells that have differentiated into teffector cells express CD40L and secrete cytokines.

CD40L binds to CD40 on macrophages or B lymphocytes, and cytokines bind to their receptors on the same cells. The combination of signals delivered by CD40 and cytokine receptors activates macrophages in cell-mediated immunity.

Front 168

169. What are the subsets of CD4+ helper T cells?

Back 168

TH1, TH2, and TH17.

Front 169

170. What is the role of TH1 cells?

Back 169

TH1 cells produce IFN-γ and activate phagocytes to eliminate ingested microbes, and stimulate the production of opsonizing and complement-binding antibodies.

Front 170

171. What is the role of TH2 cells?

Back 170

TH2 cells, which produce IL-4 and IL-5, stimulate IgE production and activate eosinophils, which function mainly in defense against helminths.

They also produce IL-4 and IL-13, which promote the expulsion of parasites and microbes from mucosal organs by stimulating mucus secretions.

Lastly, they also produce IL-4, IL-10, and IL-13, which inhibit the microbicidal activities of macrophages and thus suppress the TH1 cell mediated immunity.

Front 171

172. What is the role of TH17 cells?

Back 171

TH17 cells, which produce IL-17, are implicated in several inflammatory diseases and may play a role in defense against bacterial infections.

TH17 cells secrete IL-17 and IL-22, and are the principal mediators of inflammation.

Front 172

173. What causes TH1 development?

Back 172

TH1 differentiation is driven by a combination of IL-12 and IFN-γ

Front 173

174. What causes TH2 development?

Back 173

TH2 differentiation is stimulated by IL-4.

Front 174

175. What causes TH17 development?

Back 174

The development and maintenance of TH17 cells require inflammatory cytokines such as IL-6 and IL-1; IL-23, and TGF-β.

Front 175

176. Memory T cells require what to stay alive?

Back 175

IL-7

Front 176

177. What is cell-mediated immunity?

Back 176

Cell-mediated immunity is the arm of adaptive immunity that eradicates infections by intracellular microbes.

Cell-mediated immune reactions are of two types: CD4+ T cells activate macrophages to kill ingested microbes that are able to survive in the vesicles of phagocytes, and CD8+ CTLs kill cells harboring microbes in their cytoplasms, thereby eliminating reservoirs of infection.

Front 177

178. Where are effector T cells generated?

Back 177

Effector T cells are generated in peripheral lymphoid organs, mainly lymph nodes draining sites of microbe entry, by the activation of naive T lympocytes. The effector T cells are able to migrate to any site of infection.

Front 178

179. Why do effector T cells migrate to sites of infection?

Back 178

They migrate to sites of infection b/c these lymphocytes express high levels of adhesion molecules are chemokine receptors that bind to ligands expressed or displayed on endothelium after exposure to microbes and in response to chemokines produced at the site.

Front 179

180. What changes occur in the profiles of adhesion molecules and chemokine receptors on T lymphocytes after differentiation?

Back 179

Activated T cells decrease expression of the receptor for the chemokines that are produced in the T cell zones of lymph nodes and at the same time increase expression of the receptor for sphingosine 1-phosphate, that is present at high concentrations in the blood. As a result, the activated T cells are induced to migrate out of the lymph nodes and into the peripheral tissues.

Front 180

181. What controls the migration of T lymphocytes?

Back 180

Activated T cells express high levels of ligands for E-selectins and P-selectins, and for LFA-1, and VLA-4.

The endothelium at the site of infection is exposed to cytokines such as TNF and IL-1, which act on the endothelial cells to increase expression of E- and P-selectins as well as ligands for integrins, especially ICAM-1 (ligand for LFA-1) and VCAM-1 (ligand for VLA-4).

Front 181

182. What is the process of migration for effector T cells?

Back 181

Effector T cells that are passing thru the blood vessels at the infection site bind first to the selectins, leading to rolling interactions. Effector T cells also express receptors for chemokines at the inflammatory sites. The rolling T cells recognize these chemokines, leading to increased binding affinity of the integrins for their ligands and firm adhesion of the T cells to to endothelium.

After the effector T lymphs are arrested on the endothelium, the chemokines stimulate the motility of the adherent leukocytes. The net result is that the T cells migrate out of the blood vessels to the site of infection.

Front 182

183. What changes occur in the profiles of adhesion molecules and chemokine receptors on T lymphocytes after activation?

Back 182

T cells decrease expression of receptors for chemokines and L-selectin, the adhesion molecule that mediates naive T cells migration into lymph nodes.

Therefore, activated T cells tend to stay out of normal lymph nodes.

Front 183

184. The migration of T cells is dependent/independent of antigen?

Back 183

The migration of T cells is independent of antigen, but cells that recognize microbial antigens in tissues are retained at these sites.

Also, differentiated effector T cells appear to be less dependent on costimulation than are naive cells. Therefore, the proliferation and differentiation of naive T cells are confined to lymphoid organs, where dendritic cells display antigens, but the functions of effector T cells may be directed at any host cell displaying microbial antigens, not just dendritic cells.

Front 184

185. What is delayed-type hypersensitivity (DTH)?

Back 184

The ability of T cells to activate macrophages is dependent on antigen recognition, accounting for the specificity of the reaction. Essentially, the same reaction may be elicited by injecting a microbial protein into the skin of an individual who has been immunized against the microbe by prior infection or vaccination.

This is called DTH, b/c it occurs 24-48 hours after an immunized individual is challenged with a microbial protein, and b/c it reflects an increased sensitivity to antigen challenge.

DTH reactions are manifested by infiltrates of T cells and blood monocytes into the tissue, edema and fibrin deposition caused by increased vascular permeability in response to cytokines produced by CD4+ T cells, and tissues damage induced by the products of macrophages activated by T cells.

Front 185

186. Effector T lymphocytes of the TH1 subset that recognize macrophage-associated antigens activate the macrophages by...?

Back 185

CD40L and CD40 interactions and by secreting the macrophage-activating cytokine IFN-γ.

Binding of IFN-γ to its receptor functions together with engagement of CD40 to trigger biochemicical signaling pathways that lead to the production of several transcription factors.

These transcription factors turn on the transcription of genes that encode lysosomal proteases and enzymes that stimulate the synthesis of microbicidal reactive oxygen species and NO.

Front 186

187. Activated macrophages also secrete...?

Back 186

Activated macrophages also secrete cytokines that induce inflammation: TNF, IL-1, chemokines, and activate T cells (IL-12), and they express more MHC molecules and costimulators, which enhance T cell responses.

Front 187

188. Is macrophage activation useful for defense against microbes such as viruses that live and replicate only in the cytoplasm?

Back 187

No, b/c the microbicidal mechanisms of macrophages are largely limited to vesicles.

Front 188

189. What is the histological characteristics of chronic cell-mediated immune responses?

Back 188

Granulomas, which are collections of activated lymphocytes and macrophages around the microbe with fibrosis and tissue necrosis.

Front 189

190. What is alternative macrophage activation?

Back 189

Several cytokines produced by TH2 cells, such as IL-4 and IL-13 also can activate macrophages to express mannose receptors and IL-13 acts on fibroblasts to increase collagen syntehsis and fibrosis. This type of macrophage resposne is called alternative macrophage activation, to distinguish it form classical activation, which enhances microbicidal functions.

Alternative macrophage activation mediated by TH2 cytokines may play a role in tissue repair and may contribute to tissue damage in the setting of chronic parasitic infections and allergic disease.

Front 190

191. Leishmania major infections require what to eliminate infections?

Back 190

THe protozoal parasite L. major livers inside macrophages, and its elimination requires the activation of the macrophages by L. major-specific TH1 cells.

A response with TH2 cells would be inadequate to eliminate infections.

Front 191

192. Tuberculoid form response vs. destructive lepromatous form response

1/2

Back 191

Mycobacterium leprae, a bacterium that lives inside macrophages, may be eliminated by CMI mechanisms. Some person infected w/M. leprae are unable to eradicate the infection, which will progress to the classic destructive lesions of lepromatous leprosy.

