Pbl Exam 9 Case 6

Front 1

1. What is responsible for the kidney graft rejections?

Back 1

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 2

2. What is Cellular rejection and what are the two ways in which it is induced?

Back 2

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 3

3. What is the direct pathway of cellular rejection?

Back 3

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 4

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

Back 4

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 5

5. What is the indirect pathway of cellular rejection?

Back 5

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 6

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

Back 6

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 7

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

Back 7

*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 8

8. What about antibody-mediated rejections?

Back 8

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

Front 9

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

Back 9

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 10

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

Back 10

The graft vasculature, sometimes referred to as rejection vasculitis.

Front 11

11. What is the morphology of hyperacute rejection?

Back 11

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 12

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

Back 12

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 13

13. What is the morphology of acute rejection?

Back 13

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 14

14. What is the morphology of acute cellular rejection?

Back 14

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 15

15. Why is recognition of cellular rejection important?

Back 15

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

Front 16

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

Back 16

Acute humor 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 17

17. What is the morphology of chronic rejection?

Back 17

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 18

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

Back 18

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 19

19. What is GvH disease?

Back 19

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 20

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

Back 20

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 21

21. What is acute GvH disease?

Back 21

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 22

22. What is a frequent accompaniment of GvH disease?

Back 22

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 23

23. What is chronic GvH disease?

Back 23

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 24

24. How can one prevent GvH?

Back 24

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 25

25. What is immunologic tolerance?

Self tolerance?

Back 25

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 26

26. What is central tolerance?

Back 26

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 27

27. What is the role of AIRE?

Back 27

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 28

28. What is peripheral tolerance?

Back 28

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 29

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

Back 29

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 30

30. Mutations in Foxp3 result in...?

Back 30

Foxp3 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 31

31. What causes the autoimmune lymphoproliferative syndrome?

Back 31

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 32

32. What is the mechanism of autoimmune disease?

Back 32

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 33

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

Back 33

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 34

34. What is epitope spreading?

Back 34

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 35

35. What is SLE?

Back 35

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 36

36. What is the fundamental defect in SLE?

Back 36

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

ANAs are directed against several nuclear antigens.

Front 37

37. What are the four categories of ANAs?

Back 37

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

Front 38

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

Back 38

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 39

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

Back 39

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 40

40. What about antiphospholipids in pts with SLE?

Back 40

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 41

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

Back 41

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 42

42. What are the genetic factors in SLE?

Back 42

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 43

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

Back 43

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 44

44. What drugs can produce an SLE like syndrome?

Back 44

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

Front 45

45. What about UV light?

Back 45

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 46

46. What about SLE and sex hormones?

Back 46

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 47

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

Back 47

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 48

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

Back 48

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 49

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

Back 49

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 50

50. So what is an LE cell?

Back 50

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 51

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

Back 51

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 52

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

Back 52

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 53

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

Back 53

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 54

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

Back 54

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 55

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

Back 55

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 56

56. What indicates active disease in diffuse proliferative glomerulonephritis?

Back 56

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

Front 57

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

Back 57

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 58

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

Back 58

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 59

59. Where are the deposits in membranous glomerulonephritis?

Back 59

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 60

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

Back 60

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

Front 61

61. What is a wire loop lesion?

Back 61

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 62

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

Back 62

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 63

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

Back 63

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 64

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

Back 64

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 65

65. What is the morphology of the CNS change sin SLE?

Back 65

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 66

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

Back 66

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 67

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

Back 67

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 68

68. What is the link between SLE and endocarditis?

Back 68

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 69

69. What about coronary atherosclerosis and SLE?

Back 69

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 70

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

Back 70

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 71

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

Back 71

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 72

72. What is the typical patient like with SLE?

Back 72

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 73

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

Back 73

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 e the presenting manifestation as well as the dominant clinical problem.

Front 74

75. What is the course of SLE disease?

Back 74

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 75

75. What is chronic discoid lupus erythematosus?

Back 75

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 76

76. What is subacute cutaneous lupus erythematosus?

Back 76

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 77

77. What is drug induced lupus erythematosus?

Back 77

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 78

78. What is Sjogren syndrome?

Back 78

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 79

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

Back 79

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 80

80. What are the antibodies in Sjogrens syndrome?

Back 80

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 81

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

Back 81

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

Front 82

82. What HLA alleles are associated with Sjogrens?

Back 82

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 83

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

Back 83

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

Front 84

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

Back 84

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 85

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

Back 85

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 86

86. What about extraglandular tissue involvement in Sjogrens?

Back 86

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 87

87. What are the clinical manifestations in Sjogrens?

Back 87

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 88

88. What is Mikulicz syndrome?

Back 88

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 89

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

Back 89

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 90

90. What is systemic sclerosis or scleroderma?

Back 90

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 91

91. What are the two forms of systemic sclerosis?

Back 91

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 92

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

Back 92

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 93

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

Back 93

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 94

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

Back 94

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 95

95. What genes are implicated in systemic sclerosis?

Back 95

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

Front 96

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

Back 96

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 97

97. What about anticentromere antibody?

Back 97

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 98

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

Back 98

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 99

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

Back 99

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 100

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

Back 100

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 101

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

Back 101

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 102

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

Back 102

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 103

103. What about hypertension and systemic sclerosis?

Back 103

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 104

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

Back 104

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 105

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

Back 105

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 106

106. What is the typical presentation of systemic sclerosis?

Back 106

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 107

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

Back 107

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

Front 108

108. What does CREST stand form?

Back 108

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

Front 109

109. What are the clinical features of CREST?

Back 109

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 110

110. What is mixed connective tissue disease?

Back 110

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 111

111. How is mixed connective tissue disease diagnosed?

Back 111

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 112

112. What is X-linked agammaglobulinemia of Bruton?

Back 112

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 113

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

Back 113

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 114

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

Back 114

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 115

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

Back 115

H. influenzae, Strep pneumoniae, or Staph aureus.

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

Front 116

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

Back 116

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 117

117. What is common variable immunodeficiency?

Back 117

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 118

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

Back 118

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 119

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

Back 119

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 120

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

Back 120

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 121

121. What is isolated IgA deficiency?

Back 121

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 122

122. What is the basic defect in IgA deficiency?

Back 122

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 123

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

Back 123

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 124

124. What is hyper-IgM syndrome?

Back 124

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 125

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

Back 125

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 126

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

Back 126

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 127

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

Back 127

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 128

128. What is DiGeorge syndrome (thymic hypoplasia)?

Back 128

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 129

129. What are the clinical features of DiGeorge syndrome?

Back 129

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 130

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

Back 130

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 131

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

Back 131

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 132

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

Back 132

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 133

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

Back 133

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 134

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

Back 134

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 135

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

Back 135

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 136

136. What is bare lymphocyte syndrome?

Back 136

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 137

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

Back 137

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 138

138. What is Wiskott-Aldrich syndrome?

Back 138

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 139

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

Back 139

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 140

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

Back 140

Thrombocytopenia
⇅ ⇅
Eczema ⇆ Immunodeficiency

Front 141

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

Back 141

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 incidenceof an SLE-like autoimmune disease.

