{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HLA‐DRB5 is one of the MHC class II genes that, together with its tightly linked partner HLA‐DRB1, forms part of the DR2 haplotype and contributes to antigen presentation and modulation of adaptive immune responses. Several independent studies have now implicated this gene region in affecting disease susceptibility and clinical outcome. For example, fine‐mapping in patients with adverse drug reactions to the COX‐2 inhibitor lumiracoxib revealed that a common haplotype including HLA‐DRB5*0101 (together with HLA‐DRB1*1501, HLA‐DQB1*0602, and HLA‐DQA1*0102) is strongly associated with liver injury, suggesting that structural and/or expression differences in these class II molecules may alter antigen presentation and modify inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In multiple sclerosis (MS), the interplay between HLA‐DRB1 and HLA‐DRB5 has been dissected in several family‐based and population studies. Although HLA‐DRB1*15 alleles confer strong susceptibility to MS, analyses leveraging populations with greater haplotypic diversity have revealed that the presence of HLA‐DRB5 (typically as HLA‐DRB5*0101) may actually attenuate disease severity. In fact, individuals lacking functional HLA‐DRB5 (so‐called “DRB5‐null” subjects) appear to be at higher risk for a more progressive disease course, highlighting a potential immunomodulatory and disease‐protective role for HLA‐DRB5 in MS"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, genetic studies of immune‐mediated conditions, such as certain drug allergies, have identified variants spanning the intergenic region between HLA‐DRA and HLA‐DRB5 as predictors of reactivity. These findings suggest that differences in the structure or expression levels of the DRB5 gene product may modulate antigen presentation efficiency and alter downstream T‐cell responses in settings of heightened immune sensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these observations support a role for HLA‐DRB5 as more than a passive marker in the MHC region. Rather, it appears that HLA‐DRB5 functionally contributes to the fine‐tuning of immune responses by influencing the repertoire of peptides presented to T cells. This, in turn, affects both disease susceptibility—particularly in neuroinflammatory disorders and immunologically driven adverse drug reactions—and the clinical course of diseases such as MS. As such, HLA‐DRB5 represents a potential target for more refined immunotherapeutic strategies and may serve as a biomarker for dissection of disease heterogeneity.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jonathan B Singer, Steve Lewitzky, Elisabeth Leroy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.632"}], "href": "https://doi.org/10.1038/ng.632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20639878"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20639878"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Stacy J Caillier, Farren Briggs, Bruce A C Cree, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Uncoupling the roles of HLA-DRB1 and HLA-DRB5 genes in multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.181.8.5473"}], "href": "https://doi.org/10.4049/jimmunol.181.8.5473"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18832704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18832704"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "A Ligers, D A Dyment, C J Willer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/323480"}], "href": "https://doi.org/10.1086/323480"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11519010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11519010"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jean-Louis Guéant, Antonino Romano, Jose-Antonio Cornejo-Garcia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Allergy Clin Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaci.2014.07.047"}], "href": "https://doi.org/10.1016/j.jaci.2014.07.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25224099"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25224099"}]}]}]}