Hypersensitivity

Terminology

  • Hypersensitivity: An exaggerated or inappropriate immune response to an antigen that results in tissue damage and disease. This can be immediate or delayed.

  • Allergy: A specific type of hypersensitivity reaction to usually harmless environmental antigens (allergens).

  • Autoimmunity: A condition where the immune system mistakenly attacks and damages the body's own tissues, recognizing self-antigens as foreign.

  • Alloimmunity: An immune response mounted against antigens from genetically dissimilar individuals of the same species, often seen in transfusions or organ transplants.

Mechanisms of Hypersensitivity

  • Timing: Hypersensitivity reactions can manifest with varying kinetics:

    • Immediate: Occurs within seconds to hours after exposure to the antigen, typically involving antibodies (Types I, II, III).

    • Delayed: Develops hours to days after antigen exposure, primarily mediated by T cells (Type IV).

  • Anaphylaxis: A severe, potentially life-threatening systemic hypersensitivity reaction characterized by rapid onset of symptoms, including widespread vasodilation, increased vascular permeability, bronchial constriction, and potentially leading to cardiovascular shock and respiratory distress.

Type I: IgE-mediated Hypersensitivity

  • Mechanism: Initiated when environmental antigens (allergens) stimulate B cells to produce immunoglobulin E (IgE) antibodies. These IgE antibodies then bind to the surface of mast cells and basophils via their Fc region. Upon subsequent exposure to the same allergen, the antigen cross-links the IgE molecules on the mast cell surface, triggering degranulation. This rapid release of preformed mediators (like histamine, proteases) and newly synthesized mediators (like leukotrienes, prostaglandins) causes the characteristic symptoms.

  • Symptoms: Range from localized reactions such as urticaria (hives), allergic rhinitis (hay fever) with sneezing and watery eyes, and asthma (bronchial constriction) to systemic anaphylaxis which can include angioedema, hypotension, and shock.

  • Atopy: A genetic predisposition to develop allergic reactions, often characterized by higher serum IgE levels and increased sensitivity to common allergens. Atopic individuals often have a family history of allergies.

  • Treatment:

    • Antihistamines: Block histamine H1 receptors, reducing symptoms like itching, sneezing, and runny nose.

    • Epinephrine: A life-saving treatment for anaphylaxis, counteracting vasodilation, bronchoconstriction, and increasing cardiac output.

    • Corticosteroids: Reduce inflammation in severe or persistent cases.

    • Desensitization (Allergy Shots): Involves injecting increasing doses of allergens over time to shift the immune response from IgE production to IgG, which can block the allergen before it binds to IgE on mast cells.

Type II: Tissue-specific Hypersensitivity (Cytotoxic)

  • Mechanism: Involves antibodies (IgG or IgM) binding to specific antigens on the surface of target cells or tissues. This antigen-antibody binding can lead to cell damage or destruction through several pathways:

    • Complement-mediated lysis: Activation of the classical complement pathway, leading to the formation of the membrane attack complex (MAC) and cell lysis.

    • Opsonization and phagocytosis: Antibodies or complement proteins (C3b) coat the target cell, marking it for destruction by phagocytes like macrophages.

    • Antibody-dependent cellular cytotoxicity (ADCC): Antibodies tag target cells for destruction by natural killer (NK) cells.

    • Modulation of cellular function: Antibodies bind to cell surface receptors, either stimulating (e.g., Grave's disease affecting TSH receptors) or blocking (e.g., Myasthenia Gravis affecting acetylcholine receptors) normal cellular function.

  • Symptoms: Depend on the specific tissue or organ targeted. Examples include:

    • Transfusion reactions: Due to ABO blood group mismatches.

    • Hemolytic disease of the newborn: Rh incompatibility.

    • Autoimmune hemolytic anemia: Antibodies target red blood cells.

    • Grave's disease: Antibodies stimulate thyroid-stimulating hormone (TSH) receptors, leading to hyperthyroidism.

    • Myasthenia gravis: Antibodies block acetylcholine receptors at the neuromuscular junction, causing muscle weakness.

