HLA genes are highly polymorphic; that is, there are alternative forms (alleles) of each gene at each locus (estimated to number over 10,000 for all HLA genes and over 3500 for HLA-B alleles alone). Each individual expresses only one set of HLA genes. It is believed that the polymorphism of MHC genes evolved to enable display of and response to any conceivable microbial peptide encountered in the environment. As a result of the polymorphism, a virtually infinite number of combinations of HLA molecules exists in the population. The HLA genes are closely linked on chromosome 6, so they are passed from parent to offspring en bloc and behave like a single locus with respect to their inheritance patterns. Each set of maternal and paternal HLA genes is referred to as an HLA haplotype. Because of this mode of inheritance, the probability that siblings will share the same two HLA haplotypes is 25%. By contrast, in most populations the probability that an unrelated donor will share the same two HLA haplotypes is very low. The implications of HLA polymorphism for transplantation are obvious; because each person has HLA alleles that differ to some extent from those of every other unrelated individual, grafts from unrelated donors will elicit immune responses in the recipient and be rejected. Only identical twins can accept grafts from one another, without fear of rejection. Even grafts from a donor to a sibling with the same HLA haplotype may be rejected because of differences in so-called “minor histocompatibility loci”, other sets of polymorphic genes that are likely to differ by chance. (The only exception to this rule, of course, are identical twins) In fact, HLA molecules were discovered in the course of early attempts at tissue transplantation, because HLA molecules of the graft evoke immune responses that eventually lead to graft destruction http://ebooksmedicine.net
Class II MHC Complement Cytokines Class I MHC molecules proteins, others molecules
Fig. 5.6 The human leukocyte antigen (HLA) complex and the structure of HLA molecules. (A) The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA-DM) are located in the class II region (not shown). (B) Schematic diagrams and crystal structures of class I and class II HLA molecules. (Crystal structures are courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena, California.) (discussed later). This ability of MHC molecules to trigger immune responses is the reason these molecules are often called antigens.
The inheritance of particular MHC alleles influences both protective and harmful immune responses. The ability of any given MHC allele to bind the peptide antigens generated from a particular pathogen will determine whether a specific person’s T cells can recognize and mount a protective response to that pathogen. Conversely, if the antigen is ragweed pollen and the response is an allergic reaction, inheritance of some HLA genes may make individuals susceptible to hay fever, the colloquial name for ragweed allergy.
Finally, many autoimmune diseases are associated with particular HLA alleles. We return to a discussion of these associations when we consider autoimmunity.
B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the mediators of humoral immunity. B cells make up 10% to 20% of the circulating peripheral lymphocyte population. They also are present in bone marrow and in the follicles of peripheral (secondary) lymphoid organs.