Human Leukocyte Antigen (HLA) proteins are molecules on the surface of most cells in your body, encoded by a family of genes on chromosome 6. These proteins create a unique biological signature for each person. The immune system uses this signature to distinguish the body’s own cells from foreign ones, a process that is fundamental to its operation.
The Immune System’s Identification System
The primary function of HLA proteins is to present fragments of proteins, known as peptides, from within the cell. This display allows immune cells, specifically T-cells, to survey the health of cells throughout the body. By examining these peptides, T-cells can distinguish between the body’s own healthy proteins (“self”) and those from foreign invaders like viruses or bacteria (“non-self”).
There are two main classes of HLA proteins. Class I HLA molecules are found on nearly all nucleated cells and present peptides from proteins made inside the cell. If a cell is infected with a virus, it will display viral peptides on its Class I HLA molecules. This signals to cytotoxic T-cells that the cell is compromised and must be destroyed.
Class II HLA molecules have a more specialized function and are found only on antigen-presenting cells, such as dendritic cells, macrophages, and B-cells. These immune cells engulf pathogens from outside the cell. After breaking down these foreign entities, they present the peptide fragments on their Class II HLA molecules. This presentation activates helper T-cells, which then orchestrate a broader immune response, like producing antibodies.
Role in Organ and Tissue Transplantation
The HLA system’s role in distinguishing self from non-self is central to organ and tissue transplantation. When an organ is transplanted, the recipient’s immune system may identify the donor’s cells as foreign due to differences in their HLA proteins. A successful transplant, therefore, hinges on finding a donor with an HLA type as similar as possible to the recipient’s.
If the HLA match is poor, the recipient’s T-cells recognize the donor organ’s HLA proteins as foreign, triggering an immune response known as rejection. This attack can damage the new organ and lead to transplant failure. The most significant HLA genes for matching are HLA-DR, followed by HLA-B and HLA-A.
To prevent rejection, a laboratory test called HLA typing is performed before a transplant to identify the specific HLA alleles of both the donor and recipient. This determines their degree of compatibility. Family members, particularly siblings, are often the best potential donors as they are more likely to have inherited the same HLA types. Even with a good match, recipients require lifelong immunosuppressant medications to protect the transplanted organ.
Connection to Autoimmune Disorders
The HLA system can sometimes malfunction and contribute to autoimmune disorders, where the immune system mistakenly attacks the body’s own healthy tissues. This occurs when it loses the ability to distinguish between “self” and “non-self.” Certain HLA gene variations, or alleles, are strongly associated with an increased genetic risk for developing specific autoimmune diseases.
These associations do not mean that having a particular HLA variant guarantees the development of a disease, but it does increase susceptibility. For example, the presence of HLA-DQ2 and HLA-DQ8 alleles is found in the vast majority of individuals with celiac disease, a disorder where the immune system reacts to gluten and attacks the lining of the small intestine.
Another example is the link between the HLA-B27 allele and ankylosing spondylitis, a type of inflammatory arthritis affecting the spine. While the exact mechanisms are still being researched, it is believed that certain HLA proteins may be more prone to presenting self-peptides in a way that provokes an immune attack. This misidentification can cause chronic inflammation and tissue damage.
Influence on Disease and Drug Reactions
HLA proteins also influence responses to infectious diseases and certain medications. A person’s specific set of HLA alleles can affect their susceptibility or resistance to pathogens, explaining why some individuals clear an infection quickly while others develop a more severe illness. For instance, different HLA types have been linked to varying rates of HIV infection progression.
The HLA system is also a factor in predicting adverse drug reactions, as a specific allele can make an individual highly susceptible to a severe reaction to a medication. A prominent example is the link between the HLA-B5701 allele and a hypersensitivity reaction to abacavir, a drug used to treat HIV.
Before prescribing abacavir, doctors screen patients for the HLA-B5701 allele. If a patient carries this genetic variant, the drug is avoided due to the high risk of a dangerous immune reaction. This use of HLA information to guide treatment is a growing area of personalized medicine that improves patient safety.
Genetic Inheritance and Diversity
The diversity of HLA proteins results from their genetic inheritance. The HLA genes are located in a cluster on chromosome 6 and are inherited from parents in a linked set known as a haplotype. Each parent passes down one haplotype to their child.
This genetic system is one of the most polymorphic in the human genome, with thousands of different HLA alleles in the population. This diversity is an advantage for human survival, as a wide array of HLA molecules across the population means humanity is better equipped to fight a vast range of pathogens. If everyone had the same HLA type, a single new virus could be devastating.
This diversity may also play a role in human behavior, with some research suggesting it influences mate selection. The “sweaty T-shirt study” indicated that individuals may be subconsciously attracted to the scent of others with different HLA types. The evolutionary theory is that choosing a mate with a dissimilar HLA profile would give offspring a more varied set of HLA genes and a more robust immune system.