Diabetes mellitus exacerbates experimental autoimmune myasthenia gravis via modulating both adaptive and innate immunity

Abstract

Background Diabetes 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. Methods In 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. Results Our 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. Conclusions Diabetes 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.

Systemic Inflammatory Response Index, a Potential Inflammatory Biomarker in Disease Severity of Myasthenia Gravis: A Pilot Retrospective Study

“…While existing literature supports the notion that diabetes mellitus exacerbates experimental autoimmune MG via modulating both adaptive and innate immunity and aggravates humoral immune response in MG by promoting differentiation and activation of circulating Tfh cells. 35 , 36 Unfortunately, our study did not yield any statistically significant findings related to diabetes. This may be attributed to potential uneven data distribution due to the limited size of our cohort.…”

Altered serum levels of cytokines in patients with myasthenia gravis

“…Among those with late-onset MG (LOMG), diabetes mellitus (DM) is frequently observed [ 18 ]. Therefore, patients with LOMG were divided into the following two groups: LOMG with diabetic mellitus (LOMG + DM) and LOMG without diabetes mellitus (LOMG).…”

Pathophysiology of RAGE in inflammatory diseases

“…The findings suggest that RAGE and its ligand S100B play an important role in EAMG progression by regulating T cell responses and inducing splenocyte-derived AChR-specific antibody production (156). In another study on EAMG rats, EAMG rats with diabetes mellitus showed more symptoms of muscle weakness and poorer clinical scores compared to controls by an unclear mechanism, which was considered to be related to elevated levels of AGEs caused by hyperglycemia, which triggers inflammation by binding to specific receptors, and AGEs induced maturation of dendritic cells (DCs) and enhanced their ability to stimulate T cell proliferation and cytokine production (157).…”