Pbl Exam 10 Case 8

Front 1

1. What are type I hypersensitivity reactions?

Back 1

Immediate hypersenitivity, or type I, is a type of pathologic reaction that is caused by the release of mediators from mast cells. This reaction most commonly is triggered by the production of IgE antibody against environmental antigens and the binding of IgE to mast cells in various tissues.

Front 2

2. What are type II hypersensitivity reactions?

Back 2

Antibodies other than IgE may cause diseases in two ways:

Antibodies directed against cell or tissue antigens can damage these cells or tissues or impair their function. These diseases are said to be antibody mediated and represent type II hypersensitivity.

Front 3

3. What are type III hypersensitivity reactions?

Back 3

Sometimes, antibodies against soluble antigens may form complexes w/the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury.

Such diseases are called type III hypersensitivity reactions.

Front 4

4. What are type IV hypersensitivity reactions?

Back 4

Some diseases result from the reactions of T lymphocytes, often against self antigens in tissues.

These T cell-mediated diseases represent type IV hypersensitivity.

Front 5

5. What is a type I hypersensitivity reaction?

What is it mediated by?

Back 5

Type I hypersensitivity is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen w/antibody bound to mast cells in individuals previously sensitized to the antigen.

Immediate hypersensitivity is mediated by IgE antibodies directed against specific antigens (allergens).

Synthesis of IgE antibody requires the induction of CD4+ helper T cells of the TH2 type; these TH2 cells produce multiple cytokines that contribute to various aspects of this response.

Front 6

6. What cytokine is essential for IgE synthesis?

What is the first step in IgE synthesis?

Back 6

IL-4, produced by TH2 cells, is essential for IgE synthesis.

The first step in the synthesis of IgE is the presentation of the antigen to naive CD4+ helper T cells by dendritic cells that capture the antigen from its site of entry.

Front 7

7. What cytokines are responsible for promoting production and survival of eosinophils - important effector cells in type I hypersensitivity reactions?

Back 7

IL-5, IL-3, and granulocyte-macrophage colony stimulating factor (GM-CSF) promote production and survival of eosinophils.

Front 8

8. What occurs in the initial phase of a type I hypersensitivity reaction?

Four things are released...

Back 8

Primary mast cell mediators that include the initial rapid response include:
1. Biogenic amines (e.g. histamine) which cause bronchial smooth muscle contraction, increased vascular permeability and dilation, and increased mucous gland secretions.
2. Chemotactic mediators (e.g. eosinophil chemotactic factors and neutrophil chemotactic factors)
3. Enzymes contained in granule matrix (e..g chymase, tryptase) that generate kinins and activated complement by acting on their precursor proteins.
4. Proteoglycans (e.g. heparin)

Front 9

9. What are the characteristics of the initial response?

Back 9

The initial response is characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions.

These changes usually become evident within 5-30 minutes after exposure to an allergen and tend to subside in 60 minutes.

Front 10

10. What occurs in the second, delayed phase of a type I hypersensitivity reaction?

What drives this phase?

Back 10

This stage is characterized by an intense inflammatory cell infiltration with associated tissue damage. This late secondary phase is driven by lipid mediators and cytokines produced by the activated mast cells.

Front 11

11. What are mast cells?

Back 11

Mast cells are bone marrow-derived cells that are widely distributed in the tissues. They are found predominantly near blood vessels and nerves and in subepithelial sites, where local immediate hypersensitivity reactions tend to occur.

Front 12

12. How are mast cells activated?

Back 12

Mast cells (and basophils) are activated by the cross-linking of high-affinity IgE Fc receptors; in addition mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a, both of which act by binding to their receptors on the mast cell membrane.

Front 13

13.What are basophils?

Back 13

Basophils are similar to mast cells in many respects, including the presence of cell-surface IgE Fc receptors as well as cytoplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in extremely small numbers.

Front 14

14. Most immediate hypersensitivity reactions are mediated by...?

Back 14

IgE antibodies.IgE-secreting B cells differentiate from naive B cells, and this process is dependent on the activity of CD4+ helper T cells of the TH2 type.

*Hence, TH2 cells are pivotal in the pathogenesis of type I hypersensitivity.

Front 15

15. What 6 allergens can trigger mast cell and basophil degranulation?

Back 15

1. Complement fragments (C3a and C5a (anaphylatoxins)
2. Certain drugs i.e. codeine, morphine, adenosine
3. Mellitin (bee venom)
4. Sunlight
5. Trauma
6. Heat/cold

Front 16

16. Where are IgE antibodies synthesized in response to prior exposure to allergens are normally bound to where?

Back 16

Mast cells and basophils via specific surface Fc receptors.

On re-exposure, allergen bind to and cross-links the IgE on mast cells and results in:
1. Degranulation of vesicles containing primary mediators
2. De novo synthesis and release of secondary mediators

Front 17

17. What are the 4 lipid mediators produced by the mast cells in the delayed phase?

What is the role of each lipid mediator?

Back 17

1. Leukotriene B4 is highly chemcotactic for neutrophils, monocytes, and eosinophils
2. Leukotrienes C4, D4, and E4 are 1000x more potent than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. These also cause marked mucous gland secretion
3. Prostaglandin D2 causes intense bronchospasm, vasodilation, and mucous secretion
4. Platelet-activating factor causes platelet aggregation, histamine release, bronchoconstriction, vasodilation, and increased vascular permeability. It also has proinflammatory effects, such as chemoattraction and degranulation of neutrophils

Front 18

18. In sum, what do the lipid mediators lead to?

Back 18

The lipid mediators are generated by sequential reactions in the mast-cell membranes that lead to activation of phospholipase A2, an enzyme that acts on the membrane phospholipids to yield arachidonic acid.

This is the parent compound from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways.

Front 19

19. What are the important cytokine mediators in type I hypersensitivity reactions?

Back 19

The cytokines include TNF, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF, as well as chemokines, such as macrophage inflammatory protein (MIP)-1α and (MIP)-1β.

Mast cell derived TNF and chemokines are important mediators of the inflammatory response seen at the site of allergic inflammation. Inflammatory cells that accumulate at the sites of type I hypersensitivity reactions are additional sources of cytokines and of histamine-releasing factors that cause further mast-cell degranulation.

Front 20

20. What cytokines can epithelial cells produce?

Back 20

IL-6, IL-8 and GM-CSF

Front 21

21. The development of immediate hypersensitivity reactions is dependent on...?

Back 21

The development of immediate hypersensitivity reactions is dependent on the coordinated actions of a variety of chemotactic, vasoactive, and spasmogenic compounds.

Front 22

22. What is the role of TNF-α in type I hypersensitivity reactions?

Back 22

TNF-α in particular is a powerful proinflammatory cytokine that recruits and activates many additional inflammatory cells.

Recruited inflammatory cells also release cytokines, and TNF-α-activated epithelial cells secrete chemokines (e.g. eotaxin and RANTES) that recruit eosinophils.

Front 23

23. What is the role of eosinophils in type I hypersensitivity reactions?

Back 23

Eosinophils are particularly important in late-phase responses; they cause tissue damage by releasing major basic protein and eosinophil cationic protein.

Front 24

24. What does atopy mean?

Back 24

Atopy refers to a predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens.

Atopic individuals seem to have a higher serum IgE level, and more IL-4 producing TH2 cells, compared w/the general population.

Front 25

25. What are the genetic components of immediate hypersensitivity?

Back 25

A positive family history of allergy is found in 50% of atopic individuals.

Candidate genes have been mapped to 5q31 for asthma, where genes for the cytokines IL-3, 4, 5, 9, 13, and GM-CSF are located, consistent with the idea that these cytokines are involved in the reactions.

Linkage has also been noted to 6p, close to the HLA complex, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens.

Another asthma associated locus is on chromosome 11q13, the location of the gene encoding the β chain of the high-affinity IgE receptor.

Front 26

26. What is the summary of type I hypersensitivity reactions?

Back 26

Type I hypersensitivity is a complex disorder resulting from an IgE mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated in large part by the induction of TH2 type helper T cells that promote synthesis of IgE and accumulation of inflammatory cells, particularly eosinophils. The clinical features result form release of mast-cell mediators as well as the accumulation of an eosinophil-rich inflammatory exudate.

Front 27

27. What is systemic anaphylaxis?

Back 27

Systemic anaphylaxis typically follows parenteral or oral administration of an allergen. The severity reflects the level of sensitization, and even minuscule doses may induce anaphylactic shock in an appropriate host.

Pruritus, urticaria, and erythema occur minutes after exposure, followed by bronchoconstriction and laryngeal edema; this can escalate into laryngeal obstruction, hypotensive shock, and death within minutes to hours.

Front 28

28. What are local immediate hypersensitivity reactions?

Back 28

These reactions are exemplified by atopic allergies. There is a hereditary predisposition affecting 10% of the population (mapping to 5q31, where many of the TH2 type cytokines are located).

Affected individuals tend to develop local type I responses to common inhaled or ingested allergens.

Symptoms include urticaria, angioedema, rhinitis, and asthma.