Front 142

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

Back 142

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

Front 143

143. What causes hereditary angioedema?

Back 143

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 144

144. What causes paroxysmal nocturnal hemoglobinuria?

Back 144

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.

Front 145

145. Where are the muscarinic receptors?

Back 145

Muscarinic cholinergic transmission occurs mainly at autonomic ganglia, at end organs innervated by the parasympathetic division of the ANS, and in the CNS.

These receptors act thru G proteins and thus there is a latency of 100-250 ms associated with muscarinic responses.

Front 146

146. Where are the nicotinic receptors?

Back 146

Nicotinic cholinergic receptors are at autonomic ganglia and in the CNS and in the NMJ for skeletal muscle.

All nicotinic receptors are ligand-gated cation-selective channels and have a rapid response of only 5 ms.

Front 147

147. What are the inhibitors of ACh synthesis, storage, and release?

Back 147

Drugs that inhibit the synthesis, storage, or release of ACh include:

Hemicholinium-3
Vesamicol
Botulinum toxin

Front 148

148. What are the uses for hemicholinium-3 and vesamicol?

Back 148

Hemicholinium-3 blocks the high-affinity transporter for choline, and thus prevents the uptake of choline required for ACh synthesis.

Vesamicol blocks the ACh-H+ antiporter that is used to transport ACh into vesicles, thereby preventing the storage of ACh.

*Both of these compounds are utilized only in research settings.

Front 149

149. Botulinum toxin

Back 149

MOA: Botulinum toxin, produced by C. botulinum, degrades synaptobrevin and thus prevents synaptic vesicle fusion w/the axon terminal (presynaptic) membrane).

PURPOSE: Focal dystonias, toticollis, achalasia, strabismus, blepharospasm, pain syndromes, wrinkles, hyperhidrosis

ADVERSE: Cardiac arrhythmia, syncope, hepatotoxicity, anaphylaxis, injection site pain, dyspepsia, dysphagia, muscle weakness, neck pain, eyelid ptosis, fever

CONTRA: Hypersensitivity; infection at the injection site.

Front 150

150. What are the 5 inhibitors of ACh degradation?

Back 150

1. Edrophonium
2. Neostigmine
3. Pyridostigmine
4. Ambenonium
5. Physostigmine

Front 151

151. Edrophonium
Neostigmine
Pyridostigmine
Ambenonium
Physostigmine

Back 151

MOA: Inhibit AChE by binding to the enzyme's active site

PURPOSE: (1) Dx of myasthenia gravis, Lambert Eaton syndrome, and disroders resutling in muscle weakness (edrophonium) (2) Urinary or GI motility agent, glaucoma, NMJ diseases such as myasthenia gravis, (neostigmine, pyridostigmine, ambenonium) (3) Reversal of anticholinergic txoicity or induced paralysis in surgery (physostigmine)

ADVERSE: Seizure, bronchospasm, cardiac arrhythmia, bradycardia, cardiac arrest, hypotension or hypertension, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis

CONTRA: Mechanical interstinal or urinary obstruction, concomitant choline ester or depolarizing NM blocker use, cardiovascular disease

Front 152

152. Therapeutic notes for the inhibitors of ACh degradation (5)

Back 152

1. Edrophonium is short acting (2-10 min); rapid onset of action makes edrophonium useful for the Dx of muscle weakness
2. For chronic treatment of myasthenia gravis, longer acting cholinesterase inhibitors such as pyridostigmine, neostigmine, and ambenonium are preferred.
3. Neostigmine also has direct cholinergic agonist effect at Nm receptors
4. Topical application of cholinesterase inhibitors to the cornea of the eye decreases intraocular pressure by facilitating the outflow of aqueous humor
5. Non-polar structure makes physostigmine useful for combating CNS anticholinergic toxicity.

Front 153

153. What is diisopropyl fluorophosphate?

Back 153

MOA: An organophosphate compound used as an insecticide,a s a substrate for the production of organophosphate chemical weapons, and formerly as a topical miotic medication in ophthalmology

PURPOSE: NA

ADVERSE: Respiratory paralysis, bradycardia, bronchospasm, fasciculations, muscle cramps, weakness, CNS depression, agitation, confusion, delirium, coma, bronchorrhea, salivation, lacrimation, diaphoresis, vomiting, diarrhea, miosis

Front 154

154. In organophosphate poisoning, the AChE-organophosphate complex is subject to...?

Back 154

Aging, in which oxygen-phosphorus bonds w/in the inhibitor are broken spontaneously in favor of stronger bonds between the enzyme and the inhibitor. Once aging occurs, the duration of AChE inhibition is increased even further.

However, if strong nucleophiles, such as pralidoxime, are administered before aging has occur, it is possible to recover enzymatic function from the inhibited AChE.

Front 155

155. Tacrine, Donepezil, Rivastigmine, Galantamine

Back 155

MOA: AChE inhibitors

PURPOSE: Mild to moderate Alzheimer's disease, dementia

ADVERSE: Diarrhea, nausea, vomiting, cramps, anorexia, vivid dreams

CONTRA: Treatment associated liver function test abnormalities (tacrine)

NOTES: Tacrine, donepezil, and galantamine produce modest symptomatic benefits in AD; Rivastigmine affects both AChE and butyrylcholinesterase by forming a carbamoylate complex w/the enzymes; Galantamine also acts as a non-potentiating ligand of nicotinic receptors.

Front 156

156. What are the muscarinic receptor agonists?

Back 156

1. Methacholine
2. Carbachol
3. Bethanechol
4. Cevimeline
5. Pilocarpine

Front 157

157. Methacholine

Back 157

MOA: Methacholine is 3x more resistant to hydrolysis by AChE than is ACh. This agent is relatively selective for cardiovascular muscarinic cholinergic receptors

PURPOSE: Dx of asthma

ADVERSE: Dyspnea, lightheadedness, headache, pruritus, throat irritation

CONTRA: Recent heart attack or stroke; aortic aneurysm; uncontrolled hypertension

NOTES: In the Dx of asthma; the bronchial hyperreactivity that is characteristic of asthma causes an exaggerated bronchoconstriction response to parasympathomimetics.

