1. Hypersensitivity, Autoimmunity and Immunodeficiency Part II Nancy L Jones, MD August 24, 2011

2. Autoimmune Disease  Immune reaction to self antigens  Organ or cell specific disorders  Multi-system disorders  Collagen vascular or connective tissue disease

3. Autoimmune disease  Immunologic tolerance  Self tolerance  Central tolerance  Peripheral tolerance

4. Autoimmune disease self tolerance  Central tolerance  Deletion of self reactive T and B cells during development  Thymus- negative selection by apoptosis of T cell expressing receptor for autologous antigens  Bone marrow- deletion of self reactive B cells by apoptosis  Slippage occurs

5. Delves, P. J. et al. N Engl J Med 2000;343:37-49 Positive and Negative Selection in the Thymus

6. Kamradt, T. et al. N Engl J Med 2001;344:655-664 Central Mechanisms of the Induction of Tolerance

7. Autoimmune disease Self tolerance  Peripheral tolerance  Self reactive T cell escape negative selection in thymus and must be deleted from periphery  Anergy  Encounter with Ag by APC lacking appropriate MHC molecule and costimulatory molecules for T cell  Lack of specific T helper cell for B cell functional inactivation not death

8.  Peripheral suppression by regulatory T cells which express CD25, a chains of the IL-2 receptor, which require IL-2 for generation and survival  Also express transcription factor FoxP3  Mutation of FOXP3 gene responsible for systemic autoimmune disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)  Excrete immunosuppressive cytokines IL-10 and TGF-β  Activation-induced cell death  Apoptosis by Fas-Fas ligand system mutations of which cause lymphoproliferative syndrome  Peripheral suppression by regulatory T cells Autoimmune disease Self tolerance

10. Mechanisms of Autoimmunity  Failure of tolerance  Single gene mutation  Failure of activation –induced cell death  Breakdown of T cell anergy  Bypass of B cell requirement for T cell help  Failure of T cell mediated suppression  Molecular mimicry  Polyclonal lymphocyte activation  Release of sequestered antigens  Exposure of cryptic self and epitope spreading

11. Wekerle, H. et al. N Engl J Med 2003;349:185-186 Modeling a Mimic

12. Albert, L. J. et al. N Engl J Med 1999;341:2068-2074 The Peripheral Immune Repertoire and Molecular Mimicry

13. Genetic factors in autoimmunity  Familial clustering  Greater occurrence in monozygotic v. dizygotic twins  Linkage with HLA antigens  Especially class II alleles (HLA-DR, _DQ)

14. Infection in autoimmunity  Act as triggers  Cross reacting epitopes  Bypass T cell tolerance by forming immunogenic units  Act as non-specific polyclonal B cell or T cell mitogens  Up-regulate co-stimulators via necrosis and inflammation  Facilitate cryptic antigen presentation and induce epitope spread

15. Systemic Lupus Erythematosus SLE  Systemic disorder primarily affecting skin, kidneys, serosal membranes, joints, and the heart  ANA  Diagnostic criteria  1: 2500 (1:700 in childbearing age)  1:245 in African American women  Usually presents in second or third decade  9:1 female to male

16. Diagnostic Criteria  Malar rash  Discoid rash  Photosensitivity  Oral ulcers  Arthritis  Serositis  Renal disorder  Neurologic disorder  Hematologic disorder  Immunologic disorder  Antinuclear antibody  Patient is said to have SLE if any 4 or more of the 11 are present serially or simultaneously during any interval of observation

17. SLE  Defect in self tolerance  Antinuclear antibodies (ANA)  Anti DNA  Anti histone  Anti non histone proteins bound to RNA  Anti nucleolar antigens

18. SLE  Patterns of Immunofluorescence  Homogeneous or diffuse  Chromatin, histones and DS DNA antibodies  Rim or peripheral  Double stranded DNA (DS DNA) antibodies  Speckled  Most common, histones and ribonucleoprotein antibodies  Nucleolar  Nucleolar RNA antibodies

19. Homogenous IF Staining

20. Rim IF Pattern

21. Anti-native DNA IF Pattern DS-DNA

22. SLE  Immunofluorescence  Highly sensitive  Not highly specific  Patterns are not absolutely specific for type of antibody  Antibodies to DS DNA and to Smith (Sm) antigen (non- DNA) are virtually diagnostic of SLE

23. SLE  Antibodies to rbc’s. wbc’s and platelets  Antiphospholipid antibodies in 40-50% of patients  False positive syphilis serology  Lupus anticoagulant or the antiphospholipid antibody syndrome

24. SLE  Genetic factors  25% concordance in monozygotic twins vs. 1 to 3% in dizygotic twins  Increased risk of developing disease in family members with 20% unaffected showing autoantibodies  Association of HLA-DQ locus and SLE  ~6% have deficiencies of complement