Front 29

29. What is antibody-mediated (type II) hypersensitivity?

Back 29

Type II hypersensitivity is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix.

The antigenic determinants may be intrinsic to the cell membrane or matrix, or they may take the form of an exogenous antigen such as a drug metabolite that is adsorbed on a cell surface or matrix.

In either case, the hypersensitivity reaction results from the binding of antibodies to normal or altered cell surface antigens. Most of these reactions involve the effector mechanisms that are used by antibodies, namely the complement system and phagocytes.

Front 30

30. What are the 3 major pathways in type II hypersensitivity reactions?

Back 30

1. Opsonization and complement- and Fc receptor-mediated phagocytosis

2. Complement- and Fc receptor-mediated inflammation

3. Antibody-mediated cellular dysfunction

Front 31

31. Opsonization and complement- and Fc receptor-mediated phagocytosis

Back 31

Cells can be directed lysed via the C5-C9 complement membrane attack complex (MAC) or they can be opsonized (enhanced phagocytosis) as a result of fixation of antibody or C3b fragments.

Low concentrations of bound antibody (IgG or IgE) can also cause cell lysis (w/o phagocytosis) by nonsensitized cells bearing Fc receptors (e.g. NK cells, so called antibody-dependent cell mediated cytotoxicity (ADCC).

Front 32

32. What is antibody-dependent cell mediated cytotoxicity (ADCC)?

Back 32

This form of antibody mediated cell injury does not involve fixation of complement but instead requires the cooperation of leukocytes.

Cells that are coated with low concentrations of IgG antibody are killed by a variety of effector cells, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis.

Front 33

33. What mediates ADCC?

Back 33

ADCC may be mediated by monocytes, neutrophils, eosinophils, and NK cells.

Although, in most instances, IgG antibodies are involved in ADCC, in certain cases, e.g. eosinophil-mediated cytotoxicity against parasites), IgE antibodies are used.

Front 34

34. In what 4 situations does antibody-mediated cell destruction and phagocytosis occur?

Back 34

1. Transfusion reactions, in which cells from an incompatible donor react w/and are opsonized by preformed antibody in the host.
2. Erythroblastosis fetalis, in which there is an antigenic difference between the mother and the fetus, and antibodies (of the IgG class) from the mother cross the placenta and cause destruction of fetal red cells.
3. Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are then destroyed.
4. Certain drug reactions, in which antibodies are produced that react w/the drug, which may be attached to the surface of erythrocytes or other cells.

Front 35

35. What is complement- and Fc receptor-mediated inflammation?

Back 35

The deposition of antibodies w/subsequent complement activation, e.g. C5a, in the extracellular matrix leads to the recruitment and activation of nonspecific inflammatory cells (neutrophils and macrophages).

These activated cells can release injurious proteases and reactive oxygen species that lead to tissue pathology.

Ex: glomerulonephritis, vascular rejection in organ grafts.

Front 36

36. Antibody-mediated cellular destruction

What are some diseases that exemplify this mechanism?

Back 36

In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.

For example, in myasthenia gravis, antibodies reactive w/ACh receptors in the motor end-plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

In pemphigus vulgaris, antibodies against desmosomes disrupt intercellular junctions in epidermis, leading to the formation of skin vesicles.

The converse (i.e. antibody-mediated stimulation of cell function) is noted in Graves disease. In this disorder, antibodies against the TSH receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Front 37

37. What is immune complex-mediated (type III) hypersensitivity?

Back 37

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition.

The toxic reaction is initiated when antigen combines w/antibody within the circulation and these are deposited, typically in vessel walls, or the complexes are formed at extravascular sites where antigen may have been deposited previously (in situ immune complexes).

Front 38

38. What are the 2 general types of antigens that cause cell mediated injury?

Back 38

1. The antigen may be exogenous, such as a foreign protein, a bacterium, or a virus
2. Under some circumstances, the individual can produce antibody against self-components -endogenous antigens.

The latter can be circulating antigens present in the blood or, more commonly, antigenic components of one's own cells and tissues.

Front 39

39. What is systemic immune complex disease?

Back 39

Systemic immune complex disease is characterized by circulating immune complexes that are systemically deposited.

Acute serum sickness is the prototypical systemic immune complex disease. it is caused by administration of large amts of a foreign protein; after inoculation, newly synthesized antibodies complex w/the foreign antigen to form circulating immune complexes

Front 40

40. Do larger or smaller immune complexes circulate for longer periods of time?

Back 40

Smaller immune complexes circulate for longer periods of time b/c they bind w/low avidity to mononuclear phagocytes and are ineffectively cleared; these complexes are prone to deposit within a capillary or arteriolar walls, causing vasculitis.

With continued antibody production, large immune complexes eventually form; these are cleared by phagocytes, ending the disease process.

Front 41

41. What other factors enhance immune complex deposition?

Back 41

Immune complex deposition is enhanced by increased vascular permeability resulting from inflammatory cell activation by immune complex binding to Fc or C3b receptors.

The activated inflammatory cells release vasoactive mediators, including cytokines.

Front 42

42. Deposition of immune complexes causes...?

Back 42

Deposition of immune complexes activates the complement cascade and subsequent tissue injury derives largely from complement-mediated inflammation and cells bearing Fc receptors.

Front 43

43. C3b does...?

C5a does...?

Back 43

C3b enhances opsonization

C5a (chemotactic factor) release promotes neutrophil and monoctyte recruitment w/subsequent protease and reactive oxygen species elaboration.

Front 44

44. C3a and C5a do...?

Back 44

C3a and C5a release increases vascular permeability and causes smooth muscle contraction

Front 45

45. What is the relationship between immune complexes and platelet aggregation?

Back 45

Immune complexes also aggregate platelets (w/subsequent degranulation) and activate factor XII (Hageman factor).

Both of these reactions augment the inflammatory process and initiate the formation of microthrombi. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.

The coagulation cascade and kinin systems are thus involved as well.

Front 46

46. What is the pathogenesis of immune complex disorders?

Back 46

Complement-fixing antibodies (IgG and IgM) and antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) induce pathologic lesions of immune complex disorders.

B/c IgA can activate complement by the alternative pathway, IgA-containing complexes may also induce tissue injury. The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of complement greatly reduces the severity of the lesions.

Front 47

47. What is the morphology of immune complex injury?

Back 47

The morphologic consequences of immune complex injury are dominated by acute necrotizing vasculitis, with necrosis of the vessel wall and intense neutrophilic infiltration. The necrotic tissue and deposits of immune complexes, complement, and plasma protein produce a smudgy eosinophilic deposit that obscures the underlying cellular detain *an appearance termed fibrinoid necrosis.

When complexes are deposited in kidney glomeruli, the affected glomeruli are hypercellular b/c of swelling and proliferation of endothelial and mesangial cells, accompanied b neutrophilic and monocytic infiltration.

The complexes can be seen on immunofluorescence microscopy as *granular lumpy deposits* of immunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane.

Front 48

48. Disease progression in immune complex injury

Back 48

With time and clearance of the inciting antigen and immune complex, the lesions resolve.

In chronic serum sickness, resulting from recurrent or prolonged antigen exposures and ongoing immune complex deposition (e.g. systemic lupus erthematosus, SLE), there is intimal thickening and vascular and/or parenchymal scarring.

Front 49

49. What is the local immune complex disease (Arthus reaction)?

Back 49

The Arthus reaction is a localized are of tissue necrosis resutling from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in an immune animal having circulating antibodies against the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally which precipitate in the vessel walls and trigger and inflammatory reaction.

In contrast to IgE mediated type I reactions, which appear immediately, the Arthus lesion develops over a few hours and reaches a peak 4-10 hours after injection.

Front 50

50. What is the morphology of local immune complex disease (Arthus reaction)?

Back 50

It can be seen as an area of visible edema w/severe hemorrhage followed occasionally by ulceration.

Immunofluorescent stain reveal complement, immunoglobulins, and fibrinogen deposited in the vessel walls, usually the venules, and histologically the vessels show fibrinoid necrosis and inflammation. Thrombi are formed in the vessels, resulting in local ischemic injury.

Front 51

51.What is cell mediated (type IV) hypersensitivity?

Back 51

Cell mediated hypersensitivity is initiated by specifically sensitized T lymphocytes and includes delayed-type hypersensitivity mediated by CD4+ T cells, and T-cell mediated cytotoxicity, mediated by CD8+ T cells.

It is the principal pattern of immunologic response not only to a variety of intracellular microbiologic agents, such as Mycobacterium tuberculosis, but also to many viruses, fungi, protozoa, and parasites.

Front 52

52. What is delayed type hypersensitivity? What drives it?

Back 52

This resposne is largely mediated by CD4+ TH1 cells that secrete specific cytokines after encounter w/processed antigen expressed by APCs.

The TH1 response is driven by IL-12 secreted by activated macrophages.

Front 53

53. What is the morphology of delayed type hypersensitivity?

1/2

Back 53

Morphologically, delayed type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular "cuffing".

