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Autoimmunity I

Autoimmunity I. Matt McReynolds. Definition Direct proof Indirect evidence Circumstantial Diseases Antibody-mediated Immunecomplex-mediated T cell-mediated Models. Outline. Autoimmunity. “Friendly-fire”: Immune response to self Autoimmune disease:

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Autoimmunity I

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  1. Autoimmunity I Matt McReynolds

  2. Definition Direct proof Indirect evidence Circumstantial Diseases Antibody-mediated Immunecomplex-mediated T cell-mediated Models Outline

  3. Autoimmunity • “Friendly-fire”: Immune response to self • Autoimmune disease: When the immunological recognition of self with the involvement of antibody, complement, immune complexes, and cell-mediated immunity progresses from being benign to pathologic.

  4. Autoimmunity • Autoimmune responses occur all the time with little to no consequence. • Theory of “autoimmune diseases” was only recently accepted in the 1950’s and 60’s.

  5. Autoimmunity • Prevalence of autoimmune diseases in Western countries has been estimated at 3 - 7% (Marmont, AM. 2000 Ann Rev Med 51:115-134) • Organ specific or non-specific • Humoral or Cell-mediated

  6. Defining a disease as autoimmune • Direct Proof – requires transmissibility • Antibody or lymphocyte transfer • Animal models • Humans to animals (pemphigus vulgaris and bullous pemphigoid) • Humans • Mother to fetus (eg. myasthenia gravis) • T cell transfer not feasible – MHC • Diseases: Idiopathic thrombocytopenic purpura, Graves' disease

  7. Defining a disease as autoimmune • Indirect Proof • Identify target Ag in humans • Reproduce model disease with homologous Ag in animal • AChR  EAMG, collagen I  EAA, myosin  EAM, myelin  EAE • Majority of autoimmune diseases

  8. Defining a disease as autoimmune • Indirect Proof • Identify target Ag in humans • Reproduce model disease with homologous Ag in animal • AChR  EAMG, collagen I  EAA, myosin  EAM, myelin  EAE • Study genetically predisposed animal models • (NZB x NZW)F1 mice  model of SLE

  9. Defining a disease as autoimmune • Indirect Proof • Identify target Ag in humans • Study genetically predisposed animal models • Isolate self-reactive Ab or T cells from target organs • Anti-erythrocyte Abs – hemolytic anemia • Anti-DNA Abs – SLE

  10. Defining a disease as autoimmune • Circumstantial evidence - "markers" descriptive of autoimmune disease • Familial tendency • Lymphocyte infiltration • Specific MHC II allele association • Immune complex deposition • Clinical improvement with immunosuppressive agents

  11. Diseases • Antibody Mediated • Immune-complex mediated • T-cell mediated

  12. Diseases • Antibody Mediated - produced either by antibodies binding to antigens on cells or tissue or by Ag-Ab complex deposition in vessel walls. • Autoimmune Hemolytic Anemia • Myasthenia Gravis • Graves’ Disease • Rheumatic Fever • Immune-complex mediated • T-cell mediated

  13. Autoimmune Hemolytic Anemia • Self Ag: red blood cells (RBC’s) • Can be associated with systemic lupus erythematosus • Mechanisms of Ab-mediated destruction • Opsonization and digestion by macrophage • Complement cascade and lysis of RBC • Also the principal mechanism for thrombocytopenic purpura

  14. Autoimmune Hemolytic Anemia • Antibody/agglutinins groups • Warm: react at 37C, Rh antigen • IgG  phagocytosis • Cold: react <37C, I or i antigens • IgM  complement and lysis • Occurs in limbs or skin upon temperature drop • Induced • Penicillin (hapten), Methyldopa (warm), Mycoplasma pneumoniae or viruses (cold)

  15. Myasthenia Gravis (MG) • Self Ag: Acetylcholine Receptor (AChR) at the neuromuscular junction • Women in late 20s / Men in their 50’s • Prevalence in the US is estimated at 14/100,000 population, approximately 36,000 cases • Thymus: hypertrophy, 10% have thymoma • HLA class II • Blood test, Acetylcholinesterase (AChE) inhibitor (edrophonium) used for diagnosis

  16. MG • Changes in motor endplate: • Abs bind complement • Inflammatory cell response • Destruction of endplate and AChR • Abs block cation channels of the receptor and prevent propagation of action potentials

  17. MG

  18. MG • Seronegative or positive for antiAChR Abs • 95% pos in generalized disease • 60% pos in localized (occular) disease • Seropositivity is not associated with disease severity, but Ab titers decrease with immunosuppression

  19. Occular MG • Functional Hypothesis: slight weakness in ocular and eye-lid muscles is far less tolerable than generalized weakness. • Immunologic Hypothesis: Difference in Ab’s associated with ocular muscle. • Physiological Hypothesis: Ocular muscles are predisposed to MG because of their size,innervation and activity.

  20. Occular MG Symptoms: • Inability to align eyes • Droopy eye-lids

  21. MG • Muscle weakness improves with rest • Chewing, swallowing (dysphagia), breathing (dyspnea), speaking (dysarthria) • Ptosis (droopy eye lids), diplopia (2x vision) • Inner ear: hyperacusis (acute hearing due to heightened irritability of nerve pathway) • Neck flexor muscles, limb

  22. Pourmand R. 1997.

  23. Graves’ Disease • Self Ag: Thyroid-stimulating Hormone Receptor (TSHR) • Hyperthyroidism • TSH receptor is activated independent of the pituitary • Familial, HLA II, Ab titer:Disease severity, neonatal hyperthyroidism from maternal IgG

  24. Normal

  25. Normal Graves’ Disease

  26. Graves’ Diagnosis • Blood test: • T3 and T4 are markedly elevated • TSH levels are low or absent. • Serum Ab detection • Goiter

  27. Graves’ Symptoms • Cardiac – arrhythmias (a-fib), tachycardias, widened pulse pressure • Endocrine – weight loss, increased basal metabolic rate • Dermatological – profuse sweating, clubbing of fingernails • Neurological – tremor, weakness, proximal myopathy • Ophthalmological – thyroid eye disease, proptosis.

