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Immunology

I, II, III, & IV

Let’s discuss one of the most clinically relevant concepts in immunology: Hypersensitivity. This is what happens when our normally protective immune system goes into overdrive, responding to an antigen in an exaggerated or inappropriate way that ends up causing tissue damage and disease. It’s the very definition of “the cure is worse than the disease.” It’s not a failure to respond, but an over-enthusiastic response that causes collateral damage

The classic framework for understanding these reactions is the Gell and Coombs classification, which divides them into four types. As an MLS, you must know these inside and out, because they are the fundamental mechanisms behind allergies, transfusion reactions, autoimmune diseases, and even our tests for tuberculosis

To make this memorable, think of the four types as four different kinds of military or espionage operations gone wrong: * Type I: A rapid, explosive trap triggered by a spy (IgE) * Type II: A targeted assassination against a specific “tagged” cell * Type III: Collateral damage from a messy battle, leaving behind debris (immune complexes) that clogs up vital systems * Type IV: A delayed ground assault led by troops (T-cells), not missiles (antibodies)

Type I: The Immediate “Allergy Alarm”

This is the classic allergic reaction. It is immediate, powerful, and mediated by IgE antibodies

  • Core Concept: An antibody (IgE) arms a landmine (a mast cell), which then detonates upon a second exposure to the antigen (allergen)
  • Key Players: IgE, Mast Cells, Basophils, and their inflammatory mediator, Histamine
  • Mechanism (A Two-Act Play)
    1. Sensitization Phase (First Exposure) A person is exposed to an allergen (e.g., pollen). Their immune system inappropriately produces IgE antibodies against it. This IgE doesn’t stay in the blood; its Fc region binds with very high affinity to Fc receptors on the surface of mast cells in the tissues and basophils in the blood. This process is silent—the person has no symptoms. The “landmine” is now armed and waiting
    2. Activation/Effector Phase (Subsequent Exposures) The person is exposed to the same allergen again. The allergen binds to the Fab portions of the IgE that is already coating the mast cells. This cross-linking of the IgE molecules sends a powerful activation signal into the mast cell, causing it to degranulate—instantly releasing a flood of pre-formed inflammatory mediators, most famously histamine
  • Timing: Extremely rapid, with symptoms developing within minutes of exposure
  • Clinical/Laboratory Examples
    • Localized Reactions: Allergic rhinitis (hay fever), food allergies, hives (urticaria), and asthma
    • Systemic Anaphylaxis: The most dangerous outcome. Widespread mast cell degranulation causes massive vasodilation and bronchoconstriction, leading to a life-threatening drop in blood pressure and airway closure
    • Laboratory Diagnosis: We can measure a patient’s total IgE level, but it’s more clinically useful to measure allergen-specific IgE in the serum (using methods like RAST or modern immunoassays) to identify the specific trigger

Type II: The Targeted Cytotoxic Attack

This reaction involves antibodies (IgG or IgM) that are directed against antigens on the surface of a specific cell or tissue. The antibody acts like a tag, marking the cell for destruction

  • Core Concept: “Friendly fire.” An antibody directly binds to a cell, marking it for destruction by the immune system’s killer machinery
  • Key Players: IgG, IgM, Complement, Phagocytes, and NK cells. The target is a cell-surface antigen
  • Mechanisms of Damage (Three ways to destroy)
    1. Complement-Mediated Lysis The IgG or IgM antibody binds to the cell. Its Fc region activates the classical complement pathway, leading to the formation of the Membrane Attack Complex (MAC), which punches holes in the cell and causes it to lyse
    2. Opsonization and Phagocytosis The cell is coated with IgG. Phagocytes (like macrophages) have Fc receptors that recognize and bind to the IgG-coated cell, leading to its engulfment and destruction
    3. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Natural Killer (NK) cells use their Fc receptors to bind to the IgG-coated cell and release cytotoxic granules to kill it directly
  • Timing: Tends to occur within hours to a day
  • Clinical/Laboratory Examples
    • Transfusion Reactions: A patient with type A blood is given type B blood. Their pre-formed anti-B antibodies (IgM) immediately attack the donor red blood cells, causing massive intravascular hemolysis
    • Hemolytic Disease of the Fetus and Newborn (HDFN): An Rh-negative mother develops IgG anti-D antibodies against her Rh-positive fetus. These IgG antibodies cross the placenta and destroy the fetal red blood cells
    • Autoimmune Examples: Goodpasture’s syndrome (antibodies attack the basement membrane of the kidneys and lungs) and the unique case of Graves’ disease, where the antibody doesn’t destroy the cell but stimulates the TSH receptor, causing hyperthyroidism
    • Laboratory Diagnosis: The key test is the Direct Antiglobulin Test (DAT), which detects if a patient’s red blood cells are coated with antibody in vivo

