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Chapter 13 Innate and Adaptive Immunity    293

up the specified antigen. This interaction (B cell–T cell–APC) is restricted by the presence of cellular products genetically encoded by a self-recognition protein, called a major histocom- patibility complex (MHC) molecule. This allows the lympho- cyte to differentiate between self and foreign peptides. Once the B and T lymphocytes are activated and amplified by cytokines released as part of the innate response, the lym- phocytes divide several times to form populations or clones of cells that continue to differentiate into several types of effec- tor and memory cells. In the adaptive immune response, the effector cells destroy the antigens and the memory cells retain the ability to target antigen during future encounters. In order for the adaptive immune response to function prop- erly, it must be able to discriminate between molecules that are native to the body and those that are foreign or harmful to the body. The T lymphocytes are designed to respond to a limitless number of antigens, but at the same time they need to be able to ignore self-antigens expressed on tissues. The MHC molecules enable the lymphocytes to do just this. The MHC is a large cluster of genes located on the short arm of chromosome 6. The complex occupies approximately 4 mil- lion base pairs and contains 128 different genes, only some of which play a role in the immune response. The MHC genes are divided in three classes: I, II, and III, based upon their underlying function (Fig. 13.7). Major Histocompatibility Complex Molecules

The class I and II MHC genes are responsible for encod- ing human leukocyte antigens (HLAs), which are proteins found on cell surfaces and define the individual’s tissue type. These molecules are present on the cell surface glycoproteins that form the basis for human tissue typing. Each individual has a unique collection of MHC proteins representing a unique set of polymorphisms. MHC polymorphisms affect immune responses as well as susceptibility to a number of diseases. Because of the number of MHC genes and the possibility of several alleles for each gene, it is almost impossible for any two individuals to have an identical MHC profile. The class I and II MHC genes also encode proteins that play an important role in antigen presentation. Protein frag- ments from inside the cell are displayed by MHC complex on the cell surface, allowing the immune system to differentiate between the body’s own tissues and foreign substances. Cells, which present unfamiliar peptide fragments on the cell sur- face, are attacked and destroyed by the B and T lymphocytes. Class III MHC genes encode for many of the components of the complement system and play an important role in the innate immune process. The MHC-I complexes contain a groove that accommo- dates a peptide fragment. T-cytotoxic cells can only become activated if they are presented with a foreign antigen peptide. MHC-1 complexes may present degraded viral protein frag- ments from infected cells. Class II MHC (MHC-II) molecules are found only on phagocytic APCs, immune cells that engulf foreign particles including bacteria and other microbes. This includes the macrophages, DCs, and B lymphocytes, which communicate with the antigen receptor and CD4 molecule on T-helper lymphocytes. Like class I MHC proteins, class II MHC proteins have a groove or cleft that binds a fragment of antigen. However, these bind fragments from pathogens that have been engulfed and digested during the process of phagocytosis. The engulfed pathogen is degraded into free peptide fragments within cyto- plasmic vesicles and then complexed with the MHC-II mol- ecules on the surface of the cells. 26,27 T-helper cells recognize these complexes on the surface of APCs and become activated. The first human MHC proteins discovered are called human leukocyte antigens ( HLAs ) and are so named because they were identified on the surface of white blood cells. HLAs are the major target involved in organ transplant rejection and as a result are the focus of a great deal of research in immu- nology. Recent analysis of the genes for the HLA molecules has allowed for better understanding of the proteins involved in this response. The classic human MHC-I molecules are divided into types called HLA-A, HLA-B, and HLA-C, and the MHC-II molecules are identified as HLA-DR, HLA-DP, and HLA-DQ (Table 13.3). Multiple alleles or alternative genes can occupy each of the gene loci that encode for HLA molecules. More than 350 possible alleles for the A locus, 650 alleles for the B locus, and 180 alleles for the C locus have been identified. These genes and their expressed MHC molecules are designated by a letter and numbers ( i.e., HLA-B27).

CD8

CD4

T C

cell

T H

cell

CD8

TCR

TCR

CD4

MHC-II

MHC-I

APC

Virus- infected cell

MHC-I molecule with viral antigen peptide or epitope

MHC-II molecule with antigen peptide or epitope

FIGURE 13.7  •  Recognition by a T-cell receptor (TCR) on a CD4 + helper T (T H ) cell of an epitope associated with a class II major histocom- patibility complex (MHC) molecule on an antigen-presenting cell (APC) and by a TCR on a CD8 + cytotoxic T (T C ) cell of an epitope associated with a class I MHC molecule on a virus-infected cell.