Porth's Pathophysiology, 9e

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UNIT IV Infection, Inflammation, and Immunity

TABLE 13.3 PROPERTIES OF CLASS I AND II MHC MOLECULES

PROPERTIES

HLA ANTIGENS

DISTRIBUTION

FUNCTIONS

Present processed antigen to cytotoxic CD8 + T cells; restrict cytolysis to virus-infected cells, tumor cells, and transplanted cells Present processed antigenic fragments to CD4 + T cells; necessary for effective interaction among immune cells

Class I MHC HLA-A, HLA-B, HLA-C Virtually all nucleated cells

Class II MHC HLA-DR, HLA-DP, HLA-DQ

Immune cells, antigen-

presenting cells, B cells, and macrophages

HLA, human leukocyte antigen; MHC, major histocompatibility complex.

HLA genes are inherited as a unit, called a haplotype , because the class I and II MHC genes are closely linked on one chromosome. Since each person inherits one chromo- some from each parent, each person has two HLA haplotypes. Tissue typing in forensics and organ transplantation involves the identification of these haplotypes. In organ or tissue transplantation, the closer the matching of HLA types, the greater is the probability of identical antigens and the lower the chance of rejection. However, not all people that develop organ rejection after transplantation develop anti-HLA anti- bodies. ­Non-HLA target antigens exist including the MHC class I chain-related antigens A (MICA). 28 These antigens are expressed on epithelial cells, monocytes, fibroblasts, and endothelial cells. Therefore, donor-specific antibodies are not detected prior to organ tissue typing prior to transplantation because they are not expressed on the leukocytes tested. 28 Antigen-Presenting Cells During the adaptive immune response, activation of a T lym- phocyte requires the recognition of a foreign peptide (anti- gen) bound to a self-MHC molecule. This process requires that stimulatory signals be delivered simultaneously to the T lymphocyte by another specialized cell known as an ­ antigen- presenting cell (APC) . Therefore, APCs play a key role in bridging the innate and adaptive immune systems through cytokine-driven up-regulation of MHC-II molecules. Cells that function as APCs must be able to express both classes of MHC molecules and include DCs, monocytes, macrophages, and B lymphocytes residing in lymphoid fol- licles. Under certain conditions, endothelial cells are also able to function as APCs. APCs have been shown to play a key role in the development of autoimmune diseases and atherosclero- sis. Activated T lymphocytes appear to be proatherogenic, and in experimental models, APC and T-cell deficiency have been associated with up to an 80% reduction in atherosclerosis. 29 Macrophages function as a principal APC. They are key cells of the mononuclear phagocytic system and engulf and digest microbes and other foreign substances that gain access to the body. Since macrophages arise from monocytes in the blood, they can move freely throughout the body to the appro- priate site of action. Tissue macrophages are scattered in con- nective tissue or clustered in organs such as the lung ( i.e., alve- olar macrophages), liver ( i.e., Kupffer cells), spleen, lymph

nodes, peritoneum, central nervous system ( i.e., microglial cells), and other areas. Macrophages are activated during the innate immune response where they engulf and break down complex antigens into peptide fragments. These fragments can then be associated with MHC-II molecules for presentation to cells of the “cell-mediated” response so that self–nonself rec- ognition and activation of the immune response can occur. DCs are also responsible for presenting processed anti- gen to activated T lymphocytes. The starlike structure of the DCs provides an extensive surface area rich in MHC-II mol- ecules and other non-HLA molecules important for initiation of adaptive immunity. DCs are found throughout the body in tissues where antigen enters the body and in the peripheral lymphoid tissues. Both DCs and macrophages are capable of “specialization” depending upon their location in the body. For example, Langerhans cells are specialized DCs in the skin, whereas follicular DCs are found in the lymph nodes. Langerhans cells transport antigens found on the skin to nearby lymph nodes for destruction. They are also involved in the development of cell-mediated immune reactions such as allergic type IV contact dermatitis. Finally, DCs are found in the mucosal lining of the bowel and have been implicated in the development of inflammatory bowel diseases such as Crohn disease and ulcerative colitis, where they present anti- gens to the B and T lymphocytes through the production of proinflammatory cytokines. 22 The humoral immune response is mediated by antibodies, which are produced by the B lymphocytes. The primary func- tions of the B lymphocytes are the elimination of extracellular microbes and toxins and subsequent “memory” for a height- ened response during future encounters. Humoral immunity is more important than cellular immunity in defending against microbes with capsules rich in polysaccharides and lipid tox- ins because only the B lymphocytes are capable of responding to and producing antibodies specific for many types of these molecules. The T cells, which are the mediators of cellular immunity, respond primarily to surface protein antigens. B lymphocytes are produced in the bone borrow and are classified according to the MHC-II proteins, Ig, and B Lymphocytes and Humoral Immunity