The Clinical Relevance And Functional Research Of BTLA Polymorphisms And Susceptibility Of Severe Trauma Complications

Objective: B and T lymphocyte attenuator(BTLA)is recently discovered as a inhibitory receptor which have been demonstrated to inhibit T cell activation and proliferation.T lymphocytes are the main effector cells in the immunological regulation of sepsis,B and T lymphocyte attenuator(BTLA)is a useful biomarker to characterize the immunological state of patients with sepsis.In this study,we investigated the association between genetic variations of the BTLA gene and the morbidity of sepsis and multiple organ dysfunction syndrome(MODs)in patients with major trauma.Methods: Rs1982809,rs9288952 and rs9288953 were selected from the entire BTLA gene as tag Single Nucleotide Polymorphisms(tag SNPs)and were genotyped using improved multiplex ligation detection reaction(i MLDR)in 562 unrelated patients with major trauma.To further elucidated the mechanism,Two plasmids were constructed containing rs1982809 T or C allele,m RNA stability,BTLA 3'-untranslated region(3'-UTR)activity were measured by RT-q PCR and a reporter gene assay,while the expression of BTLA on T lymphocytes was measured by flow cytometric analysis.Results: Only rs1982809 which locates in the 3'-UTR of BTLA revealed a strong clinical relevance,showing a higher sepsis morbidity rate and MOD scores and a stronger immune inflammatory response in C allele carriers of trauma patients.The percentage of circulating BTLA+CD4+CD3+ T lymphocytes was significantly lower in rs1982809 CC carriers than TT carriers.Luciferase activity showed a lower activity in the cells transfected with the plasmid containing the C allele than that of T allele.Thus,the differential expression of BTLA on T lymphocytes may be caused by the different 3'-UTR activity of rs1982809 T/C.Conclusion: The rs1982809 polymorphism of BTLA is not only a useful clinical biomarker for the prognostic assessment of sepsis and MODS but also a functional SNP that affects BTLA 3'-UTR activities and the expression of BTLA on peripheral blood T lymphocytes.