Autoimmune disorders

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Autoimmune disorders

  1. 1. Autoimmunity Dr K V CHAKRADHAR ASSISTANT PROFESSOR, DEPARTMENT OF MICROBIOLOGY, NRIIMS.
  2. 2. What is Autoimmunity?  Activation of an immune response against self-tissue  Specific breakdown of mechanisms responsible for tolerance to self-antigens
  3. 3. History  Discovery and rediscovery of autoimmunity  Ehrlich (1901)- Horror autotoxicus  Julius Donath and Karl Landsteiner (1904) – PKH  Ernest Witebsky (1950)- Demonstrated the induction of autoimmunity in an animal model of chronic thyroiditis
  4. 4. Proposed mechanisms of immunity
  5. 5. Sequestered antigen Polyclonal B-cell activation Loss of suppressor cells Escape of auto reactive clones Proposed mechanisms for induction of immunity Cross reactive antigens Altered self antigens
  6. 6. Sequestered antigen  Late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.).  Accidental traumatic injury or surgery,  Initiation of an autoimmune disease.
  7. 7. Damage to immunologically privileged sites can lead to autoimmunity
  8. 8. Escape of auto-reactive clones  The negative selection in the thymus may not be fully functional to eliminate self reactive cells.  Not all self antigens may be represented in the thymus or certain antigens may not be properly processed and presented.
  9. 9. Lack of regulatory T cells  There are fewer regulatory T-cells in many autoimmune diseases.
  10. 10. Cross reactive antigens  Post streptococcal nephritis and carditis (Rheumatic fever)  Anticardiolipin antibodies during syphilis  Association spondylitis.  Molecular mimicry – homologous sequences are seen between Klebsiella and ankylosing  Arthritogenic Shigella flexneri and HLA-B27  Mycobacterium tuberculosis and  Joint membranes, Coxsackie B and myocardium.
  11. 11. Antigenic alteration  This is due to physical, chemical, biological influences. (Radiation, light, cold, drugs, viral infections)
  12. 12. Polyclonal B activation  Gram-negative bacteria- endotoxin (LPS) , Cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
  13. 13. Interplaying factors
  14. 14. Genetic Factors
  15. 15. Genetic predisposition for autoimmunity  Association between certain HLA types and autoimmune diseases has been noted (HLA: B8, B27, DR2, DR3, DR4, DR5 etc.).
  16. 16. Many autoimmune diseases are associated with certain HLA types and with gender
  17. 17. Environmental Factors
  18. 18. Diseases Pathogen Grave’s disease Yersinia enterocolitica Immune haemolytic anaemia Epstein-Barr virus, Mycoplasma pneumoniae Kawasaki disease Staphylococcus aureus, Streptococci, Yersinia pseudotuberculosis Henoch-Schoenlein purpura β-hemolytic Streptococcus Rheumatoid arthritis Mycobacterium tuberculosis Polyarteritis nodosa Hepatitis B and C viruses, Human Immunodeficiency virus Spondylarthropathies Enterobacteriacae,. Klebsiella spp. Reiter’s disease Enterobacteriacae, Chlamydia trachomatis Systemic lupus erythematosus Retroviruses Crohn’s disease Mycobacterium paratuberculosis Celiac disease Adenoviruses Psoriasis Retroviruses, Streptococci
  19. 19. Occupational and other exposures associated with autoimmune disease Exposure Disease Silica Systemic sclerosis, SLE, RA Solvents Systemic sclerosis, Multiple sclerosis, RA Pesticides RA UV radiation Multiple sclerosis, Dermatomyositis Cigarette smoking RA, Autoimmune thyroid disease
  20. 20. Gender predominance in autoimmune diseases
  21. 21. Types of Autoimmune diseases  Classified on the basis of: Organ specificity and Systemic diseases Based on pathogenic organisms Based on type of hypersensitivity reaction
  22. 22. Organ specific and Systemic autoimmune diseases
  23. 23. Disease Self-antigen Immune response ORGAN SPECIFIC AUTOIMMUNE DISEASE Addison’s disease Adrenal cells Auto-antibodies Autoimmune hemolytic RBC membrane proteins anaemia Auto-antibodies Goodpasture’s syndrome Renal and lung basement membranes Auto-antibodies Hashimoto’s thyroiditis Thyroid protein and cells TDTH cell auto-antibodies ITP Platelet membrane peoteins Auto-antibodies IDDM Pancreatic β-cells TDTH cell auto-antibodies Myasthenia gravis Acetylcholine receptor Auto-antibodies (blocking) Pernicious anaemia Gastric parietal cells, Intrinsic factor Auto-antibodies PSGN Kidney Ag-Ab complex Spontaneous infertility Sperm Auto-antibodies
