Type Iv HypersensitivityEdit

Type IV hypersensitivity, also known as delayed-type hypersensitivity, is a form of immune reaction that relies on antigen-specific T cells rather than antibodies. It is one of the four traditional categories of hypersensitivity reactions, alongside Type I, Type II, and Type III. Because it is mediated by cell-based immunity, the clinical manifestations usually appear after a lag—typically 24 to 72 hours—following exposure to the offending antigen. The reaction reflects coordination between antigen-presenting cells, T lymphocytes, and activated macrophages, and it can drive processes ranging from localized dermatitis to granulomatous inflammation and tissue injury in affected organs.

In Type IV hypersensitivity, the central players are T cells. Antigens are captured by professional antigen-presenting cells (such as dendritic cells and, in the skin, Langerhans cells) and presented to T cells in the context of major histocompatibility complex (MHC) molecules. Upon re-exposure, sensitized T cells release cytokines that recruit and activate macrophages and other inflammatory cells, leading to tissue damage. This arm of the immune system is important for defense against intracellular pathogens but can cause pathology when responses are excessive or misdirected. See how this contrasts with antibody-mediated processes in hypersensitivity and with other primary immune mechanisms involving cytotoxic T lymphocytes and helper T cell.

Mechanisms

  • sensitization and elicitation
    • Initial exposure to a contactant or antigen leads to uptake by antigen-presenting cells and presentation to naive T cells. A pool of memory T cells is generated, primed to respond upon subsequent encounters. The elicitation phase occurs when the antigen is encountered again; previously primed T cells activate and secrete cytokines that recruit macrophages and other effector cells to the site of exposure.
    • Key cytokines include interferon-gamma (IFN-γ) and interleukin-2 (IL-2), which activate macrophages and promote sustained inflammation. Depending on the subset of T cells involved, other cytokine patterns can emerge.
  • subtypes (IVa to IVd)
    • IVa: Th1-dominated responses with macrophage activation and granuloma formation in contexts such as tuberculin reactions and certain forms of contact dermatitis.
    • IVb: cytokine patterns that may recruit eosinophils and involve different chemokines, contributing to eosinophil-rich infiltrates in some reactions.
    • IVc: primarily cytotoxic CD8+ T cells that can directly kill antigen-expressing cells, as seen in some drug-related reactions and graft contexts.
    • IVd: T cells that produce neutrophil-attracting chemokines (e.g., IL-8), leading to neutrophilic inflammation in select settings.
  • tissues and histology
    • The hallmark is accumulation of T cells and macrophages at the site of antigen exposure, often with granuloma formation in persistent or difficult-to-eradicate antigenic stimuli. Skin, ocular, pulmonary, and musculoskeletal tissues can be involved depending on the antigen and exposure route.

Clinical manifestations

  • contact dermatitis
    • Common examples include reactions to metals such as nickel, fragrances, preservatives, and plant-derived haptens like urushiol from poison ivy. The eruption is typically pruritic, with erythema, vesiculation, and epithelial involvement at the contact site.
  • tuberculin and other skin test reactions
    • Intradermal injection of certain antigens (e.g., purified protein derivatives) elicits a delayed induration and erythema reaction in individuals previously sensitized to the antigen. These tests illustrate a classic Type IV mechanism and are used for screening and diagnosis of latent or active infections.
  • granulomatous inflammation
    • Persistent antigenic stimulation can lead to granuloma formation, as seen in chronic infections (e.g., certain mycobacterial infections) and noninfectious conditions such as granulomatous diseases. Histology often shows organized collections of macrophages, sometimes fused into giant cells, surrounded by lymphocytes.
  • drug reactions and graft-related processes
    • Some drug-induced reactions and immune-mediated graft responses involve cytotoxic T cells that target antigen-expressing cells, potentially causing extensive tissue injury in organs such as skin or mucosa. The pattern and severity can range from mild dermatitis to life-threatening mucocutaneous disease.

Diagnosis

  • history and exposure assessment
    • Identifying prior sensitization to a chemical, metal, plant-derived hapten, or other antigen helps determine the likelihood of a Type IV reaction.
  • skin testing and patch testing
    • Patch testing is used to identify contact allergens by applying suspected agents to the skin and observing for a delayed reaction. Patch test results require controlled interpretation and clinical correlation.
  • biopsy and histology
    • In uncertain cases, tissue biopsy from affected sites may reveal a lymphocytic and macrophage-rich infiltrate with features consistent with a Type IV process, and may show granuloma formation in chronic or ongoing reactions.
  • laboratory and imaging studies
    • Laboratory tests are generally adjunctive, helping to exclude other forms of hypersensitivity or infectious etiologies. Imaging may be employed when organ involvement or systemic disease is suspected.

Treatment and management

  • avoidance and exposure control
    • Identifying and avoiding the offending antigen is central to long-term management for many contact-related Type IV reactions.
  • anti-inflammatory therapy
    • Topical corticosteroids are commonly used for localized skin reactions. Systemic corticosteroids may be considered for extensive or severe disease, though their use is balanced against potential side effects and is guided by clinical judgment.
  • immunomodulatory approaches
    • In persistent or systemic forms, additional therapies that modulate T-cell responses or macrophage activity can be considered. The choice of therapy depends on the organ involved, the severity of disease, and individual patient risk factors.
  • management of specific contexts
    • In transplant medicine or GVHD-like contexts, interventions aim to balance immune suppression with infection risk and overall graft function. In infectious settings associated with granulomatous inflammation, antimicrobial therapy is tailored to the underlying pathogen.

See also