Hipersensitivitas

01Pathophysiology

Hypersensitivity reactions represent an exaggerated or misdirected immune response that causes tissue damage. The Gell and Coombs classification divides them into four types based on the effector mechanism involved. Understanding the mechanism behind each type is the key to predicting the timing of symptoms, the pattern of organ damage, and the diagnostic findings you will encounter in a vignette.

Type I (Immediate, IgE-mediated) occurs in two phases. During initial sensitization, antigen-presenting cells process the allergen and present it to Th2 helper cells, which release IL-4 and IL-13. These cytokines drive B-cell class switching to IgE production. The secreted IgE binds to high-affinity FcεRI receptors on mast cells and basophils (this is the sensitization phase, and no symptoms occur here). Upon re-exposure, the allergen cross-links two adjacent surface-bound IgE molecules, triggering mast cell degranulation. The immediate phase (within minutes) releases preformed mediators including histamine, proteases, and heparin, causing vasodilation, increased vascular permeability, and smooth muscle contraction. The late phase (4 to 8 hours later) involves newly synthesized mediators: leukotrienes (especially LTC4, LTD4, LTE4, which cause prolonged bronchoconstriction) and prostaglandins. This two-phase mechanism explains why a patient with anaphylaxis can have a biphasic reaction, initially improving and then deteriorating hours later.

Type II (Antibody-mediated, Cytotoxic) involves IgG or IgM antibodies directed against antigens on cell surfaces or in the extracellular matrix. Once bound, tissue damage occurs through three sub-mechanisms. First, complement activation via the classical pathway leads to formation of the membrane attack complex (MAC, C5b-C9), directly lysing the target cell. This is the mechanism in acute hemolytic transfusion reactions. Second, opsonization and phagocytosis occur when the Fc portion of the bound antibody is recognized by macrophages and neutrophils. This is the mechanism in autoimmune hemolytic anemia and hemolytic disease of the newborn. Third, antibody-mediated cellular dysfunction occurs without cell destruction; the antibody either stimulates or blocks a receptor. Graves disease (thyroid-stimulating antibodies activate the TSH receptor) and myasthenia gravis (antibodies block the acetylcholine receptor) are the classic exam examples of this non-cytotoxic sub-type.

Type III (Immune Complex-mediated) occurs when antigen-antibody complexes (usually IgG) form in the circulation and deposit in tissues, particularly in vessel walls, glomeruli, and joints. Small to intermediate-sized complexes are the most pathogenic because they evade clearance by the mononuclear phagocyte system. Once deposited, these complexes activate complement (consuming C3 and C4, which is why serum complement levels drop), recruit neutrophils via C5a (a potent chemotactic factor), and trigger an inflammatory response that damages the surrounding tissue. The resulting pattern is vasculitis, glomerulonephritis, and arthritis. The Arthus reaction is the localized form (antigen injected into skin of a pre-sensitized individual, causing local vasculitis in 4 to 10 hours), while serum sickness is the systemic prototype (widespread complex deposition causing fever, urticaria, arthralgia, lymphadenopathy, and proteinuria 7 to 14 days after antigen exposure).

Type IV (Delayed-type, Cell-mediated) is the only type that does not involve antibodies. Instead, T lymphocytes are the effector cells. Upon initial antigen exposure, antigen-presenting cells (particularly dendritic cells and macrophages) process the antigen and present it via MHC class II to naive CD4+ T cells, which differentiate into Th1 cells. On re-exposure, sensitized Th1 cells recognize the antigen and release cytokines (IFN-gamma, TNF-alpha, IL-2). IFN-gamma activates macrophages, which become the primary effectors causing tissue damage. This process takes 24 to 72 hours, which is why it is called "delayed-type." Granuloma formation occurs when macrophages cannot eliminate the antigen (as in tuberculosis or sarcoidosis); they fuse into multinucleated giant cells and become surrounded by a rim of lymphocytes. CD8+ cytotoxic T cells also participate in certain Type IV reactions (such as contact dermatitis and graft rejection), directly killing target cells through perforin and granzyme release.

02Classification and Clinical Manifestation

Type II sub-classification (high-yield for exam questions):

Type IV sub-classification:

03Diagnostic Workup

For Type I, when a patient presents with acute anaphylaxis (hypotension, urticaria, bronchospasm minutes after an exposure), the diagnosis is clinical. The best confirmatory lab is serum tryptase, drawn within 1 to 3 hours of symptom onset. A normal tryptase does not rule out anaphylaxis, but an elevated level strongly supports it. Once the patient is stable, skin prick testing is the best initial test to identify the offending allergen. If skin testing is contraindicated (patient cannot stop antihistamines, extensive skin disease, or history of life-threatening reaction to the suspected allergen), serum allergen-IgE (ImmunoCAP) is the alternative.

For Type II, the workup depends on the target antigen. In suspected autoimmune hemolytic anemia, the direct Coombs test is the best initial test. It detects antibodies or complement already bound to the patient's own red blood cells. The indirect Coombs test detects free antibodies in the serum and is used for cross-matching blood before transfusion and for diagnosing HDN in the mother. For organ-targeted Type II reactions such as Goodpasture syndrome, the key diagnostic finding is linear immunofluorescence on kidney or lung biopsy (anti-GBM antibodies depositing in a smooth, continuous line along the basement membrane). This linear pattern distinguishes Type II from Type III, where the immunofluorescence pattern is granular.

