Major histocompatibility complex (MHC) structure and function

INTRODUCTION — The principal antigenic barrier to transplantation is a series of molecules which are polypeptide products of a closely linked cluster of genes known, in humans, as the major histocompatibility complex (MHC) [1]. The MHC is highly polymorphic from individual to individual and segregates in families in a Mendelian codominant fashion.

In humans, these MHC molecules are called human leukocyte antigens (HLA), and they are located on the short arm of chromosome 6. Each parent provides a haplotype (a linked set of MHC genes) to each offspring in Mendelian codominant inheritance. The protein products of the MHC have been classified into three classes: class I and II (both of which are involved in antigen presentation) and III molecules. Class I and II proteins are integral components of the immune system whose primary role is the presentation of peptide antigen to T-cell receptor. Class III proteins comprise a mixture of complement, chemokine, and cytokine genes that are not involved in antigen presentation.

The following is a general overview of MHC structure and function. Details of MHC use in transplantation are discussed separately. (See "Kidney transplantation in adults: HLA matching and outcomes" and "Transplantation immunobiology".)

MHC CLASSES — The genes of the human leukocyte antigen (HLA) locus are located on the short arm of chromosome 6. They encode two distinct classes of antigen-presenting cell surface molecules: class I and class II [2]. Class I molecules are expressed on the surfaces of virtually all nucleated cells at varying densities, while class II molecules are more restricted to cells of the immune system, primarily B lymphocytes and monocytes. However, cytokines secreted by lymphocytes and monocytes during immune activation can cause dramatic increases in class II HLA antigen expression, even on cell types that normally have little or no surface expression [3]. (See "Human leukocyte antigens (HLA): A roadmap".)

There are three different class I (HLA-A, -B, -C) and class II (HLA-DQ, -DR, -DP) antigens. Studies in renal transplantation indicate that mismatches at the A, B, and DR loci are associated with worse allograft survival. (See "Kidney transplantation in adults: HLA matching and outcomes".)

It is now understood that the principal task of the immune system is to distinguish self from non-self. HLA molecules provide the crucial surface upon which the antigen receptors on T lymphocytes recognize foreign (non-self) antigens. On antigen-presenting cells such as macrophages, class II molecules present antigenic fragments to the CD4+ inducer (or helper) T cells, while class I molecules function at the effector phase of immunity by presenting antigens to CD8+ T cells, which generally have cytotoxic or suppressor function [1]. This process of antigen presentation consists of the binding of a single T-cell receptor to a complex on the surface of an antigen-presenting cell consisting of the MHC molecule and a peptide fragment derived from the foreign antigen (figure 1 and figure 2).

An ever-expanding number of immune-related genes has been found in additional areas of the MHC in the class III and class IV regions through the use of molecular biologic techniques, such as screenings of complementary deoxyribonucleic acid (cDNA), cosmid, and yeast artificial chromosome libraries and genomic sequencing [4]. These contiguous regions lie between the class I and class II genomic areas.

●The class III region contains several components of the complement system, C4, C2, and Bf. (See "Overview and clinical assessment of the complement system".)

●The class IV region, located between the class III and I areas, comprises a relatively large cluster of immune-related genes. These include the genes for tumor necrosis factor (TNF)-alpha and -beta, as well as numerous less characterized genes or gene families, such as B144, AIF1, and the MIC family.

MHC STRUCTURE — Crystallization of the class I human leukocyte antigen (HLA)-A2 molecule has permitted visualization of how antigen presentation might occur [5]. X-ray diffraction analysis reveals a distinct groove on the external face of the molecule that is 20 x 10 x 10 angstroms in size. This site can bind antigen peptide fragments containing eight to nine amino acids [6,7], although it appears that recognition involves the binding of only two amino acids [8]; how this might occur is not known. The sides of the groove are formed by two alpha-helical structures, and the floor is formed by eight antiparallel beta pleats. Other class I alleles, and at least the class II HLA-DR1 molecule, have a virtually identical core structure; however, the bound peptide in the class II molecules is longer, containing 13 to 26 amino acids [9].

