Autoimmunity

Aka: Autoimmunity, Autoimmune Condition, Autoimmune Disease, Self-Tolerance, Central Tolerance to Self Antigen, Peripheral Tolerance to Self Antigen, Regulatory T-Cell, Autoreactive Lymphocyte, Tolerance Induction to Self Antigen, Autosensitivity

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II. Epidemiology

  1. Women account for 75% of Autoimmunity
  2. Age of onset is most common in young adult women

III. Physiology: Self-Tolerance

  1. Background
    1. Self-Tolerance prevents immune response to self-Antigens (body fighting itself)
  2. Central Tolerance (eliminate autoreactive cells that attack self)
    1. T-Cells (Thymus)
      1. Autoreactive T-Cells are eliminated (apoptosis) before release into peripheral circulation (negative selection)
      2. Lower affinity autoreactive T-Cells are released into circulation as Regulatory T Cells for peripheral tolerance
    2. B-Cells (Bone Marrow)
      1. Autoreactive B-Cells are eliminated (apoptosis) before release into peripheral circulation (negative selection) OR
      2. Receptor Editing allows B Cells to redefine Ig Light chain, and therefore no longer self-reactive
  3. Peripheral Tolerance (immunologically deactive autoreactive cells)
    1. T-Cells
      1. Deletion: Autoreactive cells are killed (apoptosis)
      2. Anergy: Autoreactive T-Cells become inactive, unresponsive to Antigen stimulation
      3. Suppression: Regulatory T-Cells inhibit autoreactive T-Cells, preventing self-Antigen reaction
    2. B-Cells
      1. T-Helper Cells are typically absent for self-Antigen, and the autoreactive B-Cells remain inactive or die

IV. Risk Factors

  1. Genetic Predisposition to Autoimmunity
    1. Major Histocompatibility Complex (MHC) Defects - Human Leukocyte Antigen (HLA) I and II specific allotypes
      1. Example: Type 1 Diabetes Mellitus is associated with DR3 and DR4 HLA types
    2. Non-MHC Genetic Defects
      1. Example: Autoimmune Lymphoproliferative Syndrome is associated with Fas Gene Mutation
  2. Environmental Predisposition to Autoimmunity
    1. Infectious Disease (e.g. Coxsackie Virus B and Type 1 Diabetes Mellitus)

V. Mechanism

  1. Mediators of Autoimmunity
    1. T-Cell mediated self tissue destruction
      1. Autoreactive CD4+ T Cells (with or without CD8+ T Cells)
    2. Autoantibody
      1. IgG Antibody produced in autoreactive B Cells and facilitated by autoreactive Autoreactive CD4+ T Cells
  2. Mechanisms
    1. Molecular mimicry
      1. Microbes (Strep. pyogenes) presents Antigen similar to human organ Antigens (e.g. Heart Valves)
      2. T-Cells and B-Cells respond to microbe Antigens, but also respond to other host tissue Antigens
    2. Polyclonal Lymphocyte activation
      1. Polyclonal activators (e.g. EBV, CMV) non-specifically activate B-Cells including autoreactive cells
      2. Other polyclonal activators (e.g. lectin plant Protein including PHA) activate T Cells
    3. Sequestered Antigen Release
      1. Non-exposed tissue Antigens (e.g. behind blood-brain barrier) may be exposed with injury (e.g. Head Injury)
    4. Antigen Spreading
      1. Initial auoreactive B-Cells and T-Cells respond to a single host tissue Antigen
      2. With injury and inflammation, additional host Antigens are exposed and become targets of Autoimmunity
  3. Predisposing factors
    1. Autoimmunity increases with age: lower self tolerance
    2. Genetic predisposition
  4. Protective factors
    1. Autoimmunity less common where high Antigen exposure
    2. Protective exposures in first year of life
      1. Eating dirt
      2. Living on a farm
      3. House pet
      4. Day care
    3. References
      1. Weiss (2002) N Engl J Med 347:930 [PubMed]