There is an associated increased microvascular permeability caused by mechanisms similar to those in other forms of inflammation. Not unexpectedly, plasma proteins escape, giving rise to dermal edema and deposition of fibrin in the interstitium.

Front 54

54. What is the morphology of delayed type hypersensitivity?

2/2

Back 54

A classic example is the tuberculin reaction, which is produced by the intracutaneous injection of tuberculin, a protein LPS component of the tubercle bacillus.

With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, the initial perivascular lymphatic infiltrate is replaced by macrophages over 2-3 weeks.

The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells and are then referred to as eptheliod cells. A microscopic aggregation of epithleiod cells, usually surrounded by a collar of lymphocytes, is referred to as a granuloma. This pattern of inflammation is called granulomatous inflammation.

Front 55

55. What are the TH1 cytokines?

Back 55

TH1 cytokines include IFN-γ, IL-2, and TNF-α; these cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.

Front 56

56. What is the importance of IL-12?

Back 56

IL-12, a cytokine produced by macrophages and dendritic cells, is critical for the induction of the TH1 response and hence delayed hypersensitivity. On initial encounter w/a microbe, the macrophages and dendritic cells that are presenting microbial antigens secrete IL-12, which drives the differentiation of naive CD4+ helper cells to TH1 cells.

These, in turn, produce other cytokines. IL-12 is also a potent inducer of IFN-γ secretion by T cells and NK cells. IFN-γ further augments the differentiation of TH1 cells.

Front 57

57. What is the importance of IFN-γ?

Back 57

IFN-γ has many effects and is the key mediator of delayed type hypersensitivity. Most importantly, it is a powerful activator of macrophages.

Activated macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II molecules on the surface, thus facilitating further antigen presentation; they secrete several polypeptide growth factors, such as PDGF, which stimulate fibroblast proliferation and augment collagen synthesis; they secrete TNF, IL-1, and chemokines, which promote inflammation, and they produce more IL-12, thereby amplifying the TH1 response.

Front 58

58. What does IL-2 do?

Back 58

IL-2 causes autocrine and paracrine proliferation of T cells, which accumulates at sites of delayed hypersensitivity; included in this infiltrate are some antigen specific CD4+ TH1 cells and many more bystander T ells that are recruited to the site.

Front 59

59. What 3 things do TNF and lymphotoxin do to endothelial cells?

Back 59

1. Increased secretion of prostacyclin, which, in turn, favors increased blood flow causing local vasodilation
2. Increased expression of P-E selectins, adhesion molecules that promote attachment of the passing lymphocytes and monocytes
3. Induction and secretion of chemokines such as IL-8

Together, all these changes in the endothelium facilitate the extravasation of lymphocytes and monocytes at the site of the delayed hypersensitivity reaction.

Front 60

60. What is T cell-mediated cytotoxicity?

Back 60

Generation of cytotoxic T lymphocytes is the principal pattern of response to many viral infection and to tumor cells.

CTLs also contribute to allograft rejection. CTL-induced injury is mediated by perforin-granzyme and Fas-FasL pathways that ultimately induce apoptosis.

Front 61

61. What is perforin?

Back 61

Perforin can perforate the plasma membranes of the target cells that are under attack by CD8+ lymphocytes. At first, CD8+ T cells come in close contact w/the target cells; this is followed by polymerization of the released perforin molecules and their insertion into the target cell membranes, thus drilling holes into the membranes.

In addition, the perforin pores allow water to enter the cells, thus causing osmotic lysis.

Front 62

62. What are granzymes?

Back 62

The CTL granules contain proteases called granzymes, which are delivered into the target cells via the perforin-induced pores.

Once within the cells, granzymes activate caspases, which induce apoptosis of the target cells.

Front 63

53. What is responsible for the kidney graft rejections?

Back 63

The antigens responsible for such rejection in humans are those of the HLA system.

Rejection is a complex process in which both CMI and circulating antibodies play a role.

Front 64

64. What is cellular rejection and what are the two ways in which it is induced?

Back 64

T-cell mediated graft rejection is called cellular rejection, and it is induced by 2 mechanisms: destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated CD4+ helper cells.

Front 65

65. What is the direct pathway of cellular rejection?

Back 65

In the direct pathway, T cells of the the transplant recipient recognize allogeneic (donor) MHC moledules on the surface of the APCs in the graft.

It is believed that dendritic cells carried in the donor organs are the most important immunogens b/c they not only richly express class I and II HLA molecules but also are endowed with costimulatory molecules (e.g., B7-1 and B7-2).

Front 66

66. If T cells are normally restricted to recognizing foreign peptides displayed by self MHC molecules, why should these T cells recognize foreign MHC?

Back 66

Such recognition has been explained by assuming that allogeneic MHC molecules, with their bound peptides, resemble, or mimic, the self MHC foreign peptide complexes that are recognized by self-MHC restricted T cells.

Front 67

67. What is the indirect pathway of cellular rejection?

Back 67

The recipient T lymphocytes recognize antigens of the graft donor after they are presented by the recipient's own APCs.

Thus, the indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens.

Front 68

68. What is the principal mechanism of cellular rejection in the indirect pathway?

Back 68

When T cells react to a graft by the indirect pathway, the principal mechanism of cellular rejection may be T cell cytokine production and delayed hypersensitivity.

Front 69

69. So what pathway is the major one in acute rejection vs. chronic cellular rejection?

Back 69

*It is postulated that the direct pathway is the major pathway in acute cellular rejection, whereas the indirect pathway is more important in chronic rejection.

Front 70

70. What about antibody-mediated rejections?

Back 70

Antibodies evoked against alloantigens in the graft can also mediate rejection. This process is called humoral rejection and can take 2 forms.

Front 71

71. What are the two forms of antibody mediate rejections?

Back 71

1. Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient.

2. Acute humoral rejection, in which recipients not previously sensitized to transplantation antigens are exposed to the class I and class II HLA antigens of the donor evoke antibodies. These antibodies may cause injury by complement dependent cytotoxicity, inflammation, and ADCC.

Front 72

72. Where is the initial target of the antibodies in rejection?

Back 72

The graft vasculature, sometimes referred to as rejection vasculitis.

Front 73

73. What is the morphology of hyperacute rejection?

Back 73

This form of rejection occurs w/in minutes or hours after transplant and can sometimes be recognized immediately.

A hyperactutely rejecting kidney becomes rapidly cyanotic, mottled, and flaccid and may excrete a mere few drops of bloody urine. Ig and complement are deposited in the vessel wall, and EM discloses early endothelial injury together with fibrin-platelet thrombi.

***These early lesions point to an antigen-antibody reaction at the level of the vascular endothelium.

Front 74

74. What are the features of the kidney in a hyperacute rejection?

Back 74

The glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls. The kidney cortex then undergoes outright infarction (necrosis) and these kidneys have to be removed.

Front 75

75. What is the morphology of acute rejection?

Back 75

This may occur w/in days of transplantation in the untreated recipient or may appear suddenly moths or years later when immunosuppresion therapy has been stopped.

Acute graft rejection is a combined process in which both cellular and humoral tissue injuries contribute. Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by an interstitial mononuclear cell infiltrate.

Front 76

76. What is the morphology of acute cellular rejection?

Back 76

This is most commonly seen w/in the initial months after transplant and is heralded by an elevation of serum creatinine levels followed by renal failure. Histologically, there may be extensive interstitial mononuclear cell infiltration and edema as well as mild interstitial hemorrhage.

There is focal tubular necrosis, and CD8+ cells may also injure vascular endothelial cells, causing endothelitis.

Front 77

77. Why is recognition of cellular rejection important?

Back 77

In the absence of an accompanying arteritis, pts promptly response to immunosuppressive therapy, such as cyclosporine.

Front 78

78. What is the morphology of acute humoral rejection (rejection vasculitis)?

Back 78

Acute humoral rejection is mediated primarily by antidonor antibodies, and hence it is manifested mainly by damage to the blood vessels. This may take the form of necrotizing vasculitis with endothelial cell necrosis, neutrophilic infiltration, deposition of Ig, complement, and fibrin, and thrombosis.

Such lesions are associated w/extensive necrosis of the renal parenchyma. The resultant narrowing of the arterioles may cause infarction or renal cortical atrophy.

Front 79

79. What is the morphology of chronic rejection?

Back 79

Pts w/chronic rejection present clinically w/a progressive rise in serum creatinine over a period of 4-6 mos. Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy w/loss of renal parenchyma.

The vascular changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries. These vascular lesions result in renal ischemia, manifested by glomerular loss, interstitial fibrosis and tubular atrophy, and shrinkage of the renal parenchyma. The glomeruli may show duplication of the basement membranes (called chronic transplant glomerulopathy).

Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates containing large numbers of plasma cells and numerous eosinophils.

Front 80

80. What features distinguish bone marrow transplants from solid organ transplants?

Back 80

In most of the conditiosn in which bone marrow transplantation in indicated, the recipient is irradiated w/lethal doses either to destroy the malignant cells (e.g., leukemias), or to create a graft bed (aplastic anemias).

Three major problems can arise:
1. GvH disease
2. Transplant rejection
3. Immunodeficiency

Front 81

81.What is GvH disease?

