The MHC Locus and the HLA System
Dr. med. Kaimo Hirv, Dr. rer. nat. Barbara Grumbt
The discovery of the major histocompatibility complex (abbr. MHC) has its origin in tissue transplantation. If tissue is transplanted from one individual to a genetically different individual of the same species, the recipient recognizes the transplant as foreign and destroys it. In humans, this system was first discovered by J. Dausset and R. Payne in 1964 and has been characterized in detail for the last 40 years using immunologic and increasingly also molecular genetic methods. In vertebrates, the MHC locus consists of several genes encoding proteins that are crucial for immune recognition, tissue compatibility (histocompatibility) in transplantations and immunologic individuality. In humans, the HLA (humane leukocyte antigen) system, located on the short arm of chromosome 6, is an important component of the MHC locus. The “classic” MHC genes are divided into two regions which encode two classes of HLA molecules: HLA class I (HLA-A, -B, -C) and HLA class II (HLA-DR, -DQ, -DP). The entire HLA complex comprises approx. 4,000 kilobases (kb), while the HLA class I region contains approx. 1,800 kb and the HLA class II region approx. 1,000 kb. The HLA system is highly polymorphic, i.e. there are several genetic variants (alleles) for most gene loci.
The gene products of the “classic” HLA-A, -B and -C genes (class I) are glycoproteins located on the cell membrane and are expressed with varying quantity on nucleated somatic cells. The gene products of the “classic” HLA class II genes are two non-covalent associated, membrane-anchored polypeptide chains. The HLA-DR subregion contains a monomorphic gene for the ?-chain (DRA) and 9 genes for the ß chains (DRB1-DRB9). The DRB1 gene encodes the polymorphic proportion of the HLA-DR specifities. The “classic” HLA class II molecules can be detected on antigen-presenting cells (such as peripheral B lymphocytes, macrophages, dendritic cells or activated lymphocytes).
The central immunobiological role of the two HLA molecule classes is antigen presentation. According to the allelic variant, every HLA molecule binds a specific set of peptides. In essence, cytotoxic T cells (Tc or T8) recognize the HLA class I molecules in complex with the peptide in the binding pocket, while T helper lymphocytes (Th or T4) detect the HLA class II peptide complex. The polymorphism of the HLA system causes the presentation of a wide range of peptides of different antigenic origin. This ensures that a variety of individuals can develop an immune response against infectious or foreign agents. Through the presentation of the body’s own peptides, the immune system learns recognition of “self”. Failure of self-recognition may cause autoimmune disorders.
The valid nomenclature for the factors of the HLA system is determined by the WHO nomenclature committee. Serologically typed HLA antigens are given one letter for the gene location and one number for the antigen variant, e.g. HLA-B8. Molecular genetic HLA alleles are termed according to the gene location, an "*" and four numbers according to allele group, alleles with amino acid substitution, alleles with synonymous nucleotide substitutions in the exons and nucleotide substitution in the introns, e.g. HLA-A*24:02:01:01. Typing at allele group level (e.g. HLA-A*24, low resolution) or at allele level (e.g. two numbers, e.g. HLA-A*24:02, high resolution) is usually sufficient.
We type HLA class I and class II alleles with molecular genetic methods using direct DNA sequencing (sequence-based typing, SBT), sequence-specific oligonucleotide probes (SSO) or sequence specific primers (PCR SSP). DNA sequencing offers the most reliable results and highest resolution. As an alternative to the conventional Sanger sequencing, next generation sequencing (NGS) is currently successfully used for HLA typing.
The typing of HLA markers plays a major role in transplantation and transfusion medicine as well as in differential diagnostics of certain diseases associated with the presence of a defined HLA allele. Different HLA-associated diseases such as narcolepsy (HLA-DQB1*06:02), Bechterew’s disease (HLA-B+27) or certain autoimmune disorders have been more or less strongly associated with a specific HLA determinant. This information can be used as an additional marker in differential diagnostics (see also table in “HLA characteristics and disease associations”). Today, it is undisputed that matching HLA characteristic of the organ donor and the recipient has a positive impact on the success of the transplantation of solid organs (www.ctstransplant.org). In transfusion medicine, patients with anti-HLA antibodies may have to be transfused with HLA compatible thrombocytes, if necessary.
The HLA system plays a crucial role in the selection of bone marrow and blood stem cell donors. The allogeneic bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are therapy of choice for malignant diseases and malfunctioning of hematopoietic organs. Umbilical cord blood transplantation represents an alternative to blood stem cell or bone marrow transplantation. A generally recognized criterion for a successful transplantation of stem cells is thought to be tissue tolerance of donor and recipient; i.e. the matching of HLA-A, -B and -C as well as HLA-DRB1 and -DQB1 characteristics. Today, transplantations among genetically HLA-identical siblings and among unrelated bone marrow donors are equally successful. Since, however, only approx. 35% of all patients in Western Europe have an HLA-identical donor sibling, an increasing number of HLA-identical donors are found through registries. In the consensus paper of the German transplantation specialists and immunogeneticists, the criteria for the selection of a suitable donor from a register for stem cell transplantation were determined. These criteria demand matching of HLA-A*, -B*, -C* with at least low resolution and matching of HLA-DRB1* and -DQB1* with high resolution for unrelated BMT. Under consideration of these criteria, donors can currently be found for approx. 80% of all patients with hematologic diseases who do not have a related donor. At present, there are approx. 20 million voluntary donors worldwide, who have been registered anonymously in national (e.g. German National Registry of Blood Stem Cell Donors, ZKRD) or other international registries. The search and referral of BM donors is conducted internationally via the online-linkage of the ZKRD with worldwide registries.