In other patients, the bacteria induce strong CMI responses w/activated T cells and macrophages around the infection and few surviving microbes; this form is the tuberculoid leprosy.

Front 192

193. Tuberculoid form response vs. destructive lepromatous form response

2/2

Back 192

Some studies have shown that the tuberculoid form is associated w/the activation of M. leprae-specific TH1 cells, whereas the destructive lepromatous form is associated with a defect in TH1 cell activation or a TH2 dominant response.

Front 193

194. What is the mechanism of killing of infected cells by CD8+ cytotoxic T lymphocytes?

Back 193

CTLs recognize class I MHC peptides in infected cells and form tight adhesions (conjugates) with these cells. Adhesion molecules, such as integrins, stabilize the binding of CTLs to infected cells.

The CTLs are activated to relase their granule contents toward the infected cell. The granule contents are taken into the target cell by receptor-mediated endocytosis, and granzymes are released into the cytoplasm by a perforin-dependent mechanism. Granzymes then induce apoptosis.

Front 194

195. What are the two granule proteins that are critical for killing?

Back 194

Granzymes and perforins.

Granzymes are enzymes that cleave and thereby activate enzymes called caspases that are present in the cytoplasm of target cells, and the active caspases induce apoptosis.

Perforin is necessary for delivery of granzymes into the cytoplasm of the target cell.

Front 195

196. What is the Fas ligand?

Back 195

Activated CTLs also express a membrane protein called Fas ligand, which binds to a death-inducing receptor, called Fas (CD95), on target cells.

Engagement of Fas activates caspases and induces target cell apoptosis; this pathway of killing does not require granule exocytosis and is probably a minor pathway.

Front 196

197. What is the hallmark of apoptosis?

Back 196

DNA fragmentation. The mechanisms that induce DNA fragmentation also break down DNA of microbes living inside the infected cells.

Each CTL can kill a target cell, detach, and go on to kill additional targets.

Front 197

198. How do both CD4+ and CD8+ T cells work together?

Back 197

If microbes are phagocytosed and remain sequestered in macrophage vesicles, CD4+ T cells may be adequate to eradicate these infections by secreting IFN-γ and activating the microbicidal mechanisms of the macrophages.

If, however, the microbes are able to escape from vesicles into the cytoplasm, they become resistant to T cell-mediated macrophage activation, and their elimination requires killing of the infected cells by CD8+ CTLs.

Front 198

199. What are some mechanisms microbes have evolved to resist cell mediated immunity?

Back 198

These mechanisms include inhibiting phagolysome fusion, escaping from the vesicles of phagocytes, inhibiting the assembly of class I MHC-peptide complexes, and producing inhibitory cytokines or decoy cytokine receptors.

Front 199

200. What are the three ways in which infectious agents establish infection and damage tissues?

Back 199

1. They can contact or enter host cells and directly cause cell death.
2. They may release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis.
3. They can induce host cellular responses that although directed against the invader, cause additional tissue damage.

Front 200

201. What is tissue tropism?

What are teh four factors that determine tissue tropism? Which is the major determinant?

Back 200

The predilection for viruses to infect certain cells and not others is called tissue tropism and is determined by several factors, including:
1. *Host cell receptors for the virus
2. Cellular transcription factors that recognize viral enhancer and promoter sequences
3. Anatomic barriers
4. Local temp, pH, and host defenses

*Major determinant

Front 201

202. What are examples of specific cell surface proteins that viruses bind to?

Back 201

HIV gp120 binds to CD4+ cells and to the chemokine receptors CXCR4 CCR5.

Rhinoviruses bind to the same site on ICAM-1 as LFA-1.

Front 202

203. What is an example of cellular transcription factors that recognize viral enhancer and promoter sequences?

Back 202

JC virus can only infect oligodendroglia in the CNS b/c the promoter and enhancer DNA sequences upstream from the viral genes are active in glial cells but not in neurons or endothelial cells.

Front 203

205. What are the four ways in which viruses kill host cells?

Back 203

1. Inhibiting host DNA, RNA, or protein synthesis (poliovirus)
2. Damaging the plasma membrane (HIV)
3. Lysing cells (rhinoviruses and influenza viruses)
4. Inducing a host immune response to virus infected cells (HBV)

Front 204

206. What is the definition of bacterial virulence?

Back 204

Bacterial damage to host tissues depends on the ability of the bacteria to adhere to host cells, invade cells and tissues, or deliver toxins.

Front 205

207. How do bacteria adhere to host cells?

Back 205

Adhesins are bacterial surface molecules that bind to host cells.

Fimbriae or pili are filamentous proteins on the surface of Gram-negative bacteria. The stalks of pili are composed of conserved repeating subunits, while the variable AAs on the tips of the pili determine the binding specificity of the bacteria.

Front 206

208. How does Strep. pyogenes adhere to host cells?

Back 206

The fibrillae covering the surface of the Gram-positive organism Strep pyogenes are composed of lipoteichoic acids and M protein.

Lipoteichoic acids are hydrophobic and bind to fibronectin and to the surface of buccal epithelial cells.

M protein, the second component of S. pyogenes fibrillae, prevents phagocytosis by host macrophages.

Front 207

209. How does E. coli cause UTI?

Back 207

Strains of E. coli uniquely express a specific P pilus, which binds to a gal(α1-4)gal moiety expressed on uroepithelial cells.

Front 208

210. How does N. gonorrhoeae mediate adherence?

Back 208

Pili on N. gonorrhoeae mediate adherence of bacteria to host cells and can also act as targets of the antibody response against N. gonorrhoeae.

Variation in the type of pili expressed is an important mechanism by which N. gonorrhoeae escapes the immune response.

Front 209

211. How does tuberculosis enter host cells?

Back 209

Coating of bacteria w/antibodies or the complement protein C3b (opsonization) normally results in phagocytosis of bacteria by macrophages. Like many bacteria, M. tuberculosis activates the alternative complement pathway, resulting in opsonization by C3b.

In addition, M. tuberculosis binds to the CR3 complement receptor on macrophages and is endocytosed in the cell. To avoid destruction, M. tuberculosis blocks fusion of the lysosome w/the phagosome.

Front 210

212. How can intracellular bacteria kill host cells?

Back 210

Intracellular bacteria can kill host cells by rapid replication and lysis (Shigella and E.coli) or may permit host cell viability while evading intracellular defenses and proliferating within endosomes.

Front 211

213. What are endotoxins?

Back 211

Endotoxin (LPS) is a cell wall component of gram-negative bacteria; it causes septic shock by inducing high levels of TNF, IL-1, and IL-12.

Front 212

214. What are exotoxins?

What are three mechanisms they use?

Back 212

Exotoxins are proteins released by bacteria that damage host tissues by several mechanisms:

1. Extracellular enzymes destroy tissue integrity by digesting structural proteins (S. aureus exfoliative toxin)
2. Exotoxins can have a binding (B) component that delivers a toxic active (A) component into the cell cytoplasm, where it alters signaling pathways to cause cell death (Bacillus anthracis toxin).
3. The components of neurotoxins block neurotransmitter release, causing paralysis (Clostridium species).

Front 213

215. What are superantigens, and how do they cause toxic shock syndrome?

Back 213

Superantigens are bacterial toxins that stimulate very large number of T lymphocytes by binding to conserved portions of the T-cell receptor, leading to massive T-lymphocyte proliferation and cytokine release. The high levels of cytokines can lead to capillary leak and shock.

Superantigens made by Staph aureus and Strep pyogenes cause TSS.

Front 214

216. What are three examples of the injurious effects of host immunity?

Back 214

1. Granulomatous responses to certain microbes (e.g. M. tuberculosis) function to sequester the pathogen, but can cause tissue damage and fibrosis.
2. Liver damage following HBV infection is due to the immune response against infected liver cells.
3. Post-streptococcal glomerulonephritis occurs when anti-streptococcal antibodies form complexes w/streptococcal antigens and deposit in renal glomeruli and produce nephritis.

