McCance 9 - Hypersensitivity: Types I-IV

Hypersensitivity Overview

• Hypersensitivity is an altered immune response to an antigen, resulting in disease or host damage.
• Hypersensitivity reactions are classified by antigen source: allergy, autoimmunity, and alloimmunity.
• They are also classified by disease-causing mechanisms into four types: I, II, III, and IV.

Type I Hypersensitivity: IgE-Mediated

• This type is mediated by antigen-specific IgE and mast cell products.
• These are the most common allergies triggered by environmental antigens.
• Sensitization requires repeated antigen exposure to elicit enough IgE.
• IgE binds to high-affinity Fc receptors on mast cells, and subsequent allergen exposure cross-links surface IgE.
• Cross-linking leads to mast cell degranulation and mediator release.
• Immediate hypersensitivity reactions occur within minutes to hours of re-exposure.
• Anaphylaxis is the most rapid and severe immediate reaction, which can be systemic or cutaneous.
• Symptoms of anaphylaxis include itching, erythema, headaches, breathing difficulties, shock, and potential death.
• Histamine, the most potent mediator, causes bronchial constriction, increased vascular permeability, and vasodilation, acting through H1 and H2 receptors.
• H2 receptor activation decreases histamine release via negative feedback.
• Histamine enhances eosinophil chemotactic factor of anaphylaxis (ECF-A), attracting eosinophils.
• Mast cells synthesize lipid-derived mediators with prolonged effects similar to histamine, such as leukotrienes, platelet-activating factor (PAF), and prostaglandins.
• Atopic individuals produce more IgE, have more mast cell Fc receptors, and have more responsive airways/skin.
• Clinical manifestations are mainly due to histamine's effects on the GI tract, skin, and respiratory tract.
• Examples include urticaria, allergic rhinitis, bronchial asthma, and food allergies.
• Diagnosis involves food challenges, skin tests, and laboratory tests for total and allergen-specific IgE.
• Desensitization involves injecting small allergen doses to reduce reaction severity, inducing blocking IgG antibodies.

Type II Hypersensitivity: Tissue-Specific

• This is characterized by a specific cell or tissue being the target of an immune response.
• IgG or IgM antibodies bind to tissue-specific or tissue-attached antigens.
• Five mechanisms of tissue destruction include complement-mediated lysis.
• Complement-mediated lysis causes cell lysis via the membrane attack complex (e.g., autoimmune hemolytic anemia, ABO-mismatched transfusion).
• The second is phagocytosis, where IgG and C3b opsonize cells for macrophage phagocytosis (e.g., autoimmune thrombocytopenia, Rh incompatibility).
• The third is neutrophil-mediated damage, where antibodies and complement attract neutrophils that release lysosomal enzymes (e.g., some drug allergies).
• The fourth is antibody-dependent cell-mediated cytotoxicity (ADCC) where NK cells recognize antibody on targets via Fc receptors and release toxic substances.
• The fifth is modulation of cellular function, where antibodies bind to cell surface receptors, causing malfunction without destruction (e.g., Graves disease, myasthenia gravis).

Type III Hypersensitivity: Immune Complex-Mediated

• These are caused by antigen-antibody (immune) complexes formed in the circulation.
• These complexes deposit in vessel walls or extravascular tissues.
• Unlike type II, antibodies bind to soluble antigens released into blood or body fluids.
• Reactions in type III are not organ specific.
• Harmful effects are due to complement activation, generating chemotactic factors (C3a, C5a) for neutrophils.
• Neutrophils bind to antibody and C3b in the complexes, releasing lysosomal enzymes and causing tissue damage.
• Intermediate-sized immune complexes are most likely to deposit in target tissues.
• These tissues can include kidneys, vessels, and joints.
• Deposition can result in glomerulonephritis, vasculitis, or arthritis.
• Immune complex formation is dynamic and is affected by the ratio of antigen to antibody, antibody class, and antigen quantity.
• Complement levels may decrease (hypocomplementemia) during active disease due to complement activation.
• Serum sickness is a systemic type III hypersensitivity caused by immune complex deposition throughout the body.
• Arthus reaction, due to repeated local antigen exposure, is a localized immune complex-mediated inflammatory response.

Type IV Hypersensitivity: Cell-Mediated

• This type is mediated by T lymphocytes (Tc cells or lymphokine-producing Th1 and Th17 cells) and does not involve antibodies.
• Delayed hypersensitivity reactions may take hours to days to appear and reach maximum severity.
• Tc cells directly attack and destroy cellular targets, such as graft rejection and virally infected cells.
• In type 1 diabetes mellitus, T cells destroy pancreatic beta cells.
• Th1 and Th17 cells produce cytokines (e.g., IFN-γ) that recruit and activate phagocytic cells, leading to tissue destruction.
• The tuberculin skin test is an example of delayed hypersensitivity skin test.
• Allergic contact dermatitis is a type IV allergic hypersensitivity where haptens react with skin proteins.

Antigenic Targets by Hypersensitivity Type

• Type I targets environmental antigens (allergens) like pollen, food, dust, molds, and animal dander. Type I can occur against self or alloantigens.
• Type II targets tissue-specific antigens on cell surfaces or attached environmental antigens (drugs).
• Type III targets soluble antigens (environmental, infectious, or self).
• Type IV targets environmental or self-antigens.

