A 40yrs old man has chronic cough with fever for several months . The radiography reveals a diffuse reticulonodular Patten's.microscopically on transbronchial biopsy there are focal areas of inflammation conraining epithioid cell granuloma , Langerhans cells, lymphocytes, these findings are typically for which of the following type of hypersensitivity immunological response

Ref Robbins 9/e p 210 T Cell-Mediated (Type IV) Hypersensitivity Several autoimmune disorders, as well as pathologic reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells (Table 4-5). The occurrence and significance of T lymphocyte-mediated tissue injury have been increasingly appreciated as the methods for detecting and purifying T cells from patients' circulation and lesions have improved. This group of diseases is of great clinical interest because many of the new, rationally designed biologic therapies for immune-mediated inflam- matory diseases have been developed to target abnormal T cell reactions. Two types of T cell reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the cytokines are produced mainly by CD4+ T cells, and (2) direct cell cytotoxicity, mediated by CD8+ T cells (Fig. 4-12). In inflammation, exemplified by the delayed-type hypersensitivity (DTH) reaction, CD4+ T cells of the TH1 and TH17 subsets secrete cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury. In cell-mediated cytotoxicity, cytotoxic CD8+ T cells are responsible for tissue damage. Inflammatory Reactions Elicited by CD4+ T Cells The sequence of events in T cell-mediated inflammatory reactions begins with the first exposure to antigen and is essentially the same as the reactions of cell-mediated immunity (Fig. 4-4). Naive CD4+ T lymphocytes recognize peptide antigens of self or microbial proteins in association with class II MHC molecules on the surface of DCs (or macrophages) that have processed the antigens. If the DCs produce IL-12, the naive T cells differentiate into effector cells of the TH1 type. The cytokine IFN-g, made by NK cells and by the TH1 cells themselves, fuher promotes TH1 dif- ferentiation, providing a powerful positive feedback loop. If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the CD4+ cells develop into TH17 effectors. On subsequent exposure to the antigen, the previously generated effector cells are recruited to the site of antigen exposure and are activated by the antigen presented by local APCs. The TH1 cells secrete IFN-g, which is the most potent macrophage- activating cytokine known. Activated macrophages have increased phagocytic and microbicidal activity. Activated macrophages also express more class II MHC molecules and costimulators, leading to augmented antigen presenta- tion capacity, and the cells secrete more IL-12, thus stimu- lating more TH1 responses. Upon activation by antigen, TH17 effector cells secrete IL-17 and several other cytokines, which promote the recruitment of neutrophils (and mono- cytes) and thus induce inflammation. Because the cyto- kines produced by the T cells enhance leukocyte recruitment and activation, these inflammatory reactions become chronic unless the offending agent is eliminated or the cycle is interrupted therapeutically. In fact, inflammation occurs as an early response to microbes and dead cells (Chapter 2), but it is greatly increased and prolonged when T cells are involved. 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. Figure 4-12 Mechanisms of T cell-mediated (type IV) hypersensitivity reactions. A, In cytokine-mediated inflammatory reactions, CD4+ T cells respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ CTLs directly kill tissue cells. APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes. Cytokine-mediated inflammation Inflammation Tissue injury APC presenting tissue antigen Normal tissue CD4+ T cell Cell killing and tissue injury CD8+ CTLs Cytokines T cell-mediated cytolysis A B 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). T Cell-Mediated Cytotoxicity In this form of T cell-mediated tissue injury, CD8+ CTLs kill antigen-bearing target cells. As discussed earlier, class I MHC molecules bind to intracellular peptide antigens and present the peptides to CD8+ T lymphocytes, stimulat- ing the differentiation of these T cells into effector cells called CTLs. CTLs play a critical role in resistance to virus infections and some tumors. The principal mechanism of killing by CTLs is dependent on the perforin-granzyme system. Perforin and granzymes are stored in the granules of CTLs and are rapidly released when CTLs engage their targets (cells bearing the appropriate class I MHC-bound peptides). Perforin binds to the plasma membrane of th target cells and promotes the entry of granzymes, which are proteases that specifically cleave and thereby activate cellular caspases. These enzymes induce apoptotic death of the target cells (Chapter 1). CTLs play an impoant role in the rejection of solid-organ transplants and may contribute to many immunologic diseases, such as type 1 diabetes (in which insulin-producing b cells in pancreatic islets are destroyed by an autoimmune T cell reaction). CD8+ T cells may also secrete IFN-g and contribute to cytokine-mediated inflammation, but less so than CD4+ cells. Figure 4-14 Granulomatous inflammation. A, A section of a lymph node shows several granulomas, each made up of an aggregate of epi- thelioid 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. Note the role played by T cell-derived cytokines. (A, Couesy of Dr. Trace Worrell, Depament of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) A Antigen-presenting cell CD4+ TH1 cell IL-12 TNF Monocytes Fibroblast IFN-g Giant cell Epithelioid cell B Lymphocyte Macrophage Antigen SUMMARY Mechanisms of T Cell-Mediated Hypersensitivity Reactions * Cytokine-mediated inflammation: CD4+ T cells are acti- vated by exposure to a protein antigen and differentiate into TH1 and TH17 effector cells. Subsequent exposure to the antigen results in the secretion of cytokines. IFN-g activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation. * T cell-mediated cytotoxicity: CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-g. With the basic mechanisms of pathologic immune reac- tions as background, we now proceed to a consideration of two categories of reactions that are of great clinical impor- tance: autoimmunity and transplant rejection. Figure 4-13 Delayed-type hypersensitivity reaction in the skin. A, Peri- vascular accumulation ("cuffing") of mononuclear inflammatory cells (lymphocytes and macrophages), with associated dermal edema and fibrin deposition. B, Immunoperoxidase staining reveals a predomiA nantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies. (B, Couesy of Dr. Louis Picker, Depament of Pathology, Oregon Health & Science University, Poland, Oregon.)