Front 215

217. What are four mechanisms microbes use for evasion?

Back 215

1. Remaining inaccessible to the host immune system
2. Varying or shedding antigens
3. Resisting innate immune defense
4. Preventing T-cell activation or impairing effective T-cell antimicrobial responses by specific or nonspecific immunosupression.

Front 216

218. What are some examples of microbes remaining inaccessible to the host immune system?

Back 216

Microbes that propagate in the lumen of the intestine (e.g. toxin producing C. diff) or gallbladder (e.g. salmonella typhi) are concealed from many host immune defenses.

Viruses that are shed from the luminal surface of epithelial cells (e.g. CMV in urine) or those that infect that keratinized epithelium are inaccesible to the host humoral immune system.

Some organizisms establish infections by rapidly invading host cells before the host humoral response beceoms effective (e.g. malaria sporozoites entering liver cells, Trichinella and Traypanosoma cruzi entering skeletal or cardiac muscles).

Lastly, viral latency is the ultimate strategy for hiding antigens from the immune system. During the latent stage, many viral genes are not expressed.

Front 217

219. What are some microorganisms that constantly change surface antigens?

Back 217

The low fidelity of viral RNA polymerases (HIV and many respiratory virusses) and reassortment of viral genomes (influenza viruses) lead to viral antigenic variation.

The spirochete Borrelia recurrentis repeatedly switches its surface antigens and the Lyme disease Borreliae use similar mechanisms.

Cercariae of Schistosoma mansoni shed their antigens w/in minutes of penetrating the skin.

Front 218

220. What are two categories of genetic immunodeficiencies?

Back 218

a. B cells (X-linked agammaglobulinemia is associated w/S. pneumoniae, H. influenzae, S. aureus, rotavirus,and enterovirus infections).

b. Complement protein deficiency (S. pneumoniae, H. influenzae, and N. meningitidis infectiosn)
c. Neutrophil function (S. aureus infections)

Front 219

221. Acquired immunodeficiencies

Back 219

HIV infection kills T-helper cells, and is associated w/viral (HSV, and VZV, bacterial (many), and parasitic infections (cryptococcus).

Immunosuppression in organ transplantation or during bone marrow engraftment renders patients susceptible to virtually all organisms, including common environmental microbes (Aspergillus and Pseudomonas).

Front 220

222. What is suppurative (polymorphonuclear) inflammation?

Back 220

This pattern is the reaction to acute tissue damage, characterized by increased vascular permeability and leukocytic infiltration, predominantly of neutrophils.

This response is mostly evoked from gram-positive cocci and gram-negative rods. Massing of neutrophils forms pus.

Front 221

223. What are the varying sizes of suppurative inflammation?

Back 221

Lesions vary from tine microabscesses to diffuse involvement of entire lung lobes (S. pneumoniae); these may resolve w/o sequelae (pneumococcal pneumonia) or scar (Klebsiella pneumoniae).

Front 222

224. What is mononuclear inflammation?

Back 222

Diffuse, predominantly mononuclear, interstitial infiltrates are a common feature of all chronic inflammatory processes, but when they develop acutely, they often are a response to viruses, intracellular bacteria, or intracellular parrasites.

Which mononuclear cell predominates withing the inflammatory lesions depends on the host immune resposne to the organism: plasma cells in chancres of primary syphilis, lymphocytes in viral infections of the brain, or macrophages in M. avium-intracellulare infections of AIDS patients.

Front 223

225. What is granulomatous inflammation?

Back 223

Granulomatous inflammation is a distinctive form of mononuclear inflammation usually evokes by infectious agents that resist eradications (e.g. M. tuberculosis, Histoplasmosis capsulatus, shistosome eggs) and are capable of stimulating strong T cell-mediated immunity.

*Granulomatous inflammation is characterized by accumulation of activated macrophages called "epitheliod" cells, which may fuse to form giant cells. In some cases there is a central are of caseous necrosis.

Front 224

226. What is cytopathic-cytoproliferative inflammation?

Back 224

These reactions are usually produced by viruses. The lesions are characterized by cell necrosis or cellular proliferation, usually w/sparse inflammatory cells. Some viruses replicate w/in cells and make viral aggregates that are visible as inclusion bodies (e.g. HSV or adenovirus) or induce cells to fuse and form multinucleated cells called polykaryons.

Focal cell damage in the skin may cause epithelial cells to become detached, forming blisters.

Front 225

227. What is necrotizing inflammation?

Back 225

C. perfringens and other organisms that secrete powerful toxins can cause such rapid and severe necrosis (gangrenous necrosis) that tissue damage is the dominant feature. B/c few inflammatory cells are present, these lesions resemble infarcts w/disruption or loss of basophilic nuclear staining and preservation of cellular outlines.

Front 226

228. What is chronic inflammation?

Back 226

Outcomes range from complete healing to scarring; excessive scarring may cause dysfunction (e.g. the "pipe-stem" fibrosis of the liver or fibrosis of the bladder wall caused by shistosomal eggs or the constrictive fibrous pericarditis in tuberculosis).

The inflammation may be severe despite a paucity of organisms (M. tuberculosis).

Front 227

229. Why are different patterns of inflammation encountered?

Back 227

The patterns of inflammation may be mixed b/c of multiple simultaneous infections; the same microbe may also cause different patterns in different patients due to host idiosyncratic responses (e.g. mostly lymphocytes in patients exhibiting tuberculoid leprosy and mostly macrophages in patients exhibiting lepromatous leprosy).

Patterns should be consistent w/the organisms cultured or identified via microscopy.

Front 228

230. What are transient virus infection?

Back 228

The viruses that cause transient infections are structurally heterogeneous, but each elicits and effective immune response that eliminates the virus and may or may not confer lifelong protection.

The mumps virus, for example, has only one serotype and infects people only once, whereas other transient viruses, such as influenza, can repeatedly infect the same individual owing to antigenic variation.

Front 229

231. What is measles?

Back 229

Measle (Rubeola) virus is a leading cause of vaccine-preventable death and illness worldwide. Measles virus is an RNA paramyxovirus that causes a characteristic rash on the face, trunk, and proximal extremities. It can cause severe disease in people w/defects in cellular immunity.

Front 230

232. What is the pathogenesis of measles?

Back 230

Measles virus is a single-stranded RNA virus of the paramyxovirus family that includes mumps, RSV, parainfluenza virus, and human metapneumovirus.

Two cell surface receptors have been identified in measles virus: CD46, a complement regulatory protein that inactivates C3 convertases; and signaling lymphocytic activation molecule (SLAM), a molecule involved in T -cell activation. CD46 is expressed on all nucleated cells, while SLAM is expressed on cells of the immune system. Both of these receptors bind the viral hemagglutinin protein.

Front 231

233. How does measles spread, and how does it infect the body?

Back 231

Measles is spread by respiratory droplets, initially multipliies within upper respiratory epithelial cells, and then spreads to lymphatic tissues, where it can replicate in mononuclear cells, including T cells, macrophages, and dendritic cells. Virus then spreads by the blood throughout the body.

Front 232

234. What are the clinical characteristics of measles?

Back 232

Most children develop T cell mediated immunity to measles that controls the viral infection and produces the measles rash, a hypersensitivity reaction to viral antigens in the skin. Measles may cause croup, pneumonia, diarrhea w/protein losing enteropathy, ketatitis w/scarring and blindness, encephalitis, and hemorrhagic rashes ("black measles") in malnourished children w/poor medical care.

Subacute sclerosing panencephalitis and measles inclusion body encephalitis are rare late complications of measles in immunocompromised individuals.

