Human Leukocyte Antigens (HLA) are proteins found on the surface of most cells, encoded by genes on chromosome six known as the Major Histocompatibility Complex (MHC). HLA proteins act as markers, allowing the immune system to recognize which cells belong to the body. This recognition system is characterized by extreme variability, or polymorphism, with thousands of different versions existing across the human population. This high variation is a defense mechanism, helping the immune system respond to a vast array of pathogens and foreign substances. An individual’s unique combination of HLA types dictates how their immune system reacts to disease or transplanted tissue.
The Role of HLA in Immune Recognition
The function of HLA proteins is to present small protein fragments, called peptides, to T-cells, the immune system’s specialized surveillance cells. HLA proteins operate in two main classes, each with a distinct role in this process.
Class I HLA proteins (HLA-A, HLA-B, and HLA-C) are expressed on nearly all nucleated cells. These molecules display peptides originating from inside the cell, such as fragments of viral proteins if the cell is infected. If a cytotoxic CD8+ T-cell recognizes the fragment as foreign, it signals the destruction of the infected cell. This mechanism is the primary defense against intracellular pathogens like viruses and certain cancers.
Class II HLA proteins (HLA-DR, HLA-DQ, and HLA-DP) are typically found only on specialized immune cells, called antigen-presenting cells. These proteins display peptides originating from outside the cell, such as fragments of engulfed bacteria. Helper CD4+ T-cells recognize these complexes and coordinate a broader immune response, including antibody production by B-cells. The HLA system ensures a comprehensive and targeted immune reaction by presenting both internal and external threats.
Understanding HLA Nomenclature and Classification
The complexity of the HLA system is reflected in its naming convention, which allows precise identification of unique subtypes. Classification is first divided into the two functional groups, Class I and Class II, corresponding to the main gene loci involved. The genes at these loci, such as \(HLA-A\), \(HLA-B\), \(HLA-C\), and \(HLA-DRB1\), are the most commonly studied.
HLA nomenclature uses a series of numbers separated by colons, with each pair of digits representing a higher level of precision. For example, in the designation \(HLA-A02:01:01\), the first two digits (\(02\)) refer to the serological antigen group, representing a broad family of similar HLA proteins. This initial grouping is often referred to as low-resolution typing.
The next two digits (\(01\)) denote the specific allele or subtype, representing a protein with a unique amino acid sequence. This high-resolution typing distinguishes between functionally distinct HLA proteins. Further digits represent variations in the DNA sequence that do not change the protein structure, providing the most detailed genetic definition. Even a single amino acid difference in the HLA protein can dramatically change how the immune system responds.
HLA Subtypes in Organ and Stem Cell Matching
The polymorphism of the HLA system makes matching subtypes a significant challenge in transplantation medicine. If a patient receives tissue with foreign HLA proteins, the immune system triggers allorecognition, which can lead to the destruction of the transplanted tissue, known as graft rejection.
For solid organ transplants (e.g., kidney or heart), matching the recipient and donor for the major HLA loci—\(HLA-A\), \(HLA-B\), and \(HLA-DR\)—is a strong predictor of success. Although immunosuppressive drugs can manage some mismatch, a closer match minimizes the risk of hyperacute or accelerated rejection.
Hematopoietic stem cell transplantation (HSCT) replaces the patient’s entire immune system and requires an exceptionally precise match at the allele level. For unrelated donors, the standard is often a high-resolution match at eight key alleles: \(HLA-A\), \(HLA-B\), \(HLA-C\), and \(HLA-DRB1\) on both inherited chromosomes (an \(8/8\) match).
A mismatch in HSCT risks rejection and significantly increases the probability of Graft-versus-Host Disease (GVHD). GVHD occurs when the donor’s immune cells recognize the recipient’s healthy tissues as foreign and attack them. High-resolution matching, including additional loci like \(HLA-DQ\) and \(HLA-DP\), is pursued to minimize the likelihood and severity of this complication.
How HLA Subtypes Influence Disease Risk
Specific HLA subtypes are associated with susceptibility to certain autoimmune and infectious diseases. This occurs because the structure of an HLA protein may be poor at presenting specific peptides to T-cells. The resulting dysregulation can lead the immune system to mistakenly target the body’s own tissues.
A well-known example is the \(HLA-B27\) subtype, strongly linked to seronegative spondyloarthropathies, such as Ankylosing Spondylitis. \(HLA-B27\) is found in over 90% of individuals with this condition, indicating a powerful genetic link.
Other associations include \(HLA-DR4\) with Rheumatoid Arthritis, and \(HLA-DQ2\) and \(HLA-DQ8\) with Type 1 Diabetes and Celiac Disease. Having a disease-associated HLA subtype increases genetic predisposition, but it does not guarantee the disease will manifest. Disease development typically requires a combination of genetic risk and environmental triggers.
Determining Your HLA Profile
Identifying an individual’s specific HLA profile, known as HLA typing or histocompatibility testing, has become increasingly sophisticated. Early methods used serological testing, relying on antibodies to group HLA proteins based on surface characteristics. These methods provided only low-resolution results and often failed to distinguish between functionally unique subtypes.
Modern HLA typing relies almost entirely on molecular, DNA-based technologies to achieve high-resolution detail. A sample of blood, saliva, or tissue is collected to extract the genetic material containing the HLA genes. Techniques such as Sequence-Based Typing (SBT) and Next-Generation Sequencing (NGS) are now standard, as they directly read the nucleotide sequence of the HLA genes.
This precise sequencing allows for allele-level identification, providing the high resolution required for demanding clinical applications, such as stem cell donor registries. Accurate HLA typing is fundamental for assessing compatibility for transplantation, stratifying disease risk, and guiding personalized medical treatments.