Front 158

158. Carbachol, bethanechol, cevimeline, pilocarpine

Back 158

MOA: Carbachol has enhanced nicotinic action relative to other choline esters; Bethanechol is almost completely selective for muscarinic receptors; Pilocarpine and cevimeline (an M1 and M3 agonist) are used to treat xerostomia

PURPOSE: Glaucoma (carbachol); Urinary tract motility agent (bethanechol); Xerostomia in Sjogren's syndrome (cevimeline and pilocarpine)

ADVERSE: sweating, shivering, nausea, dizziness, increased frequency of urination, rhinitis

CONTRA: Acute iritis or glaucoma after cataract extraction; narrow-angle (angle-closure glaucoma)

Front 159

159. Therapeutic notes for carbachol

Back 159

Carbachol has enhanced nicotinic action relative to other choline esters.

Carbachol cannot be used systemically b/c of its unpredictable nicotinic action at autonomic ganglia.

Topical application of carbachol to the cornea of the eye results in both pupillary constriction (miosis) and decreased intraocular pressure.

Front 160

160. What is the only nicotinic receptor agonist?

Back 160

Succinylcholine

Succinylcholine is a choline ester that has a high affinity for nicotinic receptors and is resistant to AChE.

It is used to induce paralysis during surgery by means of depolarizing blockage. This effect can be caused by any direct nAChR agonist b/c such drugs activate cholinergic channels and produce depolarization of the cell membrane. To produce depolarizing blockage, the agent must persist at the neuroeffector junction and activate the nicotinic receptor channels continuously.

Front 161

161. Succinylcholine

Back 161

MOA: Stimulate opening of nicotinic ACh receptor channel and produce depolarization of the cell membrane; it persists at the neuroeffector junction and activate the nicotinic receptor channels continuously, which results in inactivation of voltage-gated sodium channels so that they cannot open to support further action potentials.

PURPOSE: Induction of neuromuscular blockade in surgery; intubation

ADVERSE: Bradyarrhythmia, cardiac arrest, cardiac arrhythmia, malignant hyperthermia, rhabdomyolysis, respiratory depression, muscle rigidity, myalgia, raised intraocular pressure

CONTRA: Personal or family history of malignant hyperthermia, skeletal muscle myopathies, UMN injury, extensive denervation of skeletal muscle

Front 162

162. What are two therapeutic considerations for succinylcholine?

Back 162

1. Short duration of action makes it the DOC for paralysis during intubation
2. It causes transient fasciculations

Front 163

163. What are muscarinic receptor antagonists?

Back 163

Anticholinergic compounds that act on muscarinic receptors are used to produce a parasympatholytic effect in target organs.

By blocking normal cholinergic tone, these compounds allow sympathetic responses to predominate.

Front 164

164. Atropine

Back 164

MOA: A naturally occurring alkaloid that is a muscarinic receptor antagonist. It has mainly muscarinic activity, marginal nicotinic effect

PURPOSE: AChE overdose, acute, symptomatic bradycardia, premedication for anesthetic procedure, excessive salivation and mucus secretion during surgery, antidote to mushroom poisoning

ADVERSE: Cardiac arrhythmia, coma, respiratory depression, raised intraocular pressure, tachycardia, constipation, xerostomia, blurred vision

CONTRA: Narrow-angle glaucoma

Front 165

165. What are two therapeutic considerations for atropine

Back 165

1. Mainly muscarinic activity, marginal nicotinic effect
2. More effective at reversal of exogenous rather than endogenous cholinergic activity

Front 166

166. Scopolamine

Back 166

MOA: Tertiary amine that has significant CNS effects; muscarinic receptor antagonists

PURPOSE: Motion sickness; nausea and vomiting

ADVERSE: Alteration in heart rate, drug-induced psychosis, somnolence, xerostomia, blurred vision

CONTRA: Narrow-angle glaucoma

NOTES: Delivered transdermal patch.

Front 167

167. Pirenzepine, methscopolamine, glycopyrrolate

Back 167

MOA: Muscarinic receptor antagonists alternative or additive agents to standard peptic ulcer diseases

PURPOSE: Peptic ulcer disease surgically-induced or vagally-induced bradycardia (glycopyrrolate)

ADVERSE: Cardiac arrhythmia, malignant hyperthermia, anaphylaxis, seizure, constipation, xerostomia, urinary retention, decreased sweating

CONTRA: GI obstruction, narrow-angle glaucoma

NOTES: Methscopolamine and glycopyrrolate have delayed but measurable CNS cognitive anticholinergic effects.

Front 168

168. Ipratropium, tiotropium

Back 168

MOA: Muscarinic receptor antagonists

PURPOSE: COPD, asthma

ADVERSE: Paralytic ileus, anaphylaxis, oropharyngea edema, abnormal taste in mouth, xerostomia (nasal spray)

CONTRA: Hypersensitivity

NOTES: Ipratropium is more effective than β-adrenergic agonists in the treatment of COPD, but less effective in treating asthma. Relative to ipratropium, tiotropium has been shown to have similar, and possibly superior, efficacy as a bronchodilator in the treatment of COPD.

Front 169

169. Oxybutynin, propantheline, terodiline, tolterodine, trospium, darifenacin, solifenacin

Back 169

MOA: Oxybutynin, propantheline, tolterodine, and trospium are nonspecific muscarinic receptor antagonists, whereas darifenacin and solifenacine are selective M3 receptor antagonists

PURPOSE: Hyperreflexic and overactive bladder, urge incontinence

ADVERSE: Constipation, diarrhea, nausea, dry mouth, application-site erythema, pruritus

CONTRA: Narrow angle glaucoma; use w/caution in pts with BPH

NOTES: Tolterodine may cause less dry mouth than oxybutynin, and the newer M3-selective agents darifenacin and solifenacin may cause less dry mouth and constipation than nonselective agents.

Front 170

170. What are nicotinic receptor antagonists used for?

Back 170

Selective nicotinic receptor antagonists are used primarily to produce nondepolarizing (competitive) neuromuscular blockade during surgical procedures.

Non-depolarizing NMJ blocking agents act by antagonizing nicotinic ACh receptors directly, thus preventing endogenous ACh binding and subsequent muscle cell depolarization.

This leads to a flaccid paralysis similar in presentation to that of myasthenia gravis.

