HLA Structure and Function - Professor Richard Kirk 2023

Transplant Immunology: Background
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HLA Structure and Function

Human Leukocyte Antigen (HLA)

Each human nucleated cell wall contains glycoproteins called human leukocyte antigens (HLA). The HLA genes (also called major histocompatibility complex - MHC) reside on chromosome 6 and specify the HLA glycoproteins on the cell membrane. They are divided into groups or classes. Class I codes for HLA-A, -B & -C which are found on nucleated cells membranes (almost all cells except red blood cells and cornified cells cornified cells in the skin, hair, and nails). Class II codes for HLA-DP, -DQ, -DR and these are only found on antigen presenting cells (e.g. macrophages, dendritic cells, B cells). Class III codes for the production of other molecules (e.g. cytokines, complement) involved in the immune process. Although HLA glycoproteins are the vehicle for presenting foreign antigens to lymphocytes HLA the exact molecular structure of the HLA glycoprotein is very variable between individuals. This variation is called polymorphism and occurs to such an extent that each individual is unique and is exploited by the body so that the adaptive immune system uses the HLA glycoproteins to recognise self from non-self.

HLA Expression

The expression of HLA glycoproteins on the cell surface is under tight control. Not only does expression vary between Class I & II on cell types, but there is also variation within classes e.g. HLA-C is expressed at much lower levels than HLA-A or HLA-B and even between individuals - which may be up to 30 fold for some alleles e.g. HLA-A2. Another example is healthy renal microvascular endothelial cells where HLA-DR is found at much higher levels than HLA-DQ or HLA-DP. The level of expression is controlled by, amongst other mechanisms, microRNAs, cytokines and the delicate balance of HLA production, expression and degradation. HLA expression is therefore not static, but very dynamic enabling it to respond to different conditions. For example HLA-B is not usually expressed unless there is inflammation. In the transplant context then, cell mediated rejection causes inflammation which leads to HLA additional expression, allowing HLA-donor specific HLA antibodies to compound the situation by initiating antibody mediated rejection. Anti rejection treatment reduces inflammation, HLA expression is reduced and despite the presence of circulating donor specific antibodies graft function may return to normal. This is because if the antigen (HLA) is not expressed then there is nothing for the antibody in interact with.

HLA Nomenclature

Each person's unique HLA type is often called the "tissue type". The HLA laboratory uses serological or genomic techniques to determine the HLA (often called "tissue type"). The serological test is less detailed than the genomic test as can be seen in Figure 1 where Cw15 is identified by genomic testing but not by serological testing. HLA nomenclature is complex. At the highest level (allele) HLA is used in conjunction with a letter e.g. HLA-A*68 but more detailed genomic typing allows a specific protein at a given HLA locus to be identified (Figure 2).

Each HLA allele is made up of proteins. A single antibody can react to more than one HLA allele because alleles contain amino acid sequences on their surface (epitopes) that may occur on more than one HLA allele. For example A2 and A68 share a common epitope. Epitopes are made of smaller sequences called eplets to which antibodies bind. Eplets are not necessarily linear but folding of their structure (functional eplet) may present a different target for an antibody (Figure 3).

Figure 2. http://hla.alleles.org

Human Leukocyte Antigen Function

The main function of HLA class I glycoproteins is to present antigens processed endogenously to CD8+ T Cells. Typically antigens from infecting bacteria, viruses, intracellular parasites, or self-molecules are degraded by the proteosome to make small peptides (Figure 4). These are then bound to HLA Class I, pass though several intracellular organs (e.g. endoplasmic reticulum) and then emerge on the cell membrane to be presented to CD4+ helper T cells.

Antigen presenting cells that find non-self extracellular proteins are taken into the cell by phagocytosis and degraded to peptides in endosomes and lysosomes. The peptides are then bound to HLA class II glycoproteins and eventually extruded and held on the APC cell surface where they can be recognized by CD4+ T cells (Figure 5).