Autoimmune diseases
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AUTOIMMUNE DISEASES

AUTOIMMUNE DISEASES

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Autoimmune diseases Presentation Transcript

  • 1. AUTOIMMUNE DISEASES Elamurugan. A 1559, VIM PhD Scholar
  • 2. Points to be discussed… • What is autoimmunity ? • Mechanisms of autoimmunity • Animal models • Organ specific diseases • Systemic disease • Diagnosis • Therapy
  • 3. Introduction • Paul Ehrlich – ‘Horror Autotoxicus’ • Adaptive immunity double edged sword • Recently role of innate immunity reported • Failure of self-tolerance in T & B cells • Beneficial autoimmunity!!! (Band 3 of RBC) • Environmental • Familial association
  • 4. AUTOIMMUNITY Normal IR Hidden antigens Tissue alterations Molecular alteration Newly synthesized antigens Molecular mimicry Abnormal IR Failure of regulatory control Micriochimerism Failure of Apoptosis Lymphoid tumors Self-reactive T cells Virus infections Genetic predisposition Hormonal influences
  • 5. Hidden antigens • Hidden antigens – Myelin basic protein – autoimmune encephalitis – Injury to testis – Chronic hepatitis – TB, Trypanosomiasis • Molecular changes – Rheumatoid factor (RF) - Ab to Fc part of IgG – Immunoconglutinins (IK) – C2, C4, C3
  • 6. Molecular mimicry Hit-and-run process  • Tryp. cruzi – cardiac muscle • M protein of Strep. – cardiac myosin • EBV DNA polymerase – MBP  Multiple sclerosis • Polio virus VP2 – Ach  Myasthenia gravis • Omp of Borrelia – LFA-1  Lyme disease • Microbial HSP  RA, SLE • Mycoplasma hyopneumoniae – pig lungs  enzootic pneumonia • Leptospira interrogans  Perioidic ophthalmia • Klebsiella – HLA B27  Ankylosing spondylitis
  • 7. • Epitope spreading – normal IR to exogenous antigen that subsequently spreads to recognize self antigens – Thyrotoxicosis, Diabetes • Receptor editing • MHC expression – High levels of MHC I, II - Pancratic β cells  IDDM – Thyroid acinar cells – MHC II  Grave’s disease – PHA  MHC II – IFN γ  MHC II  SLE
  • 8. • Virus induced – Due to molecular mimicry & bystander activation – Reovirus  polyendocrine disease – Type C retrovirus  auto-Ab to nucleic acids, RBC • Microchimerism – Exchange of cells between mother and foetus – Women  Scleroderma – Boys  Dermatomyositis
  • 9. Failure of regulatory control • Autoimmune proliferative syndrome/ ALPS – Mutation in Fas (lpr/lpr mice) • APECED – Mendelian inheritance – Defect in gene encoding AIRE, expressed in thymus, pancreas, adrenal cortex – Expression of peripheral tissue self antigen on thymic medullary epithelial cells – Central tolerance • IPEX, Scurfy mice – Mutation in Foxp3 gene leads to defects in formation of CD4+/CD25+ T reg cells
  • 10. Animal models • Non-obese diabetic (NOD) mouse - IDDM • (NZB NZW)F1 mouse - SLE • Obese strain chicken (OS) – Hashimoto’s Thyroiditis • Bio breeding rats (BB rat) - Spontaneous autoimmune type I diabetes • New Zealand Black mouse – Spontaneous autoimmune haemolytic anemia
  • 11. Role of immune cells and its products • Animal models implicated the role of CD4+ • TH1/TH2 balance • TH1 cells and cytokines promotes (IL 2, TNF α, IFN γ) • TH2 cells and cytokines inhibits (IL 4)
  • 12. Based on Immunopathology TYPE I HS TYPE II HS TYPE III HS TYPE IV HS Milk allergy Autoimmune hemolytic anemia SLE IDDM Autoimmune thrombocytopen ic purpura Rheumatoid arthritis Rheumatoid arthritis Goodpasture’s syndrome Pemphigus vulgaris Acute rheumatic fever
  • 13. Organ specific diseases Disease Self antigen Immune response Addison’s diseases Adrenal cells Auto-Ab Autoimmune haemolytic anemia RBC membrane proteins Auto-Ab Goodpasture’s disease Renal & lung basement mem Auto-Ab Grave’s disease TSH receptor Auto-Ab (Stimulating) Myasthenia gravis Ach receptor Auto-Ab (Blocking) Idiopathic thrombocytopenia purpura Platelet mem proteins Auto-Ab Pernicious anemia Gastric parietal cells, intrinsic factor Autoantibodies IDDM Pancreatic beta cells TH1 cells, auto Ab Hashimoto’s thyroiditis Thyroid proteins and cells TH1 cells, auto Ab