Front 233

235. What is the morphology of measles infection?

Back 233

The blotchy, reddish brown rash of measles virus infection on the face, trunk, and proximal extremities is produced by dilated skin vessels, edema, and a moderate, nonspecific mononuclear perivascular infiltrate.

Ulcerated mucosal lesions in the oral cavity (Koplik spots) are marked by necrosis, neutrophilic exudate, and neovascularization.

The lymphoid organs typically have marked follicular hyperplasia, large germinal centers, and randomly distributed multineculeate giant cells, called Warthin-Finkeldey cells, which have eosinophilic nuclear and cytoplasmic inclusion bodies. These are pathognomonic of measles.

Front 234

236. What is mumps virus?

Back 234

Like measles virus, mumps virus is a member of the paramyxovirus family. Mumps virus infects salivary gland ductal epithelial cells, resulting in desquamation of involved cells, edema, and inflammation that leads to the classic signs of mumps: salivary gland pain and swelling.

Front 235

237. What is the pathogenesis of mumps?

Back 235

Mumps virus has two types of surface glycoproteins, one w/hemagglutinin and neuraminidase activities and the other w/cell fusion and hemolytic activities.

Mumps viruses enter the upper respiratory tract thru inhalation of droplets, spread to draining lymph nodes, where they replicate in lymphocytes, and then spread thru the blood to the salivary and other glands.

Front 236

238. What is the most common extrasalivary gland complication of mumps infection?

Back 236

Aseptic meningitis, which occurs in about 10% of cases.

Other locales it can spread to are the CNS, testis and ovary, and pancreas.

Front 237

239. What is the morphology of mumps parotitis?

Back 237

In mumps parotitis, which is bilateral in 70% of cases, affected glands are enlarged, have a doughy consistency, and are moist, glistening, and reddish brown on cross-section.

On microscopic exam, the gland interstitium is edematous and diffusely infiltrated by macrophages, lymphocytes, and plasma cells, which compress acini and ducts. Neutrophils and necrotic debris may fill the ductal lumen and cause focal damage to the ductal epithelium.

Front 238

240. What is the morphology of mumps orchitis?

Back 238

In mumps orchitis, testicular swelling may be marked, caused by edema, mononuclear cell infiltration, and focal hemorrhages. B/c the testis is tightly contatined w/in the tunica albuginea, parenchyma swelling may compromise the blood supply and cause areas of infarction.

Sterility, when it occurs, is caused by scars and atrophy of the testis after resolution of viral infection.

Front 239

241. What is poliovirus?

Back 239

Poliovirus is a spherical, unencapsulated RNA virus of the enterovirus genus. Poliovirus, like other enteroviruses, is spread via the fecal-oral route. It first infects tissues in the oropharynx, is secreted into the saliva and swallowed, and the multiplies in the intestinal mucosa and lymph nodes, causing a transient viremia and fever.

Front 240

242. What is the pathogenesis of poliovirus infection?

Back 240

The species specificity of poliovirus for humans is determined by particular amino acid residues that are present in the human receptor, CD155, which is an immunoglobulin superfamily member. Although most polio infections are asymptomatic, in about 1/100 persons, poliovirus invades the CNS and replicates in motor neurons of the spinal cord (spinal poliomyelitis) or brain stem (bulbar poliomyelitis).

Virus spread to the nervous system may be secondary to viremia or by retrograde transport of the virus along axons of motor neurons.

Front 241

243. What is the west nile virus?

Back 241

West nile virus is an arthropod borne virus of the flavivirus group, which also includes viruses that cause dengue fever, Eastern encephalitis, and yellow fever.

It is transmitted by mosquitoes to birds and to mammals. Humans are usually incidental hosts.

Front 242

244. What are the clinical features of west nile virus?

Back 242

West nile virus infection is generally asymptomatic, but in 20% of infected individuals it gives rise to a mild, short-lived febrile illness associated w/headache and myalgia. A maculopapular rash is seen in approx half the cases. CNS complications (meningitis, encephalitis, meningoencephalitis) are not frequent. They manifest as acute flaccid paralysis, clinically indistinguishable from polio.

Perivascular and leptomeningeal chronic inflammation, microglial nodules, and neuronophagia predominantly involving the temporal lobes and brain stem have been observed in the brains of patients who have died from WNV.

Front 243

245. Who is at greatest risk of complications from WNV?

Back 243

The immunosuppressed and elderly individuals are at greatest risk.

Development of meningoencephaltis carries a 10% mortality rate; survivors may exhibit long-term cognitive and neurologic impairment.

Front 244

246. What are viral hemorrhagic fevers?

Back 244

These fevers are systemic infections characterized by fever and hemorrhage. They are caused by enveloped RNA viruses in four different families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses.

Although structurally distinct, these viruses all depend on an animal or insect host for survival and transmission. Humans are infected when they come into contact with infected hosts or insect vectors.

Front 245

247. What are the clinical characteristics of viral hemorrhagic fevers?

Back 245

Hemorrhagic fever viruses produce a spectrum of illnesses, ranging from relatively mild acute disease characterized by fever, headache, myalgia, rash, neutropenia, and thrombocytopenia to severe, life-threatening disease in which there is sudden hemodynamic deterioration and shock.

There are no cures or effective drugs therapy for viral hemorrhagic fevers.

Front 246

248. What is the pathogenesis of viral hemorrhagic fevers?

Back 246

These viruses enter the bloodstream by a number of routes, including the bite of an insect, and following inhalation or mucous membrane expsoure. All cause disease during the period of viremia except for hantaviruses.

Endothelial cell infection occurs w/the majority of VHF viruses. The hemorrhagic manifestations are due to thrombocytopenia or severe platelet or endothelial dysfunction. Typically, there is increased vascular permeability. Infections with many VHF viruses stimulates cytokine production, which may contribute to severe cytopathic effects or DIC.

Front 247

249. What are herpesvirus infections?

Back 247

Herpesviruses are large encapsulated viruses that have a double-stranded DNA genome that encodes 70 proteins. These cause acute infection followed by latent infection in which the virus persists in a noninfectious form, w/periodic reactivation and shedding of infectious virus.

There are 9 types of human herpesviruses, belonging to three subgroups defined by the type of cell most frequently infected and the site of latency.

Front 248

250. What is the herpes simplex virus (HSV-1 and HSV-2)?

Back 248

HSV-1 and HSV-2 differ serologically but are genetically similar and cause a similar set of primary and recurrent infections. Both viruses replicate in the skin and the mucous membranes at the site of entrance of the virus (usually oropharynx or genitals), where they produce infectious virions and cause vesicular lesions of the epidermis. The viruses spread to sensory neurons that innervate these primary sites of replication.

Front 249

251. What is the pathogenesis of HSV?

Back 249

Viral nucleocapsids are transported along axons to the neuronal cell bodies, where the viruses establish latent infection. During latency, the viral DNA remains w/in the nucleus of the neuron, and only latency-associated viral mRNAs are synthesized. In this state, no viral proteins appear to be produced, thus allowing the virus to evade immune recognition.

Reactivation of HSV-1 and HSV-2 may occur repeatedly w/or w/o symptoms, and results in the spread of virus from the neurons to the skin or to mucous membranes.

Reactivation from latency occurs in the presence of host immunity, and herpesviruses have developed ways to avoid immune recognition.

Front 250

252. How can HSV avoid antiviral CTL?

Back 250

HSV can evade antiviral CTL by inhibiting the MHC class I recognition pathway, and elude humoral immune defenses by producing receptors for the Fc domain of immunoglobulin and inhibitors of complement.

Front 251

253. What is the major cause of corneal blindness in the US?

What else does this virus cause?

Back 251

In addition to causing cutaneous lesions, HSV-1 is the major cause of corneal blindness.

It is though to be due to direct viral damage.

*HSV-1 is also the major cause of fatal sporadic encephalitis in the US, when the virus spread to the brain, particularly in the temporal lobes and orbital gyri of the frontal lobes.

