| Gene Symbol | HLA-B |
|---|---|
| Full Name | Major Histocompatibility Complex Class I B |
| Chromosomal Location | 6p21.3 |
| NCBI Gene ID | 3135 |
| OMIM | 142830 |
| Ensembl ID | ENSG00000206428 |
| UniProt ID | P01889 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, ALS, Stroke |
| Expression | All nucleated cells, microglia, immune cells |
HLA-B (Major Histocompatibility Complex Class I B) is a gene located on chromosome 6p21.3 that encodes the 44 kDa heavy chain of the HLA class I molecule. HLA-B is one of the most polymorphic genes in the human genome, with over 6,000 known alleles[1]. It plays a critical role in adaptive immune surveillance by presenting endogenously synthesized peptide antigens to CD8+ cytotoxic T lymphocytes, enabling recognition and elimination of infected or abnormal cells[2].
HLA molecules also interact with killer cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells, regulating NK cell activity through a sophisticated system of activating and inhibitory signals. This HLA-KIR interaction pathway has been implicated in neuroinflammatory processes relevant to Alzheimer's disease and Parkinson's disease[3].
HLA-B folds around an 8-11 amino acid peptide derived from intracellular protein processing. The peptide-binding groove (alpha-1 and alpha-2 domains) contains polymorphic residues that determine which peptides can bind, shaping the repertoire of antigens presented to T-cells[4]. Each HLA-B molecule presents approximately 10,000-20,000 different peptide species at the cell surface.
The conserved alpha-3 domain of HLA-B interacts with the CD8 co-receptor on cytotoxic T lymphocytes, providing a co-stimulatory signal that enhances T-cell receptor (TCR) engagement. This HLA-B/CD8 interaction is critical for the activation and clonal expansion of virus-specific and tumor-reactive CD8+ T-cells.
HLA-B interacts with KIR receptors on NK cells. Specific HLA-B alleles either activate or inhibit NK cell cytotoxicity through this pathway. In the brain, microglial expression of HLA-B and its interaction with NK cell KIRs may regulate neuroinflammatory responses[5].
HLA class II genes (including HLA-DRB1) have been associated with AD risk, but HLA-B associations are emerging. Microglial HLA-B expression increases in AD brains, reflecting an active immune response. The HLA-B/KIR interaction pathway may modulate microglial activation states, influencing amyloid clearance efficiency and neuroinflammatory burden[3:1].
Specific HLA-B variants modify Parkinson's disease risk through modulation of the adaptive immune response in the brain. HLA-B alleles may influence autoimmune components of PD pathogenesis, particularly in cases with earlier onset. Microglial HLA-B presentation of neuronal antigens could trigger cytotoxic CD8+ T-cell responses targeting dopaminergic neurons. Several GWAS studies have identified the MHC region on chromosome 6p21 as a PD risk locus.
HLA-B27:05 and HLA-B44:02 alleles are associated with MS susceptibility and disease course. HLA-B44:02 may be protective against MS onset, while HLA-B27:05 is linked to atypical MS presentations with prominent spinal cord involvement.
HLA associations have been reported in ALS cohorts, suggesting immune-mediated mechanisms may contribute to motor neuron degeneration. The MHC region harboring HLA-B shows pleiotropic effects across neurodegenerative diseases.
HLA-B alleles influence susceptibility to ischemic stroke, likely through immune-mediated mechanisms affecting vascular inflammation and atherogenesis[6].
HLA-B is constitutively expressed at high levels on all nucleated cells:
HLA-B expression is upregulated by interferon-gamma (IFN-γ), inflammatory cytokines, and viral infections.
| Variant | Association | Effect |
|---|---|---|
| HLA-B*07:02 | Neutral | Common in European populations |
| HLA-B*27:05 | MS, ankylosing spondylitis | Autoimmune risk |
| HLA-B*44:02 | MS (protective) | Modulates disease risk |
| HLA-B*57:01 | HIV control | Enhanced viral peptide presentation |
| HLA-B*35:01 | Stroke risk | Altered immune response |
Klein J, Sato A. The HLA system. N Engl J Med. 2000. ↩︎
Shiina T, et al. The HLA genomic sequence landscape. Immunogenetics. 2009. ↩︎
Hamzelou J, et al. HLA and Alzheimer's disease risk. Lancet Neurol. 2021. ↩︎ ↩︎
Sidney J, et al. Five HLA-B57 allotypes differentially associate with peptide and HIV-1 Gag antigen recognition. Immunol Rev. 2012. ↩︎
Hindorff LA, et al. Loci associated with susceptibility to immune-mediated diseases. Nat Genet. 2009. ↩︎
Neumann-Haefelin C, et al. HLA-B in stroke and cerebrovascular disease. Cerebrovasc Dis. 2008. ↩︎