Front 171

171. Pancuronium, tubocurarine, vecuronium, rocuronium, mivacurium

Back 171

MOA: Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (nondepolarizing blockade)

PURPOSE: Induction of neuromuscular blockade in surgery, intubation

ADVERSE: Hypertension, tachyarrhythmia, apnea, bronchospasm, respiratory failure, salivation, flushing (mivacurium)

CONTRA: Hypersensitivity

Front 172

172. Therapeutic considerations for pancuronium, tubocurarine, vecuronium, rocuronium, mivacurium

Back 172

Pancuronium and tubocurarine are long-acting agents; vecuronium and rocuronium are intermediate-acting agents; mivacurium is a short acting agent.

Nondepolarizing blocking agents have variable adverse effects associated with ganglionic blockade, which can be reversed by administration of AChE inhibitors.

Front 173

173. Trimethaphan and mecamylamine

Back 173

MOA: Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (nondepolarizing blockade)

PURPOSE: Hypertension in pts with acute aortic dissection

ADVERSE: Paralytic ileus, urinary retention, respiratory arrest, syncope, orthostatic hypotension, dyspepsia, diplopia, sedation

CONTRA: Asphyxia, uncorrected respiratory insufficiency, neonates at risk for paralytic or meconium ileus, shock, coronary insufficiency, glaucoma, recent MI, pyloric stenosis, renal insufficiency, pts treated with sulfonamides

Front 174

174. Therapeutic considerations for trimethaphan and mecamylamine

Back 174

Mecamylamine and trimethaphan are administered when ganglionic blockade is desired.

These drugs lower BP while simultaneously blunting the sympathetic reflexes that would normally cause a deleterious rise in pressure at the site of the tear in cases of aortic dissection.

Front 175

175. What are the characteristics of skeletal muscle?

Back 175

Skeletal muscle cells are long, cylindrical fibers that run the length of the muscle. The cell membrane surrounding the fibers is called the sarcolemma.

In addition to the sarcoplasmic reticulum, another membrane structure, the traverse tubules (T-tubules) are thousands of invaginations of the sarcolemma that tunnel from the surface toward the center of the muscle to make contact w/the terminal cisterns of the sarcoplasmic reticulum.

Front 176

176. What is the purpose of the T-tubules?

Back 176

B/c the T-tubules are open to the outside of the muscle fiber and are filled w/ECF, the muscle action potential that propagates along the surface of the muscle fiber's sarcolemma travels into the T-tubules and to the sarcoplasmic reticulum.

Front 177

177. Why are there striations in skeletal muscle?

Back 177

This is attributable to the presence and organization of myofibrils in the cells. Myofibrils consists of thin and thick filaments.

The contractile proteins actin and myosin are contained w/in the filaments - myosin in the thick filaments and actin in the thin.

Front 178

178. What are the two types of muscle fibers?

Back 178

Fast-twitch (Type II) or slow twitch (Type I).

I saw one slow red ox

Front 179

179. What are the characteristics of type I fibers?

Back 179

The slow twitch fibers or type I (aka slow-oxidative fibers), contain large amts of mitochondria and myoglobin (giving them a red color), utilize respiration and oxidative phosphorylation for energy, and are relatively resistant to fatigue.

They have low glycogen content. They develop force slowly but maintain contractions longer than fast-twitch fibers.

Front 180

180. What are the characteristics of type II fibers?

Back 180

The fast twitch fibers, or type II, can be subdivided as type IIa or type IIb.

Type IIb fibers (aka fast-glycolytic fibers) have few mitochondria and low levels of myoglobin (they appear white). They are rich in glycogen and use glycogenolysis and glycolysis as their primary energy source. These muscles are prone to fatigue, b/c continued reliance on glycolysis to produce ATP leads to an increase in lactic acid levels.

Type IIa fibers (aka fast-oxidative glycolytic fibers) have properties of both type I and IIb fibers and thus display functional characteristics of both fiber types.

Front 181

181. Where are type I fiber muscles found?

Back 181

Type I fibers are found in postural muscles such as the psoas in the back or the soleus in the leg.

Type II fibers are more prevalent in the large muscles of the limbs that are responsible for sudden, powerful movements.

*EOM would also have more of type II fibers.

Front 182

182. What are the characteristics of smooth muscle cells?

Back 182

Smooth muscle cells have a single nucleus, and display no striations under the microscope.

The contraction of smooth muscle is involuntary. In contrast to skeletal muscle, these cells have the ability to maintain tension for extended periods, and do so with low use of energy.

Front 183

183. What are the characteristics of cardiac muscle cells?

Back 183

These cells are similar to skeletal muscle in that they are striated, but they are regulated involuntarily. The cells are quadrangular in shape and form a network with other cells thru tight membrane junctions and gap junctions. The multicellular contact allow the cells to act as a common unit and to contract and relax synchronously.

These cells are designed for endurance and consistency. They depend on aerobic metabolism for their energy needs b/c they contain many mitochondria and little glycogen.

Preferred substrate is fatty acids.

Front 184

184. How does the contraction of muscle occur?

Steps 1-3

Back 184

1. ACh is released at the NMJ
2. Binding of ACh on the muscle membrane stimulates the opening of sodium channels on the sarcolemma which causes a massive influx of sodium ions and generates an action potential at the motor end plate of the NMJ
3. The action potential sweeps across the surface of the muscle fiber and down the T-tubules to the sarcoplasmic reticulum, where it initiates the release of calcium from its lumen, via the ryanodine receptor

Front 185

185. How does the contraction of muscle occur?

Steps 4 - 6

Back 185

4. The calcium ions binds to troponin, resulting in a conformation change in the troponin-tropomyosin complexes so that they move away from the myosin binding sites on the actin
5. When they binding site becomes available, the myosin head attaches to the myosin-binding site on actin which is followed by a conformational change in the myosin head, which shortens the sarcomere.
6. After the change, ATP binds the myosin head, which detaches from the actin and is available to bind another myosin-binding site on the actin

Front 186

186. What is necessary for muscle contraction?

Back 186

As long as calcium ion and ATP remain available, the myosin heads will repeat this cycle of attachment, pivoting, and detachment.

This movement requires ATP, and when ATP levels are low, the ability of the muscle to relax or contract is compromised.

Front 187

187. How is the calcium removed from the sarcoplasmic reticulum after muscle contraction?

Back 187

As the calcium release channel closes, the calcium is pumped back into the SR against its concentration gradient using the energy requiring protein SERCA, and contraction stops.

Front 188

188. Why is PFK-2 not regulated by phosphorylation in skeletal muscle?

How is it regulated in cardiac muscle?

Back 188

This is b/c the skeletal muscle isozyme of PFK-2 lacks the regulatory serine residue, which is phosphorylated in the liver.

However, the cardiac isozyme of PFK-2 is phosphorylated and activated by a kinase cascade initiated by insulin. This allows the heart to activate glycolysis and to use blood glucose when blood glucose levels are low.