Back 81

GvH disease occurs in any situation in which immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and the transferred cells recognize alloantigens in the host.

GvH disease occurs most commonly in the setting of allogeneic bone marrow transplantation but may also follow transplantation of solid organs rich in lymphoid cells (e.g., the liver) or transfusion of un-irradiated blood).

Front 82

82. What happens when irradiated or immunosuppressed recipients receive normal bone marrow cells from allogeneic donors?

Back 82

The immunocompetent T cells present in the donor marrow recognize the recipient's HLA antigens as foreign and react against them via CD4+ and CD8+ T cells.

Front 83

83. What is acute GvH disease?

Back 83

Acute GvH disease occurs w/in days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines.

Desquamation of the skin, destruction of the bile ducts leading to jaundice, and bloody diarrhea are all possible consequences.

Front 84

84. What is a frequent accompaniment of GvH disease?

Back 84

Immunodeficiency; may be a result of prior treatment, myeloablative prep for the graft, etc...

***Affected individuals are profoundly susceptible to infections, and infections with CMV is particularly important. CMV-induced pneumonitis can be a fatal complication.

Front 85

85. What is chronic GvH disease?

Back 85

Chronic GvH disease may follow the acute syndrome or may occur insidiously. These pts have extensive cutaneous injury, w/destruction of skin appendages and fibrosis of the dermis. The changes may resemble systemic sclerosis.

Chronic liver disease manifested by cholestatic jaundice is also frequent. Damage to the GI mucosa may cause esophageal strictures. The immune system is devastated, w/involution of the thymus and depletion of the lymphocytes in the lymph nodes.

These patients experience recurrent and life-threatening infections.

Front 86

86. How can one prevent GvH?

Back 86

B/c GvH disease is mediated by T lymphocytes contained in the donor bone marrow, depletion of donor T cells before transfusion virtually eliminates the disease.

This is a mixed blessing, however, in that the incidence of graft failure and the recurrent of disease in leukemic pts increases.

It seems that the T cells not only mediate GvH disease but also are required for engraftment of the transplanted marrow stem cells and control of leukemic cells. The latter, called graft-vs-leukemia effect, can be dramatic.

Front 87

87. What is immunologic tolerance?

Self tolerance?

Back 87

Immunologic tolerance is a state in which the individual is incapable of developing an immune response to a specific antigen.

Self tolerance refers to lack of responsiveness to an individual's own antigens.

Front 88

88. What is central tolerance?

Back 88

This refers to death (deletion) of self-reactive T- and B-lymphocyte clones during their maturation in the central lymphoid organs (the thymus for T cells and the bone marrow for B cells).

T lymphs bear that bear receptors for self-antigens undergo apoptosis w/in the thymus during the process of T cell maturation. It is proposed that many autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic APCs in associated with self-MHC molecules.

The developing T cells that express high-affinity receptors for such self antigens are negatively selected, or deleted.

Front 89

89. What is the role of AIRE?

Back 89

A protein called AIRE (autoimmune regulator) is thought to stimulate expression of many "peripheral" self antigens in the thymus and is thus critical for deletion of immature self-reactive T cells.

Mutations in the AIRE gene are the cause of an autoimmune polyendocrinopathy.

Front 90

90. What is peripheral tolerance?

Back 90

Those self-reactive T cells that escape intrathymic negative selection can inflict tissue injury unless they are deleted or muzzled in the peripheral tissues.

Front 91

91. What are 4 ways in which peripheral tolerance muzzles or deletes these self-reactive T cells?

Back 91

1. Anergy (remove costimulatory signals)
2. Suppression by regulatory T cells (CD4+ cells that express CD25, IL2, IL-10, and TGF-beta)
3. Clonal deletion by activation induced cell death (Fas CD95)
4. Antigen sequestration (antigens become hidden b/c they are blocked off in the eye, testis, etc...)

Front 92

92. Mutations in Foxp3 result in...?

Back 92

oxp3 is required for the development and function of CD4+ CD25+ regulatory T cells.

Mutations result in severe autoimmunity in humans; causes IPEX (Immune dysregulation, Polyendocrinopathy, Eneropathy, X-linked).

Front 93

93. What causes the autoimmune lymphoproliferative syndrome?

Back 93

A small number of pts have been identified with SLE-like autoimmunity and generalized lymphoproliferation associated with mutations in the FAS gene; this disease is called the autoimmune lymphoproliferative syndrome.

Front 94

94. What is the mechanism of autoimmune disease?

Back 94

The development of autoimmunity is related to the inheritance of susceptibility genes, which may influence the maintenance of self-tolerance, and environmental triggers, particularly infections, which promote the activation of self-reactive lymphocytes.

Front 95

95. What are the two possible mechanism that explain the link btwn infections and autoimmunity?

Back 95

1. Infections may up-regulate the expression of costimulators on APCs.
2. Some microbes may express antigens that have the same AA sequences as self-antigens (molecular mimicry)

Front 96

96. What is epitope spreading?

Back 96

An important mechanism for the persistence and evolution of autoimmune disease is the phenomenon of epitope spreading. Infections, and even the initial autoimmune response, may release and damage self-antigens and expose epitopes of the antigens that are normally concealed from the immune system, or cryptic.

The result is continuing activation of new lymphocytes that recognize these previously cryptic epitopes.

Regardless of the initial trigger of the autoimmune response, the progression and chronicity of the response may be maintained by continued recruitment of autoreactive T cells that recognize normally cryptic self-determinants. Thus, the immune response spreads to determinants that were not initially recognized.

Front 97

97. What is SLE?

Back 97

SLE is characterized by an array of autoantibodies, particular ANAs. Acute or insidious in its onset, it is a chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney, and serosal membranes. Virtually every other organ in the body may also be affected.

SLE is a fairly common disease, w/a prevalence as high as 1/2500. SLE is predominantly a disease of women. The disease is more common and severe in African American women.

Although SLE usually arises in the 20's and 30's it may become manifest at any age.

Front 98

98. What is the fundamental defect in SLE?

Back 98

The fundamental defect in SLE is a failure of the mechanisms that maintain self tolerance.

ANAs are directed against several nuclear antigens.

Front 99

99. What are the four categories of ANAs?

Back 99

1. Antibodies to DNA
2. Antibodies to histones
3. Antibodies to nonhistone proteins bound to RNA
4. Antibodies to nucleolar antigens

Front 100

100. What are the 4 basic patterns of nuclear fluorescence?

Back 100

1. Homogeneous or diffuse nuclear staining usually reflects antibodies to chromatin, histones, and occasionally, double stranded DNA (anti-histone)
2. Rim or peripheral staining patterns are most commonly indicative of antibodies to double stranded DNA (Anti-DNA)
3. Speckled pattern refers to the presence of uniform or variable sized speckles. This is one of the most commonly observed pattern and therefore the least specific (SS-A, SS-B, anti-Sm)
4. Nuucleolar pattern refers to the presence of few discrete spots of fluorescence w/in the nucleus and represents antibodies to nucleolar RNA (Anti-RNP)

Front 101

101. What are the antibodies that are diagnostic of SLE?

Back 101

ANA is positive in virtually every pt w/SLE, however, pts with other autoimmune diseases also freq score positive.

*Antibodies to double-stranded DNA and the so called Smith (Sm) antigen are virtually diagnostic of SLE.

Front 102

102. What about antiphospholipids in pts with SLE?

Back 102

Antiphospholipid antibodies are present in about half of lupus pts. Antibodies against the phospholipid-B2-glycoprotein complex also bind to cardiolipin antigen, mainly used in syphilis serology, and therefore lupus pts may have a false positive test for syphilis.

Front 103

103. Besides the false positive syphilis test, what are some other consequences of having antiphospholipid antibodies?

Back 103

Some of these antibodies interfere w/in vitro clotting tests, such as PTT. Despite having a circulating anticoagulant that delays clotting, these pts have complications associated w/a hypercoagulable state.

They have venous and arterial thromboses, which may be associated w/recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. (Known as secondary antiphospholipid antibody syndrome)

Front 104

104. What are the genetic factors in SLE?

Back 104

1. Family members of pts have an increased risk of developing SLE
2. There is a higher rate of concordance in monozygotic twins when compared w/dizygotic twins
3. Specific allels of the HLA-Dq locus have been linked to the production of anti-double-stranded DNA, anti-Sm, and antiphospholipid antibodies
4. Some lupus pts have an inherited deficiency of early complement components, such as C2, C4, or C1q

Front 105

105. Why would a deficiency in the early components of the complement system be a problem?

Back 105

Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition. Mice w/o C4 are prone to develop lupus like autoimmunity.

It has also bee proposed that deficiency of C1q results in failure of phagocytic clearance of apoptotic cells.

Front 106

106. What drugs can produce an SLE like syndrome?

Back 106

Hydralazine, procainamide, and D-penicillamine can induce an SLE-like response in humans

Front 107

107. What about UV light and SLE?

Back 107

Exposure to UV light is another factor that exacerbates the disease. It induces keratinocytes to produce IL-1, a factor known to influence the immune response. In addition, UV radiation may induce apoptosis in cells, and alter the DNA in such a way that it becomes immunogenic.