25. SLE  Non genetic factors  Drug induced lupus  Sex hormones  UV exposure  Immunologic factors  CD4+ T cell as effector cell  Mechanisms of tissue injury  Autoantibodies as mediator  Visceral injury by type III hypersensitivity  RBC, WBC, and platelet injury by type II hypersensitivity

26. SLE  LE bodies or hematoxylin bodies in tissue  LE cell in vitro

29. SLE  Morphology  Deposition of immune complexes  Acute necrotizing vasculitis  Chronic stages with fibrosis and luminal narrowing

30. SLE  Skin  Malar rash  Liquifactive degeneration of basal layer  Immune complexes and complement at dermal- epidermal junction  Joints involved frequently  Swelling with mononuclear cell infiltrate without destruction

31. Malar Rash

32. SLE

33. Discoid Lupus

34. Skin Biopsy in SLE

35. IF Pattern in Skin Biopsy in SLE Anti IgG deposition

36. SLE  CNS  Focal neurological deficit or neuropsychiatric symptoms  Intimal proliferation in small vessels due to antiphospholipid antibodies; anti-synaptic membrane protein antibodies have been found

37. SLE Fixed brain Fresh brain Demyelinated plaquesAcute vasculitis

38. SLE  Spleen  Onion skin lesions  Splenomegaly with follicular hyperplasia and plasma cells in red pulp  Serosal membranes  Pericardium and pleura  Serous effusions  Fibrinous exudates  Fibrous obliteration of space

39. SLE

40.  Heart  Pericarditis  Myocarditis  Libman-Sacks endocarditis  Coronary artery disease  hypertension

41. The Heart in SLE Libman Sachs endocarditis Accelerated atherosclerosis In SLE

42. The Kidney in SLE  Kidney  Renal failure is most common cause of death  Glomerulonephritis  Class I normal by LM, EM, IF (rare)  Class II mesangial lupus nephritis (20%)  Class III focal proliferative glomerulonephritis (25%)  Class IV diffuse proliferative glomerulonephritis (~50%) most serious  Class V membranous glomerulonephritis (15%)

43. Gross Appearance of Kidney in SLE

44. Renal Microscopic changes in SLE Class I Class III with wire loops (thin arrow) And hematoxylin body (thick arrow)

45. Renal Microscopic changes in SLE Focal Segmental GN with normal glomerulus (thin arrow), areas of necrosis in two (thick arrows) and global damage to glomerulus (double arrow) Focal segmental GN with necrotic tuft (thin arrow), epithelial crescent (thick arrow) and tuft adherent to Bowman’s capsule (double arrow)

46. Clinical Course in SLE  Clinical manifestations  Difficult to diagnose in many cases  Protean organ and system involvement  Course variable  Benign, indolent  Malignant, rapid  Remissions and relapses  Rx steroids/ immunosuppressive  90% 5 year survival  80% 10 year survival

47. Clinical Manifestations  Hematologic100% of patients  Arthritis90% of patients  Skin85% of patients  Fever83% of patients  Fatigue81% of patients  Weight Loss63% of patients  Renal50% of patients  CNS50% of patients  Pleuritis46% of patients  Myalgia33% of patients  Pericarditis25% of patients  Gastrointestinal21% of patients  Raynaud’s phenomenon20% of patients  Ocular15% of patients  Peripheral neuropathy14% of patients

48. Major Causes of Death in SLE  Renal failure  Intercurrent infections  Diffuse CNS involvement

49. Sjögren Syndrome  Dry eyes (keratoconjunctivitis sicca)  Dry mouth (xerostomia)  Immune mediated destruction of lacrimal and salivary glands (ductal epithelial cells are primary target)  Primary form – sicca syndrome  Secondary form – associated with other autoimmune disorder esp. RA, SLE polymyositis, systemic sclerosis, vasculitis or thyroiditis in about 60% of patients

50. Sjögren Syndrome  Autoantibodies to SS-A (Ro), SS-B (La) RNP ags  Association with systemic disease and high anti SS-A  RF present even in absence of RA  Initial polyclonal B cell proliferation  Genetic factors  Inheritance of certain MHC II molecules  Loss of tolerance of CD4+ T cells

51. Sjögren Syndrome  Morphology  Lacrimal, salivary and other secretory glands involved  Intense lymphocyte and plasma cell infiltrates with germinal center formation  Loss of normal architecture  Mucosal atrophy  Ulceration or perforation of nasal septum  Bronchitis, laryngitis, pneumonia

