Type IV hypersensitivity reactions differ from other types in various ways:

- It is delayed type (occurs after 48–72 hours of antigen exposure)

- It is cell-mediated; characteristic cells called TDTH cells (delayed type of hypersensitivity T cells) are the principal mediators of type IV reactions

- Tissue injury occurs predominantly due to activated macrophages.

Mechanism of Type IV Reactions

Type IV hypersensitivity reactions occur through two phases—(1) sensitization and (2) effector phases (Figs 1A and B).

Fig1. A and B: Mechanism of delayed type hypersensitivity: A. Sensitization phase; B. Effector phase.

 Abbreviations: APCs, antigen presenting cells; MHC, major histocompatibility complex; TNF, tumor necrosis factor; IFN, interferons; DTH, delayed type hypersensitivity; MCAF, monocyte chemotactic and activating factor; MIF migration inhibitory factor; GM-CSF, granulocyte monocyte colony stimulating factor.

Sensitization Phase

 This is the initial phase of 1–2 weeks occurring following antigenic exposure (Fig. 1A).

- During this period, the antigen presenting cells (APCs) process and present the antigenic peptides along with MHC-II to the helper T cells. TH cells are differentiated to form T_DTH cells  

- Most T_DTH cells are derived from TH 1 cells; but occasionally other T cells, such as CD8+ T cells and CD4+ TH 17 can also act as T_DTH cells.

 Effector Phase

 The T_DTH cells, on subsequent contact with the antigen, secrete variety of cytokines which attract and recruit various inflammatory cells (e.g. macrophages) at the site of DTH reaction (Fig. 1B).

Role of DTH: Protective vs Tissue Damage Response

 Through type IV hypersensitivity reactions, host attempts to provide defense against many intracellular microorganisms such as M. tuberculosis as well as several chemicals and nickel salts (Table 1). Always, the attempts do not result in protection.

Table1. examples of delayed-type hypersensitivity (DtH).

Protective Response

 Under normal circumstances, the pathogens are usually cleared with little tissue damage; mediated by the enhanced microbicidal potency of activated macrophages.

Tissue Damage Response

 However, in conditions, when the intracellular microbes escape the macrophage killing mechanisms; the enhanced phagocytic activity and release of various lytic enzymes by the activated macrophages in an attempt to kill the pathogen leads to nonspecific tissue destruction.

Pathology of DTH Reaction (Granuloma Formation)

Continuous DTH reaction for killing the intracellular microbes (especially persistent and/or nondegradable antigens) leads to formation of granuloma (e.g. tubercles in leprosy and tuberculosis).

- The initial TH cell infiltrate is progressively replaced by macrophages in 2–3 weeks. Macrophages transform into two type of cells:

 1. They become large, flat, and eosinophilic; denoted as epithelioid cells

2. The epithelioid cells occasionally fuse (induced by IFN-γ) to form multinucleated giant cells.

 Granuloma consists of an inner zone of epithelioid cells, typically surrounded by a collar of lymphocytes and a peripheral rim of fibroblasts and connective tissue (Fig. 2).

Fig2. Structure of granuloma.

Tuberculin Test

Tuberculin test

 is the prototype of delayed hypersensitivity. In sensitized individuals, (i.e. who possess sensitized TDTH cells due to prior contact with M. tuberculosis); when a preparation of tuberculin antigen (glycerol extract of the tubercle bacillus) is injected intradermally, a local reaction develops after 48–72 hours consisting of induration surrounded by erythema.

Contact Dermatitis

 Many antigens such as nickel, poison oak, etc. (Table 16.6) act by producing DTH response:

- Most of these substances are haptens; they complex with skin proteins, which act as carrier to make the haptens immunogenic

- This hapten-skin protein complex is internalized by skin APCs (e.g. Langerhans cells), then presented to TH cells to induce a TDH reaction

- Activated macrophages release lytic enzymes which result in skin lesions (e.g. redness and pustule seen following contact with poison oak).

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مواضيع ذات صلة

Humoral Immunodeficiency (B Cell Defects)

Type III Hypersensitivity Reaction

Type II Hypersensitivity Reaction

Detection of Type I Hypersensitivity

Manifestations of Type I Reaction

Mechanism of Type I Hypersensitivity

Self-Recognition (Tolerance)

Hypersensitivity Reactions

Humoral/Antibody-Mediated Immune Response

Cell-Mediated Immune Response

Helper T Cells (Activation AND Differentiation)

Type III (Immune Complex) Reactions