Front 108

108. What about SLE and sex hormones?

Back 108

Sex hormones seem to exert an important influence on the occurrence and manifestations of SLE.

During the reproductive years, the freq of SLE is 10x greater in women than in men, and exacerbation has been noted during normal menses and pregnancy.

Front 109

109. What type of immune cells is responsible for the tissue damaging response?

Back 109

It appear that the production of tissue-damaging antibodies is driven by self antigens and results from an antigenic-specific helper T cell-dependent B-cell response w/many characteristics of responses to foreign antigens.

***These observations have places the onus of driving the autoimmune response squarely on helper T cells.

Front 110

110. What mediates most of the visceral lesions in SLE?

Back 110

Most of the visceral lesions are mediated by immune complexes (type III hypersenstivity)

Autoantibodies against red cells, white cells, and platelets opsonize these cells and promote phagocytosis and lysis.

*There is no evidence that ANAs can penetrate intact cells.

Front 111

111. What happens then, if a cell nuclei is exposed?

Back 111

If cell nuclei are exposed, the ANAs can bind to them. In tissues, the nuclei of dmaged cells react with ANAs, lose their chromatin patter, and become homogeneous, to produce so called lupus erythematosus (LE) bodies or hematoxylin bodies).

Front 112

112. So what is an LE cell?

Back 112

The LE cell is any phagocytic leukocyte (neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell. Sometimes LE cells are found in pericardial or pleural effusions in patients.

Front 113

113. What is the morphology of the kidney in SLE?

Back 113

The kidney is a freq target of injury in SLE. *The principal mechanism of injury is immune complex deposition in renal structures, including glomeruli, tubular and peritubular capillary basement membranes, and larger blood vessels.

Front 114

114. What are the 5 classes of morphologic changes in lupus nephritis?

Back 114

1. Minimal or no detectable abnormality
2. Mesangial lupus glomerulonephritis
3. Focal proliferative glomerulonephritis
4. Diffuse proliferative glomerulonephritis
5. Membranous glomerulonephritis

*none of these patterns is specific for lupus.

Front 115

115. What is the morphology of mesangial lupus glomerulonephritis (class 2)?

Back 115

Mesangial lupus glomerulonephritis is characterized by mesangial cell proliferation and lack of involvement of glomerular capillary walls. It is seen in 10-25% of pts, most have minimal manifestations such as mild hematuria or transient proteinuria. There is a slight to moderate increase in the intercapillary mesangial matrix as well as the number of mesangial cells.

***Granular mesangial deposits of Ig and complement are always present*. Such deposits presumably reflect the early change b/c filtered immune complexes accumulate primarily in the mesangium.

Front 116

116. What is the morphology of focal proliferative glomerulonephritis (class 3)?

Back 116

Focal proliferative glomerulonephritis is seen in 20-35% of pts. It is a focal lesion, affecting fewer than 50% of the glomeruli and generally only portions of each glomerulus. Typically, one or two tufts in an otherwise normal glomerulus exhibit swelling and proliferation of endothelial and mesangial cells, infiltration with neutrophils, and sometimes fibrinoid deposits and intercapillary thrombi.

*Focal lesions are associated with hematuria and proteinuria. In some pts, the nephritis progresses to diffuse proliferative disease.

Front 117

117. What is the morphology of diffuse proliferative glomerulonephritis (class 4)?

Back 117

This is the most serious of the renal lesions in SLE, occurring in 35-60% of pts who undergo biopsy.

***Anatomic changes are dominated by proliferation of endothelial, mesangial, and sometimes, epithelial cells, producing in some cases epithelial crescents that fill the Bowman space.***

Front 118

118. What indicates active disease in diffuse proliferative glomerulonephritis?

Back 118

The presence of fibrinoid necrosis, crescents, prominent infiltration by leukocytes, cell death as indicated by apoptotic bodies, and hyaline thrombi indicates active disease.

Front 119

119. What are the clinical features of pts with diffuse proliferative glomerulonephritis?

Back 119

Most or all glomeruli are involved in both kidneys and the entire glomerulus is freq affected.

Pts with diffuse lesions are usually overtly symptomatic, showing microscopic or gross hematuria as well as proteinuria that is severe enough to cause the nephrotic syndrome in more than 50% of pts. Hypertension and mild to severe renal insufficiency are also common.

Front 120

120. Review- what is membranous glomerulonephritis (class 5)?

Back 120

Membranous glomerulonephritis is a designation given to glomerular disease in which the principal histologic change consists of widespread thickening of the capillary walls. This type of lesion is seen in 10-15% of pts with SLE and is almost always accompanied by severe proteinuria w/the nephrotic syndrome.

There are granular deposits of Ig and complement regularly present in the mesangium alone or along the entire basement membrane.

Front 121

121.Where are the deposits in membranous glomerulonephritis?

Back 121

In membranous glomerulonephritis (class 5), the deposits are predominantly btwn the basement membrane and the visceral epithelial cell (subepithelial), a location similar to that of deposits in other types of membraneous nephropathy.

Front 122

122.Where are the deposits in class 3 and 4?

Back 122

Subendothelial deposits (between the endothelium and the basement membrane) are most commonly seen in the proliferative types (classes 3 and 4).

Front 123

123. What is a wire loop lesion?

Back 123

When extensive and confluent, subendothelial deposits create a homogeneous thickening of the capillary wall, which can be seen by means of light microscopy as a wire loop lesion.

Such wire loops are often found in the diffuse proliferative type of glomerulonephritis (class 4) but can also be present in the focal (class 3) and membranous (class 5) types.

*They usually reflect active disease.

Front 124

124. What are the morphologic changes in the interstitium and tubules in pts with SLE?

Back 124

These changes are frequently present in pts with SLE, especially in associated with diffuse proliferative glomerulonephritis (class 4).

In a few cases, tubulointerstitial lesions may be the dominant abnormality. Granular deposits composed of Ig and complement similar to those seen in glomeruli are present in the tubular basement membranes in about 50% of pts with SLE, a pattern indicative of so-called tubular immune complex disease.

Front 125

125.What are the morphologic changes of the skin in SLE?

Back 125

The skin is involved in the majority of pts. Characteristic erythema affects the facial butterfly area (bridge of nose and cheeks) in approx 50% of pts, but a similar rash may also be seen on the extremities and trunk. Exposure to sunlight incites or accentuates the erythema.

***Histologically the involved areas show liquefactive degeneration of the basal layer of the epidermis together with edema at the dermal junction. In the dermis there is variable edema and perivascular mononuclear infiltrates. There is deposition of Ig and complement along the dermoepidermal junction. Vasculitis with fibrinoid necrosis of the vessels may be prominent.

Front 126

126. What is the morphology of the joint involvement in SLE?

Back 126

Joint involvement is frequent, the typical lesion being a nonerosive synovitis w/little deformity. ***The latter fact distinguishes the arthritis from that sen in RA.

In the acute phases of arthritis in SLE, there is exudation of neutrophils and fibrin into the synovium and a perivascular mononuclear cell infiltrate in the subsynovial tissue.

Front 127

127. What is the morphology of the CNS changes in SLE?

Back 127

There can be acute vasculitis with resultant focal neurologic symptoms. However, histologic studies fail to reveal significant vasculitis.

*Instead, noninflammatory occlusion of small vessels by intimal proliferation is sometimes noticed. These changes are believed to result from damage to the endothelium by antiphospholipid antibodies.

Front 128

128. What about pericarditis and other serosal cavity involvement in SLE?

Back 128

Inflammation of the serosal lining membranes may be acute, subacute, or chronic. During the active phases, the mesothelial surfaces are sometimes covered with fibrinous exudate. Later the become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity.

Front 129

129. What is the main manifestation of the cardiovascular system in SLE?

Back 129

Pericarditis is the main form. Symptomatic or asymptomatic pericardial involvement is present in the majority of patients. Myocarditis, manifested as nonspecific mononuclear cell infiltration, may also be present but it is less common.

Additionally, subtle or overt valvular abnormalities are fairly common in SLE. *They affect mainly the mitral and aortic valves and are manifested as diffuse valve thickening that may be associated w/dysfunction (stenosis or regurgitation).

Front 130

130. What is the link between SLE and endocarditis?

Back 130

Valvular endocarditis may occur in the form of nonbacterial verrucous endocarditis. ***This is single or multiple irregular, 1-3 mm warty deposits on any valve in the heart, distinctively on either surface of the leaflets***

By comparison, the vegetations in infectious endocarditis are considerably larger, and those in rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets.

Front 131

131. What about coronary atherosclerosis and SLE?

Back 131

An increasing number of pts have clinical evidence of coronary artery disease owing to coronary atherosclerosis. This complication is noted particularly in young pts w/long-standing disease and especially in those who have been treated w/corticosteroids.

Immune complexes and antiphospholipid antibodies may deposit on the endothelium, causing damage and promoting atherosclerosis

Front 132

132. What is the morphology of the spleen in SLE?

Back 132

May be moderately enlarged. Capsular thickening is common, as is follicular hyperplasia.

