| Objective:In addition to affecting the thyroid,Graves’ disease can also damage other tissues or organs,such as Graves’ ophthalmopathy(GO).It is a relatively rare disfigurement and disabling orbital disease.Go is pathologically characterized by an immunological inflammatory response to the eye tissues.The infiltration of several kinds of cells lead to the inflammatory.According to studies,autoantigen and immune cells can cause the disease,but we do not understand the mechanism of its onset.A number of studies have shown that miRNA dysfunction in exosomes can lead to the occurrence and development of various types of autoimmune diseases.Our study aims to explore differences in the expression profiles of exosome miRNAs in GO patients: giving a better theory for the use of serum exosome miRNAs for the targeted treatment of autoimmune diseases.The effect of selenium on the long-term prognosis of Graves ophthalmopathy was investigated.Method:1.Analysis of differences in the expression profiles of exosome miRNAs in GO patients: Serums of 6 Graves ophthalmopathy patients were collected,exosomes were extracted,and exosome identification and second-generation sequencing of exosome miRNAs were performed to predict target genes.2.Analysis of long-term prognosis of selenium intervention for Graves ophthalmopathy: 74 patients with mild to moderate Graves ophthalmopathy who were enrolled in the the First Clinical College of CMU were enrolled in a double-blind controlled trial.The patients in the selenium treatment group were given 200 μg selenium yeast tablets orally.Patients in the control group received the same dose of placebo orally and were discontinued 6 months later.The included patients were evaluated before treatment,6 months after treatment,and 5 years after withdrawal of the drug.The patients’ thyroid function、TPOAb、TGAb and TRAb were detected,the ocular symptoms and signs were examined,the ocular inflammatory activity and severity of the patients were evaluated,and the subjects were scored for Graves ophthalmopathy quality of life.SPSS23.0 statistical software was used to analyze the data.Result:1.Differential expression of serum exosome miRNAs in GO patients: 1)The expression of 30 miRNAs in GO patients was significantly different from that in healthy control population(p<0.05),and 18 up-regulated and 12 down-regulated miRNAs.2)GO enrichment targets are mainly in the "signal transduction processes",the "cell membrane components" and the "protein binding functions".Based on the enrichment analysis of KEGG,the top three enrichment pathways in the order of p value were " P53 signal transduction process","HIF1 signaling process","Ubiquitin regulated protein degradation".The "cancer pathway" is the pathway with the most genes counted.3)Among the predicted target genes,there were 19 low expression genes and 10 high expression genes,among which the low expression genes CYP19A1,AIFM2 and eIF1AY encoded proteins involved in cell growth,apoptosis or down-regulation of cell cycle.AIFM2 and UTY encode proteins with antioxidant activity,PRDM1 encodes proteins involved in the establishment of T lymphocytes in non-lymphoid organs,and DDX3Y not only encodes proteins that stimulate interferon α,but also encodes proteins that affect interferon β pathway.ITIH5 encodes a protein that is involved in stabilizing the extracellular matrix.Among the overexpressed genes,PAX9 and FGF14 encode proteins that are conducive to cell growth and proliferation,PLEKHA2 encodes a protein involved in the binding of lipid and fibroconnectin,and RNF144 b encodes a protein involved in the inhibition of apoptosis.2.Analysis of long-term prognosis of selenium intervention in Graves ophthalmopathy: 1)After 6 months of treatment,the symptoms of scruff feeling and conjunctival congestion in the selenium treatment group were obviously recuded in comparison with the control group(p<0.05),and there was no statistical significance in the progress of ocular symptoms in the selenium treatment group in comparison with the control group after 5 years of withdrawal of selenium.2)After 6 months of treatment,CAS scores in the selenium treatment group were obviously recuded than before(p<0.05),while CAS scores in the control group were not significantly different from those before treatment.After 5 years of withdrawal,CAS scores were all obviously lower than before(p<0.05).3)Treated by 6 months,the degree of ocular protrusion in both groups was not significantly improved.After 5 years of withdrawal,the degree of ocular protrusion in both groups was significantly reduced(p<0.05).4)Treated by 6 months,there was no statistically obvious distinction in eyelid cleft between the two groups after 5 years of withdrawal.5)treatment for 6 months,selenium treatment group visual function score,the score of social psychology,the scale score significantly higher than before treatment(p< 0.05)and control group in visual function score,the score of social psychology,the scale was no statistically significant differences in the total score,5 years,the drug was stopped in the two groups of visual function score,the score of social psychology,the scale scores than before treatment were obviously higher(p< 0.05).6)After 6 months of treatment,TRAB level in the selenium treatment group was obviously reduced than before(p <0.05),and there was no significant difference in the TRAB level in the control group compared with that before treatment.After 5 years of withdrawal,TRAB level was all obviously reduced than before(p <0.05).It was no obvious distinction in the positive rate of TRAB between the two groups after 5 years of drug withdrawal.7)The positive rates of TPOAb or TGAb in selenium treatment group and control group after 5 years of withdrawal were significantly higher than those before treatment(p <0.05).8)At 5 years after drug withdrawal,the prognosis of patients with normal thyroid function was statistically significant different from that of patients with abnormal thyroid function(p <0.05),the prognosis of TRAb negative patients was statistically significant different from that of TRAb positive patients(p <0.05).Conclusion:1.Differential expression of serum miRNAs in GO patients: 18 miRNAs were up-regulated and 12 miRNAs were down-regulated in GO patients.Based on the enrichment analysis of KEGG,the top three enrichment pathways in the order of p value were " P53 signal transduction process","HIF1 signaling process","Ubiquitin regulated protein degradation" The "cancer pathway" is the pathway with the most genes counted.Among the 29 target genes we finally predicted,CYP19A1,AIFM2,eIF1AY,AIFM2,UTY,PRDM1,DDX3Y,ITIH5,PAX9,FGF14,PLEKHA2,RNF144B may all play important roles in the pathogenesis of Graves ophthalmopathy.2.Analysis of long-term prognosis of selenium intervention for Graves ophthalmopathy:Selenium treatment at 6 months obviously ameliorated eye disease activity,ocular signs and symptoms,and eye disease specific quality of life in comparison with placebo.Long-term follow-up observation was made until 5 years after drug withdrawal,regardless of whether the patients had received selenium treatment or not,GO inflammatory activity,ocular symptoms and signs,quality of life were all obviously ameliorated,and TRAb level was obviously reduced.Selenium intervention for 6 months had no effect on the long-term efficacy and prognosis of Graves ophthalmopathy.Follow-up observation showed that the prognostic improvement rate of patients with normal thyroid function and negative TRAb was obviously higher than that of patients with abnormal thyroid function and positive TRAb. |
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