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Human Leukocyte Antigen (HLA) System

By Peter J. Delves, PhD, Professor of Immunology, Division of Infection & Immunity, Faculty of Medical Sciences, University College London, London, UK

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The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, 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. 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 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. Lymphocytes that express CD8 molecules react with class I MHC molecules. These lymphocytes 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 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 Ag-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, -DQ, or -DR region of chromosome 6. Lymphocytes reactive to class II molecules express CD4 and are often helper T 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 three heat shock proteins.

Individual serologically defined antigens encoded by the class I and 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 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 -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,

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