The central penicilliary arteries show thickening and perivascular fibrosis, producing so-called onion skin lesions.

Front 133

133. What is the morphology of the lungs in SLE?

Back 133

Pleuritis and pleural effusions are the most common pulmonary manifestations, affecting almost 50% of pts. Less commonly, there is evidence of alveolar injury.

In some cases there is chronic interstitial fibrosis, but again, non of these changes is specific for SLE.

Front 134

134. What is the typical patient like with SLE?

Back 134

Typically, the pt is a young woman with some, but not necessarily all, of the following features: a butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints, pleuritic chest pain, and photosensitivity.

In many pts, however, the presentation of SLE is subtle and puzzling, taking forms such as a FUO, abnormal urinary findings, or joint disease masquerading as RA.

Front 135

135. What are the diagnostic findings in most pts with SLE?

Back 135

ANAs can be found in virtually 100% of pts. Antibodies against double stranded DNA and Sm antigen are virtually diagnostic of SLE.

Laboratory evidence of some hematologic derangement is seen in virtually every case, but in some pts, anemia or thrombocytopenia may be the presenting manifestation as well as the dominant clinical problem.

Front 136

136. What is the course of SLE disease?

Back 136

Variable and unpredictable. More often, with appropriate therapy, the disease is characterized by flare ups and remissions spanning a period of years or even decades. During acute flare-ups, increased formation of immune complexes and the accompanying complement activation often result in hypocomplementemia.

Disease exacerbations are usually treated by corticosteroids or other immunosuppressant drugs.

*The most common causes of death are renal failure and intercurrent infections. Coronary artery disease is also becoming an important cause of death.

Front 137

137. What is chronic discoid lupus erythematosus?

Back 137

Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare.

It is characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. The face and scalp are usually affected, but widely disseminated lesions occasionally occur. There is also Ig and C3 deposition at the dermoepidermal junction.

***Approx 35% of pts show a positive ANA test, but antibodies to double stranded DNA are rarely present.

Front 138

138. What is subacute cutaneous lupus erythematosus?

Back 138

Subacute cutaneous lupus erythematosus also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria.

*The skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some pts. Most patients have mild systemic symptoms consistent with SLE.

*Furthermore, there is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype.

Front 139

139. What is drug induced lupus erythematosus?

Back 139

A LE like syndrome may develop in pts receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and D-penicillamine. Although multiple organs are affected, renal and CNS involvemen tis distinctly uncommon.

***Anti-double stranded DNA antibodies are rare, but there is an extremely high freq of antihistone antibodies***

Front 140

140. What is Sjogren syndrome?

Back 140

Sjogren syndrome is a chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of the lacrimal and salivary glands. It occurs as an isolated disorder (sicca syndrome), or more often in association with another autoimmune disease (secondary form).

Front 141

141. What causes the characteristic decrease in tears and saliva in Sjogren syndrome?

Back 141

They are the result of lymphocytic infiltration and fibrosis of the lacrimal and salivary glands.

The infiltrate contains predominantly activated CD4+ helper T cells and some B cells, including plasma cells that secrete antibody locally.

Front 142

142. What are the antibodies in Sjogrens syndrome?

Back 142

About 75% of pts have rheumatoid factor regardless of whether coexisting RA is present or not. ANAs are detected in 50 to 80% of pts.

*Most important, however, are antibodies directed against two ribonucleoprotein antigens, SS-A (Ro) and SS-B (La), which can be detected in up to 90% of pts by highly sensitive techniques.

Front 143

143. Patients with SS-A antibodies in high titers are...?

Back 143

More likely to have early disease onset, longer disease duration, and extraglandular manifestations, such as cutaneous vasculitis and nephritis.

Front 144

144. What HLA alleles are associated with Sjogrens?

Back 144

There is linkage of the primary form with HLA-B8, HLA-DR3, and DRW52 as well as HLA-DQA1 and HLA-DQB1.

In pts with anti-SS-A or anti-AA-B antibodies, specific alleles of HLA-DQA1 and HLA-DQB1 are frequent.

*This suggests that, as in SLE, inheritance of certain class II molecules predisposes to the development of particular antibodies.

Front 145

145. What initiates the primary cause of tissue injury in Sjogrens?

Back 145

Sjogrens is in all likelihood initiated by CD4+ T cells.

Front 146

146. What is the earliest histologic finding in both the major and minor salivary glands in Sjogrens?

Back 146

Periductal and perivascular lymphocytic infiltration.

Eventually it becomes extensive, and in the larger salivary glands, lymphoid follicles w/germinal centers can bee seen. The ductal lining epithelial cells may show hyperplasia, thus obstructing the ducts. Later, there is atrophy and replacement with fat.

Front 147

147. The lack of tears leads to...?

Back 147

The lack of tears leads to drying of the corneal epithelium, which becomes inflamed, eroded, and ulcerated; the oral mucosa may atrophy, w/inflammatory fissuring and ulceration; and dryness and crusting of the nose made lead to ulcerations and even perforation of the nasal septum.

Front 148

148. What about extraglandular tissue involvement in Sjogrens?

Back 148

In approx 25% of cases, extraglandular tissues, such as kidneys, lungs, skin, CNS, and muscles, are also involved. These are more common in pts with high titers of anti-SS-A antibodies.

In contrast to SLE, glomerular lesions are extremely rare in Sjogrens.

However, defects of tubular function, including renal tubular acidosis, uricosuria, and phosphaturia, are often seen and are associated histologically with tubulointerstitial nephritis.

Front 149

149. What are the clinical manifestations in Sjogrens?

Back 149

Sjogrens occurs most commonly in older women, typically between ages 50 and 60. The keratoconjunctivitis produces blurring of vision, burning and itching, and thick secretions accumulate in the conjunctival sac. The xerostomia results in difficulty in swallowing solid foods, a decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa.

Parotid gland enlargement is present in half the patients; dryness of the nasal mucosa, epistaxis, recurrent bronchitis, and pneumonitis are other symptoms.

Front 150

150. What is Mikulicz syndrome?

Back 150

The combination of lacrimal and salivary gland involvement is called Mikulicz syndrome.

Sarcoidosis, leukemia, lymphoma, and other tumors likewise produce Mikulicz syndrome. Thus, biopsy of the lip to examine minor salivary glands is essential for the Dx of Sjogrens.

Front 151

151. What is the link between Sjogrens and B cell problems?

Back 151

Clear cut non-Hodgkin lymphomas mostly of the B cell type, have developed in the salivary glands and lymph nodes in some pts, and it is believed that patients with Sjogrens have an approximately 40x increased risk of developing lymphoid malignancies.

Front 152

152. What is systemic sclerosis or scleroderma?

Back 152

Systemic sclerosis is a chronic disease of unknown etiology characterized by abnormal accumulation of fibrous tissue in the skin and multiple organs. It is characterized by excessive fibrosis throughout the body. The skin is most commonly affected, but the GI tract, kidneys, heart, muscles, and lungs are also freq involved.

In the majority, it progresses to visceral involvement with death from renal failure, cardiac failure, pulmonary insufficiency, or interstitial malabsorption.

Front 153

153. What are the two forms of systemic sclerosis?

Back 153

1. Diffuse scleroderma, characterized by widespread skin involvement at onset, with rapid progression and early visceral involvement

2. Limited scleroderma, in which the skin involvement is often confined to fingers, forearms, and face. Some pts have CREST syndrome.

Front 154

154. What is the likely trigger for the excessive fibrosis in systemic sclerosis?

Back 154

A combination of abnormal immune responses and vascular damage, resulting in local accumulation of growth factors that act on fibroblasts and stimulate collagen production.

*It is proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that recruit and activate inflammatory cells, including mast cells and macrophages.

Front 155

155. What is released in the skin and other affected tissues in systemic sclerosis?

Back 155

The accumulated T cells and other inflammatory cells release a variety of mediates, such as histamine, heparin, IL-1, IL02, IL-13, TNF, PDGF, and TGF-B.

***Several of these mediators, including TGF-B, IL-13, and PDGF, can stimulate transcription of genes that encode collagen and other extracellular matrix proteins (e.g., fibronectin) in fibroblasts.

Front 156

156. What feature of systemic sclerosis is consistently present in the early course of the disease?

Back 156

Microvascular disease. Intimal proliferation is evident in 100% of digital arteries of pts with systemic sclerosis. Telltale signs of endothelial injury and increased platelet activation have also been noted.

Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring.

Front 157

157. What genes are implicated in systemic sclerosis?

Back 157

HLA class II genes, as well as fibrillin-1.

Front 158

158. What are the antibodies present in pts with diffuse systemic sclerosis?

Back 158

Virtually all pts have ANAs that react w/a variety of intranuclear antigens.

Anti-DNA topoisomerase I (anti-Scl 70), is highly specific, and it is present in 28-70% of pts with diffuse systemic sclerosis.

Patients have have this antibody are more likely to have pulmonary fibrosis and peripheral vascular disease.

