Which type of hypersensitivity reaction has the longest delay in onset, specifically referring to a Type IV (cell-mediated) hypersensitivity reaction?

From the Guidelines

Type IV hypersensitivity reactions, specifically cell-mediated hypersensitivity, have the longest delay in onset, typically occurring 24-72 hours after exposure to the triggering antigen. This is evident from the reaction to intracutaneously injected tuberculin, a classic example of a delayed hypersensitivity reaction, which reaches its peak more than 24 hours after injection, with maximal induration at 48 to 72 hours 1. The delayed course of this reaction is due to the time required for T cells to recognize the antigen, release lymphokines, and induce induration through local vasodilatation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area. Key features of this reaction include:

• Its delayed course, reaching a peak more than 24 hours after injection of the antigen
• Its indurated character
• Its occasional vesiculation and necrosis
• Reactivity of the PPD provides a general measure of a person’s cellular immune responsiveness, as noted in the study published in the American Journal of Respiratory and Critical Care Medicine 1. Some individuals, such as the elderly or those being tested for the first time, may experience a delayed reaction that does not peak until after 72 hours, but this does not alter the interpretation of the test. Immediate hypersensitivity reactions to tuberculin or constituents of the diluent can also occur but are distinct from delayed hypersensitivity reactions and typically disappear by 24 hours. The understanding of this delayed-type hypersensitivity is crucial for distinguishing it from other types of hypersensitivity reactions and for guiding appropriate treatment and management strategies.

From the Research

Type IV Hypersensitivity Reaction

• Type IV hypersensitivity reaction, also known as cell-mediated or delayed-type hypersensitivity, is characterized by a delayed onset, typically occurring 48-72 hours after exposure to the antigen 2.
• The reaction involves the activation of T cells, specifically CD4+ and CD8+ T cells, which release cytokines and chemokines, leading to inflammation and tissue damage 2, 3.
• The delayed onset of Type IV hypersensitivity reaction is due to the time required for T cell activation, proliferation, and differentiation into effector cells 4.

Subtypes of Type IV Hypersensitivity Reaction

• Type IV hypersensitivity reaction has been subclassified into four subtypes: IVa, IVb, IVc, and IVd, each with distinct cytokine profiles and clinical manifestations 2.
• Type IVa is characterized by Th1 cells and monocyte-directed cytokines, such as IFN-γ and IL-1, and is often associated with contact dermatitis 2.
• Type IVc is characterized by CD8+ T cells and cytotoxic cytokines, such as perforin and granzyme B, and is often associated with bullous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis 2.
• Type IVd is characterized by CD4+ and CD8+ T cells and neutrophil-directed cytokines, such as IL-8 and GM-CSF, and is often associated with pustular exanthema reactions, such as acute generalized exanthematous pustulosis (AGEP) 2.

Diagnostic Approaches

• Diagnostic approaches for delayed-type hypersensitivity reactions include patch testing, delayed intradermal testing, and drug challenges, as well as in vitro assays, such as lymphocyte transformation test (LTT) and cytokine release enzyme-linked ImmunoSpot (ELISpot) assay 5, 4.
• Genetic markers, such as human leukocyte antigen (HLA), have also been identified as potential diagnostic tools for delayed-type hypersensitivity reactions 5, 3.