| Myasthenia gravis(MG)is an autoimmune disease(AID)which is mediated by acetylcholine receptor antibody(AChR-Ab)in neuro-muscular junction(NMJ).Also in MG,the humoral immunity,cellular immunity and complement participate and the multiple sets of muscles are involved.Most researchers believe that the morbidity of MG is associated with the abnormal immune response in thymus.Nonetheless,the facts that the patients would repeat MG attack after thymectomy may indicate that there might be important regulatory factors for the morbidity of MG in humanity peripheral blood.AIRE is a transcription factor and the majority of AIRE signal has been shown to come from medullary thymic epithelial cells(m TECs).The express of AIRE could not only be responsible for negative selection events,but also be associated with tissue-related antigens.Studies demonstrated that it might be the mechanism of AIDs such as MG,that immature lymphocytes escaped the disorganized environment without being eliminated by negative selection of thymocytes through the thymic medulla where self-tolerance was induced.In addition,Extra-thymic cells that express AIRE have been described.Recent evidence suggested that the induction of certain antigen-specific regulatory T-cells that translocate to tumors and peripheral tissues could be AIRE dependent and might contribute to tissue-specific tolerance.And possibly AIRE protein performs a fundamental function in the peripheral blood: the regulation,especially in the sense of activation,of the process of gene transcription deputed to the presentation of self-antigens to the antigen-presenting cells.Extrathymic cells that express AIRE interact with CD4+ T cells and induce immunotolerance via functional inactivation of interacting T cells and independently of the induction of regulatory T cells.So it's necessary to investigate the regulatory mechanism of AIRE.Tfh cells,a CD4+ T cell subset,are regarded as the major helper T cell population specialized in providing help towards B cells.Tfh cells have been shown to play a crucial role in instructing B cells to form plasma cells which provide sufficient supply of high-affinity antibodies.Tfh cells are present in the germinal centers(GCs),and guide B cells migration into their follicles via the chemokine receptor CXCR5.Another pivotal population of T cell is Tfr cell,a recently described regulatory CD4+ T cell subset localized to the GC.Recent studies found that Tfr cells inhibited Tfh cells' function and limited GCs reactions.Tfr cells have originated from Foxp3+ regulatory T cells(Treg),with the dual characteristics of Tfh and Treg cells.Tfh and Tfr cells are found to be involved in the pathophysiological process of many AIDs,and are correlated with regulation for immune responses.Thus,the two T-cell subsets,Tfh and Tfr cells,are indispensable for the balance between immune activation and tolerance,and the breakdown of such a balance can result in MG.However,there has been little report to reveal that whether the AIRE and Tfr/Tfh cells have different expressions in different condition of patients with MG;whether these different expressions will improve before and after the treatment;and whether the AIRE and Tfr/Tfh balance have correlations with disease severity.ObjectThis study discussed the contribution of AIRE,Tfh and Tfr cells which was found to be involved in the pathophysiological process of MG in the peripheral blood.It tried to study the changes of AIRE,Tfh/Tfr ratio by group division and comparison before and after treatment,and the correlation of AIRE,Tfh/Tfr ratio with disease severity of MG.Meanwhile this study further explored the effect of AIRE,Tfh and Tfr cells on peripheral immunity in MG as a means of a theoretical basis for further research.MethodsDetailed clinical data and peripheral blood samples were collected at the Department of Neurology,Tangdu Hospital of Fourth Military Medical University during December 2015 to April 2016.Acording to the severity of MG,the clinical data of MG patients were divided into generalized MG(GMG)group,ocular MG(OMG)group,and healthy control group.And 10 of MG patients(5 GMG and 5 OMG patients)returned for a follow-up examination after being treated for a month.The percentages of AIRE expression,Tfh and Tfr cells were measured by flow cytometry method.Results1.GMG group had lower expression of AIRE compared with control group(P=0.010),while it was found no significance between OMG group and control group(P=0.068),same as OMG group and GMG group(P=0.196).The Tfh/Tfr ratio in GMG group was higher than that in OMG group and control group(P=0.036,P<0.001).And between OMG group and control group,the former was higher than the latter(P=0.005).2.There were significant differences in AIRE and Tfh/Tfr ratio before and after the treatment(P=0.001,P=0.008).The expression of AIRE in GMG patiens after therapy was higher than that in GMG group before therapy(P=0.019),but with no difference among OMG group and control group(P=0.128,P=0.998).And the expression of AIRE in OMG patiens after therapy was higher than that in GMG group before therapy(P=0.041),but with no difference among OMG group and control group(P=0.447,P=0.997).The Tfh/Tfr ratio in GMG patiens after therapy was lower than that in GMG group before therapy(P=0.006),and higher than that in control group(P=0.001),while there was no significant difference with OMG group(P=0.724).But the Tfh/Tfr ratio in OMG patiens after therapy was lower than that in GMG group before therapy(P=0.026),while there was no significant difference among OMG group and control group(P=0.994,P=0.052).3.The expression of AIRE was negatively related to MGFA and QMGs(P=0.019,P<0.001).However,Tfh/Tfr ratios were positively correlated to MGFA and QMGs(P=0.002,P=0.015).ConclusionsAIRE,Tfh and Tfr cells might participate in the pathogenesis of MG in the peripheral blood,and might be responsible for controlling the autoantibodies.Further studies are needed to clarity our comprehension of AIRE properties,and at the same time to disclose the details of AIRE-related events in the preservation of the self-tolerance. |
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