Disease relevance of BTNL2

• Sarcoidosis is associated with a truncating splice site mutation in BTNL2 [1].
• Association of the BTNL2 rs2076530 single nucleotide polymorphism with Graves' disease appears to be secondary to DRB1 exon 2 position beta74 [2].
• Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15 [3].
• Because of its localization in the gut and potential role in the immune system, BTNL2 expression was analyzed in a mouse model of inflammatory bowel disease [4].
• BTNL2 is overexpressed during both the asymptomatic and symptomatic phase of the Mdr1a knockout model of spontaneous colitis [4].

High impact information on BTNL2

• BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1 [1].
• The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule [5].
• Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2 [5].
• Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans [5].
• The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1 [3].

Biological context of BTNL2

• Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease [1].
• We demonstrate that like many other genes from the MHC, BTL-II is polymorphic in a selection of diverse HLA haplotypes [6].
• The six discernable exons of the BTL-II locus encode a small hydrophobic amino acid sequence (which may be a signal peptide), two immunoglobulin domains, a small 7-amino acid, heptad repeat-like exon, and a further two immunoglobulin domains [6].
• However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS [3].
• The splice-site polymorphism in the BTNL2 gene was also investigated by RFLP analysis [7].

Anatomical context of BTNL2

• BTNL2 mRNA is highly expressed in lymphoid tissues as well as in intestine [8].
• TaqMan and Northern blot analysis indicate BTNL2 is predominantly expressed in digestive tract tissues, in particular small intestine and Peyer's patches [4].
• Immunohistochemistry with BTNL2-specific Abs further localizes BTNL2 to epithelial and dendritic cells within these tissues [4].
• The bacterium Mycobacterium tuberculosis can induce the expression of the sarcoidosis susceptibility gene BTNL2 in monocyte-derived macrophages [9].

Other interactions of BTNL2

• Recent studies in sarcoidosis have identified association of a single nucleotide polymorphism (SNP) rs2076530 within BTNL2, a potential T-cell inhibitor, independent of the known DRB1 association [2].
• Genotyping of the BTNL2 gene rs2076530 polymorphism was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay [10].
• Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus [10].
• The RXRB gene was analysed as well as a splice-site variation of the butyrophilin-like (BTNL2) gene which is also located within the respective region [7].
• The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association [3].

Analytical, diagnostic and therapeutic context of BTNL2

• BTNL2 is thus the first member of the butyrophilin family that regulates T cell activation, which has implications in immune diseases and immunotherapy [8].

References