Types and Mechanisms of Hypersensitivity Reactions
Introduction to Hypersensitivity
Hypersensitivity reactions happen when the immune system responds excessively or inappropriately to an antigen, causing tissue damage instead of protection. These reactions range from mild allergic symptoms to life-threatening emergencies like anaphylaxis.
The Gell and Coombs classification divides hypersensitivities into four types based on the immune mechanism involved. Types I, II, and III are antibody-mediated (involving different immunoglobulin classes), while Type IV is cell-mediated (driven by T cells rather than antibodies). This distinction matters because it determines how quickly symptoms appear, what kind of tissue damage occurs, and how you treat the condition.
Types of Hypersensitivity Reactions
Type I (Immediate) Hypersensitivity
Type I reactions are the classic "allergies" most people think of. They're mediated by IgE antibodies and unfold in two phases:
- Sensitization phase: On first exposure to an allergen (pollen, peanut protein, bee venom, etc.), the immune system produces IgE antibodies specific to that allergen. These IgE molecules bind to receptors on mast cells (in tissues) and basophils (in blood), essentially "arming" them.
- Re-exposure and degranulation: On subsequent exposure, the allergen cross-links two adjacent IgE molecules on the mast cell surface. This triggers degranulation, releasing preformed mediators like histamine, along with newly synthesized leukotrienes and prostaglandins.
These mediators cause vasodilation, smooth muscle contraction, increased vascular permeability, and mucus secretion. The clinical result depends on where the reaction occurs:
- Localized: allergic rhinitis (nasal passages), asthma (bronchioles), hives (skin)
- Systemic: anaphylaxis, a rapid, whole-body response that can cause airway constriction, a dangerous drop in blood pressure, and death if untreated
Because mast cells release preformed mediators, symptoms can begin within minutes of exposure.
Type II (Antibody-Mediated/Cytotoxic) Hypersensitivity
In Type II reactions, IgG or IgM antibodies bind directly to antigens on the surface of host cells. This is different from Type I, where antibodies sit on mast cells waiting for free-floating allergen. Here, the antibodies target cells themselves.
Once antibodies coat the cell surface, destruction happens through several pathways:
- Complement activation: The classical complement pathway is triggered, forming a membrane attack complex (MAC) that lyses the target cell.
- Opsonization and phagocytosis: Complement fragments (like C3b) and the Fc region of the bound antibody tag the cell for destruction by phagocytes.
- Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells recognize the Fc portion of bound antibodies and kill the coated cell.
Examples include autoimmune hemolytic anemia (antibodies target your own red blood cells), Goodpasture syndrome (antibodies attack basement membranes in the kidneys and lungs), and transfusion reactions from mismatched blood.
Type III (Immune Complex-Mediated) Hypersensitivity
Type III reactions involve antigen-antibody complexes (immune complexes) that form in the blood and then deposit in tissues, especially in blood vessel walls, joints, and kidney glomeruli.
Normally, immune complexes are cleared by phagocytes. Problems arise when complexes form in excess or aren't cleared efficiently:
- Soluble antigen-antibody complexes circulate in the bloodstream.
- Complexes deposit in tissues, particularly where blood is filtered or flow is turbulent.
- Deposited complexes activate complement, generating chemotactic factors (C3a, C5a) that recruit neutrophils.
- Neutrophils attempt to phagocytose the complexes but release lysosomal enzymes and reactive oxygen species, damaging surrounding tissue.
Examples include serum sickness (a systemic reaction to foreign proteins), systemic lupus erythematosus (SLE), and the Arthus reaction (a localized response at an injection site).
The key difference between Type II and Type III: In Type II, antibodies bind antigens on cell surfaces. In Type III, antibodies bind soluble antigens to form circulating complexes that deposit elsewhere.
Type IV (Delayed-Type) Hypersensitivity
Type IV is the only hypersensitivity that does not involve antibodies. Instead, it's driven by T cells (primarily CD4+ T helper cells and sometimes CD8+ cytotoxic T cells). Because T cell recruitment and activation take time, symptoms don't appear until 24–72 hours after exposure.
The process works like this:
- Antigen-presenting cells (APCs) process the antigen and present it to T cells.
- Sensitized T helper cells release cytokines (like IFN-γ and TNF) that recruit and activate macrophages.
- Activated macrophages cause localized inflammation and tissue damage.
Classic examples:
- Contact dermatitis from poison ivy, nickel, or latex (the allergen is a hapten that binds to skin proteins)
- Tuberculin skin test (PPD/Mantoux test): A positive result (induration at the injection site after 48–72 hours) indicates prior sensitization to Mycobacterium tuberculosis antigens
- Graft rejection (the cellular component)
Blood Type Incompatibility Issues
Blood type incompatibilities are clinically important examples of Type II hypersensitivity. They involve antibodies targeting antigens on red blood cell surfaces.