Autoimmunity

• Autoimmunity involves a disturbance in immunologic tolerance to self-antigens.
• Autoimmune diseases result from an initiating event in a genetically predisposed individual.
• These can be familial and linked to susceptibility genes.
• HLA antigens are often associated with increased risk.
• Immunologic tolerance to self-antigens is established through central and peripheral tolerance.
• Breakdown of peripheral tolerance is more common in autoimmune disease.
• Mechanisms for tolerance breakdown include sequestered antigen, infectious disease (molecular mimicry), and neoantigen.
• Additional mechanisms include forbidden clone, defective peripheral tolerance, microchimerism, and endogenous retroviruses (HERVs).

Alloimmunity

• Alloimmunity is the immune system's reaction against antigens on tissues of other members of the same species.
• Clinically relevant examples include transient neonatal alloimmunity, transplant rejection, and transfusion reactions.
• In transient neonatal alloimmunity, maternal alloantibodies cross the placenta and cause disease in the fetus or neonate.

Systemic Lupus Erythematosus (SLE)

• SLE is a chronic, multisystem, inflammatory autoimmune disease.
• It is characterized by a large variety of autoantibodies against self-components.
• The most characteristic autoantibodies are against nucleic acids (DNA) and nuclear materials.
• Deposition of circulating immune complexes causes tissue damage in various organs.
• This disease is more common in women and Blacks, with a genetic predisposition.
• It can be triggered by environmental agents and certain drugs.
• Clinical manifestations are diverse and include arthralgias, arthritis, vasculitis, rash, renal disease, hematologic abnormalities, and cardiovascular diseases.
• Diagnosis is based on clinical findings and laboratory tests.
• Treatment involves corticosteroids, antimalarial medications, and immunosuppressive drugs.

Tissue Rejection

• Blood group antigens (ABO system) on erythrocytes are major targets of transfusion reactions.
• Individuals have antibodies against the ABO antigens they lack.
• Rh blood group antigens also cause transfusion reactions and hemolytic disease of the newborn.
• Graft rejection is primarily directed against major histocompatibility complex (MHC) molecules, also called human leukocyte antigens (HLAs).
• HLA matching is crucial for graft acceptance.
• Hyperacute rejection is immediate due to preexisting recipient antibodies against donor HLA antigens (type II hypersensitivity).
• Acute rejection is cell-mediated rejection by recipient T cells (type IV hypersensitivity).
• Chronic rejection is slow, progressive organ failure due to cell-mediated and antibody-mediated injury.

Deficiencies in Immunity

• Deficiencies in immunity are insufficient immune responses that fail to protect against foreign antigens.
• Deficiencies can be classified as primary (congenital) or secondary (acquired).
• Initial presentation often involves increased susceptibility to infections, autoimmunity, or malignancy.

Primary Immune Deficiencies

• These mostly result from single gene defects.
• They are individually rare, but collectively more common than some well-known diseases.
• Examples include combined deficiencies, predominantly antibody deficiencies and immune dysregulation.
• Other examples include phagocyte defects, innate immunity defects, autoinflammatory disorders, and complement defects.
• DiGeorge syndrome involves thymic aplasia/hypoplasia leading to decreased T cells.
• SCID involves a total lack of T-cell function and severe B-cell deficiency.
• Selective IgA deficiency is relatively common.
• CGD results from defects in the respiratory burst in phagocytes.
• Defects in the membrane attack complex often lead to Neisseria infections.

Secondary Immune Deficiencies

• These are far more common than primary deficiencies.
• Complications of other physiologic or pathophysiologic conditions.
• Examples include normal physiologic conditions, psychologic stresses, and dietary insufficiencies.
• Additional examples include malignancies, medical treatments, and infections.
• Further examples include lifestyle factors, chronic diseases, and metabolic diseases or genetic syndromes.

Evaluation and Care of Immune Deficiency

• Routine care must consider the ineffectiveness of the immune system.
• Vaccination with attenuated (live) vaccines may be unsafe.
• There is a risk for graft-versus-host disease (GVHD) from transfused blood.
• The presenting symptom is often recurrent severe infections.
• Evaluation involves detailed history, physical examination, and complete blood count (CBC).
• Further evaluation involves quantitative determination of immunoglobulins ,total complement assay ,genetic analysis, quantification of lymphocyte subpopulations, measurement of antibody responses to specific antigens.
• It also involves T-cell immunity assessment via delayed hypersensitivity skin tests.
• Treatment strategies include gamma-globulin therapy, hematopoietic stem cell transplantation and bone marrow transplantation .
• Further treatments include T-cell depletion of donor grafts, mesenchymal stem cells and transplantation of fetal thymic tissue or epithelial cells.
• Additional treatments include enzyme replacement therapy, treatment with soluble immune modulators and gene therapy.

Factors Contributing to Hypersensitivity

• The precise cause of hypersensitivity is not fully understood.
• Generally accepted contributing factors include genetic factors, infectious factors, and environmental factors.
• Most hypersensitivity diseases develop due to interactions of an initial "insult," the individual's genetic makeup, and an immunologic process.
• An original "insult" alters immunologic homeostasis, a steady state of tolerance to self-antigens and lack of reaction to environmental antigens.