1. Immune Disorders Kimiko Suzue, MD PhD October 4, 2011

2. Question 101
A 20 year old medical student develops a skin rash on her arms and hands 2 days after hiking in the Adirondack mountains. A skin biopsy of her blisters would be expected to have the histologic appearance below, with a dense lymphocytic infiltrate. This is characteristic of which type of hypersensitivity reaction?
Type I
Type II
Type III
Type IV
Answer: D

3. Question 101
Answer: D

4. Question 101
A 20 year old medical student develops a skin rash on her arms and hands 2 days after hiking in the Adirondack mountains. A skin biopsy of her blisters would be expected to have the following histologic appearance with a dense lymphocytic infiltrate. This is characteristic of which type of hypersensitivity reaction?
Type I
Type II
Type III
Type IV
Answer: D

5. Question 102
A 55 year old woman undergoes a lip biopsy (minor salivary gland biopsy). Shown is the histology which shows a dense periductal and perivascular lymphocytic infiltrate. This biopsy most strongly supports the diagnosis of:
Amyloidosis
DiGeorge syndrome
Sjogren syndrome
Systemic sclerosis
Systemic lupus erythematosus
Answer: C
Langerman et al., The Laryngoscope 2007

6. Question 102
Answer: C
Langerman et al., The Laryngoscope 2007

7. Question 102
A 55 year old woman undergoes a lip biopsy (minor salivary gland biopsy). Shown is the histology which shows a dense periductal and perivascular lymphocytic infiltrate. This biopsy most strongly supports the diagnosis of:
Amyloidosis
DiGeorge syndrome
Sjogren syndrome
Systemic sclerosis
Systemic lupus erythematosus
Answer: C
Langerman et al., The Laryngoscope 2007

8. This renal biopsy illustrates:
Question 103
This renal biopsy illustrates:
Amyloid deposition and a Congo red stain will confirm the diagnosis
Glomerular morphology in a patient with chronic discoid lupus erythematosus
IgG deposition secondary to excessive immunoglobulin production in a patient with XLA, Bruton’s Disease.
Necrotic glomeruli caused by immune complex deposition commonly seen in type I hypersensitivity reactions
Normal histology without diagnostic abnormality
Answer: A

10. This renal biopsy illustrates:
Question 103
This renal biopsy illustrates:
Amyloid deposition and a Congo red stain will confirm the diagnosis
Glomerular morphology in a patient with chronic discoid lupus erythematosus
IgG deposition secondary to excessive immunoglobulin production in a patient with XLA, Bruton’s Disease.
Necrotic glomeruli caused by immune complex deposition commonly seen in type I hypersensitivity reactions
Normal histology without diagnostic abnormality
Answer: A

11. Question 104
A 25 year old woman presents to you with this facial rash and a 3-month history of joint pain and sporadic fevers. Her lab studies show an elevated creatinine and blood urea nitrogen level. Which of the following is FALSE?
Antibodies to double-stranded DNA and Smith antigens are virtually diagnostic for this entity.
A skin biopsy evaluated by immunofluorescence may show IgG deposition at the dermoepidermal junction.
Progressive interstitial and perivascular fibrosis in the skin and multiple organs are characteristic of this systemic disorder.
She may have a false positive test for syphilis.
She may have antibodies to SS-A ribonucleoprotein
Answer: C and E

12. Question 105
A 32-year old woman is found to have a congenital immunodeficiency that has remained largely asymptomatic throughout her life. What is her most likely diagnosis?
Adenosine deaminase deficiency
Bruton’s aggamaglobulinemia
Hyper-IgM syndrome
Isolated IgA deficiency
Wiskott-Aldrich syndrome
Answer: D

13. Question 106
A 55 year old woman has subcutaneous fibrosis in her fingers, dysphagia from esophageal fibrosis and episodic vasoconstriction of the arteries and arterioles of her extremities. What is the most likely diagnosis?
Amyloidosis
CREST syndrome
Sjogren syndrome
Systemic lupus erythematosus
Wiskott-Aldrich syndrome
Answer: B

14. Primary amyloidosis refers to:
Question 107
Primary amyloidosis refers to:
Autosomal dominant familial disorders with deposition of amyloid in peripheral and autonomic nervous system
Localized deposition of AL type amyloid associated with chronic inflammatory conditions
Microscopic amyloid deposits found in endocrine tumors such as medullary carcinoma of the thyroid gland
Systemic deposition of AA type amyloid generally seen in patients with renal failure undergoing dialysis
Systemic deposition of AL type amyloid associated to multiple myeloma and other monoclonal plasma cell dyscrasias
Answer: E

15. Question 108
Deposition of antigen-antibody complexes with activation of complement, recruitment of leukocytes by complement products and Fc receptors with release of enzymes and other toxic molecules are characteristic of all of the following, EXCEPT:
Arthus reaction
Myasthenia gravis
Polyarteritis nodosa
Serum sickness
Systemic lupus erythematosus
Answer: B

