The human leukocyte antigen (HLA) system (the major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6. It encodes cell surface molecules specialized to present antigenic peptides to the T-cell receptor (TCR) on T cells. (See also Overview of the Immune System.)
MHC molecules that present antigen (Ag) are divided into 2 main classes:
Class I MHC molecules
Class II MHC molecules
Class I MHC molecules are present as transmembrane glycoproteins on the surface of all nucleated cells. Intact class I molecules consist of an alpha heavy chain bound to a beta-2 microglobulin molecule. The heavy chain consists of 2 peptide-binding domains, an immunoglobulin (Ig)-like domain, and a transmembrane region with a cytoplasmic tail. The heavy chain of the class I molecule is encoded by genes at HLA-A, HLA-B, and HLA-C loci. T cells that express CD8 molecules react with class I MHC molecules. These T cells often have a cytotoxic function, requiring them to be capable of recognizing any infected cell. Because every nucleated cell expresses class I MHC molecules, all infected cells can act as antigen-presenting cells for CD8 T cells (CD8 binds to the nonpolymorphic part of the class I heavy chain). Some class I MHC genes encode nonclassical (ie, not CD8-binding) MHC molecules, such as HLA-G (which may play a role in protecting the fetus from the maternal immune response) and HLA-E (which presents peptides to certain receptors on natural killer [NK] cells).
Class II MHC molecules are usually present only on professional antigen-presenting cells (B cells, macrophages, dendritic cells, Langerhans cells), thymic epithelium, and activated (but not resting) T cells;.Most nucleated cells can be induced to express class II MHC molecules by interferon (IFN)-gamma. Class II MHC molecules consist of 2 polypeptide (alpha [α] and beta [β]) chains; each chain has a peptide-binding domain, an Ig-like domain, and a transmembrane region with a cytoplasmic tail. Both polypeptide chains are encoded by genes in the HLA-DP, HLA-DQ, or HLA-DR region of chromosome 6. T cells reactive to class II molecules express CD4 and are often helper cells.
The MHC class III region of the genome encodes several molecules important in inflammation; they include complement components C2, C4, and factor B; tumor necrosis factor (TNF)-alpha; lymphotoxin; and 3 heat shock proteins, which help protect cells from stress and maintain protein homeostasis.
Individual serologically defined antigens encoded by the class I and class II gene loci in the HLA system are given standard designations (eg, HLA-A1, -B5, -C1, -DR1). Alleles defined by DNA sequencing are named to identify the gene, followed by an asterisk, numbers representing the allele group (often corresponding to the serologic antigen encoded by that allele), a colon, and numbers representing the specific allele (eg, A*02:01, DRB1*01:03, DQA1*01:02). Sometimes additional numbers are added after a colon to identify allelic variants that encode identical proteins, and after another colon, other numbers are added to denote polymorphisms in introns or in 5' or 3' untranslated regions (eg, A*02:101:01:02, DRB1*03:01:01:02).
The MHC class I and class II molecules are the most immunogenic antigens that are recognized during rejection of an allogeneic transplant. The strongest determinant is HLA-DR, followed by HLA-B and HLA-A. These 3 loci are therefore the most important for matching donor and recipient.
Some autoimmune disorders are linked to specific HLA alleles—for example,
Ankylosing spondylitis and reactive arthritis to HLA-B27
Multiple sclerosis to HLA-DR2
Narcolepsy to HLA-DR2 and HLA–DQB1*06:02
Psoriasis to HLA-C*06:02
Rheumatoid arthritis to HLA-DR4
Type 1 diabetes mellitus to HLA-DQ2 and HLA-DQ8