Membrane-bound class I consists of an alpha chain (mol wt 44 kD) with three domains: a3 is close to the cell membrane, while a1 and a2 contain polymorphic sites and form the peptide-binding groove, each contributing one alpha helix and half of the beta pleated floor. The class I complex also consists of non-covalently associated beta-2-microglobulin (mol wt 12 kD), which stabilizes the complex by fitting under the a3 domain.

Class II molecules have a somewhat different structure. They contain two transmembrane chains (alpha and beta for each locus); each chain is approximately 24 kD in size and has two domains. The two distal domains associate non-covalently to form the peptide-binding pocket described above [9]. There is no association of class II molecules with beta-2-microglobulin.

MECHANISM OF ANTIGEN PRESENTATION — Foreign antigens initially do not exist in small fragments. Thus, antigen-presenting cells (such as macrophages) must have the intracellular machinery to perform the following steps:

●Make peptides for major histocompatibility complex (MHC) association from larger proteins

●Bring the self-MHC-peptide complex to the cell surface

The processing pathways are somewhat different for class I and class II molecules [10]. A detailed discussion of the mechanism of antigen presentation is presented separately. (See "Antigen-presenting cells" and "Transplantation immunobiology" and "The adaptive cellular immune response: T cells and cytokines".)

MINOR HISTOCOMPATIBILITY ANTIGENS — Minor histocompatibility antigens (MiHA) also contribute to allograft rejection. These are small endogenous peptides that occupy the antigen-binding site of donor MHC molecules. Their importance in transplantation is best described when donor and recipients share identical major histocompatibility complex (MHC) types, such as human leukocyte antigen (HLA)-matched, nonidentical twin siblings, and yet still are at rejection risk in the absence of immunosuppression.

The prototypic minor histocompatibility antigen, the male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome. Allo-responses to this antigen may explain reduced long-term graft survival observed in male-to-female organ donations. They are generally recognized by CD8⁺ cytotoxic T cells in the context of self-MHC, which leads to graft rejection. In bone marrow transplant, MiHA play an important role in graft-versus-host disease in patients who have received HLA-matched cells.

MHC class 1-related chain A and B (MICA and MICB) antigens are surface glycoproteins with functions related to innate immunity. Antibodies against MICA and/or MICB can cause antibody-mediated rejection (AMR) and graft loss [11].

SUMMARY

●The genes of the human leukocyte antigen (HLA) locus, which are located on the short arm of chromosome 6, encode distinct classes of cell surface molecules that function to distinguish self from non-self; class I major histocompatibility (MHC) molecules are expressed on the surfaces of virtually all nucleated cells at varying densities, while class II MHC molecules are generally restricted to cells of the immune system, primarily B lymphocytes and monocytes. There are three different class I (HLA-A, -B, -C) and class II (HLA-DQ, -DR, -DP) antigens. (See 'MHC classes' above.)

●The class III region of the MHC encodes genes for complement proteins, and the class IV region encodes other immune response-related genes, including those for tumor necrosis factor (TNF). (See 'MHC classes' above.)

●A distinct groove on the external face of the class I and II molecules can bind antigen peptide fragments. Membrane-bound class I consists of an alpha chain (mol wt 44 kD) with three domains that is non-covalently associated with beta-2-microglobulin (mol wt 12 kD), which stabilizes the complex. Class II molecules contain two transmembrane chains (alpha and beta for each locus); each chain is approximately 24 kD in size and has two domains. (See 'MHC structure' above.)

●Antigen-presenting cells (such as macrophages) have the intracellular machinery to make peptides for MHC association from larger proteins and to bring the self-MHC-peptide complex to the cell surface. (See 'Mechanism of antigen presentation' above.)