Human Leukocyte Antigen (HLA) typing maps specific proteins on the surface of cells, which the immune system uses to distinguish between self and non-self. These markers regulate the immune response by presenting small peptide fragments to T-cells. HLA typing is a powerful diagnostic tool with significant medical implications for transplantation, disease susceptibility, and drug safety.
Understanding the HLA Complex
The genes responsible for the HLA system are located within the major histocompatibility complex (MHC) on human Chromosome 6. This region is the most highly variable, or polymorphic, in the human genome, allowing the immune system to respond to a vast array of pathogens. HLA genes are separated into two main groups, Class I and Class II.
Class I molecules (encoded by HLA-A, -B, and -C) are found on almost all nucleated cells and present peptides derived from inside the cell to CD8+ T-cells. Class II molecules (encoded by HLA-DR, -DQ, and -DP) are primarily limited to specialized antigen-presenting cells. They present peptides derived from outside the cell, such as those from bacteria, to CD4+ helper T-cells.
Deciphering the Typing Nomenclature
HLA typing results use a standard international nomenclature system to describe the specific HLA gene version, or allele. For example, an allele might be designated as HLA-A\02:01:01:01. “HLA-A” identifies the gene locus, and the asterisk indicates molecular typing was used. The numbers following the asterisk are separated by colons into fields, providing increasing detail about the allele.
Field Interpretation
The first field (e.g., “02”) represents the allele group, often corresponding to the broad serological antigen type. Results reaching only this level are low-resolution (antigen-level), grouping alleles that produce similar surface proteins. The second field (e.g., “01”) defines a specific HLA allele by identifying non-synonymous DNA sequence changes that alter the protein’s amino acid sequence.
Typing that includes the first and second fields is high-resolution (allele-level) and is the standard for matching in many transplant settings. The third and fourth fields specify minor changes, such as synonymous mutations or changes in non-coding regions, and are less frequently reported clinically.
Interpreting Results for Transplant Compatibility
HLA typing is central to assessing compatibility between a recipient and donor, as a mismatch can lead to graft rejection. The immune system recognizes foreign HLA proteins as non-self, triggering an immune response.
Solid Organ Transplants
For solid organ transplants (e.g., kidney), six primary loci are typically considered: two each for HLA-A, HLA-B, and HLA-DR. A “perfect match” is a 6-of-6 match, meaning all six antigens are identical. While a better match generally correlates with improved long-term outcomes, successful transplants are routinely performed even without a perfect match. Rejection risk is also assessed by cross-matching, which tests the recipient’s serum for pre-existing antibodies against the donor’s HLA proteins (formed from prior pregnancies, transfusions, or transplants).
Stem Cell Transplants
Matching requirements are significantly more stringent for blood stem cell or bone marrow transplants due to the heightened risk of graft-versus-host disease (GVHD). GVHD occurs when the donor’s immune cells attack the recipient’s body. High-resolution typing is necessary, and matching is often performed at ten or more alleles across the HLA-A, -B, -C, -DRB1, and -DQB1 loci. A 10-of-10 match is the ideal goal, as a higher degree of mismatch directly increases the likelihood and severity of GVHD and graft failure.
Interpreting Results for Disease and Drug Sensitivity
Beyond transplantation, HLA typing provides insight into disease susceptibility and potential adverse drug reactions. Specific HLA alleles are statistically associated with an increased risk for various autoimmune conditions. For example, the presence of HLA-B27 is a major genetic factor linked to the inflammatory arthritis Ankylosing Spondylitis.
This association indicates an elevated risk, not a guarantee of disease, as the mechanism involves complex interactions with other genes and environmental factors. Testing serves as a diagnostic aid rather than a definitive diagnosis, as many people with HLA-B27 never develop the condition.
HLA typing also plays a role in pharmacogenomics, studying how genetic variation affects drug response. A notable example is the HLA-B\57:01 allele, which is strongly linked to a severe hypersensitivity reaction to the HIV drug abacavir. Screening for this allele before prescribing the medication is standard practice to prevent adverse events. Similar associations exist, such as HLA-B\15:02 and the risk of severe skin reactions to the anti-epileptic drug carbamazepine.