What Are HLA Alleles and Their Role in Health?

Human Leukocyte Antigens (HLAs) are proteins on the surface of most cells that act as gatekeepers for the immune system, helping it distinguish the body’s own cells from foreign invaders. An HLA allele is a specific variation of an HLA gene, which results in a unique HLA protein structure.

Each person inherits a combination of these alleles, creating a distinct cellular signature the immune system uses to identify “self.” This genetic variability is a major factor in population immunity and introduces complexities in medicine, especially in organ transplantation and disease susceptibility.

The Genetic Foundation of HLA Alleles

The genes that produce HLA proteins are on chromosome 6 in a region known as the Major Histocompatibility Complex (MHC). This complex contains many genes categorized into classes based on function. The primary HLA genes belong to two main groups: Class I (HLA-A, HLA-B, HLA-C) and Class II (HLA-DR, HLA-DQ, HLA-DP).

Variations in the DNA sequence of HLA genes, a phenomenon called polymorphism, create different alleles. These genetic differences produce HLA proteins with distinct shapes, impacting their immune function. Each person inherits one set of HLA alleles from each parent, passed down as a block, or “haplotype.”

The combination of haplotypes from both parents determines an individual’s unique HLA genotype. While a person shares half of their HLA alleles with each parent, the probability of two unrelated individuals having an identical HLA profile is extremely low.

How HLA Alleles Orchestrate Immune Defense

HLA proteins function as display platforms on the cell surface, presenting small protein fragments, called peptides, to specialized immune cells known as T cells. The specific HLA alleles an individual possesses determine which peptides their proteins can effectively bind and present. This specificity allows the immune system to launch a successful response.

HLA Class I molecules, on nearly all nucleated cells, present peptides from within the cell. If a cell is infected by a virus or becomes cancerous, it breaks down the abnormal proteins into fragments. HLA Class I proteins bind these fragments and display them on the cell surface, signaling cytotoxic T cells (CD8+ T cells) to eliminate the compromised cell.

HLA Class II molecules are found on professional antigen-presenting cells, like dendritic cells and macrophages. These cells take up external pathogens, such as bacteria, and digest them. The resulting peptides are then presented by HLA Class II molecules to helper T cells (CD4+ T cells), which coordinate a broader immune attack, stimulating B cells to produce antibodies.

The structural differences between HLA proteins mean each variant has a unique peptide-binding groove. Some HLA alleles may be very effective at presenting peptides from a particular virus, leading to a robust immune response. Other alleles might not bind those same peptides as well, resulting in a less effective defense.

HLA Alleles in Transplantation Matching

The success of organ and stem cell transplantation depends on the HLA allele compatibility between the donor and recipient. Because HLA proteins mark cells as “self,” a mismatch can cause the recipient’s immune system to identify the transplant as foreign. This recognition triggers transplant rejection, which can destroy the donated organ.

For solid organ transplants, like kidneys or hearts, surgeons seek a donor whose HLA-A, HLA-B, and HLA-DR alleles are as similar as possible to the recipient’s. A closer match reduces the intensity of the immune response, improving long-term graft survival. A good HLA match can also lower the required dosage of immunosuppressive drugs, reducing side effects.

For hematopoietic stem cell (bone marrow) transplantation, HLA matching is more stringent because the donor’s immune system is transplanted. If the donor’s HLA alleles are not a close match, the new immune cells can recognize the recipient’s body as foreign. This can lead to Graft-versus-Host Disease (GVHD), a severe condition where donor T cells attack the recipient’s tissues.

To find the best match, laboratories perform HLA typing to identify the specific alleles of the donor and recipient. This genetic comparison is essential to modern transplantation, as a closer HLA match minimizes immunological complications and increases the likelihood of a successful transplant.

Linking HLA Alleles to Disease and Drug Responses

Specific HLA alleles are strongly associated with the risk of developing certain diseases, particularly autoimmune disorders. These associations increase an individual’s susceptibility but do not guarantee disease. The presence of a specific HLA variant can influence the immune system to mistakenly attack the body’s own tissues.

For example, the HLA-B27 allele is strongly associated with ankylosing spondylitis, a type of inflammatory arthritis. Similarly, specific HLA-DQ alleles are linked to celiac disease and type 1 diabetes, where the immune system attacks the small intestine and pancreas, respectively.

HLA alleles can also predict the likelihood of severe adverse drug reactions (ADRs). An HLA protein can sometimes bind to a drug molecule and present it to T cells as if it were a foreign peptide, triggering a dangerous immune response. For instance, the HLA-B57:01 allele is linked to a hypersensitivity reaction to the HIV medication abacavir.

Another example is the link between the HLA-B15:02 allele and Stevens-Johnson syndrome when taking the anti-seizure medication carbamazepine. Consequently, pharmacogenetic testing for specific HLA alleles is now recommended before prescribing certain medications to at-risk populations, allowing clinicians to personalize treatment.

The Global Tapestry of HLA Allele Diversity

The HLA gene system is a highly polymorphic, or genetically diverse, region in the human genome, with thousands of identified alleles. This diversity is not random; it is believed to be a result of evolutionary pressure from infectious diseases over millennia.

From an evolutionary standpoint, high HLA diversity within a population is advantageous. A wide range of alleles means the human species is better equipped to recognize and fight a vast landscape of pathogens. If a new virus emerges, it is more likely that some individuals will possess HLA alleles capable of presenting its peptides, ensuring population survival.

The frequencies of specific HLA alleles vary significantly among different ethnic and geographic populations. These differences reflect ancestral migration patterns and the historical prevalence of regional pathogens. An allele that confers resistance to a local pathogen may be common in that population but rare elsewhere.

An individual’s HLA alleles are identified through HLA typing. Modern DNA-based methods like sequencing identify alleles with high precision. This information is used for transplantation and drug safety and contributes to global databases that help researchers understand population genetics and disease associations.