Type III: Immune Complex-mediated Hypersensitivity

  • Mechanism: Involves the formation of soluble antigen-antibody (immune) complexes in the bloodstream. These complexes, particularly if excessively formed or not efficiently cleared, deposit in various tissues, such as blood vessel walls, joints, and kidneys. The deposited immune complexes activate the complement system and attract inflammatory cells (e.g., neutrophils), leading to the release of lysosomal enzymes and reactive oxygen species, causing tissue damage.

  • Clinical Examples:

    • Serum sickness: A systemic reaction to foreign proteins (e.g., antivenom, certain medications) resulting in widespread immune complex deposition, causing fever, rash, joint pain, and kidney damage.

    • Arthus reaction: A localized Type III reaction characterized by pain, swelling, and redness at the site of antigen injection, often seen after repeated vaccinations or insect bites.

    • Systemic lupus erythematosus (SLE): A chronic autoimmune disease where immune complexes containing autoantigens and autoantibodies deposit in multiple organs, leading to inflammation and tissue damage in joints, kidneys, skin, and other systems.

    • Raynaud's phenomenon: Characterized by vasospasms, often in fingers and toes, exacerbated by cold and associated with immune complex deposition.

Type IV: Cell-mediated Hypersensitivity (Delayed)

  • Mechanism: Unlike other types, this reaction does not involve antibodies. Instead, it is primarily mediated by T lymphocytes. Upon re-exposure to an antigen, previously sensitized Th1 (helper T cells) or cytotoxic T lymphocytes (CTLs) are activated. Th1 cells release cytokines (e.g., interferon-gamma) that recruit and activate macrophages, leading to inflammation and cellular damage. CTLs directly kill target cells presenting the antigen. The delayed nature (24-72 hours) is due to the time required for T-cell activation, proliferation, and migration to the site of antigen exposure.

  • Symptoms: Characterized by delayed reactions, often manifesting as erythema, induration, blistering, and tissue necrosis. Examples include:

    • Contact dermatitis: An inflammatory skin reaction caused by contact with sensitizing agents like poison ivy, nickel, or certain chemicals, where T cells react to haptens bound to skin proteins.

    • Tuberculin skin test (PPD test): A diagnostic test for tuberculosis exposure, where an intradermal injection of tuberculin antigens elicits a localized indurated lesion in sensitized individuals.

    • Graft rejection (acute and chronic): T-cell mediated rejection of transplanted organs.

    • Some autoimmune diseases: Such as type 1 diabetes, where CTLs destroy pancreatic beta cells.

Allergies

  • Allergens: Common environmental triggers that provoke allergic reactions include pollen, dust mites, animal dander, insect venom, certain foods (e.g., peanuts, shellfish, milk), and medications (e.g., penicillin).

  • Histamine Effects: A primary mediator released during Type I hypersensitivity reactions. It binds to different receptors:

    • H1 receptors: Found on smooth muscle and endothelial cells; activation leads to increased vascular permeability, vasodilation (causing redness and swelling), bronchoconstriction, itching, and increased mucus secretion.

    • H2 receptors: Primarily found on gastric parietal cells; activation stimulates gastric acid secretion. H2 blockers are used to reduce stomach acid, not typically for allergy symptoms (except in conjunction for severe cases).

    • Other mediators: Mast cells also release leukotrienes (more potent and prolonged bronchoconstrictors than histamine), prostaglandins (contribute to vasodilation and pain), and proteases (cause tissue damage).

Autoimmunity and Genetic Factors

  • Mechanism: Autoimmunity arises from a breakdown of immunological tolerance, the process by which the immune system learns to distinguish self from non-self. This breakdown can occur through various mechanisms:

    • Molecular mimicry: Microbial antigens sharing structural similarities with self-antigens can trigger an immune response that cross-reacts with self-tissues (e.g., Group A Streptococcus leading to rheumatic fever).

    • Genetics: Strong association with certain major histocompatibility complex (MHC) alleles, particularly Human Leukocyte Antigens (HLA) Class I and Class II genes (e.g., HLA-DR4 in rheumatoid arthritis, HLA-B27 in ankylosing spondylitis). These genes influence antigen presentation.

    • Environmental factors: Infections, toxins, and certain drugs can trigger or exacerbate autoimmune conditions.

