17.8: Hypersensitivity Reactions: Delayed Hypersensitivity Reactions

Delayed-Type Hypersensitivity (DTH), or Type IV hypersensitivity, is a cell-mediated immune response. It occurs when T cells, rather than antibodies, mediate a reaction to specific antigens. It is characterized by a delayed onset (1-2 days) and involves the recruitment of macrophages to the inflammation site.

The initiation of a DTH response begins with the sensitization of T cells. During this phase, which lasts at least 1-2 weeks, antigen-specific T cells are activated, clonally expanded, and mature into effector T cells. Antigen-presenting cells (APCs) such as macrophages, dendritic cells, and Langerhans cells play a crucial role in transporting antigens to lymph nodes, where T cells are activated. Typically, the activated T cells during this phase are CD4⁺ T_H1 cells, although recent studies suggest that T_H17 and CD8⁺ cells also contribute.

Upon second exposure to the antigen, the effector phase of the DTH response is triggered. Previously activated T_H1 cells release cytokines such as IFN-γ, TNF-α, and lymphotoxin-α, which recruit and activate macrophages. This phase peaks 48-72 hours after antigen exposure and involves a complex interplay of nonspecific cells and mediators, leading to extensive response amplification. Activated macrophages exhibit enhanced phagocytic activity and release lytic enzymes, which can result in tissue damage.

Prolonged DTH responses can cause granulomatous reactions, a type of immune response characterized by the formation of granulomas or small areas of inflammation in the body's tissues. In these reactions, continuous macrophage activation forms multinucleated giant cells, leading to tissue necrosis.

Contact dermatitis is a common example of DTH, triggered by substances like nickel, poison ivy, and certain cosmetic chemicals. These reactive chemicals bind to skin proteins, modifying them and making them recognizable to T cells. The modified peptides are presented to T cells by MHC molecules, triggering cytokine release and inflammation. This process exemplifies the mechanisms of DTH, highlighting the significant role of T cells and macrophages in mediating the immune response and tissue inflammation.

Delayed, or Type IV, hypersensitivity reaction is a cell-mediated immune response.

It consists of two phases: sensitization and effector.

During sensitization, antigen-presenting cells present antigens to CD4⁺ T cells via MHC class II molecules, initiating the process. This involves the activation and clonal expansion of antigen-specific CD4⁺ T_H1 cells to produce mature effector T cells.

Upon re-exposure to the antigen, the effector phase begins. Here, sensitized T_H1 effector cells release cytokines such as IFN-γ and TNF-α, causing the recruitment and activation of macrophages.

These recruited macrophages exhibit increased phagocytic activity, release lytic enzymes, and produce cytokines and chemokines. This attracts more monocytes and neutrophils, contributing to tissue damage and inflammation.

For example, contact dermatitis can happen due to exposure to certain plants or metals in artificial jewelry. Reactive chemicals bind to skin proteins, generating neoantigens. These neoantigens sensitize T cells, leading to cytokine release and inflammatory cell recruitment, causing skin inflammation.