Disorders in Immunity

Overview

This chapter explores the various ways in which the immune system can malfunction, leading to disease. These disorders are broadly categorized as hypersensitivities (overreactions) and hyposensitivities (immunodeficiencies), with additional focus on autoimmunity and immune responses to transplants.

Immune System Dysfunction

Immunopathology

• Immunopathology is the study of disease states associated with abnormal immune responses, including both overactivity and underactivity.

• Abnormal immune functions are implicated in conditions such as asthma, anaphylaxis, diabetes, rheumatoid arthritis, and graft rejection.

Categories of Immune Dysfunction

• Hypersensitivity (overreactivity): Includes allergies and autoimmunity, where the immune system attacks harmless substances or the body's own tissues.

• Hyposensitivity (immunodeficiency): The immune system is underdeveloped, suppressed, or destroyed, leading to increased susceptibility to infections.

Hypersensitivity: Four Types

Classification and Mechanisms

• Type I (Immediate hypersensitivity): IgE-mediated; involves mast cells, basophils, and allergic mediators. Examples: anaphylaxis, hay fever, asthma.

• Type II (Antibody-mediated): IgG and IgM antibodies act on cell surfaces, causing cell lysis; includes some autoimmune diseases. Examples: blood group incompatibility, hemolytic disease of the newborn.

• Type III (Immune complex-mediated): Involves immune complexes deposited in tissues, leading to inflammation. Examples: serum sickness, rheumatoid arthritis.

• Type IV (T-cell-mediated): Delayed hypersensitivity; involves T cells and cytotoxic reactions. Examples: contact dermatitis, graft rejection.

Type I Hypersensitivity: Allergy and Anaphylaxis

Definitions and Key Concepts

• Allergy: Exaggerated immune response causing inflammation.

• Allergens: Antigens that induce allergic reactions in sensitive individuals.

• Atopy: Chronic local allergy (e.g., hay fever, asthma).

• Anaphylaxis: Systemic, potentially fatal reaction involving airway obstruction and circulatory collapse.

Genetic and Environmental Factors

• General susceptibility to allergies is inherited, not the specific allergy.

• Genetic basis includes increased IgE production, mast cell reactivity, and tissue susceptibility.

• Children with allergic parents have a higher risk of developing allergies.

• Hygiene Hypothesis: Reduced microbial exposure in industrialized societies may increase allergy risk.

• Breastfeeding for the first 4 months reduces risk of asthma and eczema; breast milk transfers beneficial bacteria and immune factors.

Nature and Portals of Entry of Allergens

• Proteins are the most allergenic; some allergens are haptens (small molecules that become antigenic when attached to carrier proteins).

• Allergens enter via respiratory tract, gastrointestinal tract, or skin.

• Respiratory and GI mucosa are more permeable than skin.

Role of Mast Cells and Basophils

• Mast cells are abundant in connective tissues, especially in the lungs, skin, GI, and genitourinary tracts.

• Each mast cell has 30,000–100,000 IgE receptors; binding triggers degranulation and release of inflammatory mediators.

• Allergic symptoms result from the action of these mediators on target organs, not direct allergen effects.

Key Mediators and Their Effects

• Histamine: Constricts bronchi, increases vascular permeability, causes itching and wheal-and-flare reactions.

• Bradykinin: Prolonged bronchoconstriction, increased capillary permeability, mucus secretion.

• Serotonin: Similar effects to histamine and bradykinin.

• Leukotrienes: Slow-acting, cause prolonged bronchospasm and mucus secretion.

• Prostaglandins: Regulate smooth muscle contraction, vasodilation, increased pain sensitivity; NSAIDs block their action.

Clinical Manifestations of Type I Hypersensitivity

• Hay Fever (Allergic Rhinitis): Nasal congestion, sneezing, itchy eyes, mild bronchoconstriction.

• Asthma: Episodes of impaired breathing due to bronchoconstriction; airways are hypersensitive to various stimuli.

• Atopic Dermatitis (Eczema): Itchy, inflamed skin, often beginning in infancy; can become chronic and scaly.

• Food Allergy: Common allergens include peanuts, fish, milk, eggs, shellfish, soybeans; symptoms range from GI distress to anaphylaxis.

• Drug Allergy: Allergic reactions to drugs (e.g., penicillin, sulfa drugs, aspirin) are common; often due to haptens formed during drug metabolism.

Anaphylaxis

• Cutaneous anaphylaxis: Localized wheal-and-flare reaction.

• Systemic anaphylaxis: Sudden, severe respiratory and circulatory collapse; can be fatal within minutes.

• Common triggers: bee stings, injected antibiotics, or serum.

