CD11c+ B Cells Participate in the Pathogenesis of Graves’ Disease by Secreting Thyroid Autoantibodies and Cytokines

Abstract

Graves’ disease (GD) is a common autoimmune disorder with an elevation in pathogenic autoantibodies, specifically anti-thyrotropin receptor antibodies (TRAbs), which are secreted by autoreactive B cells. To date, there has been little research on self-reactive B cells in GD. In the current study, we reported that a unique B-cell subset, CD11c+ B cells, was expanded in the peripheral blood (PB) of GD patients, as detected by flow cytometry. The frequency of CD11c+ B cells was positively correlated with serum TRAb levels. The flow cytometry data showed that CD11c expression was higher in a variety of B-cell subsets and that CD11c+ B cells presented a distinct immunophenotype compared to paired CD11c- B cells. Immunohistochemical and immunofluorescence staining indicated the presence of CD11c+CD19+ B cells in lymphocyte infiltration areas of the GD thyroid. Flow cytometric analysis of PB and fine-needle aspiration (FNA) samples showed that compared to PB CD11c+ B cells, CD11c+ B cells in the thyroid accumulated and further differentiated. We found that CD11c+ B cells from the PB of GD patients were induced to differentiate into autoreactive antibody-secreting cells (ASCs) capable of secreting TRAbs in vitro. Luminex liquid suspension chip detection data showed that CD11c+ B cells also secreted a variety of cytokines, including proinflammatory cytokines, anti-inflammatory cytokines, and chemokines, which might play roles in regulating the local inflammatory response and infiltration of lymphocytes in the thyroid. In addition, we performed a chemotaxis assay in a Transwell chamber to verify that CD11c+ B cells were recruited by thyroid follicular cells (TFCs) via the CXCR3-CXCL10 axis. In conclusion, our study determined that CD11c+ B cells were involved in the pathogenesis of GD in multiple ways and might represent a promising immunotherapeutic target in the future.

The peripheral and decidual immune cell profiles in women with recurrent pregnancy loss

“…Our results showed that the abundance of B and CD62L + B cells was significantly higher in RPL patients, indicating that the alteration of immune effectors may be associated with RPL. CD11c + B cells have been suggested to play a key play in various autoimmune diseases like graves’ disease, systemic lupus erythematosus (SLE) and Sjogren’s Syndrome ( 31 ). Programmed death-ligand 1 (PD-L1) is a critical molecule in immune suppression and the lower level of PD-L1 + B cells may also lead to poor pregnancy outcomes like RPL ( 32 ).…”

High levels of thyroid hormones promote recurrence of Graves' disease via overexpression of B‐cell‐activating factor

“…In addition, we also found overexpression of BAFF in the thyroid of an established high‐circulating T3 mouse model (for more details, see Figure S1). It is worth noting that the proportion of CD11c+ autoreactive B cells was positively correlated with TRAb, suggesting that ASCs may participate in the development of GD through the secretion of autoantibodies, which in turn leads to the recurrence of GH 14 …”

“…As reported, CD11c+ B cells also contribute to the pathogenesis of GD in multiple ways through the secretion of pro‐inflammatory cytokines (IL‐1β, IL‐6, IL‐17A, IFN‐γ, and IL‐9) and chemokines (IL‐8, CXCL10, RANTES, MIP‐1α/β, and MCP‐1) 40,41 . Based on the knowledge that CD11c+ B cells infiltrate the thyroid of patients with GD with a phenotype similar to that of CD11c+B cells in peripheral blood, 14 we further identified BAFF as a key factor causing differentiation of CD11c+IgG+ ASC subsets induced by high levels of T3, which are highly expressed in unswitched memory B cells, switched memory B cells, early memory mature B cells, germinal center B cells, plasma blasts, and plasma cells in the thyroid 14 . We found that in CD11c+ autoreactive B cells, T3 prompted the differentiation of B cells toward IgG+ B cells via BAFF, whereas in NACs, high T3 prompted the differentiation of such B cells toward IgG– B cells via BAFF, suggesting that the production effect of ASCs may be higher.…”

“…B‐cell‐activating factor (BAFF) has been found to be aberrantly expressed in a variety of autoimmune diseases and is essential for regulating B cell differentiation, immunoglobulin type switching, and antibody production 9–13 . Overexpression of BAFF in the peripheral blood of patients with GD has been found, and the frequency of CD11c+ autoreactive secretory B cells (ASCs), which may be a potential therapeutic target, was positively correlated with TRAb in the serum of patients with GD 14,15 . However, the results of studies on how THs affect immune cell function remain controversial because of the lack of a comprehensive understanding of the local role of autoimmune cell functions.…”

“…[9][10][11][12][13] Overexpression of BAFF in the peripheral blood of patients with GD has been found, and the frequency of CD11c+ autoreactive secretory B cells (ASCs), which may be a potential therapeutic target, was positively correlated with TRAb in the serum of patients with GD. 14,15 However, the results of studies on how THs affect immune cell function remain controversial because of the lack of a comprehensive understanding of the local role of autoimmune cell functions. Additionally, although TRAb is usually considered the cause of persistently elevated T3 in GD, there are few studies on the inverse effects of high-circulating TH levels on the abnormal differentiation of local ASCs in the thyroid and the production of TRAb in patients with GD.…”