Front 159

159. What about anticentromere antibody?

Back 159

Anticentromere antibody is found in 22-36% of pts with limited systemic sclerosis; however, it is also found in 9-30% of pts with primary biliary cirrhosis.

***More importantly, the majority of those with the anticentromere antibody (including those with biliary cirrhosis) have the CREST syndrome.

It is rare to have both antibodies in the same pt.

Front 160

160. What is the morphology of the skin in systemic sclerosis?

Back 160

A great majority of pts have diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face.

Histologically, there are edema and perivascular infiltrates containing CD4+ T cells, together w/swelling and degeneration of collagen fibers, which become eosinophilic. With progression, the edematous phase is replaced by progressive fibrosis of the dermis, which becomes tightly bound in subcutaneous structures.

Front 161

161. What about the symptoms in the skin specific to CREST?

Back 161

Focal and sometimes diffuse subcutaneous calcifications may develop, especially in pts with the CREST syndrome.

In advance stages, the fingers take on a tapered, clawlike appearance with limitation of motion of the joints, and the face becomes a drawn mask. Loss of blood supply may lead to cutaneous ulcerations and to atrophic changes in the terminal phalanges.

Front 162

162. What are the morphologic changes in the alimentary tract in pts with systemic sclerosis?

Back 162

The alimentary tract is affected in approx 90% of pts. Progressive atrophy and collagenous fibrous replacement of the muscular may develop at any level of the gut but are most severe in the esophagus. The lower 2/3's of the esophagus often develops a rubber-hose inflexibility.

The associated dysfunction of the lower esophageal sphincter gives rise to GERD and its complications, including Barrett metaplasia and strictures.

Front 163

163. What are the morphologic changes in the musculoskeletal system in systemic sclerosis?

Back 163

Inflammation of the synovium, associated with hypertrophy and hyperplasia of the synovial soft tissues, is common in the early stages; fibrosis later ensues.

It is evident that these changes are closely reminiscent of RA, but joint destruction is not common in systemic sclerosis.

Front 164

164. What are the morphologic changes in the kidneys in systemic sclerosis?

Back 164

Renal problems occur in 2/3s of pts with systemic sclerosis. ***The most prominent are those in the vessel walls. Interlobular arteries show intimal thickening as a result of deposition of mucinous or finely collagenous material, which stains histochemically for glycoportein and acid mucopolysaccharied.***

There is also concentric proliferation of intimal cells. These changes may resemble those seen in malignant hypertension, but in scleroderma the alterations are restricted to vessels 150-500 um in diameter and are not always associated w/hypertension.

Front 165

165. What about hypertension and systemic sclerosis?

Back 165

Hypertension does occur in about 30-30% of pts w/scleroderma, and in 20% it takes an ominously rapid, downhill course (malignant hypertension)

In hypertensive pts, vascular alterations are more pronounced and are often associated with fibrinoid necrosis involving the arterioles together with thrombosis and infarction. *It can be difficult to distinguish from malignant hypertension.

Such pts often die of renal failure, which accounts for about 50% of deaths in pts with this disease.

Front 166

166. What are the morphologic changes in the lungs in systemic sclerosis?

Back 166

The lungs are involved in more than 50% of pts w/systemic sclerosis. This involvement may manifest as pulmonary hypertension and interstitial fibrosis.

Pulmonary vasospasm, secondary to pulmonary vascular endothelial dysfunction, is considered important in the pathogenesis of pulmonary hypertension. Pulmonary fibrosis, when present, is indistinguishable from that seen in idiopathic pulmonary fibrosis.

Front 167

167. What are the morphologic changes in the heart in systemic sclerosis?

Back 167

Pericarditis w/effusion and myocardial fibrosis, along w/thickening of intramyocardial arterioles, occurs in 1/3 of the pts.

Clinical myocardial involvement, however, is less common.

Front 168

168. What is the typical presentation of systemic sclerosis?

Back 168

Systemic sclerosis is primarily a disease of women (female to male ratio 3:1) with a peak incidence in the 50-60 year age group. It tends to be more severe in blacks. Its distinctive features are striking cutaneous changes, notably skin thickening. Raynaud phenomenon is seen in virtually all pts. Dysphagia attributable to esophageal fibrosis and its resultant hypomotility are present in more than 50% of pts.

Abdominal pain, intestinal obstruction, or malabsorption syndrome w/weight loss and anemia reflect involvement of the small intestine. Respiratory difficulties owing to the pulmonary fibrosis may result in right-sided cardiac dysfunction, and myocardial fibrosis may cause either arrhythmias or cardiac failure.

Front 169

169. What is the most ominous manifestation of systemic sclerosis?

Back 169

Malignant hypertension, with its subsequent development of fatal renal failure.

Front 170

170. What does CREST stand form?

Back 170

Calcinosis, Raynaud phenomenon, Esophageal dysfunction, Sclerodactyly, Telangiectasia.

Front 171

171. What are the clinical features of CREST?

Back 171

Pts w/CREST syndrome have relatively limited involvement of skin, often confined to fingers, forearms, and face, and calcification of the subcutaneous tissues. Raynaud phenomenon and involvement of skin are the initial manifestations and often the only manifestations for several years.

Involvement of the viscera, including esophageal lesions, pulmonary hypertension, and biliary cirrhosis, occurs late, and in general the pts live longer than those with systemic sclerosis with diffuse visceral involvement at the outset.

Front 172

172. What is mixed connective tissue disease?

Back 172

This term is sometimes used to describe the disease seen in a group of pts whoa re identified clinically by the coexistence of features suggestive of SLE, polymyositis, RA, and systemic sclerosis, and *serologically by high titers of antibodies to RNP particle containing U1 RNP.

It may present with arthritis, swelling of the hands, Raynaud phenomenon, abnormal esophageal motility, myositis, leukopenia and anemia, fever, lymphadenopathy, and hypergammaglobulinemia.

Front 173

173. How is mixed connective tissue disease diagnosed?

Back 173

Besides high titers of anti-U1 RNP, two other factors have been important in distinguishing this disease - the paucity of renal disease and an extremely good response to corticosteroids, both of which could be considered indicative of a good long term prognosis.

Also, almost 85% of pts have lung involvement, which may be asymptomatic but may present as interstitial lung disease.

Front 174

174. What is X-linked agammaglobulinemia of Bruton?

Back 174

It is characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to mature into B cells.

Caused by a mutation in B-cell tyrosine kinase (Btk).

Causes recurrent bacterial infections of the respiratory tract. Tx is replacement therapy with Ig's.

Front 175

175. Why do mutations in B-cell tyrosine kinase cause agammaglobulinemia?

Back 175

In X-linked agammaglobulinemia, B-cell maturation stops after the rearrangement of heavy chain genes. B/c light chains are not produced, the complete Ig molecule cannot be assembled and transported to the cell membrane.

This block in differentiation is due to the mutations in Btk, which is normally part of the antigen receptor complex of pre-B and mature B cells. It is needed to transduce signals from the antigen receptor that are critical for driving maturation. When mutated, the pre-B cell receptor cannot deliver signals and maturation stops at this stage.

Front 176

176. What are the clinical features of X-linked agammaglobulinemia of Bruton?

Back 176

As an X-linked disease, this disorder is seen almost entirely in males. The disease usually does not become apparent until about age 6 mos, when maternal Igs are depleted. in most cases, recurrent bacterial infection of the respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, call attention to the underlying immune defect.

Front 177

177. Which are the causative organisms in X-linked agammaglobulinemia of Bruton associated respiratory infections?

Back 177

H. influenzae, Strep pneumoniae, or Staph aureus.

*Do not give immunization with live poliovirus b/c it carries the risk of paralytic poliomyelitis.

Front 178

178. What are 4 characteristics of the immune system in X-linked agammaglobulinemia of Bruton?

Back 178

1. B cells are absent or markedly decreased in the circulation, and the serum levels of all classes of Ig are depressed. Precursors of B cells that express CD19 but not membrane Ig (pre B cells) are found in normal numbers in the bone marrow
2. Germinal centers of lymph nodes, Peyer patches, the appendix, and tonsils are underdeveloped or rudimentary
3. Plasma cells are absent throughout the body
4. T cell-mediated reactions are entirely normal

Front 179

179. What is common variable immunodeficiency?

Back 179

This is hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG.

The B cells are not able to differentiate into plasma cells. There are several different defects in the ability of T cells to send appropriate activation signs to B cells.

Front 180

180. What are the clinical features of common variable immunodeficiency?

Back 180

The clinical manifestations are caused by antibody deficiency, and hence they resemble those of X-linked agammaglobulinemia. Thus, the pts typically present w/recurrent sinopulmonary pyogenic infections. In addition, about 20% of pts present with recurrent herpesvirus infections. Serious enterovirus infections causing meningoencephalitis may also occur. Pts are also prone to the dvelopment of persistent diarrhea caused by G. lamblia.

*However, it affects both sexes EQUALLY!

