Hypersensitivity Reactions Overview

Hypersensitivity reactions are exaggerated immune responses that result in tissue damage.
Hypersensitivity reactions are classified into four types: Type I, Type II, Type III, and Type IV.

Type I reactions are characterized by the production of antigen-specific IgE.
Most are in response to common environmental antigens (e.g., allergens, dust, pollen, food, drugs, and bee venom).
Genetic predisposition to Type I reactions is called atopy, which is a mutation in genes that affect IL-4 receptors, IL-4 levels, IgE receptors, Class II MHC proteins, etc.
Atopic individuals produce higher amounts of IgE, more IgE receptors on mast cells, and an increased eosinophil response.
The pathophysiology involves the activation of mast cells, which release histamine and other inflammatory mediators.
Two phases of Type I reactions:
- Initial Phase (5–30 minutes): Vasodilation, increased capillary permeability, and non-vascular smooth muscle constriction.
- Late Phase (2–8 hours): Similar responses to the initial phase, but with more intense infiltration of tissues with granulocytes (eosinophils, neutrophils) and mucosal damage.
Clinical Consequences:
- Allergic Reactions (Local Response): Itching, urticaria (hives), rhinitis, and conjunctivitis.
- Anaphylaxis (Systemic Response): Bronchospasm, bronchoconstriction, hypotension, edema and GI cramping.

Type II reactions are characterized by the destruction of a target cell through the action of antibodies against antigens on the cell's plasma membrane.
Common antigens involved in Type II reactions:
- Tissues with HLA and/or tissue-specific antigens (e.g., autoimmune reactions).
- Drugs or drug metabolites that bind to plasma membranes of cells (often RBCs or platelets).
- Transplanted tissues or organs (including blood transfusions).
Mechanisms of antigen destruction:
- Complement-Mediated Lysis: IgM/IgG reacts with antigen on the cell surface, activating complement proteins that cause plasma membrane damage and cell injury.
- Phagocytosis by Macrophages: Macrophages recognize and bind to the Fc portion of antibodies on opsonized target cells and phagocytose them.
- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): NK cells bind to the Fc portion of antibodies on opsonized target cells, releasing toxic molecules that destroy the target.
- Inducing Target Cell Malfunction: Antibodies binding to target cell receptors alter cell function (e.g., hyperthyroidism in Graves disease).

Type III reactions are characterized by immune complex formation in the circulation, depositing on endothelium of capillaries or extravascular tissue.
Common antigens involved in Type III reactions:
- Viral, bacterial, and parasitic antigens
- Pollens
- Vaccines
- Plasma/serum
- Nuclear antigens.
Pathophysiology:
- Antigen-antibody complexes form in the circulation and later deposit on endothelium or extravascular tissues.
- Complement proteins are activated.
- Neutrophils ingest the deposited complexes, causing tissue damage.
Common target tissues/disease examples:
- Kidneys: Causes glomerulonephritis.
- Blood vessels: Causes vasculitis.
- Arthus Reaction: Localized inflammatory skin lesions caused by repeated local exposure to antigens, resulting in immune complex formation in blood vessel walls.
- Raynaud Disease: Temperature-dependent immune complex (cryoglobulins) precipitation at below-normal temperatures.
- Systemic Lupus Erythematosus: Immune reaction to nuclear antigens.

Type IV reactions are cell-mediated reactions involving sensitized T lymphocytes (Tc or Th).
Examples:
- Tissue graft rejection
- Contact dermatitis (poison ivy, metals)
- Tuberculin reaction
- Diseases: Diabetes type 1, RA, MS, Crohn disease, toxic shock.
Pathophysiology of type IV hypersensitivity skin reactions:
- Allergen binds to proteins on membranes of epidermal cells, causing infiltration of T lymphocytes and macrophages.
- T lymphocytes bind to target cells, releasing enzymes (granzymes) that damage/destroy the target cell.
Manifestations of hypersensitivity are delayed by 24-72 hours.

Autoimmunity is an altered immune response that targets the body's own cells.
Immunological Tolerance is the mechanism that prevents the immune system from destroying self-antigen.

Central Tolerance: Occurs in the bone marrow and thymus, where developing B and T lymphocytes are exposed to self-antigen.
- Central T lymphocyte tolerance: Recognition of self-antigen in the thymus induces apoptosis (negative selection) of CD4 (Th) and CD8 (Tc) lymphocytes, or leads to development of regulatory T lymphocytes (Treg).
- Central B lymphocyte tolerance: Recognition of self-antigen in the bone marrow induces receptor editing, apoptosis, or anergy in B lymphocytes.
Peripheral Tolerance: Tolerance established in secondary lymphoid organs (e.g., spleen, lymph nodes) involving mature lymphocytes exposed to self-antigens.
- Peripheral T lymphocyte tolerance: Recognition of self-antigen in the periphery causes anergy or apoptosis of T cells and the secretion of fewer signaling molecules by antigen-presenting cells. Mature T lymphocytes are sensitive to Treg cell function.
- Peripheral B lymphocyte tolerance: Recognition of self-antigen in the periphery causes anergy or apoptosis, or engages inhibitory receptors.
Tolerance to Commensal Microbes: The body has a vast population of commensal microbes. An abundance of Treg cells suppress the immune response to these microbes.

Autoimmune diseases affect 1 in 5 Americans.
They are associated with genetic susceptibility and environmental triggers.
- Susceptibility Genes: Interfere with pathways responsible for self-tolerance and affect MHC (HLA) genes specifically.
- Environmental Triggers: Infection, UV radiation.

An autoimmune disease affecting skin, joints, kidneys, heart, liver, etc.
Etiology: Genetic susceptibility and environmental triggers.
Pathophysiology involves autoantibodies against nuclear antigens, causing immune complex formation and inflammation.
Clinical Consequences are associated with vessel injury and inflammation.