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Autoimmunity and Susceptibility in Women


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Autoimmunity and Susceptibility in Women

  1. 1. AUTOIMMUNITY and Susceptibility of Women Priya Phadtare
  2. 2. Outline • History • Disease states • Causes • Mouse Models of human disease • Predisposition of women to autoimmune diseases
  3. 3. Immune Regulation T cells B cells
  4. 4. Self/Non-Self Discrimination Basically means immunity against self. A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
  5. 5. Autoimmunity Origins Horror autotoxicus: Literally, the horror of self-toxicity. A term coined by the German immunologist Paul Ehrlich (1854-1915)
  6. 6. History Continued 20th Century Perceptions: • 1960s: Elimination of all self-reactive lymphocytes. • 1970s: Not all self-reactive lymphocytes are eliminated.
  7. 7. Prevalence • Affects 7.6% to 9.4% of the human population. • Two third women. • More than 40 human diseases are autoimmune in origin. • Tendency of co-existence of autoimmune diseases. – MS-Rheumatoid Arthritis – Vitiligo- Autoimmune Thyroid Disease (40% Indians)- NALP1 gene malfunctioning.
  8. 8. Failure of tolerance and disease Outcome Disease Example APS-1 MS, Uveitis, Male infetility IDDM, Hashimoto’s IPEX ALPS RA, SLE, Crohn’s
  9. 9. Failure of Central Tolerance
  10. 10. Hashimoto’s Thyroiditis •Middle Aged Women. •Sensitized TH-1 for Thyroid Antigens. •Thyroid Gland infiltration by Lymphocytes, Macrophages and Plasma Cells. •Abs against thyroglobulin and thyroid peroxidase. •Hypothyroidism •Goitre.
  11. 11. Autoimmune Anemia • Pernicious Anemia –Auto-Abs against intestinal protein on parietal cells- hampers uptake of vit B12. • Autoimmune Hemolytic Anemia –Auto-Ab against RBC Antigens –Complement Lysis- Phagocytosis of RBC.
  12. 12. Goodpasture’s Syndrome Lungs of a patient with Goodpasture’s •Auto-Abs against basement membrane Ags. •Glomeruli and Alveoli affected. •Kidney Faliure and Pulmonary Hemorrhage. •IgG and C3b deposit on the basement membrane.
  13. 13. DiabetesCTL Infiltration Macrophage Activation Cytokines Released + Lytic Enzymes Auto-Abs also Present IDDM
  14. 14. Grave’s Disease •TSH (from pituitary gland) binds to receptors on thyroid cells •Hormones Thyroxine and Triiodothyroxine. •Auto-Abs agonists. Overstimulation of Gland.
  15. 15. Myasthenia Gravis • Progressive weakening of skeletal muscles. • Auto-Abs bind to acetylcholine receptors on the motor end of the muscle cells. • AcTh cannot bind. • Antibodies ultimately destroy the muscle cells. • Antibodies act as Antagonists.
  16. 16. Examples of Systemic Autoimmunity
  17. 17. Sytemic Lupus Erythromatosus • Women 20 to 40 years • F:M Ratio 10:1 • Prevalent in African-American and Hispanic women • Auto-Abs against RBCs & Platelets- Complement mediated lysis- hemolytic anemia and thrombocytopenia • Auto-Abs against nuclear antigens- complement system activation- damage to blood vessels- vasculitis and glomerulonephritis • Neutropenia: Expression of a type 3 complement receptor (CR3) on neutrophils.
  18. 18. Multiple Sclerosis T Lymphocytes enter cerebrospinal fluid. Certain viruses pre-dispose a person for developing MS.
