Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may be evoked by contact with urushiol, the antigenic component of poison ivy or poison oak, and presents as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and structurally modifies self proteins, and peptides derived from these modified proteins are recognized by T cells and elicit the reaction. The same mechanism is responsible for many drug reactions, among the most common hypersensitivity reactions of humans. The responsible drug (often a reactive chemical) alters self proteins, including MHC molecules, and these neoantigens are recognized as foreign by T cells, leading to cytokine produc-
Fig. 5.18 Granulomatous inflammation. (A) A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells. (B) The events that give rise to the formation of granulomas in type IV hypersensitivity reactions, illustrating the role of TH1 cytokines. In some granulomatous disorders (e.g., schistosomiasis), TH2 cells also contribute to the lesions. The role of TH17 cells in granuloma formation is not proven. (A, Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)
In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-expressing target cells. Tissue destruction by CTLs may be an important component of some T cell– mediated diseases, such as type 1 diabetes. CTLs directed against cell surface histocompatibility antigens play an important role in graft rejection, which is discussed later. They also play a role in reactions against viruses. In a virus-infected cell, viral peptides are displayed by class I MHC molecules and the complex is recognized by the TCR of CD8+ T lymphocytes. The killing of infected cells leads to elimination of the infection, but in some cases, it is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis). CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions resembling DTH, especially following virus infections and exposure to some contact sensitizing agents.
Cytokine-mediated inflammation: CD4+ TcellsareactivatedbyexposuretoaproteinantigenanddifferentiateintoTH1andTH17effectorcells.Subsequentexposuretotheantigenresultsinthesecretionofcytokines.IFN-γ activatesmacrophagestoproducesubstancesthatcausetissuedamageandpromotefibrosis,andIL-17andothercytokinesrecruitleukocytes,thuspromotinginflammation.
TheclassicalTcell–mediatedinflammatoryreactionisdelayed-type hypersensitivity. ChronicTH1reactionsassociatedwithmacrophageactivationoftenleadtogranulomaformation.
T cell–mediated cytotoxicity: CD8+ cytotoxicTlymphocytes(CTLs)specificforanantigenrecognizecellsexpressingthetargetantigenandkillthesecells.CD8+ TcellsalsosecreteIFN-γ.
Now that we have described how the immune system can cause tissue damage, we turn to diseases in which normal control mechanisms fail. The prototypes of such diseases are autoimmune disorders, which are the result of failure of tolerance to self antigens.