For Type III, the hallmark lab finding is low serum complement (C3 and C4 consumed by immune complex activation of the classical pathway). In SLE, order anti-dsDNA antibodies and complement levels together; a rising anti-dsDNA titer with falling complement levels indicates active disease and is the most tested combination for monitoring lupus nephritis. Renal biopsy with immunofluorescence showing granular ("lumpy-bumpy") deposits of IgG and C3 is the gold standard for confirming immune complex glomerulonephritis.

For Type IV, the patch test is the most accurate test for identifying contact allergens. A panel of common allergens is applied to the skin under occlusion, and the site is read at 48 and 72 hours. For TB screening, the PPD (Mantoux test) relies on the same Type IV mechanism: intradermal injection of purified protein derivative, read at 48-72 hours by measuring induration (not erythema). The IGRA is an alternative that is preferred in BCG-vaccinated individuals because it does not cross-react with the vaccine.

04Management and Treatment

Anaphylaxis is the highest-priority management topic. The single most important step is intramuscular epinephrine into the anterolateral thigh. This is always the correct "next best step" regardless of what other interventions are listed. Epinephrine reverses all the pathologic features of anaphylaxis: it causes bronchodilation (beta-2), increases vascular tone and blood pressure (alpha-1), increases cardiac output (beta-1), and decreases mast cell degranulation. Antihistamines and corticosteroids are adjuncts that help with urticaria and may reduce the risk of a biphasic reaction, but they do not reverse airway obstruction or shock and should never be given instead of epinephrine.

For Type II reactions, the principle is to stop the antibody-mediated destruction. In AIHA, corticosteroids suppress antibody production and reduce splenic clearance of opsonized red blood cells. If steroids fail, rituximab (a monoclonal antibody targeting CD20 on B cells) reduces the population of antibody-producing cells. In Goodpasture syndrome, plasmapheresis physically removes anti-GBM antibodies from the circulation and is the cornerstone of acute treatment, combined with immunosuppression to prevent new antibody formation.

For Type III reactions, the first step is always removal of the offending antigen if identifiable. In serum sickness, this means discontinuing the causative drug (often a foreign protein such as anti-thymocyte globulin or certain antibiotics). Corticosteroids suppress the inflammatory cascade triggered by complement activation and immune complex deposition.

For Type IV reactions, treatment centers on antigen avoidance and corticosteroids. In contact dermatitis, topical steroids are sufficient for localized disease. For extensive involvement (more than 20% body surface area or involving the face and genitalia), systemic corticosteroids with a taper of at least 2 to 3 weeks are necessary. A common exam trap is prescribing a short 5-day steroid burst for poison ivy contact dermatitis, which leads to rebound flare once the prednisone is stopped.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get hypersensitivity questions wrong is by confusing the type based on timing and mechanism. Exam writers rely on your ability to match the clinical timeline to the underlying immune process. If symptoms appear within minutes, think Type I (IgE). If there is evidence of cell destruction with a positive Coombs test, think Type II. If the vignette describes fever, arthralgia, and rash occurring 1 to 2 weeks after a new drug or foreign protein exposure, that is serum sickness (Type III), not a drug allergy (Type I). If the rash appears 48 to 72 hours after skin contact with a known sensitizer, that is contact dermatitis (Type IV), even though the patient will describe it as an "allergic reaction."

A second trap involves the immunofluorescence pattern on renal biopsy. Linear staining means antibodies are targeting the basement membrane directly (Type II, Goodpasture). Granular staining means pre-formed immune complexes have deposited along the membrane (Type III, as in lupus nephritis or PSGN). Students who do not memorize this distinction will choose the wrong type and the wrong treatment.

A third common mistake involves anaphylaxis management. The question stem may offer IV diphenhydramine, IV methylprednisolone, and IV normal saline alongside IM epinephrine. The correct "next best step" is always IM epinephrine first. Students who select antihistamines or steroids are choosing adjuncts over the life-saving intervention. Another variant of this trap: the patient initially improves after treatment, then deteriorates 6 hours later. This is the biphasic reaction, driven by the late-phase response (leukotriene-mediated). The correct answer is to re-administer epinephrine, not to increase the antihistamine dose.

A fourth pearl: Graves disease and myasthenia gravis are both classified as Type II even though no cell is destroyed. This is because the mechanism involves an antibody binding a cell-surface receptor. The antibody in Graves disease stimulates the TSH receptor (causing hyperthyroidism), while the antibody in myasthenia gravis blocks the acetylcholine receptor (causing weakness). Students often misclassify these as Type III or Type IV because there is no hemolysis, but the classification is determined by the mechanism (antibody against a surface antigen), not by the outcome (lysis vs. dysfunction).

The core competency being tested across all hypersensitivity questions is your ability to identify the immune mechanism from the clinical scenario, connect it to the correct type, choose the appropriate diagnostic test, and sequence the management correctly.