Hypersensitivity Types I through IV

Definitions and Fundamental Concepts

• Hypersensitivity: Defined as the over-reactions of the immune system to harmless antigens. It represents a heightened and exaggerated immune response that results in tissue damage, disease, and potentially death.

• Allergen: Environmental antigens that induce a state of hypersensitivity or an allergy.

Overview of the Four Types of Hypersensitivity

• Type I (Immediate Hypersensitivity):

  • Immune Reactant: $IgE$.

  • Antigen: Soluble antigen.

  • Effector Mechanism: Mast-cell activation; release of vasoactive amines, lipid mediators, and cytokines.

  • Examples: Allergic rhinitis, asthma, systemic anaphylaxis.

• Type II (Cytotoxic Hypersensitivity):

  • Immune Reactants: $IgG$ or $IgM$.

  • Antigen: Cell- or matrix-associated antigen; cell-surface receptors.

  • Effector Mechanism: Complement activation, phagocytosis via $FcR+$ cells (phagocytes, $NK$ cells), or altered signaling.

  • Examples: Some drug allergies (e.g., penicillin), chronic urticaria (antibody against Fc\text{\textepsilon}R1\text{α}), hemolytic anemia, blood transfusion reactions.

• Type III (Immune Complex-Mediated Hypersensitivity):

  • Immune Reactant: $IgG$.

  • Antigen: Soluble antigen forming antigen-antibody complexes.

  • Effector Mechanism: Complement activation, recruitment of phagocytes (neutrophils), and platelets.

  • Examples: Serum sickness, Arthus reaction, Systemic Lupus Erythematosus ($SLE$), post-streptococcal glomerulonephritis.

• Type IV (Delayed-Type Hypersensitivity - DTH):

  • Immune Reactants: $TH1$ cells, $TH2$ cells, or Cytotoxic T Lymphocytes ($CTL$).

  • Antigen: Soluble antigen or cell-associated antigen.

  • Effector Mechanisms:

    • $TH1$ Cells: Macrophage activation via $IFN\text{-}\text{γ}$.

    • $TH2$ Cells: Eosinophil activation and mastocytosis via $IL\text{-}4$, $IL\text{-}5$, and eotaxin.

    • $CTL$: Cytotoxicity.

  • Examples: Contact dermatitis, tuberculin reaction, chronic asthma, chronic allergic rhinitis.

Detailed Analysis of Type I Hypersensitivity

• General Characteristics:

  • Commonly referred to as "allergy."

  • Occurs in individuals who produce $IgE$ antibodies against innocuous environmental antigens.

  • In contrast, most people produce $IgM$, $IgG$, or $IgA$ to these same antigens, which clear them without symptoms.

  • The reaction is extremely rapid, occurring within $30\text{ minutes}$ of encounter, hence known as "immediate" hypersensitivity.

• Atopy:

  • Type I is also known as atopy.

  • Systemic Atopic Response: Anaphylaxis, which affects the entire body.

  • Local Atopic Reaction: Symptoms are confined to the anatomical location of the affected tissue.

    • Atopic Rhinitis (Hay Fever): Localized $IgE$-mediated response in the nose.

    • Atopic Asthma: Local response in the airways and lungs resulting in inflammation.

    • Atopic Dermatitis (Eczema) / Atopic Urticaria: Localized response in the skin.

• Sources of Type I Allergens:

  • Inhaled Materials: Pollen, danders, mold spores, feces of small animals.

  • Injected Materials: Vaccines, insect venoms, drugs.

  • Ingested Materials: Orally taken drugs, food (peanuts, shellfish, eggs).

  • Contacted Materials: Plant materials, metals.

Mechanism and Mediators of Type I Hypersensitivity

• Sensitization Phase:

  1. Initial encounter with the allergen (inhaled, ingested, injected, or contacted).

  2. Antigen-presenting cells ($APC$) present the allergen to $T$ cells.

  3. $B$ cells are activated and mature into plasma cells to produce $IgE$ specific to the allergen.

  4. $IgE$ enters circulation and binds rapidly to high-affinity receptors (Fc\text{\textepsilon}R\text{ε} or $CD23$) on mast cells in tissues.

• Effector Phase:

  1. Subsequent encounter with the same allergen.

  2. Allergen cross-links the $IgE$ bound to the mast cell surface.

  3. Cross-linking triggers degranulation, releasing vasoactive amines, cytokines, chemokines, and lipids.

• Major Mediators:

  • Histamine: From mast cell/basophil granules; causes vasodilation, vessel permeability, bronchial smooth muscle contraction, mucus production, itching, and sneezing.

  • Chemotactic Factors: Recruit eosinophils and neutrophils.

  • Proteases: Increase mucus production and digest basement membranes.

  • Leukotrienes: Derived from membrane breakdown; cause vasodilation, increased permeability, and bronchial smooth muscle contraction.

  • Prostaglandins: Cause platelet aggregation and pulmonary smooth muscle contraction.

  • Platelet-Activating Factor (PAF): Triggers platelet aggregation and degranulation.

• Clinical Extremes:

  • Asthma: A chronic, reversible lung disease where airways constrict due to mast cell mediator release after encountering allergens like dust mites.