16. Question 109
The following immunodeficiencies occur due to mutations on the X-chromosome except:
Bruton’s agammaglobulinemia
DiGeorge’s syndrome
Hyper-IgM syndrome
Severe combined immunodeficiency
Wiskott-Aldrich syndrome
Answer: B

17. Question 110
Which of the following statements regarding the human leukocyte antigen system is FALSE?
Autoimmune diseases such as rheumatoid arthritis, primary Sjogren syndrome and Type 1 diabetes are associated with alleles at the HLA-DR locus.
The HLA-A, HLA-B and HLA-C antigens are the principal antigens involved in tissue graft rejection.
The HLA-B27 allele is associated with ankylosing spondylitis.
The MHC class I molecules present foreign peptides to CD8 positive T-cells.
The MCH molecules HLA-DP, DQ and DR are present on virtually all nucleated cells and platelets.
Answer: E

18. End of Quiz

19. Question 101
A 20 year old medical student develops a skin rash on her arms and hands 2 days after hiking in the Adirondack mountains. A skin biopsy of her blisters would be expected to have the following histologic appearance with a dense lymphocytic infiltrate. This is characteristic of which type of hypersensitivity reaction?
Type I
Type II
Type III
Type IV
Answer: D

20. Hypersensitivity reactions
Type I (immediate or anaphylactic) IgE
Type II (antibody-mediated) IgG IgM
Type III (immune complex-mediated) Ag-Ab complex
Type IV (cell-mediated) T-cells
delayed hypersensitivity
cytotoxic T lymphocyte (CTL)-mediated cytotoxicity 20

21. Type IV T-cell-mediated hypersensitivity21

22. Type IV Hypersensitivity
antigen (presented by HLA class II macrophages) interacts with T-cell receptor of CD4+ lymphocytes  stimulation of antigen-specific CD4+ memory T cells
subsequent contact with antigen  proliferation of CD4+ memory T cells  secretion of IL-2 and other cytokines  recruiting of macrophages and stimulation of phagocytic activity of macrophages 22

23. Delayed hypersensitivity
antigen (presented by HLA class II macrophages) interacts with T-cell receptor of CD4+ lymphocytes  stimulation of antigen-specific CD4+ memory T cells
subsequent contact with antigen  proliferation of CD4+ memory T cells  secretion of IL-2 and other cytokines  recruiting of macrophages and stimulation of phagocytic activity of macrophages 23

24. CD4 positive lymphocytes in dermis in contact dermatitis24

25. Cytotoxic T lymphocyte (CTL)-mediated cytotoxicity
Direct CD8+ T cell-mediated killing of target cells (typically tumor cells or virus-infected cells)
Specific target cell antigen recognized by T-cell receptor of CD8+ lymphocytes 25

26. Question 108
Deposition of antigen-antibody complexes with activation of complement, recruitment of leukocytes by complement products and Fc receptors with release of enzymes and other toxic molecules are characteristic of all of the following, EXCEPT:
Arthus reaction
Myasthenia gravis
Polyarteritis nodosa
Serum sickness
Systemic lupus erythematosus
Answer: B

27. Question 108
Deposition of antigen-antibody complexes with activation of complement, recruitment of leukocytes by complement products and Fc receptors with release of enzymes and other toxic molecules are characteristic of all of the following, EXCEPT:
Arthus reaction
Myasthenia gravis anti-AchR ab
Polyarteritis nodosa
Serum sickness
Systemic lupus erythematosus
Answer: B

28. Graves’ disease
Example of antibody-medated cellular dysfunction, a subtype of Type II hypersensitivity
Anti-TSH Receptor Antibody
similar mechanism in myasthenia gravis: antibodies react with acetylcholine receptors in motor end plates of skeletal muscles 28

29. Exophthalmos in Graves’ disease29

30. Graves’ disease. Note epithelial hyperplasia and scalloped colloid30

31. Goodpasture syndrome an example of Type II hypersensitivity
antiglomerular basement membrane antibodies directed against antigens in glomerular as well as in pulmonary alveolar basement membranes
clinical manifestations include glomerulonephritis and pneumonitis with hemoptysis
linear immunofluorescence 31

32. Linear immunofluorescence in Goodpasture syndrome32

33. Question 102
A 55 year old woman undergoes a lip biopsy (minor salivary gland biopsy). Shown is the histology which shows a dense periductal and perivascular lymphocytic infiltrate. This biopsy most strongly supports the diagnosis of:
Amyloidosis
DiGeorge syndrome
Sjogren syndrome
Systemic sclerosis
Systemic lupus erythematosus
Answer: C
Langerman et al., The Laryngoscope 2007

