1673-P: Plasmablasts Contribute to the Development of Type 1 Diabetes via Enhancing T-Cell Cytotoxicity

Abstract

Disturbance of innate and adaptive immune systems is responsible for β-cell destruction in type 1 diabetes (T1D). Although increasing evidence indicated a crucial role for B cells in disease pathogenesis, exactly how B-cell subsets contribute to T1D remains unclear. This study aimed to evaluate the potential role of B-cell subset in the development of T1D. We enrolled 56 people with T1D, including 8 people receiving mesenchymal stromal cell (MSC) treatment, 22 people with T2D, and 26 healthy controls. ELISPOT assay was used to assess the role of B-cell subset in activation of diabetogenic T cells. NOD mice and adoptive transfer assays were utilized to study the role of B-cell subset in T1D in vivo. Plasmablasts, but not naïve, unswitched or switched memory B cells, were increased in patients with recent-onset T1D, compared with those with long-term T1D, T2D and healthy controls. In patients with recent-onset T1D, plasmablast number negatively correlated with fasting C-peptide and area under the curve of C-peptide. Plasmablasts decreased in line with an improvement of residual β-cell function 3 months after MSC treatment. Compared with other B-cell subsets, plasmablasts expressed a high level of CD86, which negatively correlated with the residual β-cell function while positively correlated with the number of islet autoantibodies. ELISPOT assay further showed that plasmablasts isolated from participants with T1D induced a dramatic increase of interferon-γ secretion in GAD65 stimulated T cells. Compared with euglycemic NOD mice, the number of plasmablasts was increased in the spleen, pancreatic lymph nodes, and islets of diabetic NOD mice. Moreover, adoptive transfer of plasmablasts mixed with T cells from diabetic NOD mice into NOD/SCID mice accelerated the development of T1D. These data firstly demonstrated that plasmablasts play a vital role in immune disturbance, further expanding the knowledge of T1D pathogenesis. Plasmablasts may serve as a novel therapeutic target in T1D. Disclosure B. Yan: None. Q. Ling: None. J. Lu: None. D. Zhu: None.