Research On The Abnormal Expression Of CD160 And Other Costimulatory And Co-inhibitory Molecules In Autoimmune Diseases

First part: Aberrant expressions of co-stimulatory and coinhibitory molecules in autoimmune diseasesObjective Autoimmune diseases include a series of complex diseases occurring in various organs and tissues,in which abnormal immunity can lead to autoimmune attack to normal human tissues or organs and result in functional damage.Although considerable progress has been made in the study of risk factors and treatment of autoimmune diseases,the pathogeneses of most autoimmune diseases are still not fully understood.Co-signaling molecules include co-stimulatory and co-inhibitory molecules and play important roles in modulating immune responses.The roles of co-signaling molecules in autoimmune diseases have not been clearly defined.This study intended to analyze the abnormal expression of costimulatory and co-inhibitory molecules in autoimmune diseases through bioinformatics and clinical research.Methods We searched the Gene expression omnibus(GEO)database to obtain the whole-genome transcriptome datasets of peripheral blood of patients with common autoimmune diseases,and finally included 19 array datasets and 6 RNA-seq datasets.The expressions of 54 costimulatory or co-inhibitory genes in those autoimmune diseases were analyzed using Robust rank aggregation(RRA)method.We further verified the genes with the most significant abnormal expression.Results RRA discovery study suggested that CD160 was the most significant gene aberrantly expressed in autoimmune diseases(Adjusted P = 5.9E-12),followed by CD58(Adjusted P = 5.7E-06)and CD244(Adjusted P = 9.5E-05).RRA validation study also identified CD160 as the most significant gene aberrantly expressed in autoimmune diseases (Adjusted P = 5.9E-09).We further found that the aberrant expression of CD160 was statistically significant in multiple autoimmune diseases including Graves’ disease(GD)(P<0.05),and CD160 had a moderate role in diagnosing those autoimmune diseases.Flow cytometry confirmed that CD160 was differentially expressed on the surface of CD8+ T cells between GD patients and healthy controls(P=0.002),which proved the aberrant expression of CD160 in GD at the protein level.Conclusion This study suggests that CD160 is the most significant co-signaling gene aberrantly expressed in autoimmune diseases.Treatment strategy targeting CD160-related pathway may be promising for the therapy of autoimmune diseases.Second part: Associations between CD160 polymorphisms and autoimmune thyroid diseaseObjective Recent researches suggest that the CD160/HVEM/LIGHT/BTLA signaling pathway may contribute to the pathogeneses of autoimmune diseases,but the relationship between CD160 polymorphisms and autoimmune thyroid disease(AITD)has not been reported yet.This study aimed to evaluate the associations between CD160 polymorphisms and AITD.Methods A total of 1017 patients with AITD(634 GD and 383 Hashimoto’s thyroiditis)and 856 unrelated healthy controls were recruited into our study.Odds ratios(ORs)with 95% confidence interval(95%CI)were calculated through logistic regression analyses.The CD160 single nucleotide polymorphisms(SNPs)were detected using Hi-SNP highthroughput genotyping,including rs744877 and rs3766526.Result There was a statistically significant difference between GD patients and the control group with respect to both the genotype distribution(P=0.014)and allele frequency of rs744877(P=0.034).A significant association of CD160 rs744877 with AITD was observed before adjusting for age and gender under the dominant model(OR=0.79,95%CI 0.66-0.95;P=0.013)and the additive model(OR=0.77,95%CI 0.64-0.94,P=0.008),and was also observed after adjusting for age and gender under the dominant model(OR=0.78,95%CI 0.65-0.95;P=0.011)and the additive model(OR=0.76,95%CI 0.63-0.93,P=0.007).A significant association of rs744877 with GD was observed under the allele model(OR=0.84,95%CI 0.71-0.98,P=0.027),the dominant model(OR=0.74,95%CI 0.60-0.91;P=0.005),and the additive model(OR=0.72,95%CI 0.58-0.90,P=0.004).However,rs744877 was not related to Hashimoto’s thyroiditis.Furthermore,CD160 rs3766526 was not significantly related to either GD or Hashimoto’s thyroiditis.Conclusion This is the first identification of the association of CD160 rs744877 with GD,and it supports the crucial role of the CD160 pathway in the pathogenesis of GD.