Human Leukocyte Antigen (HLA) expression refers to the process by which genes on chromosome 6 direct the creation of specialized proteins. These proteins are then placed on the surface of almost every cell in the human body. Once on the surface, they function as a cellular identification card, presenting information to the immune system. The level of expression determines how many of these HLA proteins are present on a cell at any given time.
This system is fundamental to how the body distinguishes its own healthy cells from those that are foreign or compromised. For HLA, this means the more a specific HLA gene is “expressed,” the more of that corresponding HLA protein will be visible on the cell’s exterior, making its status clear to patrolling immune cells.
The Immune System’s Identification System
The primary role of HLA molecules is to present small fragments of proteins, called peptides, to the immune system. The HLA proteins act like display cases on the cell surface, holding up these peptides for inspection by specialized immune cells known as T-cells. This constant surveillance allows the immune system to monitor the health of cells throughout the body.
This identification system is divided into two main functional categories. HLA class I molecules are found on the surface of nearly all nucleated cells. They specialize in presenting peptides that originate from within the cell, a process known as the endogenous pathway. This allows the immune system to check for internal problems, such as a viral infection or cancerous changes. If a T-cell recognizes a peptide as foreign or malignant, it can initiate the destruction of the compromised cell.
A different class of molecules, HLA class II, operates on a more select group of cells. These are found only on professional “antigen-presenting cells” (APCs), such as macrophages, dendritic cells, and B cells. Unlike class I, HLA class II molecules present peptides derived from external sources that the APC has engulfed, like bacteria. This is called the exogenous pathway and serves to alert the immune system to external invaders, coordinating a larger defensive response.
Regulation of HLA Levels
The specific types of HLA proteins a person has are determined by their genes. The HLA gene cluster is the most polymorphic in the human genome, meaning there are thousands of different versions, or alleles, in the human population. This genetic diversity ensures that humanity as a whole can recognize a vast array of pathogens. Each person inherits a unique combination of these genes from their parents, resulting in a distinct HLA tissue type.
While the type of HLA is genetic, the quantity of HLA molecules on a cell’s surface can change. This process, known as expression regulation, is highly responsive to the cellular environment. During infections or periods of inflammation, cells can be prompted to increase their HLA expression. Signaling molecules called cytokines are potent inducers of HLA gene expression, making cells more visible to the immune system.
Conversely, some pathogens and cancers have developed ways to hide from the immune system by reducing HLA expression. This downregulation is a common immune evasion tactic. For instance, some viruses interfere with the process that places HLA class I molecules on the cell surface. Similarly, some cancer cells acquire mutations that shut down the genes responsible for producing HLA proteins, making them invisible to patrolling T-cells.
Medical Relevance of HLA Expression
The HLA system is medically relevant, particularly in transplantation. For an organ or stem cell transplant to be successful, the HLA type of the donor must closely match that of the recipient. If the HLA “ID cards” are too different, the recipient’s immune system will recognize the new organ as foreign and launch an attack, a process called graft rejection. This is why extensive HLA typing is performed before any transplant procedure to find the best possible match.
Certain HLA alleles are linked to an increased risk of autoimmune diseases, where the immune system mistakenly targets the body’s own healthy tissues. For example, individuals with the HLA-B27 allele have a significantly higher likelihood of developing ankylosing spondylitis. The structure of the HLA-B27 molecule is thought to present the body’s own peptides in a way that triggers a misguided immune attack.
HLA expression is also relevant to cancer treatment, as many tumors reduce their HLA expression to evade the immune system. This has led to the development of immunotherapies. Some of these treatments, known as checkpoint inhibitors, work by reinvigorating T-cells to help them recognize and attack tumor cells. Other emerging therapies aim to force cancer cells to restore their HLA expression, making them susceptible to immune destruction once more.