Abstract
BackgroundAlthough type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive.MethodsThe frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms.ResultsWe identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients.ConclusionsOur study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.
Highlights
Type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged
No significant difference was observed in the frequencies of CD38+ switched memory, CD38− switched memory, and unswitched memory B cells in patients with new-onset type 1 diabetes (T1D) when compared with the controls and the type 2 diabetes group, while the proportion of naïve B cells was decreased in the new-onset T1D group relative to the controls (Fig. 1C to F)
The most notable difference was observed in the plasmablast subset which was significantly increased in patients with new-onset T1D compared with the controls; patients with long-term T1D and type 2 diabetes showed no obvious change in the proportion and the number of plasmablasts (Fig. 1G and H)
Summary
Type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. The pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive. Type 1 diabetes (T1D) is an autoimmune disorder characterized by the progressive deterioration of pancreatic beta cell function, insulin deficiency, and hyperglycemia (Barnett 2018). Ling et al Molecular Medicine (2022) 28:18 systems (insulitis), which results in ongoing islet autoimmunity and destruction of beta cells. Emerging evidence indicates an active role of B cells directly involved in beta cell destruction. Thereafter, little progress has been made until recently, studies of human pancreas from T1D donors draw attention to the role of B cells in islet autoimmunity (Wang et al 2019; Damond et al 2019; Leete et al 2016). An in-depth analysis of B cell subsets in T1D progression is important for understanding the disease pathogenesis and determining optimal immunotherapies
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