  24. 24. Disease Self-antigen Immune response SYSTEMIC AUTOIMMUNE DISEASES Ankylosing spondylitis Vertebrae Immune complexes Multiple sclerosis Brain or white matter TH1 cell and Tc cells, auto-antibodies RA Connective tissue, IgG Auto-antibodies, Immune complexes Scleroderma Nuclei, heart, lungs, GI tract, Kidney Auto-antibodies Sjogren’s syndrome Salivary gland, liver, lacrimal gland, kidney Auto-antibodies SLE DNA, nuclear pattern, RBC and platelet membranes Auto-antibodies, Immune complexes
  25. 25. Based on pathogenic organisms
  26. 26. Disease Pathogen Host self-antigen Rheumatic fever Group A Streptococci Cardiac myosin Guillain –Barre syndrome Campylobacter jejuni Peripheral nerve ganglioside proteins Treatment-resistant Lyme arthritis Borrelia burgdorferi LFA-1 Myocarditis Group B Coxsackie virus Cardiac antigens Chagas’ disease Trypanosoma cruzi Cardiac myosin heavy chain Herpetic stromal keratitis Herpes simplex virus Corneal antigen and IgG2a Type 1 diabetes Group B Coxsackie virus Glutamate decarboxylase Myasthenia gravis Herpes simplex virus Acetylcholine receptor Multiple sclerosis Epstein Barr virus (EBV) Myelin basic protein
  27. 27. Diseases Pathogen Grave’s disease Y. enterocolitica Immune haemolytic anaemia Epstein-Barr virus, Mycoplasma pneumoniae Kawasaki disease Staphylococcus aureus, Streptococci, Yersinia pseudotuberculosis Henoch-Schoenlein purpura β-hemolytic Streptococcus Rheumatoid arthritis Mycobacterium tuberculosis Polyarteritis nodosa Hepatitis B and C viruses, Human Immunodeficiency virus Spondylarthropathies Enterobacteriacae,. Klebsiella spp. Reiter’s disease Enterobacteriacae, Chlamydia trachomatis Systemic lupus erythematosus Retroviruses Crohn’s disease Mycobacterium paratuberculosis Celiac disease Adenoviruses Psoriasis Retroviruses, Streptococci
  28. 28. Based on type of Hypersensitivity reaction
  29. 29.  Type II hypersensitivity reaction (antibodies to cell surface molecules) Disease Auto-antigen Outcome Autoimmune hemolytic anaemia Rh blood group antigens Lysis of RBC by complement and FcR+ cells→ Anaemia Autoimmune thrombocytopenic purpura Platelet integrin: GpIIb/IIIa Abnormal bleeding Goodpasture’s syndrome Basement membrane type IV collagen Glomerulonephritis, pulmonary haemorrhage Grave’s disease TSH receptor Thyroid overactivity Hashimoto’s thyroiditis Thyroglobulin, thyroid peroxidase Thyroid underactivity Hypoglycemia Insulin receptor (agonist) Low blood glucose
  30. 30. Disease Autoantigen Outcome Insulin resistant diabetes Insulin receptor (antagonist) High blood glucose, Ketoacidosis Myasthenia gravis A chain of nicotinic acetylcholine receptor Progressive weakness Pemphigus vulgaris Epidermal cadherin Skin blisters Pernicious anaemia Intrinsic factor, Gastric parietal cell Anaemia Rheumatic fever Streptococcal cell wall antigens, antibodies cross react with heart muscles Arthritis, myocarditis, heart valve scars Spontaneous infertility Sperm antigens Infertility
  31. 31. Graves’ disease (antithyroid stimulating hormone receptor {TSHR} antibodies)
  32. 32. Myasthenia gravis (anti-acetylcholine receptor antibodies)
  33. 33.  Type III: Immune complex disease Disease Autoantigen Outcome Ankylosing spondylitis Immune complexes Damage to vertebra Mixed essential cryoglobulinemia Rheumatoid factor, IgG complexes Arthritis SLE DNA, histones, ribosomes, smRNP, scRNP Glomerulonephritis, vasculitis, rash
  34. 34.  Type IV: T cell-mediated disease Disease Auto-antigen Outcome Multiple sclerosis Myelin oligodendrocyte glycoprotein Brain invasivion by CD4 cells, weakness Hashimoto’s thyroiditis Thyroid antigen Thyroid underactivity IDDM Pancreatic β-cell antigen Β-cell destruction RA Unknown synovial joint antigen Joint inflammation and destruction
  35. 35. Joint deformity in Rheumatoid arthritis
