The human body possesses a sophisticated defense system, and at its core are unique genetic instructions that help distinguish between what belongs and what does not. These instructions are found in a set of genes called Human Leukocyte Antigen, or HLA genes. HLA genes create proteins that reside on the surface of most cells, acting like a molecular identification card unique to each individual. This intricate system is fundamental to overall health, shaping how each person’s immune response reacts to the countless substances encountered daily. The proteins produced by these genes are also referred to as antigens.
The Immune System’s Identification System
HLA proteins play a role in the body’s immune surveillance. These proteins are located on the surface of nearly all nucleated cells, where their primary function is to present small fragments of proteins, known as peptides or antigens, to specialized immune cells called T-cells. If the HLA protein displays a peptide derived from a normal body protein, T-cells recognize it as “self” and do not initiate an immune response. This process ensures the immune system does not attack the body’s own tissues.
When a cell is infected by a virus or bacteria, or becomes cancerous, it produces abnormal or foreign proteins. Fragments of these “non-self” proteins are presented by HLA molecules on the cell surface. This acts as a signal, prompting T-cells to recognize the foreign antigen and trigger an immune attack to eliminate the compromised cell. The entire system is encoded by genes within a larger genetic region on chromosome 6, known as the Major Histocompatibility Complex (MHC). In humans, this complex is specifically called the HLA system.
HLA Genes and Medical Compatibility
The HLA system plays a significant role in organ transplantation. When a donor organ, such as a kidney or bone marrow, is introduced into a recipient’s body, the recipient’s immune system encounters the donor’s HLA proteins. If these HLA proteins are significantly different from the recipient’s own, the immune system identifies them as “non-self.” This recognition can trigger a strong immune response, leading to graft rejection.
To minimize rejection risk, medical professionals perform “HLA typing,” also known as tissue typing. This process determines the specific HLA profile of both donor and recipient, aiming for the closest possible match. A good HLA match leads to better graft function, fewer rejection episodes, and longer graft survival. Despite advances in immunosuppressive medications, finding a perfectly matched, unrelated donor is challenging due to the vast diversity of HLA types. Donor registries help patients find suitable donors by maintaining records of volunteer donors’ HLA characteristics.
Connection to Autoimmune Conditions
Certain variations in HLA genes are associated with an increased susceptibility to specific autoimmune diseases. In these conditions, the immune system mistakenly identifies the body’s own healthy cells and tissues as foreign invaders, attacking them. Particular HLA types may present self-peptides in a way that triggers an inappropriate immune response.
The HLA-B27 gene variant is strongly associated with ankylosing spondylitis, a chronic inflammatory condition affecting the spine. Approximately 96% of individuals with ankylosing spondylitis carry this variant. Similarly, specific HLA-DQ variants, primarily HLA-DQ2 and HLA-DQ8, are strongly linked to celiac disease, an autoimmune disorder triggered by gluten, with about 90-95% of people with celiac disease having the HLA-DQ2.5 haplotype. HLA-DQB103:02 and DQB102:01 alleles are also associated with an increased risk for type 1 diabetes. It is important to remember that possessing one of these HLA gene variants is a risk factor, not a guarantee, for developing the associated disease.
Inheritance and Diversity of HLA Genes
HLA genes are inherited in a specific manner, with an individual receiving a complete set of linked HLA genes, known as a haplotype, from each parent. This means that siblings have a 25% chance of inheriting identical HLA haplotypes from both parents, making them a perfect HLA match, a 50% chance of sharing one haplotype, and a 25% chance of sharing no haplotypes. This inheritance pattern explains why family members are often the first choice for potential transplant donors.
The human population exhibits immense variation in HLA genes, a phenomenon known as polymorphism. Thousands of different HLA alleles exist, making the HLA system the most polymorphic genetic system known in humans. This diversity benefits the species by ensuring a broad range of immune responses across the population, allowing for collective combat against pathogens and adaptation to new infectious threats. However, this polymorphism also makes finding a perfectly matched unrelated donor for transplantation difficult, as the chances of two unrelated individuals having identical HLA profiles are low.