HLA system

The human leucocyte antigen (HLA) gene family provides the genetic blueprint for a group of related proteins that help the immune system distinguish the body's own proteins (self) from proteins made by foreign invaders such as viruses and bacteria. The HLA, (referred to as the major histocompatibility complex (MHC) in the mouse and other species) consists of more than 200 genes located close together on chromosome 6. Genes in this complex are categorized into three basic groups: class I, class II, and class III. HLA class I and II genes are principally involved in immune recognition while the proteins produced by MHC class III genes have somewhat different functions; they are involved in inflammation and other immune system activities: encoding complement components, the cytokine TNFα and heat shock protein. Here we will focus on HLA class I and II molecules which are found on the surface of cells and serve the purpose of 'presenting' possible antigen to T and B cells. Both do essentially the same job. Class I HLA presents antigen peptide found within the cell, to CD8 positive (cytotoxic T cells) while Class II HLA presents antigen peptide found outside the cell, to CD4 positive (helper T cells).

HLA class I

Human have three main MHC class I genes, known as HLA-A, HLA-B and HLA-C. The proteins produced from these genes are present on the surface of almost all cells and have the capacity to bind to protein fragments (peptides) that have been exported from within the cell. MHC class I proteins display these peptides to the immune system. If the immune system recognises the peptides as foreign (such as viral or bacterial peptides), it responds by triggering the infected cell to self-destruct.

HLA class II

There are six main MHC class II genes in humans: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1 (Figure 1). Figure 1: The HLA region on chromosome 6
Figure 1: The HLA region on chromosome 6
MHC class II genes provide instructions for making proteins that are present almost exclusively on the surface of immune cells called an antigen presenting cell (APC). APCs are usually dendritic cells, macrophages or B cells. Like MHC class I proteins, these HLA class II molecules sit on the cell surface and display peptides to the immune system (Figure 2).

Figure 2: Presentation of a proinsulin peptide to a CD4 T helper cell by MHC class II
Figure 2: Presentation of a proinsulin peptide to a CD4 T helper cell by MHC class II
They have a groove in which they can attach the peptides which can come from outside the cell or could be products of the cell's own genes. Once the peptide or 'antigen' is attached, the HLA 'presents' it so that a T cell can come along and check whether the molecule is 'self' or foreign, and will either pass over it or react to its presence (either destroying the cell, or raising the alarm about the foreign substance by emitting cytokines).

HLA genes have many possible variations, allowing each person's immune system to react to a wide range of foreign invaders. Some HLA genes have hundreds of identified versions (alleles), each of which is given a particular number (such as HLA-B27). Closely related alleles are categorised together; for example, at least 40 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2743. More than 100 diseases have been associated with different alleles of HLA genes. Type 1 diabetes is associated with the HLA class II haplotypes DRB104-DQB10302 and DRB103-DQB102.


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