Front 189

189. What does fatty acid uptake by muscle require?

Back 189

It requires the participation of fatty acid-binding proteins and the usual enzymes of fatty acid oxidation.

Front 190

190. How is fatty acyl CoA uptake into the mitochondria controlled?

Back 190

Fatty acyl CoA uptake into the mitochondria is controlled by malonyl CoA, which is produced by an isozyme of acetyl CoA carboxylase (ACC-2).

Front 191

191. How is ACC-2 activity regulated?

Back 191

ACC-2 (a mitochondrial protein, linked to CPT1 in the outer mitochondrial membrane) is inhibited by phosphorylation by the AMP-activated protein kinase (AMP-PK) so that when energy levels are low, the levels of malonyl CoA drop, allowing fatty acid oxidation by the mitochondria.

Front 192

192. What is malonyl CoA decarboxylase?

Back 192

Muscle cells also contain the enzyme malonyl CoA decarboxylase, which is activated by phosphorylation by the AMP-PK. Malonyl CoA decarboxylase converts malonyl CoA to acetyl CoA, thereby relieving the inhibition of carnitine palmitoyl transferase I (CPT01) and stimulating fatty acid oxidation.

Front 193

193. Mice that have been bred to lack ACC-2 show..?

Back 193

These mice have a 50% reduction of fat stores compared with control mice.

This was shown to be attributable to a 30% increase in skeletal muscle fatty acid oxidation resulting from dysregulation of CPT1, brought about by the lack of malonyl CoA inhibition of CPT1.

Front 194

194. What type of fuels does the heart use?

Back 194

Can use a wide range of substrates:
Fatty acids
Glucose
Ketone bodies
Lactate

Lipid and glycogen: small stores for emergencies

Preferred substrate is fatty acids

Front 195

195. How does the heart use lactate?

Back 195

Lactate is generated by RBCs and working skeletal muscle. When the lactate is used by the heart, it is oxidized to carbon dioxide and water, following the pathway lactate to pyruvate, pyruvate to acetyl CoA, acetyl CoA oxidation in the TCA cycle, and ATP synthesis thru oxidative phosphorylation.

An alternative fate for lactate is its utilization in the reactions of the Cori cycle in the liver.

Front 196

196. Glucose transport into the cardiocyte occurs via...?

Back 196

Both GLUT1 and GLUT4 transporters, although approx 90% of the transporters are GLUT4.

Insulin stimulates an increase in the # of GLUT4 transporters in the cardiac cell membrane, as does myocardial ischemia.

Front 197

197. How are fatty acids transported into the cardiocytes?

Back 197

Similar to that for other muscle types - requires fatty acid binding proteins and carnitine palmitoyl transferase I for transfer into the mitochondria.

Front 198

198. How is fatty acid oxidation in cardiac muscle cells regulated?

Back 198

Via altering the activities of ACC-2 and malonyl CoA decarboxylase

Front 199

199. What happens when the blood flow to the heart is interrupted?

Back 199

The heart switches to anaerobic metabolism. The rate of glycolysis increases, but the accumulation of protons via lactate formation is detrimental to the heart. Also the levels of free fatty acids are elevated. Fatty acid oxidation occurs so rapidly that NADH accumulates in the mitochondria, which leads to more lactate formation.

As lactate production increases and intracellular pH of the heart drops, it is more difficult to maintain ion gradients across the sarcolemma. ATP hydrolysis is required to repair these gradients.

Front 200

200. Which fuels do skeletal muscles use?

Back 200

The most abundant immediate source of ATP is creatine phosphate. ATP can also be generated from glycogen stores, either anaerobically (generating lactate), or aerobically, in which case pyruvate is converted to acetyl CoA for oxidation via the TCA cycle.

Skeletal muscles are also capable of completely oxidizing the carbon skeletons of alanine, aspartate, glutamate, valine, leucine, and isoleucine, but not other AAs.

Front 201

201. Why is ATP stored as creatine phosphate?

Back 201

ATP is not a good choice as a molecule to store in quantity for energy reserves. Many reactions are activated or inhibited by ATP levels. Muscle cells solve this problem by storing high energy phosphate bonds in the form of creatine phosphate.

When every is required, creatine phosphate donates a phosphate to ADP, to regenerate ATP for muscle contraction.

Front 202

202. How is creatine synthesized?

Back 202

Creatine synthesis begins in the kidney and is completed in the liver. In the kidney, glycine combines with arginine (the group that also forms urea), is transferred to glycine, and the remainder of the arginine molecules is releases as ornithine.

Guanidinoacetate then travels to the liver, where it is methylated by S-adenosyl methionine to form creatine.

Front 203

203. How does the creatine combine with phosphate?

Back 203

The creatine formed is released from the liver and travels thru the blood to other tissues, where it reacts w/ATP to form the high-energy compound creatine phosphate.

This reaction is catalyzed by creatine phosphokinase, and is reversible.

Front 204

204. How is creatine phosphate specifically used in muscle during exercise?

Back 204

It serves as a small reservoir of high-energy phosphate that can readily regenerate ATP from ADP.

It also carries high-energy phosphate from mitochondria, where ATP is synthesized, to myosin filaments, where ATP is used for muscle contraction

Front 205

205. How is creatinine in the urine used as a gauge?

Back 205

Creatine is an unstable compound and spontaneously cyclizes forming creatinine.

Creatinine cannot be further metabolized and is excreted in the urine. The amt of creatinine excreted each day is constant and depends on muscle mass. Therefore, it can be used as a gauge for determining the amts of other compounds excreted in the urine and as an indicator of renal excretory function.

Front 206

206. Muscle fuel utilization at rest is dependent on...?

Back 206

Dependent on the serum levels of glucose, AAs, and FA's. If blood glucose and AAs are elevated, glucose will be converted to glycogen, and branched chain AA metabolism will be high.

Fatty acids will be used for acetyl CoA production and will satisfy the energy needs of the muscle under these conditions.

Front 207

207. The balance between glucose oxidation and fatty acid oxidation in the rested state is regulated by...?

Back 207

Citrate. When the muscle cell has adequate energy, citrate leaves the mitochondria and activates ACC-2, which produces malonyl CoA. The malonyl CoA inhibits carnitine palmitoyl transferase-1, thereby reducing fatty acid oxidation by the muscle.

Malonyl CoA decarboxylase is also inactive, b/c the AMP-PK is not active in the fed state. Thus, the muscle regulates its oxidation of glucose and FAs in part thru monitoring of cytoplasmic citrate levels.