  • Anaphylaxis and Shock: A systemic response involving a massive release of vasoactive amines and cytokines. Results in smooth muscle contraction in the vasculature and diaphragm, vasodilation, a significant drop in blood pressure, and breathing difficulties.

Detailed Analysis of Type II Hypersensitivity

• General Characteristics:

  • Known as cytotoxic hypersensitivity or antibody-mediated disease.

  • Involves the destruction of host cells (e.g., $RBCs$) by $IgG$ or $IgM$ antibodies bound to cell-surface antigens.

• Mechanisms of Cell Killing:

  • Complement-Mediated Lysis: The antigen-antibody complex activates the complement cascade (a system of lytic enzymes inactive in the blood). Activation on the surface of a cell (like an $RBC$) leads to direct lysis.

  • Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC):

    • Antibody binds the target cell via the $Fab$ portion.

    • The $Fc$ region of the antibody binds to $Fc$ receptors on cytotoxic cells ($NK$ cells).

    • Cytotoxic cells release hydrolytic and digestive enzymes onto the target cell's surface to kill it.

  • Opsonization:

    • The $Fab$ region binds to the antigen.

    • Phagocytic cells (neutrophils, macrophages) bind the free $Fc$ region of the antibody.

    • This cross-linking activates the phagocytes and increases the rate of phagocytosis.

  • Antibody-Mediated Cellular Dysfunction:

    • Antibodies bind to critical cell-surface receptors, impairing or dysregulating function without causing cell injury or inflammation.

    • Myasthenia Gravis: Antibodies block Acetylcholine ($ACh$) receptors.

    • Graves’ Disease: Antibodies stimulate the Thyroid Stimulating Hormone ($TSH$) receptor.

• Hemolytic Disease of the Newborn (Rh Incompatibility):

  • An $Rh\text{-}negative$ mother carries an $Rh\text{-}positive$ baby.

  • During delivery, $Rh\text{-}positive$ fetal blood enters the mother's circulation.

  • The mother produces $Rh$ antibodies.

  • In a subsequent pregnancy with another $Rh\text{-}positive$ baby, these antibodies cross the placenta and attack the fetal blood cells.

Detailed Analysis of Type III Hypersensitivity

• General Characteristics:

  • Known as immune complex-mediated hypersensitivity.

  • Caused by the accumulation and precipitation of soluble antigen-antibody (immune) complexes in tissues (skin, joints, vessels, or glomeruli).

• Mechanism of Damage:

  1. Immune Complex Formation: Exposure to exogenous or endogenous antigens triggers antibody production, forming circulating complexes.

  2. Deposition: Small aggregates filter out of circulation and deposit in organs.

  3. Inflammation: Activation of the classical complement pathway releases split products $C3a$ and $C5a$.

  4. Recruitment: $C3a$ and $C5a$ cause mast-cell degranulation and increase permeability. Neutrophils are recruited to the site, binding to the $Fc$ region of the complexes.

  5. Damage: Neutrophils release proteolytic enzymes, pro-inflammatory cytokines, and reactive oxygen species, damaging the host tissue.

• Examples:

  • Systemic Lupus Erythematosus (SLE): Autoantibodies against $DNA$ form complexes that accumulate in synovial membranes (arthritis) or the kidney basement membrane. May include Raynaud Phenomenon (numbness/cyanosis in fingers during cold).

  • Rheumatoid Arthritis: Complexes accumulate in joints.

  • Serum Sickness: Reaction to medications or foreign proteins causing fever, rash, and joint pain.

  • Post-Streptococcal Glomerulonephritis: Complexes deposit in the kidneys.

Detailed Analysis of Type IV Hypersensitivity

• General Characteristics:

  • Known as Delayed-Type Hypersensitivity ($DTH$).

  • Mediated by $T$ cells rather than antibodies.

  • Reaches peak levels between $48\text{--}72\text{ hours}$ after the second encounter with the antigen.

• Sensitization Phase:

  1. $APC$ engulfs foreign antigen and presents it via $MHC\text{-}II$.

  2. $T$ helper ($Th1$) cells recognize the complex.

  3. Activated $T$ cells secrete cytokines and proliferate.

  4. Langerhans cells (dendritic cells in the epidermis) often act as the $APC$ for contact antigens.

• Effector Phase:

  1. Upon re-exposure, memory $Th1$ cells recognize the antigen and secrete cytokines (e.g., $IFN\text{-}\text{γ}$, $TNF\text{-}\text{α}$).

  2. These factors recruit and activate macrophages, the principal effector cells.

  3. Macrophages release enzymes and cytokines, resulting in localized inflammation, erythema, edema, and tissue damage.

• Examples:

  • Tuberculin Skin Test (Mantoux Test): Purified protein derivative ($PPD$) of tubercle bacilli is injected intradermally. Memory $Th1$ cells produce induration (a raised bump) within $48\text{--}72\text{ hours}$ if the person was previously exposed or vaccinated with $BCG$.

  • Contact Dermatitis: First exposure to substances like poison ivy, nickel, or latex involves a hapten (a small molecule that becomes immunogenic only after binding to a larger carrier protein in the body). Re-exposure triggers memory $Th1$ cells to recruit macrophages and $CD8+$ $T$ cells, causing redness and itching.

Comparative Summary Table