Hypersensitivities & Autoimmune Diseases

Page 1

Physiology and Pharmacology Overview of Hypersensitivities and Autoimmune Diseases.

Page 2: Learning Objectives

• Etiology and Pathogenesis: Explain the etiology and pathogenesis of the four major classes of hypersensitivities.

• Pathological Changes: Explain the pathological changes associated with the representative diseases resulting from the four major classes of hypersensitivities.

• Chronic Inflammation: Explain how chronic inflammation contributes to tissue damage.

Page 3: Hypersensitivity Reactions

Hypersensitivity reactions involve pathological immune responses caused by:

• Autoimmunity: Reactions against self antigens.

• Allergens: Reactions against non-infectious antigens.

• Microbial Antigens: Reactions against microbial antigens resulting in an immune response that produces:

  • Excessive inflammation.

  • Antigen-antibody complex deposition.

  • Antibodies capable of cross-reactivity with self antigens.

Page 4: Classification of Hypersensitivity Reactions

The hypersensitivity reactions are classified into four major types:

1. Type I: Immediate hypersensitivities.

2. Type II: Antibody-mediated hypersensitivities.

3. Type III: Immune complex-mediated hypersensitivities.

4. Type IV: T cell-mediated hypersensitivities.

Page 5: Type I Hypersensitivities

• Common Conditions:

  • Rhinitis and sinusitis: Characterized by excessive mucous production.

  • Asthma: Results in bronchoconstriction.

  • Food Allergies: Can lead to diarrhea and vomiting; severe cases can cause anaphylaxis.

  • Anaphylaxis: Significant bronchoconstriction, vasodilation, and increased vascular permeability can result in circulatory shock and death if not treated immediately.

• Mechanism:

  • Immediate hypersensitivities occur due to allergen binding to IgE on the surface of mast cells, leading to degranulation and the release of mediators such as histamine, PGD2, and leukotrienes (LTC4 & LTD4).

  • Typically, responses are localized, resulting in a localized inflammatory response, but can also be systemic, causing erythema, urticaria, and respiratory and circulatory distress.

Page 6: Risk Factors for Type I Hypersensitivities

Factors associated with increased susceptibility to Type I hypersensitivities include:

• Genetic Factors:

  • Higher production of IL-4 by TH cells.

  • Elevated levels of IgE.

  • Some HLA haplotypes.

• Environmental Factors:

  • Exposure to pollutants.

  • Hygiene Hypothesis: The concept that excessive cleanliness may increase susceptibility.

Page 7: Type II Hypersensitivities

Mechanism:

Antibody-mediated hypersensitivities occur when antibodies bind to normal cellular proteins leading to:

1. Opsonization & Phagocytosis.

2. Complement Activation.

3. Impairment of Normal Cellular Function.

Page 8: Opsonization & Phagocytosis

• Erythrocytes and Associated Conditions:

  • Autoimmune Hemolytic Anemia: Includes transfusion reactions and erythroblastosis fetalis due to IgG from the mother crossing the placenta.

  • Primary Immunohemolytic Anemia: Idiopathic condition due to IgG binding.

• Platelets:

  • Autoimmune Thrombocytopenic Purpura: Occurs due to antibody binding to unique integrin proteins expressed by platelets.

Page 9: Complement Activation

Conditions:

1. Goodpasture Syndrome:

   • Caused by antibodies binding to proteins in the basement membranes of glomeruli and alveoli, leading to complement activation, nephritis, and impaired gas exchange.

2. Myasthenia Gravis:

   • Results from antibodies binding to acetylcholine receptors leading to impaired muscle activation and weakness.

3. Acute Rheumatic Fever:

   • Occurs in some patients post-pharyngitis caused by Streptococcus pyogenes, with antibodies cross-reacting with connective tissue in joints and heart valves.

Page 10: Impairment of Cellular Function

Condition:

• Graves Disease:

  • Hyperthyroidism resulting from antibodies binding to and activating the thyroid stimulating hormone (TSH) receptor on thyroid cells, leading to excessive production of thyroid hormones.