Front 208

208. What happens to fuel use during starvation?

Back 208

As blood glucose levels drop, insulin levels drop. This reduces the levels of GLUT4 transporters in the muscle membrane, and glucose use by muscle drops significantly. This conserves glucose for use by the nervous system and RBCs. In cardiac muscle, PFK-2 is phosphorylated and activated by insulin. The lack of insulin results in a reduced use of glucose by these cells as well.

Pyruvate dehydrogenase is inhibited by the high levels of acetyl CoA and NADH begin produced by fatty acid oxidation.

Front 209

209. What fuel becomes the muscles preferred fuel under starvation conditions?

Back 209

Fatty acids.

The AMP-PK is active b/c of lower than normal ATP levels, ACC-2 is inhibited, and malonyl CoA decarboxylase is activated, thereby retaining full activity of CPT-1.

The lack of glucose reduces the glycolytic rate, and glycogen synthesis does not occur b/c of the inactivation of glycogen synthase by epinephrine stimulated phosphorylation.

Front 210

210. What happens to fuel utilization during exercise?

Back 210

The rate of ATP utilization can be as much as 100x greater than in resting skeletal muscles. Thus, the pathways of fuel oxidation must be rapidly activated during exercise to respond to the much greater demand for ATP.

ATP and creatine phosphate would be rapidly used up if they were not continuously regenerated.

Front 211

211. Anaerobic glycolysis is especially important in what three conditions?

Back 211

1. During the initial period of exercise
2. Exercise by muscle containing predominately fast-twitch glycolytic muscle fibers, b/c these fibers have low oxidative capacity and generate most of their ATP thru glycolysis.
3. During strenuous activity, when the ATP demand exceeds the oxidative capacity of the tissue, and the increased ATP demand is met by anaerobic glycolysis

Front 212

212. What happens with anaerobic glycolysis at the onset of exercise?

Back 212

As soon as exercise begins, the demand for ATP increases. The amt of ATP present in skeletal muscle could sustain exercise for only 1.2 s if it were not regenerated, and the amt of phosphocreatine could sustain exercise for only 9 seconds if it were not regenerated.

It takes longer than 1 minute for the blood supply to exercising muscle to increase significantly as a result of vasodilation, and therefore oxidative metabolism of blood-borne glucose and fatty acids cannot increase rapidly at the onset of exercise. Thus, for the first few minutes of exercise, the conversion of glycogen to lactate provides a considerable portion of the ATP requirement.

Front 213

213. What is the glycolytic capacity like in type IIb fibers?

Back 213

These are the fast twitch fibers. In such muscles, the glycolytic capacity is high b/c the enzymes of glycolysis are present in large amts. The levels of hexokinase however are low, so very little circulating glucose is used.

The low levels of hexokinase in fast twitch glycolytic fibers prevent the muscle from drawing on blood glucose to meet this high demand for ATP, thus avoiding hypoglycemia.

Glucose-6-phosphate, formed from glycogenolysis, further inhibits hexokinase.

As a result, the tissues reloy on endogenous fuel stores (glycogen and creatine phospahte) to generate ATP

*Thus, anaerobic glycolysis is the main source of ATP during exercise of these muscle fibers.

Front 214

214. Why are glycogenolysis and glycolysis during exercise activated together?

Back 214

B/c both PFK-1 (the rate limiting enzyme of glycolysis) and glycogen phosphorylase b (the inhibited form of glycogen phosphorylase) are allosterically activated by AMP.

AMP is an ideal activator b/c its concentration is normally kept low unless ATP levels decrease.

Front 215

215. What is the ATP production in anaerobic glycolysis vs. aerobic glycolysis?

Back 215

31-33 ATP in aerobic

3 ATP in anaerobic

To compensate for the low ATp yield of anaerobic glycolysis, fast twitch muscle fibers have a much higher content of glycolytic enzymes, and the rate of glucose-6-phosphate utilization is more than 12x as fast as in slow twitch fibers.

Front 216

216. What causes muscle fatigue during exercise?

Back 216

Results from a lowering of the pH of the tissue to approx 6.4 Both aerobic and anaerobic metabolism lowers the pH.

Both the lower of pH and lactate production can cause pain.

Front 217

217. How is muscle glycogen metabolism regulated?

Back 217

Glycogen degradation in muscle is not sensitive to glucagon so there is little change in muscle glycogen stores during fasting if the individual remains at rest.

Glycogen synthase is inhibited during exercise but can be activated in resting muscle by the release of insulin after a high carb meal. Insulin activates the active form of glycogen phosphorylase b, via calcium-calmodulin release, epinephrine, and cAMP-dependent protein kinase.

Protein kinase A phosphorylates and fully activates glycogen phosphorylase kinase so that continued activation of muscle glycogen phsophorylase can occur.

Front 218

218. What happens to anaerobic glycolysis during high-intensity exercise?

Back 218

Once exercise begins, the electron-transport chain, the TCA cycle, and FA oxidation are activated by the increase in ADP and the decrease of ATP.

Pyruvate dehydrogenase remains in the active, nonphosphorylated state as long as NADH can be reoxidized in the ETC and acetyl CoA can enter the TCA cycle.

However, even though mitochondrial metabolism is working at its max capacity, additional ATP may be needed for very strenuous high intensity exercise.

Front 219

219. How is this additional ATP produced during high-intensity exercise?

Back 219

Increased AMP levels activate PFK-1 and glycogenolysis, thereby providing additional ATP from anaerobic glycolysis (the additional pyruvate produced does not enter the mitochondria but rather is converted to lactate so that glycolysis can continue).

Under these conditions, most of the pyruvate formed by glycolysis enters the TCA cycle, whereas the remainder is reduced to lactate to regenerate NAD for continued use in glycolysis.

Front 220

220. What is the fate of the lactate released during exercise?

Back 220

The lactate can be used by resting skeletal muscles or by the heart.

In such muscles, the NADH/NAD+ ratio is lower than in exercising skeletal muscle, and the lactate dehydrogenase reaction proceeds in the direction of pyruvate formation. The pyruvate that is generated is then converted to acetyl CoA and oxidized in the TCA cycle, producing energy by oxidative phosphorylation.

The second potential fate of lactate is that it will return to the liver thru the Cori cycle, where it is converted to glucose.

Front 221

221. How does lactate release change with the duration of exercise?

Back 221

Lactate release decreases w/duration of exercise. This is b/c of the aerobic oxidation of glucose and FAs, which generates more energy per fuel molecule than anaerobic metabolism, and which also produces lactic acid at a slower rate than anaerobic metabolism.

