Gene Number: 3106

Location: 6p21.33

Key Functions: Antigen presentation, immune response activation, infection defense, autoimmunity regulation

HLA-B encodes human leukocyte antigen B, a critical component of the major histocompatibility complex (MHC) class I system, which governs the presentation of endogenous peptides to cytotoxic CD8⁺ T lymphocytes. As part of the adaptive immune system, HLA-B serves as a molecular sentinel, allowing immune surveillance mechanisms to distinguish between normal “self” cells and those harboring intracellular pathogens or malignant transformations. Its activity underpins cellular immunity and contributes to immune specificity and memory.

The HLA-B molecule is a cell surface glycoprotein composed of a heavy α-chain encoded by the HLA-B gene and a light chain (β₂-microglobulin) encoded elsewhere in the genome. The α-chain contains three extracellular domains (α1, α2, α3), a transmembrane region, and a cytoplasmic tail. The peptide-binding groove, formed by the α1 and α2 domains, accommodates short peptides (typically 8–10 amino acids) derived from intracellular proteins that have been processed by the proteasome and transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing).

Once loaded with peptide, the HLA-B complex is transported to the cell surface, where it displays the peptide to CD8⁺ T cells. When a presented peptide is recognized as foreign (e.g., from viral or tumor origin), the T cell receptor (TCR) binds the HLA-B–peptide complex, triggering T-cell activation and targeted cytotoxicity against the infected or transformed cell. Through this mechanism, HLA-B provides the immune system with a real-time intracellular “snapshot,” enabling precise immunological defense.

HLA-B polymorphism represents one of the highest degrees of genetic variability in the human genome. Thousands of allelic variants (e.g., HLA-B27, HLA-B57, HLA-B15:02) exist, differing mainly in the amino acid composition of the peptide-binding groove, thereby dictating peptide specificity and immune recognition patterns. This extraordinary diversity provides population-level resilience against pathogens but also underlies significant clinical variability in immune-related conditions.

Key implications of HLA-B polymorphism include:

1. Infectious disease outcomes:Certain alleles confer protection or susceptibility to specific infections. For example, HLA-B57:01 and HLA-B27:05 are associated with slower progression of HIV infection due to efficient presentation of viral peptides and robust cytotoxic T-cell responses. Conversely, some alleles are linked to poor viral clearance or immune exhaustion.

   
   

2. Autoimmune disease associations:HLA-B27 is strongly associated with ankylosing spondylitis and related spondyloarthropathies, where aberrant antigen presentation or molecular mimicry leads to chronic inflammation. Other alleles have been linked to psoriasis, multiple sclerosis, and systemic lupus erythematosus.

   
   

3. Drug hypersensitivity reactions:Specific alleles predispose individuals to severe, sometimes life-threatening adverse drug reactions. For instance:

   • HLA-B15:02 is associated with carbamazepine-induced Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), particularly in individuals of East Asian ancestry.

   • HLA-B57:01 confers risk for abacavir hypersensitivity in HIV treatment, prompting routine genetic screening before therapy initiation.

     
     

4. Transplantation compatibility:HLA-B typing is essential for organ and hematopoietic stem cell transplantation, as mismatch between donor and recipient alleles can provoke graft rejection or graft-versus-host disease (GVHD) due to alloimmune recognition.

   
   

In addition to its classical role in antigen presentation, HLA-B influences immune regulation through interactions with natural killer (NK) cell receptors such as KIRs (killer-cell immunoglobulin-like receptors). Certain combinations of HLA-B alleles and KIR genotypes modulate NK cell activity, impacting immune tolerance, antiviral defense, and cancer immunosurveillance.

In summary, HLA-B serves as a central element in the adaptive immune defense, orchestrating the recognition and elimination of infected or aberrant cells. Its remarkable polymorphism shapes individual and population-level immune diversity but also underpins susceptibility to autoimmune diseases, infectious outcomes, and drug-induced hypersensitivity syndromes. Understanding HLA-B genetic variation is thus crucial in immunogenetics, pharmacogenomics, and precision medicine, guiding strategies for disease prevention, treatment optimization, and safe therapeutic application.