  19. 19. • Chronic Inflammation of Joints. • Auto-Abs or Rheumatoid Factors react with determinants in the Fc region of IgG. • Classsic Rheumatoid Factor: IgG Antibody. • IgM-IgG complexes deposit into the joints. • Triggers Type-III Hypersensitivity Reaction. Rheumatoid Arthritis
  20. 20. Causes of Autoimmunity
  21. 21. Mechanisms of autoimmunity • MHC Polymorphism • Release of Sequestered Antigens • Molecular mimicry • Failure of Central Tolerance • Toxins
  22. 22. Autoimmunity Associated with MHC 1. Ankylosing Spondylitis: Inflammatory disease of vertebral joints. – HLA-B27 allele of HLA-B gene present. – 90% of the cases are males. 1. IDDM: Pancreatic beta cells express high levels of class I and class II MHC. 2. Grave’s Disease: Thyroid Acinar Cells express high levels of class II MHC. – Sensitization of TH1 against cell Ags. CTLs get activated. 1. Phytohemaglutinin (PHA): Induces thyroid cells to express class II MHC.
  23. 23. 4. INF-Gama: • Increases the class II MHC molecules on: – Pancreatic Beta Cells – Intestinal Epithelial Cells – Thyroid Acinar Cells • Trauma or Viral Infection can induce an increase in INF production. (Improper T- helper cell activation) • High INF Titre found in SLE patients. • Induces production of IL-1 and TNF.
  24. 24. Release of Sequestered Self-Antigens Trauma or Bacterial Infection Self-Antigens come into circulation Interact with T cells which have escaped negative selection in thymus Auto-Abs produced; autoimmune response
  25. 25. Examples • Vasectomy: Sperm Ag released into circulation • Eye Damage: Lens Protein released into the circulation • Myocardial Infarction: Heart Muscle Antigens released into blood stream. • Myelin Basic Protein released from the Blood Brain Barrier into the circulation.
  26. 26. Damage to immunologically privileged sites can lead to autoimmunity
  27. 27. Molecular Mimcry • Virus and Bacteria possess Ag peptides similar to host cell components. (Michael Oldstone) • More that 3% virus specific Abs also bound to normal tissue of the host. • May affect migrant populations. • Ex 1: Post-rabies encephalitis: – Rabies vaccination developed by growing rabies virus in rabbit brain cells. – Ab production against rabbit brain cells which cross-react with host brain cells.
  28. 28. • Ex 2: Rheumatic Fever: Streptococcus infection
  29. 29. • Ex 3: Encephalitogenic MBP – Amino Acid residues from 61 to 69 are homologous to P3 peptide of the measles virus. – Amino Acid residues 66-67 homologous to Influenza Virus, Adenovirus, Epstein-Barr Virus, Hep-B etc (60% homology).
  30. 30. Polyclonal B-Cell Activation • Virus and Bacteria also cause non-specific polyclonal B Cell Activation. • Activators: Gram Negative Bacteria, EBV, Cytomegalovirus. • B Cells reactive to self antigens activated Auto-Abs. • Ex 1: Mononucleosis: EBV • Ex 2: SLE: Large quantity of IgM in serum. • Ex 3: AIDS: Auto-Abs to RBCs and Platelets as patients are usually co-infected with EBV and Cytomegalovirus.
  31. 31. Toxins Toxic Oil Syndrome Occurred in Spain in 1981 after people ate contaminated olive oil. lung disease and excessive IgE. • Smoking can trigger Goodpasture’s syndrome Alveolar basement membrane normally not exposed to immune system. Smoking damages alveoli, exposes collagen Anti-collagen Ab damages lung and kidney.
  32. 32. Mouse Models Human Disease Mouse Model Diabetes Non Obese Diabetic (NOD) Lupus MRLlpr (Lpr = lupus prone) Fas Gene New Zealand Black •Hemolytic Anemia (2 to 4 months) •Glomerulonephritis (18 months)
  33. 33. Hormones • Females mount a more robust immune response than the males. • TH1 pro-inflammatory response was seen to be higher. • Estrogen is immunostimulatory- pro-inflammatory. • Prolactin receptors present on B and T Cells. • Endometriosis and preeclampsia are both thought to be autoimmune in nature Hypothesis: estrogen response elements (EREs) in several genes
  34. 34. Estrogens and Autoimmunity
  35. 35. Nature Immunology  2, 777 - 780 (2001) Sex differences in autoimmunity