Front 252

254. What is the morphology of HSV lesions?

Back 252

All HSV lesions are marked by formation of large, pink to purple intranuclear inclusions (Cowdry type A) that contain intact and disrupted virions and push darkly stained host cell chromatin to teh edges of the nucleus.

Although cell and nuclear size increases only slightly, HSV produces inclusion-bearing multinucleated syncytia.

Front 253

255. What is the morphology of fever blisters or cold sores?

Back 253

HSV-1 and HSV-2 cause lesions ranging from self-limited cold sores and gingivostomatitis to life-threatening disseminated visceral infections and encephalitis.

Fever blisters or cold sores favor the facial skin around mucosal orifices (lips, nose), where their distribution is freq bilateral and independent of skin dermatomes.
Intraepithelial vesicles (blisters), which are formed by intracellular edema and ballooning degeneration of epidermal cells, freq burst and crust over, but some result in superficial ulcerations.

Front 254

256. What is the morphology of Gingivostomatitis?

Back 254

Gingivostomatitis, which is usually encountered in children, is caused by HSV-1. It is a vesicular eruption extending from the tongue to the retropharynx and causing cervical lymphadenopathy.

Swollen, erythematous HSV lesions of the fingers or palm (herpetic whitlow) occur in infants and occasionally in health-care workers.

Front 255

257. What is the morphology of genital herpes?

Back 255

Genital herpes is usually caused by HSV-2, but HSV-1 can also cause genital lesions. *Characterized by vesicles on the genital mucous membranes as well as on the external genitalia that are rapidly converted into superficial ulcerations, rimmed by an inflammatory infiltrate.

Front 256

258. What are the two forms of corneal lesions caused by HSV?

What is their morphology?

Back 256

1. Herpes epithelial keratitis:
-shows typical virus-induced cytolysis of the superficial epithelium and is sensitive to antiviral drugs.

2. Herpes stromal keratitis:
-shows infiltrates of mononuclear cells around keratinocytes and endothelial cells, leading to neovascularization, scarring, opacification of the cornea, and eventual blindness. This is an immunologic reaction to the HSV infection and responds to corticosteroid therapy.

Front 257

259. What is the Kaposi varicelliform eruption?

What is eczema herpeticum?

Back 257

Kaposi varicelliform eruption is a generalized vesiculating involvement of the skin.

Eczema herpeticum is characterized by confluent, pustular, or hemorrhagic blisters, often w/bacterial superinfection and viral dissemination to internal viscera.

Front 258

260. What is CMV?

Back 258

CMV is a β-group herpesvirus. The major envelope glycoprotein of CMV binds to EDGF receptor. CMV infects and remains latent in WBCs and can be reactivated when cellular immunity is depressed.

It causes an asymptomatic or mononucleosis-like infection in healthy individuals but devastating systemic infections in immunocompromised patients.

Front 259

261. What are the five ways in which CMV is transmitted?

Back 259

1. Transplacental transmission from a newly acquired or primary infection in a mother who does not have protective antibodies (congenital CMV).
2. Transmission of the virus thru cervical or vaginal secretions at birth or later thru breast milk (perinatal CMV).
3. Transmission thru saliva during preschool years.
4. Transmission via the veneral route is the dominant mode after about 15 y/o, but spread may also occur via respiratory secretions and the fecal-oral route.
5. Iatrogenic transmission can occur at any age thru organ transplants or by blood transfusions.

Front 260

262. What is the pathogenesis of CMV?

Back 260

CMV can induce transient but severe immunosuppression. CMV can infect dendritic cells and impair their function and maturation and their ability to stimulate T-cell responses.

Similar to other herpesviruses, CMV can elude immune responses by downmodulating MHC class I and II molecules and producing homologues of TNF receptor, IL-10, and MHC class I receptors.

CMV can both activate and evade NK cells by inducing ligands for activating receptors and class-I like proteins that engage inhibitory receptors.

Front 261

263. What is the morphology of CMV infection?

Back 261

Prominent (large) intranuclear basophilic inclusions spanning half the nuclear diameter are usually set off from the nuclear membrane by a clear halo ("owl's eyes").

In the glandular organs, the parenchymal epithelial cells are affected; in the brain, the neurons; in the lungs, the alveolar macrophages and epi- and endothelial cells; and in the kidneys, the tubular epithelial and glomerular endothelial cells. Affected cells are enlarged, and show nuclear and cellular polymorphism.

Front 262

264. What is cytomegalic inclusion disease (CID)?

Back 262

Sometimes when the virus is acquired from a mother w/primary infection (w/o IgM or IgG), classic CID develops.

CID resembles erythroblastosis fetalis. Affected infants may suffer intrauterine growth retardation, be ill, and manifest jaundice, hepatosplenomegaly, anemia, bleeding due to thrombocytopenia, and encephalitis. The brain is often smaller and may show foci of calcification.

Most infants with milder CID recover, although a few develop mental retardation later.

Front 263

265. What is CMV mononucleosis?

Back 263

The common clinical manifestation of CMV infection in immunocompetent hosts beyond the neonatal period is an infectious mononucleosis-like illness, w/fever, atypical lymphocytosis, lymphadenopathy, and hepatomegaly accompanied by abnormal liver function tests, suggesting mild hepatitis.

This disease is nearly always asymptomatic in healthy people. Most patients recover w/o any sequelae, although excretion of the virus may occur in body fluids for months to years.

Front 264

266. How does CMV affect immunosuppressed individuals?

Back 264

**CMV is the most common opportunistic pathogen in AIDS.

Disseminated CMV in immunocompromised hosts is life threatening: lungs, GI tract, and retina are primarily affected, w/associated focal necrosis and minimal inflammation.

**CMV retinitis is by far the most common form of opportunistic CMV infection.

Front 265

267. How is CMV infection diagnosed?

Back 265

Made by demonstration of characteristic morphologic alterations in tissue sections, viral culture, rising antiviral antibody titer, detection of CMV antigens, and qualitative or quantitative PCR based detection of CMV DNA.

Front 266

268. What is VZV?

Back 266

Two conditions - chickenpox and shingles- are caused by varicella zoster virus (VZV). Acute infections w/VZV cause chickenpox; reactivation of latent VZV causes shingles (aka herpes zoster).

VZV usually recurs only once, most freq in immunosuppressed or elderly persons.

Front 267

269. What is the pathogenesis of VZV?

Back 267

Like HSV, ZVZ infects mucous membranes, skin, and neurons and causes a self-limited primary infection in immunocompetent individuals. Also like HSV, VZV evades immune responses and establishes a latent infection in sensory ganglia.

In contrast to HSV, VZV is transmitted in epidemic fashion by aerosols and blood, and causes widespread vesicular skin lesions.

VZV infections neurons and/or satellite cells around neurons in the dorsal root ganglia and may recur later on.

Front 268

270. What is the morphology of the chickenpox rash?

Back 268

The chickenpox rash occurs approx 2 weeks after respiratory infection and travels in multiple waves centrifugally from the torso to the head and extremities. Each lesion progresses rapidly from a macule to a vesicle, which resembles a dewdrop on a rose petal.

On histologic exam, chickenpox vesicles contain intranuclear inclusions in the epithelial cells. After a few days, most vesicles rupture, crust over, and heal by regeneration.

Front 269

271. What is the morphology of shingles?

Back 269

Shingles rash cause vesicular lesions, which are differentiated from chickenpox by the often intense itching, burning, or sharp pain b/c of the simultaneous radiculoneuritis. This pain is especially strong when the trigeminal nerves are involved; rarely the geniculate nucleus is involved, causing facial paralysis (Ramsay Hunt syndrome).

*In the sensory ganglia, there is a dense, predominantly mononuclear infiltrate, w/herpetic intranuclear inclusions w/in neurons and their supporting cells.

Front 270

272. What causes the high mutation rate in HBV infections?

Back 270

The DNA genome is synthesized by reverse transcription of an RNA template; lack of a proofreading function in the reverse transcriptase leads to the characteristically high mutation rate.