34. Sjögren syndrome Autoimmune diseases in association with:
keratoconjunctivitis sicca (dry eyes)
xerostomia (dry mouth)
lymphocytic infiltrates with destruction of acini in lacrimal and salivary glands
ANAs
anti-SS-B (relatively specific)
anti‑SS-A (somewhat less specific) 34

37. Sjögren syndrome Lymphocytic infiltrate Residual ducts Fat replacing
Glandular
elements

38. This renal biopsy illustrates:
Question 103
This renal biopsy illustrates:
Amyloid deposition and a Congo red stain will confirm the diagnosis
Glomerular morphology in a patient with chronic discoid lupus erythematosus
IgG deposition secondary to excessive immunoglobulin production in a patient with XLA, Bruton’s Disease.
Necrotic glomeruli caused by immune complex deposition commonly seen in type I hypersensitivity reactions
Normal histology without diagnostic abnormality
Answer: A

39. Congo Red Stain

40. Polarized congo red stain of renal amyloid

41. Pathogenesis of Amyloidosis
© 2005 Elsevier 41

42. Primary amyloidosis refers to:
Question 107
Primary amyloidosis refers to:
Autosomal dominant familial disorders with deposition of amyloid in peripheral and autonomic nervous system
Localized deposition of AL type amyloid associated with chronic inflammatory conditions
Microscopic amyloid deposits found in endocrine tumors such as medullary carcinoma of the thyroid gland
Systemic deposition of AA type amyloid generally seen in patients with renal failure undergoing dialysis
Systemic deposition of AL type amyloid associated to multiple myeloma and other monoclonal plasma cell dyscrasias
Answer: E

43. Primary amyloidosis refers to:
Question 107
Primary amyloidosis refers to:
Autosomal dominant familial disorders with deposition of amyloid in peripheral and autonomic nervous system
Localized deposition of AL type amyloid associated with chronic inflammatory conditions
Microscopic amyloid deposits found in endocrine tumors such as medullary carcinoma of the thyroid gland
Systemic deposition of AA type amyloid generally seen in patients with renal failure undergoing dialysis
Systemic deposition of AL type amyloid associated to multiple myeloma and other monoclonal plasma cell dyscrasias
Answer: E

44. Question 107
Autosomal dominant familial disorders with deposition of amyloid in peripheral and autonomic nervous system
Transthyretin
Localized deposition of AL type amyloid associated with chronic inflammatory conditions
Secondary amyloidosis-Serum associated amyloid-AA
Microscopic amyloid deposits found in endocrine tumors such as medullary carcinoma of the thyroid gland
calcitonin
Systemic deposition of AA type amyloid generally seen in patients with renal failure undergoing dialysis
Beta-microglobulin
Systemic deposition of AL type amyloid associated to multiple myeloma and other monoclonal plasma cell dyscrasias
Answer: E

45. Question 110
Which of the following statements regarding the human leukocyte antigen system is FALSE?
Autoimmune diseases such as rheumatoid arthritis, primary Sjogren syndrome and Type 1 diabetes are associated with alleles at the HLA-DR locus.
The HLA-A, HLA-B and HLA-C antigens are the principal antigens involved in tissue graft rejection.
The HLA-B27 allele is associated with ankylosing spondylitis.
The MHC class I molecules present foreign peptides to CD8 positive T-cells.
The MCH molecules HLA-DP, DQ and DR are present on virtually all nucleated cells and platelets.

46. Question 104
A 25 year old woman presents to you with this facial rash and a 3-month history of joint pain and sporadic fevers. Her lab studies show an elevated creatinine and blood urea nitrogen level. Which of the following is FALSE?
Antibodies to double-stranded DNA and Smith antigens are virtually diagnostic for this entity.
A skin biopsy evaluated by immunofluorescence may show IgG deposition at the dermoepidermal junction.
Progressive interstitial and perivascular fibrosis in the skin and multiple organs are characteristic of this systemic disorder.
She may have a false positive test for syphilis.
She may have antibodies to SS-A ribonucleoprotein
Answer: C

47. Systemic Lupus Erythematosus
Head and Neck Manifestations
Malar rash (Butterfly Rash) often first sign
Erythematous maculopapular eruption after sun exposure
Oral ulceration 47

48. Butterfly Rash in Systemic Lupus Erythematosus48

49. Renal Manifestations of SLE World Health Organization (WHO) classification
I. Normal glomeruli by light microscopy (LM), IF, and EM
II. Pure mesangial alterations
III. Focal segmental (proliferative) glomerulonephritis
IV. Diffuse (proliferative) glomerulonephritis
V. Diffuse membranous glomerulonephritis
VI. Advanced sclerosing glomerulonephritis 49