  • 14. • Grave’s disease – Stimulatory auto Ab binds to TSH receptor • Myasthenis gravis – Inhibitory auto Ab binds to Ach receptor blocks Ach binds, later lysis of cells – Weakening of muscle – Tensilon Test •anticholinesterase agent edrophonium chloride regaining of muscle strength but not long time electromyography repetitive nerve stimulation progressive decline in the muscle action
  • 15. LATS
  • 16. Autoimmune anemia • Pernicious anemia – Auto-Ab to intrinsic factor in gastric parietal cells  blocks Vit B12 absorption • Autoimmune hemolytic anemia – Coombs test - RBC incubated with anti-human IgG antiserum if auto-Ab present on RBCs, cells agglutinate • Drug induced – Penicillin, Methyl dopa binds to RBC make them antigenic
  • 17. Autoimmune hemolytic anemia Class Antibody Activity Optimal temp (°C) Site of RBC removal Clinical effect I G>>M Agglutinin 37 Spleen I/V agglutination II M Hemolysin 37 Liver I/V hemolysis III G Incomplete 37 Spleen Anemia IV M Agglutinin 4 Liver Cyanosis of extremities V M Incomplete 4 liver anemia
  • 18. • Goodpasture’s syndrome – Auto-Ab to basement of kidney glomeruli, alveoli – Activation of C’ – Accumulation of C’ split products C3a, C5a attract neutrophils aggravate the condition • IDDM (Type I DM) – Destruction of pancreatic beta cells – Auto-Ab to enzyme glutamic acid decarboxylase – CTL attack  insulinitis – Activation of MΦ release of cytokines TNF-α, IFN-γ, IL1 along with auto-Ab cause DTH
  • 19. • Autoimmune thrombocytopenia – Auto-Ab to platelets – Multiple petechiae • Hashimoto’s Thyroiditis – Auto-Ab & TH1  DTH – Destruction of thyroid peroxidase, thyroglobulin involved in I2 uptake – Hypothyroidism
  • 20. Pemphigus complex • Pemphigus vulgaris – most severe – Bullae at muco-cutaneous junctions – Auto-Ab to desmoglein 3 • Pemphigus foliaceous – Auto-Ab to desmoglein 1 • Pemphigus vegetans • Pemphigus erythematosus • Bullous pemphigoid – Tense bullae under subepidermal region
  • 21. Systemic diseases Disease Self antigen Immune response Scleroderma Nuclei, heart, lungs, GIT, kidney Auto-Ab Sjogren’s syndrome Salivary gland, liver, kidney, thyroid Auto-Ab Rheumatoid arthritis Connective tissue, IgG Auto-Ab, Immune complex SLE DNA, nuclear protein, RBC, platelet mem Auto-Ab, Immune complex Ankylosing spondylitis Vertebrae Immune complex Multiple sclerosis Brain or white matter TH1 cells, TC cells, Auto-Ab
  • 22. Systemic lupus erythematous • Auto-antibodies – Specific  RBC, platelets, leukocytes – Nonspecific  nuclear antigens, cytoplasmic antigens – Discoid lupus erythematous – dog, cat, horse, human only facial skin involvement no other organs • Diagnosis – ANA to DNA, histones in serum indirect immunofluoresence assay – LE cell test phagocyte with opsonized nuclei – Lupus band test – direct immunofluoresence test of skin deposition of Ig at the dermo-epidermal junction
  • 23. Rheumatoid arthritis • Rheumatoid factor IgM reactive with Fc region of IgG • This IgM-IgG complex deposit on joints activates C’ leads to type III HS • Diagnosis – Agglutination test isologous IgG on latex beads with Fc part exposed binds with RF cause agglutination – Rose Waaler test – sheep RBC coated with canine anti-sheep RBC IgG – Mucin clot test – synovial fluid has mucin which is absent in RA so formation of non-friable clot upon addition of glacial acetic acid
  • 24. • Multiple sclerosis – Autoreactive T cells to myelin sheath – EBV DNA polymerase molecular mimicry • Sjogren’s syndrome – Triad of keratoconjunctivitis, xerostomia and rheumatoid factor – Conjunctival dryness, mouth dryness – Often associated with RA
  • 25. Treatment • Immunosuppressive drugs - – Corticostreoids, Cyclophosphamide, Cyclosporin, FK506 • Thymectomy – Myasthenia gravis • Plasmapheresis - Immune complex mediated diseases • Anti-CD4 antibodies • Blockers of TNF-α – Enbrel, Remicade, Humira • IL-1 receptor antagonists
  • 26. • Statins - decrease CRP  RA • mAb Rituxan – kills B cells thr. CD20  B cell non-Hodgkin’s lymphoma • Monoclonal antibodies to activated T cells • Anti- CD 25 antibodies (α subunit of IL 2) • mAb to appropriate MHC • Oral antigens induce tolerance