Human Leukocyte Antigens (HLAs) are proteins found on the surface of most cells, playing a fundamental role in the immune system. They function as cellular identification tags, allowing the immune system to differentiate between the body’s own cells and foreign invaders. This “self” versus “non-self” recognition is a foundational aspect of immune defense. The HLA system is the human version of the Major Histocompatibility Complex (MHC), a gene family found in many animals that serves a similar purpose.
Understanding HLA Subtypes
HLAs exhibit considerable diversity, existing in numerous distinct versions known as subtypes. This diversity originates from the genes that encode them, located on chromosome 6. Specifically, genes such as HLA-A, HLA-B, HLA-C (Class I) and HLA-DR, HLA-DQ, HLA-DP (Class II) contribute to this variability. Subtypes are more specific than broader HLA types, often differing by only a few amino acids, but these small variations can significantly influence immune function. This extensive polymorphism allows the immune system to fine-tune its response to a wide range of potential threats.
Role in Immune Recognition
The primary function of HLA subtypes involves presenting small protein fragments, called peptides, to T-cells. There are two main classes of HLA molecules.
Class I HLA molecules, encoded by HLA-A, -B, and -C genes, are found on almost all nucleated cells. They present peptides derived from inside the cell, such as from viral infections or cancerous cells, to killer T-cells (CD8+ T-cells), signaling for the destruction of the infected cell.
Class II HLA molecules, encoded by HLA-DR, -DQ, and -DP genes, are primarily expressed on specialized immune cells, including macrophages, dendritic cells, and B-cells. These molecules present peptides derived from outside the cell, such as from bacteria, to helper T-cells (CD4+ T-cells). Helper T-cells then coordinate a broader immune response, including stimulating antibody production. The specific HLA subtype determines which peptides are presented, directly impacting the immune system’s ability to recognize and respond to various pathogens and cellular changes.
Clinical Significance
HLA subtypes hold significant medical importance.
In transplantation, particularly for organs and bone marrow, matching HLA subtypes between donor and recipient is crucial. A closer HLA subtype match leads to better outcomes by reducing the risk of rejection, where the recipient’s immune system attacks the transplanted tissue, or graft-versus-host disease, where donor immune cells attack recipient tissues. Minimizing mismatches is a primary goal, as perfect matches are rare for unrelated individuals.
Certain HLA subtypes are also linked to an increased or decreased risk of developing specific diseases. For example, some subtypes are associated with autoimmune conditions such as Type 1 diabetes, rheumatoid arthritis, and celiac disease. This association occurs because the specific peptides presented by these HLA molecules might either trigger an autoimmune response against the body’s own tissues or fail to present infectious agents effectively. HLA subtypes can also influence susceptibility to infectious diseases, affecting how well an individual’s immune system responds to particular viruses or bacteria.
Furthermore, some HLA subtypes can predispose individuals to severe adverse reactions to certain medications. A notable example is the antiviral drug abacavir, used in HIV treatment. Individuals carrying the HLA-B57:01 subtype have a significantly higher risk of developing a severe hypersensitivity reaction to abacavir, making pre-screening for this subtype a standard practice before prescribing the drug.
Identifying HLA Subtypes
Identifying HLA subtypes typically involves genetic testing of a blood sample. The methods for HLA typing have evolved considerably over time, from earlier serological techniques that used antibodies to detect HLA antigens. Modern HLA typing primarily relies on molecular techniques, which directly analyze the genes encoding HLA proteins. Current molecular methods, such as Polymerase Chain Reaction (PCR) and DNA sequencing, allow for high-resolution subtyping and provide detailed genetic information about an individual’s HLA profile. Next-Generation Sequencing (NGS) has further enhanced this process, enabling the rapid and accurate determination of HLA types at an allele level, which is crucial for precise matching in clinical applications like transplantation.