Front 222

222. What is the major source of carbon for gluconeogenesis during exercise?

Back 222

Lactate. AAs and glycerol are also used.

Front 223

223. What happens to glucose output during prolonged exercise?

Back 223

During the first 40 min of exercise, glycogenolysis is mainly responsible for the glucose output of the liver. However, after 40-240 minutes of exercise, the total glucose output of the liver decreases.

This is caused by the increased utilization of fatty acids, which are being release from adipose tissue TAGs.

Glucose uptake by the muscle is stimulated by the increase in AMP levels and the activation of the AMP-activated protein kinase, which stimulates the translocation of GLUT4 transporters to the muscle membrane.

Front 224

224. The preferential utilization of fatty acids over glucose as a fuel in skeletal muscle depends on what 5 factors?

Back 224

1. The availability of free FAs in the blood
2. Inhibition of glycolysis by products of FA oxidation (Acetyl CoA, NADH, and ATP inhibit pyruvate dehydrogenase, as AMP levels drop, PFK-1 activity is decreased)
3. Glucose transport may be reduced during long term exercise due to falling insulin levels or increased fatty acids
4. Oxidation of ketone bodies also increases during exercise
5. Acetyl CoA carboxylase (ACC-2) must be inactivated for the muscle to use fatty acids. This occurs as the AMP-PK is activated and phosphorylates ACC-2 rendering it inactive.

Front 225

225. Branched chain AAs supply about how much of the ATP to resting muscle?

Back 225

About 20% of the ATP supply.

Front 226

226. What are the two functions of branched chain AA oxidation?

Back 226

1. Generation of ATP
2. Synthesis of glutamine, which effluxes from the muscle

*The highest rates of branched chain AA oxidation occur under conditions of acidosis, in which there is a higher demand for glutamine to transfer ammonia to the kidney and to buffer the urine.

Front 227

227. What about the purine nucleotide cycle and exercise?

Back 227

Exercise increase the activity of the purine nucleotide cycle, which converts aspartate to fumarate plus ammonia.

The ammonia is used to buffer the proton production and lactate production from glycolysis and the fumarate is recycled and can form glutamine.

Front 228

228. Can acetate be a fuel for skeletal muscle?

Back 228

Yes, it is an excellent fuel. It is treated by muscle as a short chain fatty acid.

It is activated to acetyl CoA in the cytosol and then transferred into the mitochondria via acetylcarnitine transferase.

Front 229

229. What is the SERCA pump?

Back 229

The SERCA pump is a transmembrane protein that is present in several different isoforms throughout the body.

Three genes encode SERCA proteins, called SERCA1, SERCA2, and SERCA3.

Front 230

230. What is SERCA1?

Back 230

The SERCA1 gene produces two transcripts, SERCA1a and SERCA1b.

SERCA1b is expressed in the fetal and neonatal fast twitch skeletal muscles, and is replaced by SERCA1a in adult fast-twitch muscles.

Front 231

231. What is SERCA2?

Back 231

The SERCA2 gene also undergoes alternative splicing, producing the SERCA2a and SERCA2b isoforms.

The SERCA2b isoform is expressed in all cell types and is associated with IP₃-regulated calcium stores. SERCA2a is the primary isoform expressed in cardiac tissue.

Front 232

232. What is the role of SERCA2a?

Back 232

SERCA2s plays an important role in cardiac contraction and relaxation.

Contraction is initiated by the release of clacium from intracellular stores, whereas relaxation occurs as the calcium is resequestered in the SR, in part mediated by the SERCA2a protein.

Front 233

233.What regulates the SERCA2a pump?

Back 233

The SERCA2a pump is regulated by its association with the protein phospholamban (PLN).

PLN associates with SERCA2a in the SR and reduces its pumping activity. B/c new contractions cannot occur until cytosolic calcium has been resequestered into the SR, a reduction in SERCA2a activity increases the relaxation time. However, when called on, the heart can increase its rate of contractions by inhibiting the activity of PLN.

Front 234

234. How is PLN's activity inhibited?

Back 234

This is accomplished by phosphorylation of PLN by protein kinase A.

Epinephrine release stimulates the heart to beat faster. This occurs thru epinephrine binding to its receptor, activating a G protein, which leads to adenylate cyclase activation, elevation of cAMP levels, and activation of protein kinase A.

Front 235

235. Mutations in PLN lead to...?

Back 235

Cardiomyopathies, primarily an autosomal dominant form of DCM.

This mutation leads to an arginine in place of cysteine at position 9 in PLN, which forms an inactive complex with PKA and blocks PKA phosphorylation of PLN.

Individuals with this form of PLN develop cardiomyopathy in their teens.

In this condition, the cardiac muscle does not pump well (b/c of the constant inhibition of SERCA2a) and becomes dilated.

Front 236

236. What causes Duchenne muscular dystrophy?

Back 236

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin, which is a structural protein located in the sarcolemma.

Dystrophin is required to maintain the integrity of the sarcolemma, and when it is absent there is a loss of muscle function, caused by breakdown of the sarcolemma.

Front 237

237. What type of mutations cause Duchenne's muscular dystrophy

Back 237

The gene is X-linked, and mutations that lead to muscular dystrophy generally result form large deletions of the gene, such that dystrophin is absent from the membrane.

Front 238

238. What causes Becker muscualr dystrophy?

Back 238

Becker muscular dystrophy, a milder form of disease, is caused by point mutations in the dystrophin gene.

In this case, dystrophin is present in the sarcolemma, but in a mutated form.

Front 239

239. What are the ryanodine receptors?

Back 239

The ryanodine receptors are calcium release channels found int eh ER and SR of muscle cells.

One type of receptor can be activated by a depolarization signal while another type is activated by calcium ions.

These proteins received their names b/c they bind ryanodine, a toxin obtained from the stem and roots of the plant Ryania.

Ryanodine inhibits SR calcium release and acts as a paralytic agent.

Front 240

240. What are pFOX inhibitors?

Back 240

A new class of drugs, known as partial fatty acid oxidation (pFOX) inhibitors, is being develops to reduce the extensive fatty acid oxidation in heart after an ischemic episode (ranolazine).

The reduction in fatty acid oxidation induced by the drug will allow glucose oxidation to occur and reduce lactate buildup in the damaged heart muscle.

Front 241

241. When serum CK levels rise, what does this indicate?

Back 241

Muscle and brain cells contain large amts of creatine phosphokinase (CK), and damage to these cells causes the enzyme to leak into the blood.

Serum CK is measured to Dx and evaluate pts who have had strokes and heart attacks. The presence of 5% or more of the CK in the blood as the muscle isoform is indicative of a heart attack.