ABO Blood Types
Four main blood types are determined by the presence or absence of A and B carbohydrate antigens on the red blood cell surface:
| Blood Type | Antigens on RBCs | Antibodies in Serum | Can Receive From |
|---|---|---|---|
| A | A | Anti-B | A, O |
| B | B | Anti-A | B, O |
| AB | A and B | Neither | A, B, AB, O (universal recipient) |
| O | Neither | Anti-A and Anti-B | O only (universal donor) |
| A critical detail: ABO antibodies are naturally occurring (they form early in life due to exposure to similar antigens on gut bacteria), so a transfusion reaction can happen on the first mismatched transfusion. You don't need prior sensitization. These natural antibodies are primarily IgM, which is very efficient at activating complement, making ABO mismatches potentially fatal. |
When mismatched blood is transfused, recipient antibodies bind donor RBCs, causing agglutination (clumping) and hemolysis (lysis via complement). This can lead to kidney failure, shock, and death.
Rh Factor
The Rh(D) antigen is either present (Rh+) or absent (Rh−) on red blood cells. Unlike ABO, Rh− individuals do not have naturally occurring anti-Rh antibodies. They only produce them after exposure to Rh+ blood (through transfusion or pregnancy).
Once sensitized, subsequent exposure to Rh+ blood triggers a rapid secondary immune response with IgG antibodies that destroy Rh+ red blood cells.
Hemolytic Disease of the Newborn (HDN)
HDN is the most clinically significant consequence of Rh incompatibility:
- An Rh− mother carries an Rh+ fetus (the fetus inherited the Rh antigen from the father).
- During delivery (or trauma/miscarriage), fetal Rh+ red blood cells enter the mother's circulation.
- The mother's immune system recognizes the Rh antigen as foreign and produces anti-Rh IgG antibodies. This usually doesn't affect the first pregnancy because sensitization happens late.
- In a subsequent pregnancy with another Rh+ fetus, the mother's anti-Rh IgG crosses the placenta (IgG is the only antibody class that can do this) and attacks fetal red blood cells.
- The fetus develops hemolytic anemia, which can cause jaundice (from bilirubin buildup), and in severe cases, hydrops fetalis (dangerous fluid accumulation).
Prevention: Rh− mothers receive RhoGAM (Rh immunoglobulin) at around 28 weeks of pregnancy and within 72 hours after delivery. RhoGAM contains anti-Rh antibodies that bind and clear any fetal Rh+ cells in the mother's blood before her immune system can mount its own response. This prevents sensitization.
Diagnosis and Treatment of Hypersensitivities
Type I Hypersensitivity
- Diagnosis: Skin prick tests (small amounts of allergen introduced into the skin; a wheal-and-flare response indicates sensitization), serum IgE levels (total and allergen-specific), basophil activation tests
- Treatment: Allergen avoidance is first-line. Antihistamines block histamine receptors to reduce symptoms. Epinephrine (EpiPen) is the emergency treatment for anaphylaxis because it reverses bronchospasm and hypotension. Desensitization (immunotherapy) involves gradually increasing allergen doses to shift the immune response from IgE toward IgG production.
Type II Hypersensitivity
- Diagnosis: Direct Coombs test detects antibodies already bound to RBCs (useful for diagnosing autoimmune hemolytic anemia or HDN). Indirect Coombs test detects free anti-RBC antibodies in serum (used for blood cross-matching). Tissue biopsy may show antibody and complement deposition.
- Treatment: Corticosteroids and immunosuppressants reduce the immune response. Plasmapheresis physically removes circulating antibodies from the blood.
Type III Hypersensitivity
- Diagnosis: Decreased serum complement levels (complement is being consumed by immune complex activation), tissue biopsy showing immune complex deposits, immunofluorescence staining reveals characteristic granular patterns of antibody/complement deposition
- Treatment: Corticosteroids and immunosuppressants to control inflammation. Plasmapheresis to remove circulating immune complexes.
Type IV Hypersensitivity
- Diagnosis: Patch testing (suspected allergens applied to the skin under adhesive patches for 48 hours; redness and induration indicate a positive result), lymphocyte transformation tests
- Treatment: Avoiding the triggering antigen. Topical or systemic corticosteroids to reduce the T cell-mediated inflammatory response.
Immune Tolerance and Hypersensitivity
Immune tolerance is the process by which the immune system learns not to attack self-antigens and harmless foreign substances. When tolerance breaks down, the result can be hypersensitivity reactions or autoimmune disease.
Tolerance operates at two levels:
- Central tolerance: During development in the thymus (T cells) and bone marrow (B cells), lymphocytes that strongly react to self-antigens are eliminated through clonal deletion (apoptosis). This removes the most dangerous self-reactive cells before they ever enter circulation.
- Peripheral tolerance: Some self-reactive lymphocytes escape central tolerance and reach the periphery. They're kept in check by mechanisms like anergy (functional inactivation when a T cell encounters antigen without proper co-stimulation), regulatory T cells (Tregs) that actively suppress immune responses, and activation-induced cell death.
Several factors influence whether tolerance holds or breaks down:
- Genetic predisposition: Certain HLA (MHC) alleles are associated with higher risk of specific hypersensitivities and autoimmune diseases
- Environmental exposures: Infections, chemical exposures, and changes in the microbiome can trigger or worsen hypersensitivity in genetically susceptible individuals
- Regulatory T cells: Tregs expressing CD4, CD25, and the transcription factor FoxP3 are critical for maintaining peripheral tolerance. Defects in Treg function are linked to autoimmune and allergic diseases