Front 181

181. What are the characteristics of the immune system in those with common variable deficiency?

Back 181

Histologically, the B cell areas of the lymphoid tissues (lymph follicles in nodes, spleen, and gut) are hyperplastic. The enlargement of B cell areas probably reflects defective immunoregulation; that is, B cells can proliferate in response to antigen but do not produce antibodies, and therefore the normal feedback inhibition by IgG is absent.

Front 182

182. What are some comorbid conditions associated with common variable immunodeficiency?

Back 182

These pts have a high freq of autoimmune diseases including RA.

The risk of lymphoid malignancy is also increased, particularly in women. A 50x increase in gastric CA has been noted.

Front 183

183. What is isolated IgA deficiency?

Back 183

Affected individuals have extremely low levels of both serum and secretory IgA. It may be familial, or acquired in associated with toxoplasmosis, measles, or some other viral infection.

B/c IgA is the major Ig in external secretions, mucosal defenses are weakened, and infections occur in the respiratory, GI, and urogenital tracts. Symptomatic pts commonly present w/recurrent sinopulmonary infections and diarrhea.

Front 184

184. What is the basic defect in IgA deficiency?

Back 184

The basic defect in IgA defciency is in the differentiateion of naive B lymphocytes to IgA producing cells.

Serum antibodies to IgA are found in approx 40% of the pts.

Front 185

185. What are the clinical features of isolated IgA deficiency?

Back 185

Sympatomatic pts commonly present with recurrent sinopulmonary infections and diarrhea. In addition, IgA deficient pts have a high freq of respiratory tract allergy and a variety of autoimmune diseases, particularly SLE and RA.

Also, it is not apparent that some individuals with IgA deficiency are also deficient in IgG subclasses; this group of pts is particularly prone to developing infections.

Front 186

186. What is hyper-IgM syndrome?

Back 186

The affected pts make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies. This is most freq a T cell disorder in which functionally abnormal T cells fail to induce B cells to make antibodies of isotypes other than IgM and to active macrophages to eliminate intracellular microbes.

***Mutations in either CD40L or CD40 prevent the T cell-B cell interaction necessary for isotype switching.

Front 187

187. If pts with hyper-IgM syndrome have an intrinsic antibody defect, why do that also have defective CMI?

Back 187

CD40L on helper T cells interacts with CD40 on macrophages and activates the macrophages to kill microbes, one of the central reactions of CMI.

CD40L-CD40 interactions are also involved in the development of CD8+ cytotoxic T lymphs, the other component of CMI.

Front 188

188. What is the classic presentation for pts with hyper-IgM syndrome?

Back 188

The pts present with recurrent pyogenic infections b/c the level of opsonizing IgG antibodies is low. In addition, they are also susceptible to pneumonia caused by the intracellular organism Pneumocystis carinii, b/c of the defect in CMI.

Front 189

189. What are the two possible mutations in hyper IgM syndrome?

Back 189

1. CD40L gene; X-linked (70%)
2. CD40 or an enzyme called activation induced deaminase, which is a DNA editing enzyme that is required for isotype switching (autosomal recessive).

Front 190

190. What is DiGeorge syndrome (thymic hypoplasia)?

Back 190

DiGeorge syndrome is an example of a T-cell deficiency that results from failure of development of the 3rd and 4th pharyngeal pouches.

The latter give rise to the thymus, the parathyroids, some of the clear cells of the thyroid, and the ultimobrnachial body. Thus, these pts have a variable loss of T cell-mediated immunity, tetany, and congenital defects of the heart and great vessels.

Front 191

191. What are the clinical features of DiGeorge syndrome?

Back 191

These pts have a variable loss of T cell-mediated immunity, tetany, and congenital defects of the heart and great vessels.

In addition, the appearance of the mouth, ears, and facies may be abnormal.

Front 192

192. What are the characteristics of the immune system in pts with DiGeorge syndrome?

Back 192

Absence of CMI is reflected in low levels of circulating T lymphocytes and a poor defense against certain fungal and viral infections. Plasma cells are present in normal numbers in lymphoid tissues, but the T-cell zones of lymphooid organs (paracortical areas of the lymph nodes and PALS of the spleen, are depleted.

Front 193

193. What are the genetic mutations associated w/DiGeorge syndrome?

Back 193

It results from the deletion of a gene that maps to chromosome 22q11. This deletion is seen in 90% of pts.

The specific gene believed to be mutated in DiGeorge syndrome is a member of the T-box family of transcription factors, which may be involved in the development of the branchial arch and the great vessels.

Front 194

194. What is severe combined immunodeficiency disease (SCID)?

Back 194

SCID represents a constellation of genetically distinct syndromes, all having in common defects in both humoral and CMI responses.

Affected infants present with prominent thrush, extensive diaper rash, and failure to thrive. Pts w/SCID are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. carinii, Pseudomonas, CMV, varicella, and other bacteria.

W/o bone marrow transplantation, death occurs w/in the first year of life.

Front 195

195. What are the genetics involved in the most common form of SCID?

Back 195

The most common form, accounting for 50-60% of cases, is X-linked, and hence SCID is more common in boys than in girls.

The genetic defect in the X-linked form is a mutation in the common γ chain subunit of cytokine receptors. The cytokine receptor that is mainly responsible for this defect is the receptor for IL-7, b/c IL-7 is required for the proliferation of lymphoid progenitors, particularly T-cell precursors. IL-2 is also very important in this case.

Front 196

196. What causes most of the remaining cases of SCID?

Back 196

The remaining cases of SCID are inherited as autosomal recessives. The most common cause of autosomal recessive SCID is a deficiency of the enzyme ADA (adenosine deaminase)

It has been proposed that deficiency of ADA leads to accumulation of deoxyadenosine and its derivatives, which are particularly toxic to immature lymphocytes, especially those of T-cell lineage. Hence there may be a greater reduction in the number of T lymphs than of B lymphs.

Front 197

197. What are 3 other forms of autosomal recessive SCID?

Back 197

1. Mutations in the recombinase activating genes (rag1 or rag2 genes)
2. Mutations of Jak3 (another common γ cytokine receptor)
3. Mutations that impair the expression of class II MHC molecules (bare lymphocyte syndrome)

Front 198

198. What is bare lymphocyte syndrome?

Back 198

Mutations impair the expression of class II MHC cells and this prevents the development of CD4+ T cells.

CD4+ T cells are involved in cellular immunity and provide help to B cells, and hence, MHC class II deficiency results in bare lymphocyte syndrome. It is usually caused by mutations in transcription factors that are required for MHC class II gene expression.

Front 199

199. How can one tell the difference between the two most common forms of SCID (ADA deficiency and γ chain mutation)

Back 199

In the two most common forms (ADA deficiency and γ chain mutation), the thymus is small and devoid of lymphoid cells.

In ADA-negative SCID, remnants of Hassall's corpuscles can be found, whereas in X-linked SCID, the thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus.

Front 200

200. What is Wiskott-Aldrich syndrome?

Back 200

Wiskott-Aldrich syndrome is an X-linked recessive disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, ending in early death.

It is caused by a defect in the WASP cytoskeletal protein involved in maintaining the integrity of the cytoskeleton as well as signal transduction.

Front 201

201. What are the features of the immune system in those with Wiskott-Aldrich syndrome?

Back 201

The thus is morphologically normal, but there is progressive secondary depletion of T lymphocytes in the peripheral blood and in the T-cell zones of the lymph nodes, with variable loss of CMI. Pts do not make antibodies to polysaccharide antigens, and the response to protein antigens is poor. Pts are also prone to developing malignant lymphomas.

Front 202

202. What are the three main features of Wiskott-Aldrich syndrome?

Back 202

Thrombocytopenia
⇅ ⇅
Eczema ⇆ Immunodeficiency

Front 203

203. What is the most common deficiency of the complement system?

Back 203

A deficiency of C2 is the most common of all. W/a deficiency of C2 or other components of the classic pathway, there is little or no increase in susceptibility to infections, but the dominant manifestation is an increased incidence of an SLE-like autoimmune disease.

Front 204

204. What about deficiency in the components of the alternative pathway?

Back 204

Deficiency of components of the alternative pathway (properdin and factor D) is rare. It is associated with recurrent pyogenic infections .

Front 205

205. What causes hereditary angioedema?

Back 205

A deficiency of C1 inhibitor gives rise to hereditary angioedema. This is an autosomal dominant disorder. The C1 inhibitor is a protease inhibitor whose target enzymes are C1r and C1s of the complement cascade, factor 12 of the coagulation pathway, and the kallikrein system.

These pts have episodes of edema affecting skin and mucosal surfaces such as the larynx and the GI tract. This may result in life threatening asphyxia or nausea, vomiting, and diarrhea after minor trauma or emotional stress.

Front 206

206. What causes paroxysmal nocturnal hemoglobinuria?

Back 206

In this disease, there are mutations in enzymes requires for glycophosphatidyl inositol (GPI) linkages.

Two of these proteins expressed on the cell surfaces in a GPI linked form are the complement regulatory proteins, decay accelerating factor, and CD59.

In the absence of these proteins, complement deposited on RBCs is not controlled, resulting in hemolysis and hemoglobinuria.