Diabetes mellitus exacerbates myasthenia gravis by upregulating CD40 expression on B cells through the RAGE-HIF-1α-HK2 pathway.

BACKGROUND

Diabetes mellitus (DM) is a risk factor for myasthenia gravis (MG) and is known to enhance humoral immune response and antibody production in experimental autoimmune myasthenia gravis (EAMG) rats, possibly due to the interaction between B-cell CD40 and T follicular helper cells (Tfh). This study was aimed to investigate the mechanism by which DM modulates B-cell CD40 regulation in individuals with MG.

METHODS

Blood samples from MG patients were collected to study changes in B cell subtypes, CD40 expression, and serum cytokine levels. Rat models were used to examine B cell CD40 expression and identify gene differences between groups. In vitro experiments were conducted to confirm gene expression and understand how glucose metabolites regulate CD40 expression on B cells.

RESULTS

Patients in the MG + DM group exhibited higher quantitative MG, daily living activity scores, fasting blood glucose, and glycosylated hemoglobin levels compared to the MG group (P < 0.05). They also had a greater percentage of certain B-cell subtypes and significantly higher CD40 expression on various B cells (naïve B cells, double-negative B cells, and CD19+CD27+CD38hi ASCs) (P < 0.05). Moreover, CD40 expression on B cells and memory B cells was significantly higher in the spleens of DM + EAMG rats than in those of EAMG rats (P < 0.05). In vitro experiments demonstrated that advanced glycation end products (AGEs), not high glucose, activated the AGEs-RAGE pathway to induce hypoxia-inducible factor 1-alpha (HIF-1α) activation, increasing B-cell HK2 and CD40 expression.

CONCLUSIONS

DM alters B-cell subsets and increases CD40 expression in patients with MG. The RAGE-HIF-1α-HK2 signaling pathway, activated by AGEs, is strongly implicated in modulating CD40 expression and may represent a potential therapeutic target for MG patients with DM.