52. Sjögren Syndrome  ~ 25% have involvement of the CNS, skin, kidneys and muscle  Kidney involvement usually mild interstitial nephritis  Synovitis, pulmonary fibrosis, peripheral neuropathy

53. Sjögren Syndrome  40 fold increased risk of developing a non-Hodgkin B cell lymphoma marginal zone lymphoma (MALT)  90% of cases in women between 35 -45 years of age  Enlargement of salivary glands  Present with dry mouth and lack of tears

54. Figure 6-38 Sjogren syndrome. A, Enlargement of the salivary gland. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 17 February 2005 02:19 PM) © 2005 Elsevier

55. Figure 6-38 Sjogren syndrome. B. Intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia in a salivary gland. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 17 February 2005 02:19 PM) © 2005 Elsevier

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

57. Systemic Sclerosis  Scleroderma  Diffuse scleroderma  Symmetric widespread skin fibrosis, with rapid progression and early visceral involvement  Limited scleroderma  CREST syndrome  Calcinosis, Raynaud’s Esophageal dysmotility, Sclerodactyly, Telangiectasia  Overlap syndromes  Either diffuse or limited scleroderma with typical features of one or more other autoimmune disease like MCTD

58. Systemic Sclerosis

60.  Anti Nuclear Protein Antibodies  Scl – 70  Diffuse scleroderma (70%)  DNA topoisomerase 1  Centromere  Limited scleroderma (90%)

61. Systemic Sclerosis  Visceral involvement includes GI tract, lungs, kidneys, heart and skeletal muscle  Occurs most commonly in women in the third to fifth decades  3:1 female to male

62. Systemic Sclerosis  Interaction of CD4+ T cells, endothelial injury and fibroblast activation by IL-1, TNF, PDGF, TGF-β and fibroblast growth factors  B cell activation with ANAs and hypergammaglobulinemia  Microvascular disease present early on progressing to ischemic injury

63. Systemic Sclerosis  Skindiffuse sclerotic atrophy  Edema at first with ultimate claw like deformity  GI tract  90% of patients esp. esophagus → Barrett’s small bowel loss of villi and microvilli → malabsorption  Musculoskeletal system  Synovial hyperplasia and inflammation without deformity  10% get inflammatory myositis  Lungs  50% of patients pulmonary HTN and/or interstitial fibrosis  Kidneys  2/3 patients changes in interlobular arteries similar to those of malignant HTN. HTN occurs in 30% and 20% of those develop malignant HTN → renal failure and death  Heart  Patchy fibrosis and thickening of intramyocardial arteries in 1/3 “cardiac Raynaud”. Cor pulmonale and RV hypertrophy due to lung changes

64. Systemic Sclerosis SkinArtery

65. Systemic Sclerosis  Clinical course  Women 50 – 60 years of age  Nearly all develop Raynaud ‘s phenomenon  Hands atrophy and become immobile  Dysphagia from esophageal involvement  Malabsorption  Dyspnea and chronic cough  Pulmonary HTN with cor pulmonale  Renal failure may lead to malignant HTN

66. Systemic Sclerosis  Clinical course  Most progress slowly and steadily downhill over many years  Life span normal if no renal involvement  10 year survival is 35 – 70%  CREST has much better prognosis  Begins frequently with Raynaud’s phenomenon with face and hand involvement only for many years

67. Inflammatory Myopathies  Rare disorders with immune mediated muscle injury and inflammation which occur alone or with other disorder such as Systemic sclerosis  Polymyositis  Dermatomyositis  Women have increased risk of developing visceral cancers (lung, ovary, stomach)  Inclusion body myositis

68. Inflammatory Myopathies  Symmetric muscle weakness beginning in large muscles of trunk, neck and limbs with difficulty climbing stairs or rising from a chair  Histology lymphocytic infiltration and degenerating and regenerating muscle fibers; pattern distinctive for each subtype  Immunologic evidence of antibody mediated injury in dermatomyositis Immunologic evidence of T cell mediated injury in polymyositis and inclusion body myositis  Jo-1 antibodies (tRNA synthetase)  Diagnosis on clinical features, ↑ creatine kinase, EMG, and biopsy

69. Inflammatory myopathies Heliotrop discoloration Around eyes Lymphocytic infiltrate

70. Inclusion Body Myositis

71. Mixed Connective Tissue Disease  Patient has symptoms of autoimmune disease, and high titers of antibodies to RNP antigen UIRNP  Arthritis, Raynaud’s phenomenon, esophageal dysmotility, myositis, leukopenia and anemia, fever, lympadenopathy and/or hypergammaglobulinemia  Renal disease very rare  Respond well to corticosteroids  Long term prognosis is good

72. Mixed Connective Tissue Disease “flea bitten kidney” in MCTD

73. Thank You