Diagnosis and Prevention

• In vitro tests: RAST (IgE levels), tryptase test, blood cell counts, histamine-release test.

• In vivo tests: Skin prick or scratch test; wheal-and-flare response measured and graded.

• Treatment: Drugs blocking immune mediators, allergen avoidance, desensitization (controlled exposure to allergen).

Type II Hypersensitivity: Antibody-Mediated Cytotoxic Reactions

Mechanism

• Involves IgG and IgM antibodies directed against cell surface antigens, leading to complement-mediated cell lysis.

• Examples: transfusion reactions, hemolytic disease of the newborn (HDN).

Rh Factor and Hemolytic Disease of the Newborn

• Rh antigen: Present in 85% of humans (Rh+); absence is Rh-.

• Rh- mothers can develop antibodies against Rh+ fetal blood cells, especially during subsequent pregnancies.

• Prevention: RhoGAM (anti-Rh immunoglobulin) administered to Rh- mothers prevents sensitization.

Type III Hypersensitivity: Immune Complex-Mediated Reactions

Mechanism

• Soluble antigen-antibody complexes form and deposit in tissues, activating complement and attracting neutrophils.

• Results in tissue inflammation and damage.

• Examples: serum sickness, acute post-streptococcal glomerulonephritis (APSGN), rheumatoid arthritis.

Type IV Hypersensitivity: T-Cell-Mediated (Delayed) Reactions

Mechanism

• Mediated by T cells responding to antigens on self or transplanted tissues.

• Symptoms develop 1–several days after exposure.

• Examples: contact dermatitis (e.g., poison ivy), tuberculin skin test, graft rejection.

Transplantation and Graft Rejection

• Host T cells recognize foreign MHC markers on grafted tissue, leading to rejection.

• Graft-versus-host disease (GVHD): Donor lymphocytes attack recipient tissues.

Autoimmunity

Overview

• Autoimmune diseases occur when the immune system attacks self-antigens.

• Can be systemic (affecting multiple organs) or organ-specific.

Causes

• Genetic predisposition (certain MHC types increase risk).

• Molecular mimicry (microbial antigens resemble self-antigens).

• Viral infections and changes in the gut microbiome may contribute.

Examples of Autoimmune Diseases

• Systemic lupus erythematosus (SLE): Autoantibodies against multiple organs and tissues.

• Rheumatoid arthritis: Immune complexes in joints cause chronic inflammation and tissue destruction.

• Graves' disease: Autoantibodies stimulate thyroid hormone production (hyperthyroidism).

• Type I diabetes: Cytotoxic T cells destroy pancreatic beta cells.

• Myasthenia gravis: Autoantibodies block acetylcholine receptors, leading to muscle weakness.

• Multiple sclerosis: T cells and autoantibodies damage myelin in the central nervous system.

Immunodeficiency Diseases (Hyposensitivity)

Overview

• Immunodeficiencies result in increased susceptibility to infections, especially by opportunistic microbes.

• Primary immunodeficiencies: Congenital, usually genetic defects affecting B cells, T cells, or both.

• Secondary immunodeficiencies: Acquired after birth due to infections (e.g., HIV/AIDS), cancer, malnutrition, or immunosuppressive therapy.

Primary Immunodeficiencies

• B-cell defects: Agammaglobulinemia, hypogammaglobulinemia, selective Ig deficiencies (most common: IgA deficiency).

• T-cell defects: Thymic aplasia (DiGeorge syndrome), leading to severe infections.

• Combined B- and T-cell defects: Severe combined immunodeficiency (SCID), ADA deficiency.

• Complement defects: Deficiency in complement proteins, leading to increased infections and autoimmune risk.

Secondary Immunodeficiencies

• Caused by infections (notably HIV/AIDS), cancers, malnutrition, pregnancy, aging, or medical treatments (irradiation, immunosuppressive drugs, removal of spleen).

• HIV targets T helper cells, leading to profound immunosuppression.

Summary Table: Primary vs. Secondary Immunodeficiencies

Key Terms and Concepts

• Immunopathology: Study of diseases caused by immune dysfunction.

• Hypersensitivity: Overactive immune response to antigens.

• Autoimmunity: Immune response against self-antigens.

• Immunodeficiency: Underactive or absent immune response.

• Allergen: Antigen that triggers an allergic response.

• Desensitization: Controlled exposure to allergens to reduce sensitivity.

Equations and Immunology Principles

• Antigen-Antibody Complex Formation:

• Complement Activation (Classical Pathway):

Additional info: These notes are based on slides and textbook content from "Microbiology Fundamentals: A Clinical Approach" (2024), Chapter 14, and are structured to provide a comprehensive yet concise review for exam preparation in a college-level microbiology course.