Front 271

273. What is EBV?

Back 271

EBV causes infectious mononucleosis, a benign, self-limited lymphoproliferative disorder, and is associated w/the development of hairy leukoplakia and a number of neoplasms, most notably certain lymphomas and naspharyngeal carcinoma.

IM is characterized by fever, generalized lymphadenopathy, splenomegaly, sort throat, and the appearance of atypical activated T lymphocytes.

Front 272

274. What is the pathogenesis of EBV?

Back 272

EBV infection begins in nasopharyngeal and oropharyngeal epithelial cells. An EBV envelope glycoprotein binds to CR2, the receptor for the C3d component of complement present on B cells. It is then followed by infection of B cells in underlying lymphoid tissues.

B cells become the eventual reservoir of latent infection. T-cell counts increase as a response to clear the EBV-infected B cells.

Front 273

275. What is X-linked agammaglobulinemia?

Back 273

Patients with X-linked agammaglobulinemia do not become latently infected w/EBV or shed virus, suggesting B cells are the main reservoir of latent infection.

Front 274

276. What are the atypical lymphocytes?

Back 274

Cellular immunity mediated by CD8+ T cells and NK cells is the most important component of this response. The atypical lymphocytes seen in the blood, so characteristic of this disease, are mainly CD8+ cytotoxic T cells, but also include CD16+ NK cells.

The reactive proliferation of T cells is largely centered in lymphoid tissues, which accounts for the lymphadenopathy and splenomegaly.

Front 275

277. What is the morphology of the peripheral blood smear in EBV?

Back 275

THe peripheral blood smear shows absolute lymphocytosis w/a total WBC count between 12,000 and 18,000 cells/μL, more than 60% of which are lymphocytes.

Many of these are large, atypical lymphocytes, 12- 16 μm in diameter, characterized by an abundant cytoplasm containing multiple clear vacuolations, an oval, indented, or folded nucleus, and scattered cytosplasmic azurophilic granules.

Front 276

278. What is the most striking feature of EBV infection in lymph nodes?

Back 276

On histologic exam, the most striking feature is the expansion of paracortical areas by activated T cells (immunoblasts).

Occasionally, EBV-infected B cells resembling Reed-Sternberg cells may be found. B cell areas (follicles) may also be hyperplastic but this is usually mild in degree.

Front 277

279. What morphologic changes take place in the spleen in EBV infection?

Back 277

The spleen is enlarged and soft and flesh; the histologic changes are analogous to those of the lymph nodes, sowing an expansion of white pulp follicles and red pulp sinusoids due to the presence of numerous activated T cells.

Front 278

280. What three things does the Dx of EBV infection rest upon?

Back 278

1. Lymphocytosis w/the characteristic atypical lymphocytes in the peripheral blood
2. A positive heterophile antibody reaction (monospot test)
3. Specific antibodies for EBV antigens (viral capsid antigens, early antigens, or EB nuclear antigens)

Front 279

281. What is X-linked lymphoproliferation syndrome (AKA Duncan disease)?

Back 279

X-linked lymphoproliferation syndrome (AKA Duncan disease) is a disorder caused by a defect in a gene, SH2D1A, that is expressed primarily in cytotoxic T cells and NK cells.

SH2D1A participates in a signaling pathway critical for an effective cellular response to EBV-infected B cells.

Patients are often normal until they are acutely infected w/EBV, often during adolescence. Failure to control EBV infection variously leads to chronic infectious mononucleosis, agammaglobulinemia, and B-cell lymphoma.

Front 280

282. What is HPV?

Back 280

HPVs are nonenveloped DNA viruses that are members of the papovavirus family. There are over 100 types. Some HPVs cause papillomas (warts), and benign tumors of squamous cells on the skin. Other HPVs are associated w/warts that can progress to malignancy, particularly squamous cell CA of the cervix and the anogenital area.

Front 281

283. What is the pathogenesis of HPV infection?

Back 281

Papilloma viruses initially infect basal cells in the epithelium, but there is limited expression of viral genes in these cells.

As they differentiate, additional genes are expressed.

*In the upper spinous layers of the epithelium, HPV leads to a characteristic perinuclear vacuolization in the epithelial cells (koilocytosis).

Front 282

284. What does HPV DNA code for?

Back 282

HPV DNA is an episomal plasmid, and virus-encoded proteins promote cell growth and malignancy.

HPV E6 stimulates ubiquinitation and degradation of p53, and HPV E7 binds to Rb, releasing the E2F transcription factor. Both of these actions dysregulate the cell cycle and may promote cellular transformation and malignancy.

Front 283

285. What are the common Gram-positive pathogens?

Back 283

Staphylococcus and Streptococcus infections are the most common.

Front 284

286. What are staphylococcal infections?

Back 284

Staph aureus organism are pyogenic, nonmotile, Gram-positive cocci that form grapelike clusters.

These bacteria cause a myriad of skin lesions (boils, carbuncles, impetigo, and scalded skin) and also cause osteomyelitis, pneumonia, endocarditis, food poisoning and TSS.

Front 285

287. How does S. aureus infect?

Back 285

S. aureus has a number of virulence factors that include:
1. Surface proteins that allow host adherence (fribrinogen, protein A)
2. Enzymes that degrade host proteins, promoting invasion and tissue destruction
3. Toxins that damage host cells membranes (hemolysins - α-toxin), or induce skin sloughing (exfoliative toxins - serine proteases), vomiting (enterotoxins), or shock (via superantigens).

Front 286

288. What is TSS?

Back 286

TSS is characterized by hypotension, renal failure, coagulopathy, liver disease, respiratory distress, a generalized erythematous rash, and soft tissue necrosis at the site of infection.

Front 287

289. What is the morphology of a furuncle, or boil?

Back 287

Excluding impetigo, staph infections are centered around the hair follicles. A furuncle, or boil, is a focal suppurative inflammation of the skin and subcutaneous tissues, either solitary or multiple or recurrent in successive crops.

Furuncles are most freq in moist, hairy areas, such as the face, axillae, groin, legs, and submammary fold.

Beginning in a single hair follicle, a boil develops into a growing and deepening abscess that eventually comes to a head by thinning and rupturing the overlying skin.

Front 288

290. What is a carbuncle? Morphology?

Back 288

A carbuncle is associated w/deeper suppuration that spreads laterally beneath the deep subcutaneous fascia and then burrows superficially to erupt in multiple adjacent skin sinuses. Typically occurs beneath skin of upper back and posterior neck.

Front 289

291. What is hidradenitis suppurativa?

Back 289

Chronic abscess formation of apocrine gland regions, most freq of the axilla, is known as hidradenitis suppurativa.

Front 290

292. What are paronychia and felons?

Back 290

Those of the nail bed (paryonychia) or on the palmar side of the fingertips (felons) are exquisitely painful.

They may follow trauma or embedded splinters and if deep enough, destroy the bone of the terminal phalanx or detach the fingernail.

Front 291

294. What is staphylococcal scalded skin syndrome (AKA Ritter disease)?

Back 291

Staphylococcal scalded skin syndrome (AKA Ritter disease) is caused by the exfoliative A and B toxins.

It is an exfoliative dermatitis that most freq occurs in children w/staph infections of the nasopharynx or skin.

There is a sunburn like rash that spreads throughout the entire body and forms fragile bullae that lead to partial or total skin loss. *The intraepithelial split in staph scaled skin syndrome is the granulosa layer, distinguishing it from other diseases which occur at the epidermal-dermal junction.

Front 292

295. What are streptococcal infections?

Back 292

These facultative or obligate anaerobic gram-positive cocci grow in pairs or chains. The bacteria are classified by the pattern of hemolysis on blood agar: β (complete or clear hemolysis, α (partial or green hemolysis), and γ (no hemolysis, rarely pathogenic).

