Delayed-type Hypersensitivity (DTH)

Overview
  • Delayed-type Hypersensitivity (DTH) is a subtype of Type IV Hypersensitivity which is induced in response to certain environmental or microbial antigens. The cellular source of immune-mediated injury are antigen-specific CD4+ T-cells which have been previously proliferated and differentiated in response to a prior exposure to the environmental or microbial antigen.
Pathogenesis
  • Overview
    • A DTH response requires the presence of effector CD4+ T-cells specific to the environmental or microbial antigen. These cells arise during an initial exposure to the antigen that does not result in any clinical consequences. Pathology only develops upon re-exposure once antigen-specific, CD4+ T-cells are present. The time between initial exposure and re-exposure may be weeks, months, or years, depending on how long antigen-specific effector CD4+ T-cells survive in the periphery. Frequently, this is a lifetime.
  • Initial Exposure
    • Initial exposure to the environmental antigen results in a cell-mediated immune response that generates antigen-specific effector CD4+ T-cells. These processes are described in detail in Cell-mediated Immunity; briefly, environmental or microbial antigens are phagocytosed by Antigen Presenting Cells such as macrophages and Dendritic Cells. These cells then degrade the antigen and display its peptides on MHC II molecules in local lymph nodes along with co-stimulatory molecules. CD4+ T-cells whose T-cell Receptor recognizes the displayed peptide:MHC II complexes undergo proliferation and differentiation into effector, antigen-specific CD4+ T-cells, especially of the Th1 Cell subtype. It is thought that the CD4+ T-cells differentiate primarily into the Th1 Cell subtype due to IL-12 which is secreted by the Antigen Presenting Cells.
  • Re-exposure
    • When tissues are re-exposed to the environmental antigen, local Antigen Presenting Cells (APCs) once again uptake the antigen, degrade it and display its peptides on MHC II. Circulating antigen-specific, effector Th1 Cells generated during the initial exposure recognize the peptide:MHC II complex and shower the APC with a variety of inflammatory cytokines which ultimately induce the pathological changes characteristic of Type IV Hypersensitivity. Classically, the Th1 Cell stimulates macrophages with Interferon-gamma which enhances the macrophage's microbial killing capacity but also induces formation of granulomas and giant cells. The Th1 Cell or its target macrophage may also release TNF-alpha and IL-1 which in turn promote intense inflammation of local tissue.
Clinical Consequences
  • Overview
    • DTH reactions likely play a role in a number of pathogenic processes (refer to interlinks). The classic cause of a localized DTH reaction is the Tuberculin Skin Test described below.
  • Tuberculin Skin Test
    • The Tuberculin Skin Test is a diagnostic tool used to determine previous infection to Mycobacterium tuberculosis. It involves subcutaneous injection of M. tuberculosis bacterial antigens and assessment of the skin two days later. An inflammatory reaction indicates the prior presence of mycobacteria-specific [CD4+ T-cells, indicating prior infection to M. tuberculosis. A positive reaction manifests as a localized area of cutaneous edema and erythema.
Morphology
  • Histologically, a positive Tuberculin Skin Test will manifest as a localized area of dermal inflammation characterized by the presence of macrophages and lymphocytes, especially around the micro-vasculature. In certain more intense DTH responses granulomas may form and may possess giant cells.