The Human Leukocyte Antigen (HLA) system is a complex group of genes that act as markers on nearly every cell in the body. These markers allow the immune system to distinguish between the body’s own cells and foreign invaders, such as bacteria or viruses. HLA-B15 is a specific variant (allele) of the HLA-B gene, which is part of this larger system. This variant has gained attention due to its strong associations with certain drug hypersensitivities and autoimmune disorders. Understanding the presence and function of the HLA-B15 allele is now an important consideration in personalized medicine and pharmacogenomics.
The Role of HLA in Immunity
The entire HLA system resides within the Major Histocompatibility Complex (MHC), located on the short arm of chromosome 6. This genetic region contains the most diverse set of genes in the human population, ensuring a wide range of immune responses. The HLA genes are broadly categorized into three classes based on their structure and function.
HLA Class I molecules, including HLA-A, HLA-B, and HLA-C, are expressed on the surface of almost all nucleated cells. Their primary function is to patrol the cell’s interior by binding to small protein fragments (peptides) originating from within the cell. If the cell is infected or has become cancerous, these internal peptides are displayed on the cell surface by the Class I molecule.
This display acts as a signal to specialized immune cells called cytotoxic T-lymphocytes (CD8+ T-cells). When a T-cell recognizes a foreign peptide presented by the Class I molecule, it initiates a targeted immune response to destroy the abnormal cell. The HLA-B gene, and its variant HLA-B15, is directly involved in this cellular surveillance mechanism.
Genetic Link to Adverse Drug Reactions
The most medically significant aspect of the HLA-B15 allele is its strong association with severe cutaneous adverse reactions (SCARs) to certain medications. Specifically, the HLA-B15:02 allele is linked to the development of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). These are life-threatening skin disorders characterized by widespread blistering, skin detachment, and erosion of mucous membranes.
This severe hypersensitivity reaction is often triggered by aromatic anti-epileptic drugs, most notably carbamazepine, which treats seizures and trigeminal neuralgia. The underlying mechanism involves a maladaptive immune response where the drug or its chemical byproducts interact directly with the HLA-B15:02 molecule. This binding alters the shape of the molecule’s peptide-binding groove.
The resulting complex is mistakenly recognized by CD8+ T-cells as a foreign antigen. These activated cytotoxic T-cells then attack the body’s own skin cells, leading to the cell death that defines SJS and TEN. Symptoms typically appear within the first few months of starting the medication.
The risk associated with HLA-B15:02 is pronounced in individuals of Southeast Asian ancestry, including populations from China, Thailand, and the Philippines, where the allele frequency can be 10 to 15 percent. Due to this strong pharmacogenetic link, regulatory bodies like the U.S. Food and Drug Administration (FDA) recommend screening for the HLA-B15:02 allele before initiating carbamazepine therapy in patients of Asian descent. This pre-screening prevents potentially fatal drug reactions.
Association with Specific Autoimmune Conditions
HLA-B15 also has connections with certain autoimmune diseases, though these links are less direct and more population-specific than the drug reaction association. One such condition is Behçet’s disease (BD), a chronic inflammatory disorder causing blood vessel inflammation that can lead to recurrent oral and genital ulcers, eye, and neurological problems. While HLA-B51 is the most recognized genetic risk factor for BD globally, studies in specific ethnic groups, such as Moroccan populations, have found an independent association with HLA-B15.
The HLA-B15 allele is also implicated in spondyloarthropathies (SpA), which are types of inflammatory arthritis primarily affecting the spine and other joints. This B15 association is distinct from the link between HLA-B27 and Ankylosing Spondylitis (AS). In certain populations, particularly in Latin America, HLA-B15 has been linked to undifferentiated Spondyloarthritis (uSpA), a form of SpA that does not fully meet the criteria for a recognized subtype.
The presence of HLA-B15 appears to favor a more peripheral pattern of arthritis, affecting joints in the limbs, rather than the severe axial involvement seen with HLA-B27-positive AS. These findings suggest that different HLA variants may predispose individuals to distinct clinical presentations. The allele increases susceptibility, but the overall risk is a complex interplay of genetic, environmental, and other factors.
Clinical Screening and Genetic Testing
Genetic testing for the HLA-B15 allele, specifically the B15:02 variant, is primarily a proactive screening measure to improve patient safety before prescribing high-risk medications. This pharmacogenomic testing is typically performed using a blood sample to analyze the patient’s DNA. The most common method is Polymerase Chain Reaction (PCR), which allows for the rapid identification of the specific HLA-B15:02 sequence.
The test results guide prescribing decisions, particularly for carbamazepine in patients of Asian ancestry. If a patient tests positive for HLA-B15:02, the clinician avoids prescribing carbamazepine and related compounds, opting instead for an alternative medication without the same genetic risk. This pre-treatment screening prevents a potentially life-threatening adverse event.
A positive test result does not guarantee a reaction, as the positive predictive value is relatively low; the vast majority of carriers will not develop SJS/TEN. However, due to the severity of the reaction, clinical management dictates choosing a safer alternative. Testing may also be used diagnostically to support the cause of a previous adverse drug reaction or to assess susceptibility in patients with an associated autoimmune condition.