VI. Associated Conditions: Dermatologic Autoimmune Conditions

  1. Psoriasis
  2. Dermatitis herpeteformis
  3. Pemphigus Vulgaris
  4. Vitiligo
  5. Alopecia Areata

VII. Associated Conditions: Endocrine Autoimmune Conditions

  1. Insulin Dependent Diabetes Mellitus
    1. Autoantibody to Pancreatic Beta Cell Antigens
  2. Grave's Disease
    1. Autoantibody: TSH Receptor Antibody (Thyroid Stimulating Immunoglobulin)
  3. Hashimoto's Thyroiditis
    1. Autoantibody: Antithyroid Peroxidase Antibody (TPO Antibody) and Antithyroglobulin Antibody (TgAb)
    2. Thyroid tissue infiltration and destruction by B-Cells and CD4+ T Cells
  4. Addison's Disease
    1. Autoantibody to Adrenal cytoplasmic P450 Antigens

VIII. Associated Conditions: Gastrointestinal Autoimmune Conditions

  1. Crohn's Disease
  2. Ulcerative Colitis
  3. Primary Biliary Cirrhosis
    1. Autoantibody to Centromere
  4. Autoimmune Hepatitis
    1. Autoantibody to hepatocyte Antigens

IX. Associated Conditions: Hematologic Autoimmune Conditions

  1. Autoimmune Hemolytic Anemia
  2. Autoimmune Thrombocytopenia
  3. Pernicious Anemia
    1. Autoantibody to Gastrointestinal Intrinsic Factor and parietal cells

X. Associated Conditions: Musculoskeletal Autoimmune Conditions

  1. Ankylosing Spondylitis
  2. Systemic Lupus Erythematosus
    1. Autoantibody to nuclear and ribosomal Antigens (dsDNA, SS-A or Ro, SS-B or La, Smith, DNA-Histone)
  3. Drug-induced Lupus
    1. Autoantibody to nuclear Antigens (dsDNA, DNA-Histone)
  4. Rheumatoid Arthritis
    1. Predisposition in patients with HLA-DR4 haplotypes (MHC Class 2)
    2. Autoantibody to nuclear Antigens (rheumatoid-associated nuclear Antigen, Ribonucleoprotein, DNA-Histone)
    3. Autoantibodies to IgG as well as IgM and IgA (Rheumatoid Factors)
      1. Autoantibody binding to Fc region of IgG results in Complement Activation and host tissue destruction
  5. Scleroderma (Systemic Sclerosis, also part of CREST Syndrome)
    1. Autoantibody to nucleolar Antigens (nucleolar-specific RNA, centromere, Ribonucleoprotein, Scl-70/Topisomerase)
  6. Polymyositis
    1. Autoantibody to nuclear Antigens (PM-Scl, Jo-1, Ribonucleoprotein)
  7. Dermatomyositis
    1. Autoantibody to nuclear Antigens (Jo-1, Mi-2)
  8. Sjogren's Syndrome
    1. Autoantibody to nuclear Antigens and cytoplasmic Antigens

XI. Associated Conditions: Neurologic Autoimmune Conditions

  1. Guillain-Barre Syndrome
  2. Multiple Sclerosis
    1. Autoantibody to brain and spinal cord myelin Proteins
  3. Myasthenia Gravis
    1. Autoantibody to Acetylcholine receptor on Muscle Cells

XII. Associated Conditions: Vascular Autoimmune Conditions

  1. Temporal Arteritis
  2. Anti-phospholipid Syndrome
  3. Granulomatosis with Polyangiitis (previously known as Wegener's Granulomatosis)
  4. Behcet's Syndrome
  5. Rheumatic Fever
    1. Autoantibody to myocardial and valvular Antigens (cross reactive to Group A Streptococcal Antigens)

XIII. Associated Conditions: Miscellaneous

  1. Goodpasture Syndrome
    1. Autoantibody to Renal and Lung Type IV Collagen

XIV. References

  1. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL, p. 32-40
  2. Zuber (2003) AAFP Board Review, Seattle

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