Historically, the major histocompatibility complex (MHC) was first discovered as a genetic locus that encoded a group of antigens responsible for the rejection of tumor grafts. It is now known that the gene products of this region are the major antigens recognized in transplantation rejection. It is also clear that the MHC molecules bind peptide antigens and present them to T cells. Hence, these molecules are responsible for T-cell antigen recognition and play a significant role in controlling a variety of basic immunologic functions. It should also be noted that the TCR is different from antibody. Antibody molecules bind antigen directly, whereas the TCR only recognizes peptide antigens presented in the context of the MHC molecule on the APC. The TCR is specific for anti gen, but the antigen must be presented on a self-MHC molecule. The TCR is also specific for the MHC molecule. Should this antigen be presented by another allelic form of the MHC molecule in vitro, the TCR does not recognize the complex. This is known as MHC restriction.

T he MHC is a cluster of well-studied genes closely associated in humans on chromosome 6. The human MHC is called the human leukocyte antigen (HLA) complex. Among the many important genes in the human MHC are those that encode the classes I, II, and III MHC proteins. As outlined in Table 8-1, MHC class I proteins are encoded by the HLA-A, -B, and -C genes. These proteins are made up of two chains: (1) a transmembrane glycoprotein of MW 45,000, non-covalently associated with (2) a non–MHC-encoded poly peptide of MW 12,000 that is known as β2-microglobulin. MHC class I molecules are expressed on nearly all nucleated cells in the body. Key exceptions are observed on cells in the retina and brain.

Class II proteins are encoded by the HLA-D region. The MHC class II proteins consist of three main families: the HLA-DP–, DQ-, and DR-encoded molecules (Table 1). This locus controls immune responsiveness and different allelic forms of these genes confer differences in the ability of an individual to mount an immune response.

Table1. Important Features of Human MHC Classes I and II Gene Products

The HLA-D locus-encoded molecules are cell surface heterodimers that contain two subunits designated α and β that have molecular weights of approximately 33,000 and 29,000 Da, respectively. Unlike class I proteins, the MHC class II proteins have a rather restricted tissue distribution and are constitutively expressed on macrophages, dendritic cells, and B cells. However, the expression of these molecules on other cell types (eg, endothelial cells or epithelial cells) requires induction by IFN-γ.

T he MHC class I locus also contains genes that encode proteins required in antigen processing (eg, transporters associated with antigen processing [TAPs] (Figure 1). The MHC class III locus encodes complement proteins and several cytokines.

Fig1. Antigen-processing pathways (MHC classes I and II). (Modified and reproduced with permission from Parslow TG, et al [editors]: Medical Immunology, 10th ed. McGraw-Hill, 2001. © The McGraw-Hill Companies, Inc.)

The MHC classes I and II genes exhibit extraordinary genetic variability. Genetic mapping studies showed that there is a high degree of polymorphism in the MHC and different individuals generally express different MHC allelic variants (MHC restriction). It has been noted that over 300 different allelic variants have been defined at some HLA loci. Currently, the MHC genes are the most polymorphic genes known. Each individual inherits a restricted set of alleles from his or her parent. A cluster of tightly linked MHC genes are inherited as a block or haplotype.

In 1987, the three-dimensional structure of the MHC classes I and II proteins was revealed using x-ray crystallography. This elegant work provided critical information on how the MHC proteins function and trigger the immune response. X-ray analysis (Figure 2) demonstrates that the entire structure looks like a cleft whose sides are formed by the α helices and whose floor is shaped by the β-pleated sheets. The x-ray analysis also shows that the cleft is occupied by a peptide. In essence, the TCR sees the peptide antigen bound in a cleft provided by the MHC protein. Figure 3A illustrates this interaction.

The MHC proteins display broad specificity for peptide antigens. In fact, many different peptides can be presented by a different MHC allele. A key to this model is that the MHC polymorphism allows for the binding of many specific and different peptides in the cleft. This means that different alleles can bind and present different peptide antigens.

Fig2. Diagrammatic structure of a class I HLA molecule. (Reproduced with permission from Macmillan Publishers Ltd: Bjorkman PJ, et al: Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987;329:506. Copyright © 1987.)

Fig3. Binding of antigen by MHC and T-cell receptor (TCR). In panel A, a model of the interaction between peptide antigen, MHC, and the TCR is shown. The Vα and Vβ regions of the TCR are shown interacting with the α helices that form the peptide-binding groove of MHC. In panel B, a model of the interaction between a superantigen, MHC, and the TCR, is shown. The superantigen interacts with the Vβ region of the TCR and with class II MHC outside the peptide-binding groove. (Adapted with permission from Stites DG, et al [editors]: Medical Immunology, 9th ed. McGraw-Hill, 1997. © The McGraw-Hill Companies, Inc.)

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مواضيع ذات صلة

Cellular Basis of the Adaptive Immune Response

Mechanisms of Innate Immunity

Overview of Acute-Phase Proteins

C-Reactive Protein

Hematopoietic Stimulators

The Complement System: Diagnostic Evaluation

Biological Functions of Complement Proteins

The Complement System: Alternative Pathway

The Complement System: Classic Pathway

The Complement System

Immune-Mediated Disease

Evaluation of Immunodeficiency Syndromes