Human Leukocyte Antigens (HLA proteins) are specialized molecules found on the surface of nearly every cell in the human body. They function as unique identity markers, acting like a cellular fingerprint that tells the immune system which cells belong and which do not. The HLA system is the human version of the Major Histocompatibility Complex (MHC). HLA proteins are fundamental to the immune system’s ability to distinguish “self” from potentially harmful “non-self” invaders, initiating a defensive response against infection or disease.
The Role of HLA in Immune Surveillance
The primary function of HLA proteins is to act as presenters, displaying small fragments of protein, known as peptides or antigens, on the cell surface for inspection by specialized white blood cells called T-cells. This display mechanism is termed antigen presentation, and it allows the immune system to monitor the internal environment of all cells. The cell constantly breaks down proteins, both its own and those from any internal invaders like viruses, and the HLA molecules capture these fragments.
If a cell is healthy, the HLA protein displays a “self” peptide, and the T-cell recognizes it as normal, leaving the cell unharmed. Conversely, if a cell is infected by a virus or has become cancerous, the HLA molecules present a fragment of the foreign or abnormal protein. This presented foreign antigen acts as a signal, alerting the immune system to an internal problem.
When a T-cell encounters an HLA molecule displaying a foreign antigen, it triggers an adaptive immune response tailored to eliminate the threat. Specifically, cytotoxic T-cells, or killer T-cells, are activated to destroy the infected cell directly, preventing the spread of the pathogen. This rigorous inspection and immediate response is the core of how the body maintains its integrity against internal threats.
Genetic Diversity and HLA Classes
The HLA system is characterized by extreme genetic variability, a feature known as polymorphism, which means there are thousands of different versions, or alleles, of HLA genes across the human population. This extensive diversity ensures that humans can present and respond to a vast array of pathogens, making it difficult for any single infectious agent to wipe out the entire population. Each person inherits a specific set of HLA genes from their parents, with these genes typically inherited together as a block known as a haplotype.
HLA proteins are broadly divided into two main categories based on their structure, location, and the type of antigen they present. Class I HLA molecules are found on the surface of almost all nucleated cells in the body, including most tissue and organ cells. Their function is to primarily present peptides derived from proteins synthesized inside the cell, such as those from viruses or abnormal proteins from a tumor. These Class I molecules interact with CD8-positive cytotoxic T-cells.
In contrast, Class II HLA molecules have a restricted distribution, primarily found on specialized immune cells (antigen-presenting cells) such as B-cells, macrophages, and dendritic cells. Class II molecules present peptides that originate from outside the cell, such as fragments of bacteria or other foreign material the immune cell has engulfed. These molecules interact with CD4-positive helper T-cells, which orchestrate the broader immune response, including stimulating antibody production.
HLA and Organ Compatibility
The high degree of polymorphism in the HLA system makes HLA matching a significant factor in successful organ and tissue transplantation. When a patient receives a transplanted organ, the recipient’s immune system recognizes the donor’s HLA proteins as foreign markers. This difference from “self” HLA triggers a powerful immune attack against the transplanted tissue, a phenomenon called rejection.
To minimize the risk of rejection, doctors perform HLA typing, a process that identifies the specific HLA alleles of both the donor and the recipient. The goal is to find the closest possible match for the key HLA genes, which include HLA-A, HLA-B, and HLA-DR. A perfect or near-perfect match significantly reduces the likelihood and severity of the recipient’s immune reaction against the new organ.
The severity of rejection varies, ranging from hyperacute (occurring almost immediately) to chronic (occurring over months or years). Even with the best match, some HLA difference usually remains, necessitating the long-term use of immunosuppressive drugs. These medications dampen the recipient’s immune system activity, preventing T-cells from destroying the transplanted organ. The need for continuous immunosuppression highlights the power of HLA proteins in defining self-tissue.
Linking HLA to Health and Disease
The genetic diversity of HLA, while beneficial for pathogen defense, also links specific HLA types to susceptibility to certain diseases. Researchers have identified statistical associations between particular HLA alleles and an increased risk of developing various conditions, especially autoimmune disorders. In these diseases, the immune system mistakenly attacks healthy tissues, and a specific HLA type is often a contributing factor.
For example, the HLA-B27 allele carries a significantly higher risk of developing the inflammatory arthritis condition Ankylosing Spondylitis. The HLA-DR4 and HLA-DR3 alleles are also strongly associated with increased susceptibility to Rheumatoid Arthritis and Type 1 Diabetes, respectively. One theory is that the specific HLA protein version presents a “self” peptide in a way that T-cells misinterpret as a foreign threat, initiating an autoimmune response. Another possibility is that the HLA type is inefficient at presenting a specific pathogen, allowing an infection to trigger a cross-reaction leading to autoimmunity.