Abstract
BackgroundDiabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG). However, the impacts of DM on the progression of late-onset MG were unclear.MethodsIn this study, we examined the immune response in experimental autoimmune myasthenia gravis (EAMG) rats with DM or not. The phenotype and function of the spleen and lymph nodes were determined by flow cytometry. The serum antibodies, Tfh cells, and germinal center B cells were determined by ELISA and flow cytometry. The roles of advanced glycation end products (AGEs) in regulating Tfh cells were further explored in vitro by co-culture assays.ResultsOur results indicated clinical scores of EAMG rats were worse in diabetes rats compared to control, which was due to the increased production of anti-R97–116 antibody and antibody-secreting cells. Furthermore, diabetes induced a significant upregulation of Tfh cells and the subtypes of Tfh1 and Tfh17 cells to provide assistance for antibody production. The total percentages of B cells were increased with an activated statue of improved expression of costimulatory molecules CD80 and CD86. We found CD4+ T-cell differentiation was shifted from Treg cells towards Th1/Th17 in the DM+EAMG group compared to the EAMG group. In addition, in innate immunity, diabetic EAMG rats displayed more CXCR5 expression on NK cells. However, the expression of CXCR5 on NKT cells was down-regulated with the increased percentages of NKT cells in the DM+EAMG group. Ex vivo studies further indicated that Tfh cells were upregulated by AGEs instead of hyperglycemia. The upregulation was mediated by the existence of B cells, the mechanism of which might be attributed the elevated molecule CD40 on B cells.ConclusionsDiabetes promoted both adaptive and innate immunity and exacerbated clinical symptoms in EAMG rats. Considering the effect of diabetes, therapy in reducing blood glucose levels in MG patients might improve clinical efficacy through suppressing the both innate and adaptive immune responses. Additional studies are needed to confirm the effect of glucose or AGEs reduction to seek treatment for MG.
Highlights
Diabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG)
Diabetes mellitus (DM) is a chronic metabolic disorder caused by insulin deficiency or impaired insulin action, which is characterized by increased blood glucose levels
Diabetes exacerbated the clinical severity and reduced the splenic volume in experimental autoimmune myasthenia gravis (EAMG) rats Lewis rats were divided into two groups, control and DM
Summary
Diabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG). Diabetes mellitus (DM) is a chronic metabolic disorder caused by insulin deficiency or impaired insulin action, which is characterized by increased blood glucose levels (hyperglycemia). The accurate mechanisms remain to be fully clarified, functional alterations of the immune system and related cells could, at least in part, be attributed to hyperglycemia. Patients with hyperglycemia have increased pro-inflammatory cytokines and dysfunctional innate and adaptive immune cells, which will disrupt cellular and/or humoral immune homeostasis [2]. Hyperglycemia apparently alters the functions of immune cells, such as monocytes, neutrophils, and T or B lymphocytes [3]. T regulatory cells obtained from diabetes patients and streptozotocin (STZ)-induced diabetic mice displayed defective immunosuppressive functions [2, 4]. AGEs promote the differentiation of C D4+ T into T helper 1 (Th1) and Th17 cells [6]
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