  28. Proptosis

  29. Rheumatic Fever • Self Ag: Cardiac proteins • Follows pharyngeal infection with group A streptococci • Arthritis, carditis, chorea, s.c. nodules • Chronic, progressive valve damage • Major cause of acquired heart disease in many lesser developed countries • Molecular mimicry

  30. Diseases • Antibody Mediated • Immune-complex mediated • Systemic Lupus Erythematosus (SLE) • T-cell mediated

  31. SLE • Self Ags: ssDNA, dsDNA, nucleohistones • Causes: • Genetic predisposition • Environmental causes • Drug interactions • Response to nuclear proteins • Normal: IgM; SLE: IgG • Cellular Ags exposed during apoptosis incite an immune response • Increased Fas expression in B & T cells • Sunlight (keratinocytes)

  32. SLE Incidence • 1 / 1,000 white persons • 1 / 250 black women • Concordance: • 25% monozygotic twins • 1-2% dizygotic twins

  33. SLE Complications • Musculoskeletal: osteoporosis, joint pain • Dermatologic : malar rash, photosensitivity • CNS : psychosis, seizures • Hematological: anemia • Renal failure (complex deposition) • CV: antiphospholipid Abs  hypercoagulability • Lupus anticoagulant, anticardiolipin Ab • Thrombosis, thrombocytopenia, pregnancy loss

  34. Diseases • Antibody Mediated • Immune-complex mediated • T cell-mediated • Multiple Sclerosis • Insulin-Dependent Diabetes Mellitus • Rheumatoid Arthritis

  35. MS • Self Ag: Myelin sheath • Demyelinating plaques • Optic nerve, periventricular and spinal cord white matter, brain stem, cerebellum • Symptoms: • changes in sensation in the arms, legs or face (33%), complete or partial vision loss (optic neuritis) (16%), weakness (13%), double vision (7%), unsteadiness when walking (5%), and balance problems (3%)

  36. MS • Diagnosis • Clinical presentation • Cerebrospinal Fluid (CSF) abnormalities • Evoked potentials (visual, somatosensory) • Neurological dysfunction becomes “disseminated in space and time” • Magnetic Resonance Imaging (MRI)

  37. An axial FLAIR (fluid-attenuated inversion recovery) image shows multiple ovoid and confluent hyperintense lesions in the periventricular white matter (Panel A). Nine months later, the number and size of the lesions have substantially increased (Panel B). Noseworthy, et al. NEJM 2000. After the administration of gadolinium, many of the lesions demonstrate enhancement, indicating the breakdown of the BBB (Panel C). In Panel D, a parasagittal T1-weighted MRI scan shows "black holes" in the periventricular white matter and corpus callosum (chronic lesions).

  38. MS • Relapsing-remitting (80%) • characterized by unpredictable attacks (relapses) followed by periods of months to years of relative quiet (remission) with no new signs of disease activity • Chronic Progressive (20%) • Primary, secondary progressive • Quadriparesis; cognitive decline; visual loss; cerebellar, bowel, bladder, and sexual dysfunction

  39. Insulin-Dependent Diabetes Mellitus (IDDM) • Self Ag: insulin-secreting -islet cells of pancreas • Type I, Juvenile-onset • HLA DR3 and DR4 • Abs, T cells, adhesion molecules,  serum cytokine inhibitors, sustained expression of cytokines and Rs • TNF-, IFN-, IL-1

  40. IDDM • Symptoms: •  insulin  abnormalities in glucose metabolism  ketoacidosis, thirst, polyuria, vision disturbances • Late stages: progressive atherosclerotic vascular lesions  arterial obstruction, renal failure, blindness

  41. Rheumatoid Arthritis (RA) • Self Ag: cartilage • HLA DR4, TNF genes, HSP gene complex, infection (EBV) • Varied age (common in 20’s-40’s) • Women:Men 3:1

  42. RA •  synovial fluid with PMNs  Cartilage replaced with fibrous tissue  joint fusion • Diagnosis: • >80%: Rheumatoid Factor (RF) • IgM anti-IgG Fc • Immune involvement: • Ag-Ab complex, C’, PMNs, CD4+, CD8+, MØ, NK cells, TNF-, IL-1

  43. RA

  44. Autoimmune Models • Immunization • Self antigen • Spontaneous • Genetically susceptible strains • Induced • Virally, chemically, pharmacologically

  45. Immunization Models • Adjuvant = any substance that enhances the immune response to an antigen with which it is mixed • Does not form stable linkages w/ immunogen • Mechanisms • Convert soluble protein Ags into particulate material  ingested by MØ • Bacterial products signal MØ or DC •  cytokines

  46. Experimental Autoimmune/Allergic Encephalomyelitis (EAE) • Model of RR or chronic progressive MS • Various mouse strains • Intradermal immunization with myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) • Ascending paralyses of hind limbs, infiltration, demyelination

  47. EAE

  48. EAE • Synthetic peptides • MBP 1-9: acute, no relapses • single TCR • PLP 43-64, MBP 89-101: chronic-relapsing • epitope spreading, large TCR repertoire

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