    • Bystander activation: Tissue damage or inflammation can release sequestered self-antigens, making them accessible to the immune system.

  • Examples:

    • Rheumatic heart disease: Following Group A Streptococcal infection, antibodies against bacterial antigens cross-react with cardiac tissue (molecular mimicry).

    • Type I diabetes mellitus: Autoimmune destruction of insulin-producing pancreatic beta cells by T cells.

    • Systemic lupus erythematosus (SLE): A multi-system autoimmune disease characterized by the production of autoantibodies against various self-antigens (e.g., DNA, histones), leading to immune complex formation and widespread inflammation. Symptoms can include butterfly rash, arthritis, kidney failure, and neurological issues.

Alloimmunity

  • Mechanism: The immune system's response to non-self antigens from another individual of the same species. These antigens are often polymorphic, meaning they vary significantly between individuals. Key alloantigens include blood group antigens and Major Histocompatibility Complex (MHC) molecules.

  • Examples:

    • Neonatal alloimmunity (Hemolytic disease of the newborn): Occurs when maternal antibodies (e.g., anti-Rh antibodies) cross the placenta and attack fetal red blood cells, leading to hemolysis.

    • Transplant rejection: The immune system of the recipient recognizes donor organ antigens (primarily MHC molecules) as foreign and mounts an attack.

    • Transfusion reactions: The recipient's immune system reacts to incompatible blood group antigens present on transfused red blood cells.

Blood Groups and Transfusion Reactions

  • ABO Group: Based on the presence or absence of A and B carbohydrate antigens on red blood cell surfaces.

    • Type A: Has A antigens and anti-B antibodies in plasma.

    • Type B: Has B antigens and anti-A antibodies in plasma.

    • Type AB: Has both A and B antigens and no anti-A or anti-B antibodies (universal recipient).

    • Type O: Has neither A nor B antigens but has both anti-A and anti-B antibodies (universal donor for red blood cells).

  • Rh Factor:

    • Rh positive (Rh+Rh^{+}): Red blood cells express the Rh D antigen.

    • Rh negative (Rh−Rh^{-}): Red blood cells lack the Rh D antigen. Rh−Rh^{-} individuals do not naturally have anti-Rh antibodies but can produce them upon exposure to Rh+Rh^{+} blood, which is crucial in pregnancy and transfusions.

  • Reactions: Mismatched transfusions, especially ABO incompatible ones, can cause severe and life-threatening acute hemolytic transfusion reactions. The recipient's pre-existing antibodies (e.g., anti-A attacking A antigens) rapidly bind to donor red blood cells, activating complement, leading to massive intravascular hemolysis, hemoglobinuria, renal failure, and shock.

Graft Rejection

  • Types: Based on the timing and mechanisms of immune attack on transplanted organs:

    • Hyperacute rejection: Occurs within minutes to hours after transplantation. Caused by pre-formed antibodies (often ABO or anti-HLA antibodies) in the recipient that immediately bind to donor endothelial cells, leading to rapid complement activation, thrombosis, and ischemic necrosis of the graft.

    • Acute rejection: Develops days to months post-transplant. Primarily mediated by recipient T cells (both helper and cytotoxic) recognizing donor MHC antigens. This leads to inflammation, endothelial damage, and parenchymal cell destruction within the graft. It can often be treated with immunosuppressive drugs.

    • Chronic rejection: Occurs months to years after transplantation. Characterized by slow, progressive loss of graft function, typically involving fibrosis and vascular changes in the transplanted organ. It is thought to involve complex immune and non-immune mechanisms, including a low-grade T-cell response, antibody-mediated damage, and persistent inflammation.

  • Management: Aims to prevent and treat rejection.

    • MHC (HLA) matching: Close matching of human leukocyte antigens between donor and recipient is crucial to minimize immune recognition.

    • Immunosuppressive drugs: Used lifelong post-transplant to suppress the recipient's immune system (e.g., calcineurin inhibitors, corticosteroids, anti-proliferative agents) to prevent T-cell activation and proliferation. The challenge is balancing immunosuppression to prevent rejection with minimizing side effects like increased infection risk and malignancy.