Front 293

296. What is the most important α-hemolytic streptococcus?

Back 293

Strep pneumoniae is the most important α-hemolytic streptococcus.

S. pneumoniae is a common cause of community acquired pneumonia and meningitis in adults.

Front 294

297. What is the morphology of streptococcal infections?

Back 294

Streptococcal infections are characterized by diffuse interstitial neutrophilic infiltrates w/minimal destruction of host tissues.

The skin lesions caused by streptococci (furuncles, carbuncles, and impetigo) resemble those of staph, although w/streptococci there is less of a tendency to form discrete abscesses.

Front 295

298. What is Erysipelas?

Back 295

Erysipelas is most common among middle-aged persons in warm climates and is caused by exotoxins from superficial infections w/S. pyogenes.

It is characterized by rapidly spreading erythematous rash that has a sharp, well-demarcated border, that may form a "butterfly" distribution on the face.

Front 296

299. What is streptococcal pharyngitis?

Back 296

Streptococcal pharyngitis, which is the major antecedent of poststreptococcal glomerulonephritis, is marked by edema, epiglottic swelling, and punctate abscesses of the tonsillar crypts, sometimes accompanied by cervical lymphadenopathy.

Front 297

300. What is scarlet fever?

Back 297

Scarlet fever, associated w/tonsillitis caused by S. pyogenes, is most common between 3-15 year olds. It is manifested by a punctate erythematous rash that is most abundant over the trunk and inner aspects of the arms and legs. The face is also involved, but usualy a small area about the mouth remains unaffected to produce a circumoral pallor.

On microscopic exam, there is a characteristic acute, edematous, neutrophilic inflammatory reaction within the affected tissues (oropharynx - tongue, skin, and lymph nodes).

The inflammatory involvement of the epidermis is usually followed by hyperkeratosis of the skin, which accounts for the scaling during defervescene.

Front 298

301. What is Diphtheria?

Back 298

Diphtheria is caused by a slender Gram-positive rod w/clubbed ends, Corynebacterium diphtheriae, which is passed from person to person thru aerosole or skin shedding. C. diphtheriae causes a range of illnesses.

It most commonly causes a durable membrane at the site of growth in the oropharynx, and the release of toxin in the pharynx produces epithelial necrosis w/a fibrinosuppurative exudate.

Front 299

302. Again, what is the two-component toxin produced by Corynebacterium diphtheriae?

Back 299

Diphtheria toxin is a phage-encoded two component toxin:

A subunit blocks protein synthesis by ADP ribosylation of elongation factor-2 (leading to inactivation)

The B fragment binds to the cell surface and facilitates entry of the A subunit.

Front 300

303. What is Listeriosis?

Back 300

Listeriosis is caused by Listeria monocytogenes, a gram-positive, motile facultative intracellular bacterium that causes severe food borne infections, and meningitis in elderly and immunosuppressed people, and placental infections in pregnant women w/consequent neonatal infections.

Front 301

304. What is the pathogenesis of listeriosis?

Back 301

L. monocytogenes enters epithelial cells by binding E-cadherin and stimulating phagocytosis; the bacillus then uses listeriolysin O and those phospholipases to degrade the phagolysosome membrane to escape into the cytoplasm.

In the cytoplasm, a bacteria protein (ActA) induces actin polymerization to propel the bacteria into adjacent cells.

Front 302

305. What is the morphology of listeriosis infection and the related meningitis?

Back 302

In acute infections, it evokes an exudative pattern of inflammation w/numerous neutrophils.

The meningitis associated with is is indistinguishable from that caused by other pyogenic bacteria; however, the finding of Gram-positive, most intracellular, bacilli in the CSF is virtually diagnostic.

Front 303

306. What is anthrax?

Back 303

Bacillus anthracis is a large, spore-forming Gram-psotive rod-shaped bacterium. These bacteria are common pathogens in farm and wild animals that have contact w/soil contaminated with B. anthracis spores.

It is typically acquired thru exposure to animals or animal products such as wool or hides. There are three major anthrax syndromes.

Front 304

307. What are the three major anthrax syndromes?

Back 304

1. Cutaneous anthrax
2. Inhalational anthrax
3. GI anthrax

Front 305

308. What is cutaneous anthrax?

Back 305

Cutaneous anthrax, which makees up 95% of naturally ocurring infections, begins as a painless, pruritic papule that develops into a vesicle w/in 2 days.

As the vesicle enlarged, edema may form and there is regional lymphadenopathy.

**After it ruptures, the remaining ulcer becomes covered with a characterisitc black eschar, which dries and falls off as the patient recovers.

Front 306

309. What is inhalational anthrax?

Back 306

Inhalational anthrax enters via inhalation (DUH...) and is carried to regional lymph nodes by phagocytes where the spores germinate, and the release of toxins causes hemorrhagic mediastinitis.

After a prodromal illness of 1-6 days characterized by fever, cough, and chest or abdominal pain, there is abrupt onset of increased fever, hypoxia, and sweating.

Freq anthrax meningitis develops due to bacteremia. Inhalational anthrax rapidly leads to shock and freq death w/in 1-2 days.

Front 307

310. What is GI anthrax?

Back 307

GI anthrax is an uncommon form of infection usually caused by eating undercooked meat contaminated w/B. anthracis.

Initially, the patient has nausea, abdominal pain, and vomiting. Severe, bloody diarrhea rapidly develops, and mortality is over 50%.

Front 308

311. What is the pathogenesis of anthrax toxin?

Back 308

Anthrax toxin comprises of a B subunit (protective factor) and one of two A subunits (edema factor or lethal factor) that act in host cell cytoplasm.

Edema factor converts ATP to cAMP, leading to cellular water efflux.

Lethal factor is a protease that causes cell death by destroying mitogen-activated protein kinase kinases.

Front 309

312. What is the morphology of anthrax lesions?

Back 309

Anthrax lesions at any site are typified by necrosis and exudative inflammation of neutrophils and macrophages.

The presence of large, boxcar-shaped gram-positive extracellular bacteria in chains should suggest the diagnosis.

Front 310

313. What is Nocardia?

Back 310

Nocardia are aerobic Gram-positive bacteria that grown in distinctive branches chains. In culture, Nocardia form aerial structures w/terminal spores, resembling hyphae.

Nocardia asteroides causes respiratory infections while other species, mainly Nocardia basiliensis, infect the skin.

Respiratory infection causes an indolent illness, w/fever, weight loss, and cough.

CNS infections w/N. asteroides are also indolent and cause neurologic deficits depending on the site of infection.

Front 311

314. What is the morphology of nocardiosis?

Back 311

The Dx of nocardiosis depends on identification of slender Gram-positive organissm arranged in branching filaments. Irregular staining give sthe filaments a beaded appearance.

Nocardia stain w/modified acid fast stains (Fite-Faraco stain), unlike Actinomyces, which may appear similar on gram stain of tissue.

At any site of infection, Nocardia elicit a suppurative response w/central liquefaction and surrounding granulation and fibrosis. *Granulomas do not form.

Front 312

315. What are the three rickettsial diseases in the US?

Back 312

1. Rocky moutain spotted fever
2. Q fever
3. Murine typhus

Front 313

316. What is the cause of the rickettsial diseases?

Back 313

The causative organism, Rickettsia rickettsii, is transmitted from dogs or small wild animals to ticks and then to humans. Infection occurs primarily during warmer months, the period of greatest tick activity.

The fulminant onset of severe frontal headache, chills, fever, myalgias, and conjunctivitis occur after 2-14 days; cough and SOB develop in 25% of patients.

*Typically occurs in the southeastern US.

Front 314

317. What is the rash like in Rickettsial disease?

Back 314

The rash characteristically begins on day 3-5 of illness as 1-4 mm erythematous macules on the hands, wrists, feet and ankles. Palms and soles may also be involved. The rash may be transient, but it usually spreads to the trunk and may become petechial.

Dx is via specific complement fixation test which shows a rise in titers and allows retrospective confirmation of Dx.