50. SLE – “wire-loop” changes in glomerulus50

53. Red blood cell cast 53

54. White blood cell cast 54

55. Libman-Sacks Endocarditis in SLE Notice flat, reddish-tan vegetations
Libman-Sacks endocarditis is the most characteristic cardiac manifestation of systemic lupus erythematosus.
These lesions most commonly involves mitral and aortic valves although the other valves may be involved.
Because of their tiny size and because they seldom embolize these vegetations only rarely cause problems.
Libman-Sacks Endocarditis in SLE Notice flat, reddish-tan vegetations 55

56. Question 106
A 55 year old woman has subcutaneous fibrosis in her fingers, dysphagia from esophageal fibrosis and episodic vasoconstriction of the arteries and arterioles of her extremities. What is the most likely diagnosis?
Amyloidosis
CREST syndrome
Sjogren syndrome
Systemic lupus erythematosus
Wiskott-Aldrich syndrome
Answer: B

57. Systemic sclerosis (Scleroderma)
The term scleroderma comes from the Greek words “slerosis” meaning hard and “derma” meaning skin.
Scleroderma is a disease of connective tissues, which results from an overproduction of collagen.
There is thickening of skin on the arms, legs, face, etc and internal organs (such as the esophagus, gastrointestinal tract, lungs, heart, and kidneys are affected. 57

58. Dysphagia due to esophageal fibrosis
Systemic sclerosis is primarily (by 3:1) a disease of women. Distinctive features include:
Cutaneous changes.
Raynaud phenomenon,
Dysphagia due to esophageal fibrosis
Respiratory difficulties due to pulmonary fibrosis
Malignant hypertension, which may lead to the development of fatal renal failure 58

59. The CREST syndrome is a milder form of systemic sclerosis characterized by:
Calcinosis: painful calcium deposits in the skin.
Raynaud's phenomenon: spasm of tiny arteries in response to cold or stress.
Esophageal dysfunction: difficulty swallowing because of scarring in the esophagus.
Sclerodactyly: thickening and tightening of skin on the fingers and toes which limits motion.
Telangiectasis: tiny redspots on the hands, palms, forearems, face and lips which are caused by dilated capillaries.
Calcinosis 59

60. Antinuclear antibody tests in Systemic Sclerosis (Scleroderma)
About 75% of patients with the diffuse form of scleroderma and about 10% of patients with the localized CREST version have antinuclear antibodies directed against DNA topoisomerase (anti-Scl-70).
The CREST syndrome most commonly demonstrates anti-centromere antinuclear antibodies. 60

61. Sclerodactyly 61

70. Question 105
A 32-year old woman is found to have a congenital immunodeficiency that has remained largely asymptomatic throughout her life. What is her most likely diagnosis?
Adenosine deaminase deficiency
Bruton’s aggamaglobulinemia
Hyper-IgM syndrome
Isolated IgA deficiency
Wiskott-Aldrich syndrome
Answer: D

71. Question 109
The following immunodeficiencies occur due to mutations on the X-chromosome except:
Bruton’s agammaglobulinemia
DiGeorge’s syndrome
Hyper-IgM syndrome
Severe combined immunodeficiency
Wiskott-Aldrich syndrome
Answer: B

79. Transplant rejection 79

80. Transplant rejection
Hyperacute
Acute
Chronic
(note kidney model) 80

81. Renal transplant rejection
hyperacute rejection
primarily antibody-mediated
preexisting antibody to donor antigens
occurs within minutes of transplantation
acute rejection
primarily cell-mediated
occurs days to months after transplantation
characterized by infiltration of lymphocytes and macrophages 81

82. Renal transplant rejection
chronic rejection
primarily antibody-mediated vascular damage
months to years after transplantation 82

83. Histologic manifestations of cellular vs. humoral rejection
cellular rejection
interstitial infiltrate of T-lymphocytes and macrophages
humoral rejection
endothelial injury with thrombosis and resultant coagulation necrosis 83

84. Graft versus host (GVH) disease84

85. Graft versus host (GVH) disease
significant problem in bone marrow transplantation
immunocompetent cells are transplanted
can also be caused by whole blood transfusion in patients with severe combined immunodeficiency disease (SCID) 85

86. Graft versus host (GVH) disease
rejection of ``foreign'' host cells by engrafted T and B cells
CD8+ T cells from graft directly damage host cells
cytokines from graft CD4+ T cells recruit macrophages which damage host cells 86

87. Graft versus host (GVH) disease
liver, skin, and gastrointestinal mucosa are principal target organs
clinical features fever, rash, hepatosplenomegaly, jaundice, bloody diarrhea 87

88. Graft versus host (GVH) disease
apoptotic changes in target organs
bile ducts  jaundice
basal layer of squamous epithelium of skin  rash
intestinal epithelium (distal ileum most prominent site)  bloody diarrhea
lymphoid tissue 88

89. Apoptotic cells in basal layer of epidermis in GVHD89

90. Apoptotic cells in basal layer of crypts in GVHD90