CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro

Abstract

Introduction: Aberrant signaling within and between B and T cells, considered to be central in systemic lupus erythematosus (SLE), could depend on enhanced CD40-CD154 activation. As a result, autoreactive B cells, normally anergic, differentiate and secrete antibodies attacking several normal tissues. Thus restorating B cell homeostasis might help control this disease. In this study, two facets of SLE B cells were investigated, namely their in vitro response to CD40-CD154 and the effect of treatment with human immunoglobulins for intravenous use (IVIg). Materials and Methods: Blood samples from SLE patients and healthy volunteers were obtained and used to isolate B cells, which were activated through CD40 in the presence or absence of IVIg. The phenotype, proliferation, and differentiation of the SLE B cells were determined and compared with those of control B cells using flow cytometry and standard ELISA. Results: In this model, CD40-activated SLE B cells, as control B cells, proliferated and differentiated and were characterized by the emergence of CD19 lo CD38 ++ CD138 + CD27 ++ cells. IVIg treatment of the CD40-activated SLE B cells resulted in higher differentiation, characterized by increased secretion rates of IgG and IgM, as reported previously for control B cells. Conclusions: Taken as a whole, such accelerated differentiation of CD40-activated B cells suggests that IVIg may participate in re-equilibration of the antibody repertoire by replacing pathological antibodies by de novo harmless antibodies.

Massive immune response against IVIg interferes with response against other antigens in mice: A new mode of action?

“…Our data are in line with studies showing that IVIg stimulates B cells [54] and CD4+ T cells in vivo and in vitro [54, 55], and increased in vitro secretion of IgG [56, 57] that were highly reactive against human IgG F(ab') 2 fragments [57]. Importantly, Fab fragments isolated from one Kawasaki patient before and after IVIg treatment revealed that they displayed a higher affinity for IVIg after therapy [58].…”

Neutralization of mitogenic lectins by intravenous immunoglobulin (IVIg) prevents T cell activation: does IVIg really have a direct effect on T cells?

“…Rather, our results showed that IVIg indirectly inhibited the in vivo and in vitro T cell responses by impairing antigen presentation. Similarly, Néron et al showed that IVIg did not inhibit immunoglobulin secretion by human B cells activated by CD154 (the ligand for CD40) in the presence of cytokines such as IL-2, IL-4 and IL-10 [30], in contrast to the previously reported effects observed using PWM to stimulate B cells in the presence of IVIg [11,22,25]. Another recent report also showed the absence of a direct effect of IVIg on B cells [27].…”

Review: Intravenous Immunoglobulin and B Cells: When the Product Regulates the Producer

“…Paradoxically, IVIG increased plasma cell differentiation and IgG production in an in vitro model where B cells were cultured on a layer of CD40L‐expressing fibroblasts in the presence of IL‐4 and IL‐10 . Importantly, B cells from patients with SLE cultured in the same model were also driven to increase plasma cell differentiation in the presence of IVIG . To explain this surprising effect, which could contribute to the development of an autoimmune disease instead of limiting it, the authors proposed that IVIG promotes differentiation of newly formed plasma cells that enter into competition with the already present autoreactive plasma cells.…”