Hypersensitivities LO5

Lecture Outcome Number Five: Immunological Mechanisms of Hypersensitivity and Autoimmune Diseases

Overview

• Focus on distinguishing immunological mechanisms driving type two and type three hypersensitivities.

• Discuss autoimmune diseases: Systemic Lupus Erythematosus (SLE), Myasthenia Gravis, and Graves' Disease.

Type Two Hypersensitivity

• Definition: Type two hypersensitivity is driven by IgM or IgG antibodies that react with antigens expressed at cell surfaces.

• Mechanism:

  • Antibodies bind directly to cell surface antigens.

  • Resulting effects include:

  • Destruction of tissues expressing these autoantibodies, facilitated by innate immune cells and Fc receptors.

  • Activation of complement, leading to formation of the membrane attack complex, which lyses cells.

  • Complement also triggers inflammation by increasing cellular influx.

• Examples of Type Two Hypersensitivity:

  • Autoimmune diseases:

  • Graves' Disease: An autoimmune disorder that affects the thyroid, leading to hyperthyroidism.

  • Myasthenia Gravis: A neuromuscular autoimmune disease characterized by weakness and fatigue of skeletal muscles.

  • Vasculitis: Inflammation of blood vessels.

  • Autoimmune Hemolytic Anemia: Destruction of red blood cells by autoantibodies.

  • Various Cytopenias: Disorders involving a reduction in blood cells.

  • Allergies, including certain drug allergies that can also employ these mechanisms.

Type Three Hypersensitivity

• Definition: Type three hypersensitivity involves IgM, IgG, or potentially IgA recognizing circulating soluble antigens.

• Mechanism:

  • Immune complexes formed by antibody-antigen binding can deposit in tissues.

  • Similar to type two hypersensitivity, these complexes activate complement and Fc receptors, leading to inflammation.

• Examples of Type Three Hypersensitivity:

  • Systemic Lupus Erythematosus (SLE): A multi-organ autoimmune disease characterized by the formation of immune complexes.

  • Glomerulonephritis: Inflammation of the kidney's filtering units.

  • Serum Sickness: Reaction to proteins in antiserum derived from a non-human animal source.

  • Various drug allergies.

Comparative Mechanism Summary: Type Two vs. Type Three

• Both types involve:

  • Antibodies binding to their respective antigens.

  • Activation of Fc receptors and complement pathways.

• Key Difference:

  • Type Two: Antigen is on the cell surface.

  • Type Three: Antigen is soluble and circulating in the bloodstream.

Mechanistic Pathology in Hypersensitivity

• Type Two Hypersensitivity:

  • Mechanism by which antibody-dependent cellular cytotoxicity (ADCC) occurs:

  • Target cells display autoantigens.

  • NK cells, expressing Fc receptors, bind to the antibodies, leading to destruction of target cells.

  • Phagocytes with Fc receptors can activate upon recognition of immune complexes and release pro-inflammatory cytokines:

  • Cytokines: Interleukin 1 beta, TNF-alpha, Interleukin 6;

  • Activates vascular endothelium, leading to inflammation and fever.

  • Indicates significant tissue damage.

• Type Three Hypersensitivity:

  • Immune complexes interact with phagocytes via Fc receptors and activate the complement system, which enhances inflammatory responses:

  • C5a is an extremely potent chemokine, promoting inflammation.

  • Membrane attack complex resulting from complement activation can lysate tissues.

  • Regulatory mechanisms for macrophages and inflammation via cytokine secretion inhibit further damage and promote repair.

Specific Autoimmune Diseases

Myasthenia Gravis

• Description: Neuromuscular autoimmune disorder leading to muscle weakness and fatigue.

• Symptoms:

  • Approximately 15% of patients exhibit only minor ocular symptoms (ptosis).

  • 85% have generalized muscle weakness.

  • Rare cases can lead to respiratory muscle weakness.

• Genetic Factors:

  • Various MHC alleles and immune genes contribute to susceptibility.

• Treatment:

  • Acetylcholine esterase inhibitors, plasma exchange, intravenous immunoglobulin, and rituximab (anti-CD20 monoclonal antibody targeting B cells).

• Pathological Mechanism:

  • Autoantibodies against acetylcholine receptors lead to disease through:

  • Activation of complement damage to post-synaptic membrane.

  • Internalization of the acetylcholine receptor reducing available receptors.

  • Blocking the receptor through antibodies, preventing acetylcholine binding.

Graves' Disease

• Description: Type two hypersensitivity leading to hyperthyroidism; includes ocular symptoms such as bulging eyes.

• Symptoms:

  • Increased heart rate, blood pressure fluctuation, fever, and potentially high mortality if untreated.

• Genetic Susceptibility:

  • Strong genetic association with various MHC alleles and other immune genes.

• Treatment:

  • Drugs inhibiting thyroid function, radioactive iodine treatment, or surgery.

• Pathology:

  • Autoantibodies stimulating thyroid-stimulating hormone receptor, mimicking thyroid-stimulating hormone, leading to excessive thyroid hormone production (hyperthyroidism).

Systemic Lupus Erythematosus (SLE)

• Definition: A multi-organ autoimmune disease resulting from type three hypersensitivity.

• Characteristics:

  • Immune complexes comprising autoantibodies against DNA or associated proteins lead to multi-organ inflammation.

• Symptoms:

  • Skin rashes (butterfly rash), arthritis, renal complications, and systemic manifestations.

• Incidence: Approximately 3 per 100,000 people.

• Mortality: Improved over decades but remains higher than non-SLE population.

• Treatment:

  • Initial treatment with corticosteroids.

  • Advanced treatments including immunotherapy targeting BAF and research into targeting type I interferon pathway.

• Pathological Mechanism:

  • Immune complexes lodge in tissues, leading to vasculitis, tissue damage, and disease symptoms.

  • Plasmacytoid dendritic cells play a role in amplifying immune responses via TLR9 activation leading to excess type I interferon and BAF, promoting B cell survival and autoimmunity.