Human leukocyte antigens (HLA) are proteins found on the surface of nearly every cell in your body. Their primary job is to help your immune system distinguish between your own cells and foreign invaders like bacteria, viruses, or transplanted tissue. The genes that produce these proteins are located on chromosome 6 and are among the most variable in the entire human genome, meaning almost everyone carries a slightly different combination.
How HLA Proteins Work
Think of HLA proteins as identity tags. Each cell displays fragments of its internal contents on its surface using these proteins, like holding up a sign that says “this is what’s inside me.” Immune cells called T cells patrol the body, checking these signs. If the fragments look normal, T cells move on. If they spot something foreign, like a piece of a virus, they launch an immune attack.
This process is called antigen presentation, and it’s the foundation of how your adaptive immune system works. HLA molecules present both self and foreign protein fragments to T cell receptors, which then decide whether to tolerate what they see or trigger a defensive response. Without functioning HLA proteins, your immune system would be essentially blind.
Class I vs. Class II
HLA proteins come in two main classes, each with a different job and different distribution across the body.
Class I HLA proteins (HLA-A, HLA-B, and HLA-C) appear on the surface of almost all cells that have a nucleus. They present fragments from inside the cell to a type of immune cell called CD8+ T cells, also known as killer T cells. This is how your body detects cells that have been infected by a virus or have become cancerous. If a cell is producing abnormal proteins, Class I molecules will display those fragments, flagging the cell for destruction.
Class II HLA proteins (HLA-DR, HLA-DQ, and HLA-DP) are more selective about where they show up. They’re primarily found on specialized immune cells like macrophages, dendritic cells, and B cells. These molecules present fragments from things the immune cell has already engulfed, like bacteria, to CD4+ helper T cells. Helper T cells then coordinate the broader immune response, recruiting other immune cells and stimulating antibody production.
Why HLA Genes Are So Diverse
The HLA region is the most genetically diverse part of the human genome. Thousands of different allele variants have been identified across the HLA genes. This diversity exists for a good evolutionary reason: the wider the range of protein fragments a population can recognize, the harder it is for any single pathogen to evade everyone’s immune system. A virus that slips past one person’s HLA molecules will likely be caught by someone else’s.
You inherit one set of HLA genes from each parent, giving you two versions of each HLA protein. This combination is sometimes called your HLA type or tissue type. Because of the sheer number of possible variants, the odds of two unrelated people sharing the same full HLA type are extremely low.
HLA Naming Conventions
HLA alleles follow a specific naming system. A name like HLA-A*02:01 breaks down into parts: “A” identifies the gene, the first two digits after the asterisk (02) indicate the allele group (which roughly corresponds to the older serological classification), and the digits after the colon (01) specify the exact protein variant. This standardized system allows labs and transplant registries around the world to communicate precisely about which alleles a person carries.
Links to Autoimmune Disease
Because HLA proteins control what the immune system reacts to, certain HLA variants are strongly associated with autoimmune conditions where the body mistakenly attacks its own tissues.
One of the most striking examples is the connection between HLA-B27 and ankylosing spondylitis, an inflammatory disease that primarily affects the spine. Up to 90% of patients with ankylosing spondylitis carry the HLA-B27 allele, and this single gene contributes roughly 20% of the disease’s total heritability. Carrying HLA-B27 doesn’t guarantee you’ll develop the condition, but it substantially increases the risk.
Celiac disease shows a similarly strong HLA connection. About 90% of people with celiac disease carry the HLA-DQ2 variant, and another 5% carry HLA-DQ8. The remaining patients almost always carry at least one of the two genes that encode these proteins. Interestingly, HLA-DQ2/DQ8 testing is most useful for ruling celiac disease out rather than confirming it. The negative predictive value is very high: if you don’t carry either variant, celiac disease is extremely unlikely. But many people carry these variants without ever developing the disease, so a positive result alone doesn’t mean you have it.
Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis are among the many other conditions with documented HLA associations. Researchers have also found that T cells from patients with Parkinson’s disease recognize certain protein fragments displayed by both Class I and Class II HLA molecules, expanding the list of diseases with immune and HLA involvement.
HLA Matching in Transplantation
HLA typing became medically important because of organ and bone marrow transplantation. When a donor’s HLA proteins are too different from the recipient’s, the recipient’s immune system recognizes the transplanted tissue as foreign and attacks it. This is rejection. In bone marrow transplants, the reverse can also happen: donor immune cells attack the recipient’s body, a condition called graft-versus-host disease.
For bone marrow and stem cell transplants, HLA matching requirements are strict. The ideal scenario with a sibling donor is a 6 out of 6 match at HLA-A, HLA-B, and HLA-DRB1. When using an unrelated donor, transplant teams typically look for an 8 out of 8 match, adding HLA-C to the evaluation. A single mismatch (7 out of 8) is sometimes acceptable, though it raises the risk of transplant-related complications. For umbilical cord blood transplants, the minimum standard is a 4 out of 6 match, reflecting the fact that cord blood immune cells are less mature and somewhat more tolerant of mismatches.
Patients who have been previously exposed to foreign HLA proteins, through prior transplants, blood transfusions, or pregnancy, may develop HLA antibodies. These sensitized patients face a significantly higher risk of graft failure if the donor carries HLA types that match those antibodies, making extended HLA testing even more important.
How HLA Typing Is Done
Several laboratory methods exist for determining a person’s HLA type, and the technology has evolved considerably over the decades.
Older techniques use PCR (a method for copying specific DNA segments) with sequence-specific primers or probes. These approaches are relatively fast and inexpensive, making them suitable for routine clinical use. However, they offer lower resolution and can’t always distinguish between closely related alleles. They’re also limited to detecting previously known variants.
Next-generation sequencing has emerged as the current gold standard for high-resolution HLA typing. First demonstrated as reliable for this purpose around 2016, it can read large stretches of HLA genes including both the protein-coding regions and the surrounding DNA. This depth reduces errors in allele assignment and resolves ambiguous results that older methods can’t sort out. The tradeoff is greater cost and complexity, but for transplant matching and research purposes, the precision is often essential.
HLA and Drug Reactions
Certain HLA variants also predict severe adverse reactions to specific medications. The clearest example involves HLA-B*57:01, which is linked to a dangerous hypersensitivity reaction to abacavir, an HIV medication. Because of this association, HLA screening before prescribing abacavir is now standard practice. Patients who carry the allele are given alternative drugs instead.
This intersection of HLA typing and medication safety is part of a broader field called pharmacogenomics, where genetic testing guides drug selection. Similar HLA-drug associations have been identified for certain anti-seizure medications and gout treatments, where specific alleles predict a risk of severe skin reactions. In these cases, a simple genetic test before starting therapy can prevent a potentially life-threatening event.