Example of type 4 hypersensitivity is

Ref Robbins 9/e p209 Delayed-type hypersensitivity (DTH), described next, is an illustrative model of T cell-mediated inflammation and tissue injury. The same reactions are the underlying basis for several diseases. Contact dermatitis is an example of tissue injury resulting from T cell-mediated inflammation. It is evoked by contact with pentadecylcatechol (also known as urushiol, the active component of poison ivy and poison oak, which probably becomes antigenic by binding to a host protein). On reexposure of a previously exposed person to the plants, sensitized TH1 CD4+ cells accumulate in the dermis and migrate toward the antigen within the epidermis. Here they release cytokines that damage kera- tinocytes, causing separation of these cells and formation of an intraepidermal vesicle, and inflammation manifested as a vesicular dermatitis. It has long been thought that several systemic diseases, such as type 1 diabetes and mul- tiple sclerosis, are caused by TH1 and TH17 reactions against self antigens, and Crohn disease may be caused by uncon- trolled reactions involving the same T cells but directed against intestinal bacteria. T cell-mediated inflammation also plays a role in the rejection of transplants, described later in the chapter. Delayed-Type Hypersensitivity DTH is a T cell-mediated reaction that develops in response to antigen challenge in a previously sensitized individual. In contrast with immediate hypersensitivity, the DTH reac- tion is delayed for 12 to 48 hours, which is the time it takes for effector T cells to be recruited to the site of antigen chal- lenge and to be activated to secrete cytokines. The classic example of DTH is the tuberculin reaction, elicited by chal- lenge with a protein extract of M. tuberculosis (tuberculin) in a person who has previously been exposed to the tuber- cle bacillus. Between 8 and 12 hours after intracutaneous injection of tuberculin, a local area of erythema and indura- tion appears, reaching a peak (typically 1 to 2 cm in diam- eter) in 24 to 72 hours and thereafter slowly subsiding. On histologic examination, the DTH reaction is characterized by perivascular accumulation ("cuffing") of CD4+ helper T cells and macrophages (Fig. 4-13). Local secretion of cyto- kines by these cells leads to increased microvascular per- meability, giving rise to dermal edema and fibrin deposition; the latter is the main cause of the tissue induration in these responses. DTH reactions are mediated primarily by TH1 cells; the contribution of TH17 cells is unclear. The tubercu- lin response is used to screen populations for people who have had previous exposure to tuberculosis and therefore have circulating memory T cells specific for mycobacterial proteins. Notably, immunosuppression or loss of CD4+ T cells (e.g., resulting from HIV infection) may lead to a nega- tive tuberculin response even in the presence of a severe infection. Prolonged DTH reactions against persistent microbes or other stimuli may result in a special morphologic pattern of reaction called granulomatous inflammation. The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic, and are called epithelioid cells. The epitheli- oid cells occasionally fuse under the influence of cytokines (e.g., IFN-g) to form multinucleate giant cells. A micro- scopic aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma (Fig. 4-14, A). The process is essentially a chronic form of TH1-mediated inflammation and macrophage activation (Fig. 4-14, B). Older granulomas develop an enclosing rim of fibroblasts and connective tissue. Recognition of a granuloma is of diagnostic impoance because of the limited number of conditions that can cause it (Chapter 2).