Front 242

242. Where do the spinal nerve roots exit?

Back 242

The nerve roots exit the spinal canal via the neural (intervertebral) foramina.

Front 243

243. Where are disc herniations most common?

Back 243

Disc herniations are most common at the cervical and lumbosacral levels. For both cervical and lumbosacral disc herniations, the nerve root involved usually corresponds to the lower of the adjacent two vertebrae.

Disc herniation is most common at the C6, C7, L5, and S1 nerve roots.

Front 244

244. Cervical discs are usually constrained by...?

Back 244

The posterior longitudinal ligament.

B/c of this ligament, the cervical discs herniate laterally toward the nerve root, rather than centrally toward the spinal cord. Thus, in the cervical cord the nerve root involved usually corresponds to the lower vertebral bone of the disc space.

Front 245

245. What about the nerve roots in the lumbosacral spine?

Back 245

These nerve roots exit some distance above the intervertebral discs. As they are about to exit, the nerve roots move into the lateral recess of the spinal canal, and it is at this point that they are closest to the disc.

Front 246

246. So, what is the type/direction of disc herniation in the lumbosacral spine?

Back 246

Posterolateral disc herniations.

These usually impinge on nerve roots on their way to exit beneath the next lower vertebral bone, which corresponds to the number of the nerve root involved.

Front 247

247. What is a far lateral disc herniation?

Back 247

Occasionally, a far lateral disc herniation will reach the nerve root exiting at that level, resulting in impingement of the next higher nerve root.

For example, a far lateral L5-S1 disc herniation can cause an L5 radiculopathy.

Front 248

248. What is a central disc herniation?

Back 248

A central disc herniation at the level of the cauda equina can impinge on nerve roots lower than the level or herniation, or it can compress the spinal cord if it occurs above L1.

Front 249

249. Diabetic neuropathy causes what type of pattern?

Back 249

A distal symmetrical polyneuropathy, which results in a characteristic glove and stocking pattern of sensory loss.

Front 250

250. What are the most commonly affected nerves in acute diabetic mononeuropathy?

Back 250

CN III, femoral and sciatic nerves.

Front 251

251. What is spondylosis?

Back 251

A general term for degenerative disorders of the spine

Front 252

252. What is spondylolysis?

Back 252

Fractures that appear in the pars interarticularis, between the facet joints.

Lysis means loosening

Front 253

253. What is spondylolisthesis?

Back 253

Displacement of a vertebral body relative to the vertebral body beneath it. Anterolisthesis (anterior displacement) commonly coexists with spondylolysis.

Olisthesis means "slipping and falling".

Front 254

254. What causes a C8 radiculopathy?

Back 254

C8 radiculopathy accounts for about 6% of cervical radiculopathies, is usually caused by C7-T1 disc herniation, and is associated with weakness of the intrinsic hand muscles and decreased sensation in the fourth and fifth digits and the medial forearm.

Front 255

255. What is cauda equina syndrome?

Back 255

Impaired function of multiple nerve roots below L1 or L2 is called cauda equina syndrome. If the deficits begin at the S2 roots and below, they may be no obvious leg weakness.

Involvement of S2, S3, and S4 nerve roots can produce a distended atonic bladder w/urinary retention or overflow incontinence, constipation, decreased rectal tone, fecal incontinence, and loss of erections.

Front 256

256. What is conus medullaris syndrome?

Back 256

Cauda equina syndrome can sometimes be difficult to differentiate from conus medullaris syndrome, in which similar deficits occur as the result of a lesion in the sacral segments of the spinal cord.

Causes include compression by a central disc herniation, epidural metastases, schwannoma, meningioma, neoplastic meningitis, trauma, epidural abscess, arachnoiditis, and CMV polyradiculitis.

Front 257

257. Left neck and shoulder pain w/tingling radiating down into the 1st and 2nd fingers, accompanied by decreased pinprick and discrimative sensation; weakness of the left biceps, brachioradialis, and wrist extensors, absent left biceps and brachioradialis reflexes

Back 257

Typical left C6 radiculopathy caused by a left C50C6 disc herniation.

Front 258

258. Pain and sensory changes over the left occipital areas

Back 258

The most likely clinical localization is left C2 nerve root or left occipital nerves, caused by an epidural abscess compressing either one of these.

Front 259

259. Left shoulder pain and decreased sensation; left deltoid weakness

Back 259

The most likely diagnosis is a left C5 radiculopathy caused by a C4-C5 disc herniation or osteophytes.

Front 260

260. Weakness of the right triceps and finger extensors, w/absent right triceps reflex; right shoulder pain w/paresthesias and decreased sensation in the right 2nd finger and lateral half of 3rd finger

Back 260

C7 nerve root compression caused by right C6-C7 disc herniation.

Front 261

261. Weakness of the intrinsic muscles of the left hand; left neck and should pain, w/paresthesias and decreased sensation in the left 4th and 5th digits

Back 261

A left C8 radiculopathy caused by leftward C7-T1 disc herniation; however, an ulnar neuropathy or lower brachial plexus lesion should also be considered.

Front 262

262. Left shoulder pain, w/decreased sensation in medial arm and forearm

Back 262

Left T1 nerve root compression by T1-T2 disc fragments.

Front 263

263. Weakness of the left gastrocs and hamstrings, with absent left Achilles tendon reflex; paresthesias and decreased sensation in the left lateral calf, lateral foot including the small toe, and sole

Back 263

Most likely diagnosis is a left S1 radiculopathy caused by a left posterolateral L5-S1 disc herniation compressing the left S1 nerve root.

Front 264

264. Weakness of the right quads and iliopsoas, w/absent right patellar reflex; paresthesias and decreased sensation in the anterior thigh, shin, and medial calf

Back 264

Right femoral or L4 neuropathy caused by a right femoral neuropathy or right posterolateral L3-L4 disc herniation.

***Lesions of the femoral nerve can sometimes be distinguished from an L4 radiculopathy by testing for weakness of thigh adduction, which may be present in L4 radiculopathy but not femoral neuropathy.

Front 265

265. Weakenss of the right extensor hallucis longus, tibialis anterior, and right foot invertors and evertors; pain radiating to the right big toe reproduced by straight leg raising w/decreased sensation in the anterolateral calf and dorsum of foot

Back 265

Right posterolateral L4-L5 disc herniation compressing the right L5 nerve root.

Front 266

266. Pain in the gluteal region bilaterally w/loss of sensation in a saddle distribution over the genitals and buttocks; constipation, urinary retention, impotence, loss of rectal tone, etc...

Back 266

L5-S1 central disc herniation compressing the cauda equina