Page 11: Type III Hypersensitivities

Mechanism:

Immune complex hypersensitivities result from the deposition of antigen-antibody complexes (IgG or IgM) in small blood vessels and filtration sites (e.g., glomeruli, synovial membranes), leading to inflammation and tissue damage via complement activation and recruitment of neutrophils and macrophages.

Examples of Type III Diseases:

1. Serum Sickness:

   • Caused by antibodies binding to foreign antigens from blood transfusions.

2. Glomerulonephritis (Post-Streptococcal):

   • Antigen-M protein complexes trap in glomerular capillaries.

3. Systemic Lupus Erythematosus (SLE).

Page 12: Systemic Lupus Erythematosus (SLE)

• Autoantibodies:

  • Includes antinuclear antibodies against DNA, histones, ribonucleoproteins, nucleolar proteins, and antiphospholipid antibodies against protein-phospholipid complexes affecting erythrocytes, platelets, lymphocytes.

Page 13: Risk Factors for SLE

Immunologic Factors:

• Failure in negative selection processes of B cells and T cells.

• Overexpression of interferon-α by dendritic cells.

• Toll-like receptors (TLRs) that bind to dsDNA.

Genetic Factors:

• Gender: females are more susceptible.

• Certain HLA haplotypes.

• Complement deficiencies.

Environmental Factors:

• UV exposure raises number of apoptotic cells, leading to the release of nuclear antigens.

Page 14: Pathogenesis of SLE

• Autoantibody Complexes:

  • Binding of autoantibodies to soluble antigens leads to Type III hypersensitivity (causes vasculitis, arthritis, glomerulonephritis).

  • Non-soluble antigen binding causes Type II hypersensitivity (opsonization & phagocytosis of RBCs and platelets, leading to anemia and thrombocytopenia).

  • Secondary antiphospholipid syndrome can occur, causing thrombosis and may lead to focal cerebral ischemia and spontaneous miscarriages.

Page 15: Clinical Presentation of SLE

Highly Variable Symptoms:

• Clinical and Pathologic Manifestations Types and Prevalence in Patients (%):

  • Hematologic: 100%

  • Arthritis, Arthralgia, or Myalgia: 80-90%

  • Skin Symptoms: 85%

  • Fever: 55-85%

  • Fatigue: 80-100%

  • Weight Loss: 60%

  • Renal Issues: 50-70%

  • Neuropsychiatric Issues: 25-35%

  • Pleuritis: 15%

  • Gastrointestinal Issues: 20%

  • Raynaud phenomenon: 15-40%

  • Ocular Issues: 5-15%

  • Peripheral Neuropathy: 15%.

Page 16: Type IV Hypersensitivities

Mechanism:

T cell-mediated hypersensitivities occur due to excessive production of cytokines by TH cells, recruiting high numbers of neutrophils and macrophages causing tissue damage. Cytotoxic T lymphocytes (CTLs) may also contribute.

Page 17: Type IV Hypersensitivity Diseases

Page 18: Chronic Inflammation

Chronic inflammation can arise from conditions such as:

• Unresolved infections

• Seasonal allergies

• Osteoarthritis

• Type 2 diabetes

• Gout

• Atherosclerosis

• Autoimmune diseases: rheumatoid arthritis, psoriasis, inflammatory bowel disease.

• Dysregulated inflammasome activity is linked to many of these conditions.

• Many chronic inflammatory diseases are classified as Type IV hypersensitivity diseases characterized by excessive TH cytokine production and extensive macrophage/neutrophil recruitment, leading to tissue damage and fibrosis.

Page 19: Treating Chronic Inflammation

Cytokines associated with chronic inflammatory diseases include:

• IL-1, IL-6, IL-17, TNF-α: Treated in conditions like rheumatoid arthritis and severe COVID-19.

• IL-4, IL-13: Target conditions including atopic dermatitis (eczema), asthma.

• IL-5: For eosinophilic asthma and COPD.

• IL-6 receptor: Targeting rheumatoid arthritis and severe COVID-19.

• JAK inhibitors: For rheumatoid arthritis, psoriatic arthritis, inflammatory bowel diseases.

• TNF-α: Experienced in plaque psoriasis, psoriatic arthritis, rheumatoid arthritis.