{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Butyrophilin‐like 2 (BTNL2) is a member of the butyrophilin family with sequence homology to the B7 costimulatory molecules and has been implicated in modulating T‐cell activation. Several studies have shown that BTNL2 can function as an immunomodulatory, and likely negative, costimulatory molecule. In sarcoidosis, for example, a BTNL2 risk variant (rs2076530) disrupts normal splicing, leading to a truncated protein that lacks key domains needed for proper membrane localization and costimulatory activity, thereby potentially altering T‐cell responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the gastrointestinal tract, BTNL2 is predominantly expressed in epithelial cells and dendritic cells in tissues such as the small intestine and Peyer’s patches. Functional studies using soluble BTNL2 fusion proteins have demonstrated that BTNL2 inhibits T‐cell proliferation and cytokine production, supporting a role for BTNL2 as a negative regulator of T‐cell activation that may help maintain immune homeostasis and protect against inflammatory disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic association studies have identified disease susceptibility loci spanning BTNL2 in multiple conditions. For instance, associations have been detected in ulcerative colitis and lung adenocarcinoma (especially in patients with EGFR mutations) as well as in marginal zone lymphoma, indicating that BTNL2 may influence immune responses that contribute to both inflammatory and neoplastic disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In some populations, however, the apparent association of BTNL2 variants with disease risk is attributable to strong linkage disequilibrium with neighboring HLA alleles, suggesting that the immunomodulatory function of BTNL2 may be interwoven with HLA‐mediated antigen presentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings support a model in which BTNL2 serves as an immunological checkpoint molecule by modulating T‐cell activation. Disruption of its normal function—whether by producing a truncated protein or by genetic variation linked with nearby HLA alleles—may disturb the balance of immune regulation, thereby contributing to the pathogenesis of autoimmune, inflammatory, and even malignant diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ruta Valentonyte, Jochen Hampe, Klaus Huse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sarcoidosis is associated with a truncating splice site mutation in BTNL2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1519"}], "href": "https://doi.org/10.1038/ng1519"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15735647"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15735647"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Benjamin A Rybicki, Jose L Walewski, Mary J Maliarik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/444435"}], "href": "https://doi.org/10.1086/444435"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16080124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16080124"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Heather A Arnett, Sabine S Escobar, Eva Gonzalez-Suarez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule modulated in intestinal inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.178.3.1523"}], "href": "https://doi.org/10.4049/jimmunol.178.3.1523"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17237401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17237401"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mark S Silverberg, Judy H Cho, John D Rioux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.275"}], "href": "https://doi.org/10.1038/ng.275"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19122664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19122664"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Jie Seow, Keitaro Matsuo, Chao Agnes Hsiung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddw414"}], "href": "https://doi.org/10.1093/hmg/ddw414"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28025329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28025329"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Joseph Vijai, Zhaoming Wang, Sonja I Berndt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association study of marginal zone lymphoma shows association to the HLA region."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms6751"}], "href": "https://doi.org/10.1038/ncomms6751"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25569183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25569183"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "A Mochida, Y Kinouchi, K Negoro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tissue Antigens (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0039.2007.00866.x"}], "href": "https://doi.org/10.1111/j.1399-0039.2007.00866.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17610417"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17610417"}]}]}]}