The Change Of Follicular Regulatory T Cells In Patients With Dilated Cardiomyopathy

BackgroundDCM is a type of heterogeneous cardiomyopathy with unknown etiology and progressive disease,which is mainly characterized by ventricular chamber enlargement and systolic dysfunction of one or both ventricles.The prognosis is extremely poor,with the survival rate of patients 5-10 years after the onset of the disease being only 30%-40%.Its pathogenesis has many aspects.Recently,a large number of studies have found that among the many pathogeneses of DCM,immune impairment plays a vital role,especially the dysfunction of humoral immunity.During the progression of dilated cardiomyopathy,immunity is abnormally activated,and autoantibodies are abnormally increased through the interaction between B cells and T cells and their subsets,which participate in the occurrence and development of DCM.Activation markers such as CD69,CD25,HLA-DR and CD40 ligand on the surface of T lymphocytes were significantly increased in DCM patients.Moreover,it was found that T lymphocytes could be involved in the pathological process of DCM by direct cytotoxicity,enhancing the function of other immune cells,or assisting B cells to increase the production of pathogenic antibodies.Cytokines such as IL-6 and TNF-α were significantly increased in DCM patients and were negatively correlated with cardiac function.At the same time,anti-myocardial autoantibodies,anti-mitochondrial antibodies and anti-β1Rs antibodies all play an important role in the development,diagnosis and treatment of DCM.The main purpose of the current work was to assess Tfr cell frequency and significance in patients with dilated eardiomyopathy(DCM),and to evaluate whether these cells can be used as potential therapeutic targets for patients with DCM and bring new strategies for the treatment of DCM.ObjectiveThe follicular regulatory T cells(Tfr)play an important role in diseases of inflammation and autoimmune disorders.The main purpose of this study is to evaluate the frequency and significance of Tfr cells in patients with dilated cardiomyopathy(DCM).MethodsA total of 30 newly hospitalized DCM patients and 30 healthy controls were enrolled in the study.The frequencies of CD4+CD25+CXCR5+CD127-/lo Tfr and CD4+CXCR5+CD127+Tfli cells were determined by flow cytometry.Real-time polymerase chain reaction was used to detect the expression of various important molecules in peripheral blood mononuclear cells at the mRNA level.Meanwhile,the secretion levels of several key inflammatory cytokines,IgG and IgG3 in plasma were detected by ELISA.In addition,the correlation analysis between the frequency of Tfr and Tfh and the index of cardiac function is also carried out.ResultsCompared with the normal control group,the frequency of Tfr cells in DCM patients(1.384±0.1233)was lower than that in healthy controls(1.866±0.151)(P=0.0177),and the ratio of Tfr/Tfh in peripheral blood of DCM patients(9.329± 1.104)was significantly lower than that in healthy controls(13.15 ± 1.113)(P=0.0178).However,the proportion of Tfh cells in the control group(17.18±0.9836)was significantly higher than that in the healthy control group(4.57±0.7532).Correlation analysis showed that the proportion of Tfr in patients with DCM was positively correlated with left ventricular ejection fraction(LVEF)(R=0.47,P=0.009),but negatively correlated with N-terminal pro-brain natriuretic peptide(NT-proBNP)(R=-0.413,P=0.023).Lower mRNA expression of Foxp3(DCM:2.322±0.658,Controls:6.134±1.607),and higher Bcl-6(DCM:1.73 8± 0.163,Controls:1.104±0.002,P=0.002),ICOS(DCM:7.978±2.266,Controls:2.205±0.582,P=0.022)and PD-1(DCM:6.656±0.106,Controls:1.299±0.228,P=0.0177)mRNA expression were found in patients with DCM.The level of IL-6(Controls:5.293±0.608,DCM:8.415± 1.383,P=0.048),TNF-α(Controls:3.481 ±0.445,DCM:8.686±0.766,P<0.0001)and IL-21(Controls:7.984±0.543,DCM:17.074±1.485,P<0.0001)in the plasma was obviously increased in DCM patients.What is more,the level of IgG(DCM:23525.22±1327.623,Controls:13958,51 ±734.4485,P<0.0001)and IgG3(DCM:11833±893,Controls:4217±441.2,P<0.0001)was also increased in the DCM patients,and correlation analysis showed that Tfr frequency in DCM patients was negatively correlated with IgG(R=-0.679,P<0.001)and IgG3(R=-0.663,P<0.001),while Tfh frequency positively correlated with IgG(R=0.443,P=0.014)and IgG3(R=0.386,P=0.035).ConclusionChanges in circulating Tfr frequency may play an important immunomodulatory role in the pathogenesis of DCM.