Type III: The “Clogged Filter” Damage

This reaction is also mediated by IgG or IgM, but the problem isn’t an attack on a specific cell. Instead, the damage is caused by the deposition of soluble antigen-antibody immune complexes in tissues

  • Core Concept: The “debris” from an antigen-antibody battle (immune complexes) isn’t cleared properly, gets stuck in the small blood vessels of various organs, and causes inflammation
  • Key Players: IgG, Soluble Antigen, Immune Complexes, and Complement
  • Mechanism
    1. A large amount of soluble antigen and IgG antibody are present in the bloodstream, leading to the formation of many small immune complexes
    2. These complexes are not cleared efficiently by the phagocytic system. They circulate and get trapped in the basement membranes of small blood vessels, particularly in the kidneys (glomeruli), joints, and skin
    3. Wherever they deposit, these complexes are potent activators of the classical complement pathway
    4. Complement activation generates C3a and C5a, which are powerful anaphylatoxins that recruit neutrophils to the site. The frustrated neutrophils release their lytic enzymes in an attempt to clear the indestructible complexes, causing inflammation and damage to the surrounding healthy tissue (vasculitis)
  • Timing: The reaction develops over hours to days
  • Clinical/Laboratory Examples
    • Systemic Lupus Erythematosus (SLE): The quintessential Type III disease. Autoantibodies against nuclear antigens form immune complexes that deposit in the kidneys, causing lupus nephritis
    • Post-Streptococcal Glomerulonephritis: Following a strep infection, immune complexes formed between strep antigens and anti-strep antibodies deposit in the kidney glomeruli
    • Arthus Reaction: A localized Type III reaction seen in the skin, causing redness and swelling
    • Laboratory Diagnosis: We can detect the specific autoantibodies (like ANA or anti-dsDNA in lupus) and measure complement levels (C3 and C4). During active disease, C3 and C4 will be decreased because they are being consumed by the immune complex deposition

Type IV: The Delayed T-Cell Ground Assault

This is the only type of hypersensitivity that is not mediated by antibodies. Instead, it is a delayed reaction driven entirely by T-cells

  • Core Concept: This is not a rapid missile strike; it’s a full-scale ground invasion by an army of T-cells that takes time to mobilize and arrive at the scene
  • Key Players: T-lymphocytes (specifically CD4+ T-helper cells and CD8+ cytotoxic T-cells) and the cytokines they produce
  • Mechanism (A Two-Phase Mobilization)
    1. Sensitization Phase (First Exposure) An antigen (e.g., a chemical from poison ivy) is processed by an antigen-presenting cell (like a Langerhans cell in the skin) and presented to a naive CD4+ T-helper cell. This activates the T-cell and turns it into a long-lived memory T-cell. This is a silent process
    2. Elicitation Phase (Subsequent Exposures) Upon re-exposure, the memory T-cells are rapidly activated
      • CD4+ T-cells: release a flood of cytokines (like interferon-gamma and TNF-alpha) that recruit and activate a large number of macrophages. It is the activated macrophages and their destructive enzymes that cause the bulk of the tissue damage and inflammation
      • In some cases, CD8+ Cytotoxic T-cells directly recognize antigen on host cells and kill them
  • Timing: The response is characteristically delayed, taking 24-72 hours to develop, which is the time required to mobilize the T-cells and macrophages
  • Clinical/Laboratory Examples
    • Contact Dermatitis: The classic skin rash caused by exposure to poison ivy, nickel, or latex
    • Tuberculin (PPD) Skin Test: A perfect diagnostic example. A small amount of tuberculin antigen is injected into the skin of someone who has been previously exposed to Mycobacterium tuberculosis. If they have memory T-cells, a localized Type IV reaction will occur, causing a hard, red bump (induration) to form over 48-72 hours
    • Granulomatous Inflammation: Seen in diseases like tuberculosis and sarcoidosis, where T-cells wall off a pathogen they cannot eliminate, forming a structure called a granuloma