  36. 36. In insulin-dependent diabetes mellitus, cytotoxic T-cell kill the cells (cells that make insulin) Insulin is stained brown
  37. 37. Aetiopathogenesis  Mechanism preventing autoimmunity- “IMMUNOLOGICAL TOLERANCE”  Broadly divided into two groups: 1. Central tolerance 2. Peripheral tolerance  Anergy  Suppression by regulatory T cells  T-cell ignorance  Antigen sequestration
  38. 38. Laboratory diagnosis
  39. 39. Routine investigations asked for diagnosis for Autoimmune diseases:  Complete blood count  Peripheral smear  Synovial fluid analysis  RFT  LFT  Urine analysis  Radiological investigations- X-ray, Ultrasound, MRI, CT scan  Histopathological examination of affected
  40. 40. Laboratory diagnosis  Auto-antibodies Antinuclear antibodies (ANA) Antineutrophil Cytoplasmic Antibody (ANCA) Rheumatoid factor  Acute phase proteins  HLA typing  ASO titer
  41. 41. AUTO ANTIBODIES
  42. 42. Antinuclear antibodies  Initially discovered in the 1940s using the LE cell test  LE cell test: lacks sensitivity, specificity and predictive value  Nowadays used: Immunofluorescence anti-nuclear antibody test (IF-ANA) and EIA/ELISA  Flow cytometry and nanotechnology  Method of choice: Indirect immunofluorescence (IMF) using cultured Hep2 cells
  43. 43. Interpretation  ANA with titer, in combination with a full history and physical examination, extremely useful in the diagnosis and exclusion of connective tissue disease  Titer >1:640 should increase the suspicion  Titer <1:80 and no or few signs or symptoms of disease much smaller likelihood
  44. 44. ANA HOMOGENOUS – HEP2010
  45. 45. ANA NUCLOPLASM GRANULAR – HEP 2010
  46. 46. ANA CYTOPLASM GRANULAR;Jo 1 HEP 2010
  47. 47. ANA CYTOPLASM GRANULAR;GOLGI APPARATUS - HEP 2010
  48. 48. ANA NUCLEOLI POSITIVE – HEP 2010
  49. 49. ANA NUCLEAR DOTTED – HEP 2010
  50. 50. cANCA – ETHANOL FIXED GRANULOCYTES
  51. 51. pANCA – ETHANOL FIXED GRANULOCYTES
  52. 52. Autoimmune disease Sensitivity (%) Systemic lupus erythematosus 95-100 Scleroderma 60-80 Mixed connective tissue disease 100 Polymyositis/dermatomyositis 61 Rheumatoid arthritis 52 Rheumatoid vasculitis 30-50 Sjögren's syndrome 40-70 Drug-induced lupus 100 Discoid lupus 15 Pauciarticular juvenile chronic arthritis 71
  53. 53. Non-rheumatic disease Hashimoto's thyroiditis 46 Graves' disease 50 Autoimmune hepatitis 100 Primary autoimmune cholangitis 100 Primary pulmonary hypertension 40
  54. 54. Acute phase reactants
  55. 55. Acute phase proteins  Those proteins whose plasma concentration changes by at least 25% during inflammatory states  Occurs in association with infection, trauma, inflammatory arthritis, neoplasms.  Positive reactants/negative reactants  Most widely used – ESR, CRP
  56. 56. Conditions associated with increased CRP  Insignificant elevation (<1mg/dL)  Exercise, flu, pregnancy, gingivitis, CVA, seizures, angina  Moderate elevation (1-10mg/dL)  MI, malignancy, pancreatitis, mucosal infection, most rheumatic diseases  Marked elevation (>10mg/dL)  Acute Bacterial infection, major trauma, systemic vasculitis
  57. 57. Rheumatoid Factor  Antibodies directed against Fc portion of IgG  IgM RF usually measured  Detected by  Agglutination of IgG-sensitized sheep red cells  Bentonite or latex particles coated with human IgG  RIA  ELISA  Nephelometry
  58. 58. RF in rheumatic diseases  Rheumatoid arthritis: 26-90%  Sjögren's syndrome: 75-95%  Mixed connective tissue disease: 50-60%  Mixed cryoglobulinemia (types II and III): 40-100%  Systemic lupus erythematosus: 15-35%  Polymyositis/dermatomyositis: 5-10%
  59. 59. Rheumatoid factor titer  Higher the titer greater the likelihood of rheumatic disease  Prognostic value in RA
  60. 60. Treatment A) Symptomatic  Anti-inflammatory drugs: SLE, RA  Plasmapheresis: SLE, Guillain-Barre  Splenectomy : ITP  Anticholinesterase and thymectomy: Myasthenia gravis  Hormone replacement: Hashimoto thyroiditis, type I diabetes B) Immunosuppressive Agents:  Two Categories 1. Lympholytic: Ionizing radiation; Antiserums-Antilymphocyte serum, Antithymocyte serum, Anti-RhD 2. Lymphocytotoxic : Antimetabolites, Alkylating agents

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