Treatment is with Doxycycline.

Front 315

318. What is Human monocytic ehrlichiosis (HME?)

Back 315

Human ehrlichiosis is an acute, febrile illness caused most freq by Ehrlichia chaffeensis.

E. chaffeensis is transmitted by woodland exposure to deer or dog ticks and causes illness w/peak incidence in the summer months. *The illness characteristically begins w/fever, chills, headaches, and myalgias, w/a maculopapular rash occurring in less than a third of cases.

One half of cases are associated w/pulmonary infiltrates. ARDS often associated w/renal failure may develop. If left untreated, the mortality rate may exceed 10% in hospitalized patients.

Front 316

318. What is Human granulocytic ehrlichiosis (HGE)?

Back 316

HGE is caused by anaplasma phagocytophilum and peaks in July and occurs in areas where infected Ixodes ticks are found.

9% of patients have concurrent Lyme disease or babesiosis b/c the same tick transmits these diseases.

HGE usually exhibits a nonspecific influenza like illness w/fever, chills, malaise, headache, nausea, and vomiting, leukopenia, and thrombocytopenia.

Front 317

319. How is HME or HGE diagnosed?

Back 317

Dx of HME or HGE is made on clinical grounds w/patients w/acute febrile illnesses, which are generally associated w/decreasing leukocyte and platelet counts after tick exposure.

*Peripheral blood smears may show intracellular organisms called morulae in infected leukocytes.

Front 318

320. What are the major clinical distinctions between human ehrlichiosis and RMSF?

Back 318

RMSF have earlier, more frequent and more severe cutaneous manifestations.

Ehrlichiosis has more common pulmonary manifestations and characteristically decreasing leukocyte counts.

Front 319

321. What is Lyme disease?

Back 319

Lyme disease is a common, multisystem spirochetal infection caused by Borrelia burgdorferi and is transmitted by the tick Ixodes. Between 3 days and 3 weeks after the tick bit (of which most individuals are unaware), patients develop a febrile illness, usually associated w/headache, stiff neck, myalgias, arthralgias, and ertyhema chronicum migrans.

Enlargement of regions lymph nodes is common.

Front 320

322. What is erythema chronicum migrans?

Back 320

Erythema chronicum migrans begins as a red macule or papule at the site of the tick bite; the surrounding bright red patch expands to a diameter of up to 15 cm. Partial central clearing is often seen. The centers of lesions may become indurated, vesicular, or necrotic. Several red rings may be found w/in the outer border.

Smaller secondary lesions may appear w/in several days. Lesions are warm but nontender. The rash usually fades in approx 1 month.

Front 321

323. What are the complications of Lyme disease?

Back 321

1. Meningoencephalitis with cranial nerve involvement and peripheral radiculoneuropathy (*Bells palsy when associated w/fever is strongly suggestive of Lyme disease!)
2. Heart involvement may exhibit a AV block, myopericarditis, or cardiomegaly
3. Joint involvement eventually occurs in 60% of patients, starting with the knee

Front 322

324. What is the treatment for Lyme disease?

Back 322

Treatment w/doxycycline 200mg orally w/in 72 hours of a deer tick bite in an endemic area appears to decrease the subsequent development of Lyme disease.

Meningitis, cardiac involvement, or arthritis should be treated w/aqueous Penicillin G, or IV ceftriaxone.

Front 323

325. Should antibiotic be given for EBV infections?

Back 323

No, antibiotics -particularly ampicillin, should be avoided. The use of ampicillin causes a rash in almost all patients w/EBV infection, and this phenomenon can also be a diagnostic clue to the occurrence of EBV infection.

Front 324

326. What are the main differences between CMV mononucleosis and EBV mononucleosis?

Back 324

CMV tends to involve older patients (mean age 29) and often produces milder disease, is less likely to cause pharyngitis, and often causes high fever w/little or no peripheral lymph node enlargement.

The infrequent but serious forms of neurologic and hematologic involvement that develop in EBV infection occur less commonly w/CMV.

Front 325

327. What is acute acquired toxoplasmosis?

Back 325

Toxoplasma gondii is acquired by ingesting oocyst-contaminated meat and other foods or by exposure to cat feces.

Presentation may take the form of a mononucleosis-like syndrome, although maculopapular rash, abdominal pain caused by mesenteric and retroperitoneal lymphadenopathy, and chorioretinitis may also occur. More commonly, cervical lymph node enlargement is observed in symptomatic patients. Biopsy may be necessary to exclude lymphoma.

Front 326

328. What is the morphology of toxoplasmosis?

Back 326

Histologically, focal distention of sinuses w/mononuclear phagocytes, histiocytes blurring the margins of germinal centers, and reactive follicular hyperplasia indicates Toxoplasma infection.

Acute acquired toxoplasmosis is generally self limited in the immunologically intact host and does not require specific therapy.

Front 327

329. What is granulomatous disease?

Back 327

Disseminated tuberculosis, histoplasmosis, and sarcoidosis may be associated w/generalized lymphadenopathy, although involvement of certain lymph node chains can predominate.

Lymph node biopsy shows granulomas or nonspecific hyperplasia.

Front 328

330. What is pyogenic infection?

Back 328

S. aureus and group A streptococcal infections produce acute suppurative lymphadenitis. The most freq affected lymph nodes are submandibular, cervical, inguinal and axillary.

Pyoderma, pharyngitis, or periodontal infection may be present.

Patients are febrile and have a leukocytosis.

Penicillin G is for pharyngeal or periodontal origin. Sin involvement suggests staph infection and is indicated for nafcillin or dicloxacillin therapy.

Front 329

331. What is the most common causative agent of tuberculosis in children in the US?

Back 329

Mycobacterium scrofulaceum.

Front 330

332. What is cat-scratch disease?

Back 330

Chronic regional lymphadenopathy after exposure to cats or cat scratches should suggest the Dx. About 1 week after contact w/the cat, a local papule or pustule may develop. One week later, regional adenopathy appears. Lymph nodes may be tender or enlarge. Fever is low grade is present at all.

Lymph node biopsy shows necrotic granulomas w/giant cells and stellate abscesses surrounded by epithelial cells.

Front 331

333. What causes cat-scratch disease? How is it treated?

Back 331

Pleomorphic gram-negative bacilli (Bartonella henselae) can be identified in the first 4 weeks of illness in lymph node biopsy.

The course is usually self limited and benign but can be life threatening in the immunodeficient. No treatment is usually necessary.

Front 332

334. What is the classic cause of ulceroglandular fever?

Back 332

Tularemia. The syndrome is acquired by contact w/tissues or fluids from an infected rabbit or the bite of an infected tick.

Patients have chills, fever, ulcerated skin lesion at the site of inoculation, and painful regional adenopathy.

If acquired from rabbit: infection is on the fingers or hand and lymph node involvement is usually axillary or epitrochlear. If infection is from tick bite: the ulcer is on the lower extremities, perianal region, or trunk, and the lymphadenopathy is inguinal or femoral.

Front 333

335. What is the cause of Tularemia?

How is it treated?

Back 333

Francisella tularensis, is hazardous, and a four fold rise in agglutination titer is diagnostic. Patients should be treated presumptively w/streptomycin, 15-20 mg/kg/day for 10 days.

Front 334

336. What causes oculoglandular fever?

Back 334

Conjunctivitis w/preauricular lymphadenopathy can occur in tularemia, cat-scratch disease, sporotrichosis, lymphogranuloma venereum infection, listeriosis, and epidemic keratoconjunctivitis caused by adenovirus.

Front 335

337. What is the plague?

How is it treated?

Back 335

Bubonic plague usually exhibits fever, headache, and a large mat of inguinal or axillary lymph nodes, which go on to suppurate and drain spontaneously.

If the plague is suggested (as is from close contact with fleas and rodents), the blood cultures and aspirates of the buboes should be obtained, and tetracycline plus streptomycin should be given.