Glatiramer Acetate Stimulates Regulatory B Cell Functions.

The control of the activities of regulatory B (Breg) cells in immune disorders is an emerging therapeutic strategy for the recovery of immune homeostasis. Manipulating B cells using numerous drugs in vivo affect their regulatory functions, although a direct link has not yet been demonstrated. Glatiramer acetate (GA) is a synthetic polypeptide that is used in the treatment of inflammatory and autoimmune diseases. We experimented on an in vitro coculture system to determine its direct effects on the Breg cell properties of human B cells. We found that GA improves the B cell-dependent control of T cells' immune responses. When B cells are stimulated by GA, the T cell proliferation and their Th1 IFN-γ production are further inhibited, whereas the B cell production of IL-10 is further enhanced. GA binds preferentially to the memory B cells and the activation of sorted B cell subsets shows that GA-dependent increased Breg cell activities are specifically supported by the B cells' memory compartment. Moreover, we found that the defective regulations that emerge from the B cells of systemic lupus erythematosus patients can be restored by GA stimulation. Overall, these data demonstrate that GA stimulates the Breg functions mainly by shifting the memory B cells known to contribute to the T cell-dependent inflammatory response into Breg cells. Our results also indicate that GA treatment could be a useful therapy for recovering the Breg cells in autoimmune situations in which their activities are defective.

Influence of drug molecules on regulatory B cells.

By their suppressive functions, regulatory B (Breg) cells are considered as key elements in the control and development of various disease states. Many signals can induce Bregs in vivo and in vitro and often from heterogeneous populations. Several specific signals delivered in a timely immunological context contribute to the establishment of Bregs. These are endogenous and physiological signals or stimuli, widely discussed in the literature participating in the establishment of an effective immune response. However, exogenous signals, much less clearly identified can also be considered as Bregs inducers. These extrinsic signals are capable of directly or indirectly influencing the suppressive capacity of Bregs, but also their expansion and functional restoration in its absence. Faced with the excitement generated by the development of processes favoring the expansion of Bregs in mice for therapeutic purposes, the challenge today is to extrapolate such approaches in humans. This perspective may already be in effect.

Regulatory B cells play a key role in immune system balance.

Regulatory B cells (Bregs) may act earlier than regulatory T cells (Tregs) and may play as important a role in autoimmune and allergic diseases. Obstacles to the investigation of Bregs are the same as those encountered for Tregs: the regulatory effects are short-lived in some cases, there is no consistent phenotype (C5 expression is neither indispensable nor sufficient), differences exist across species (e.g., between humans and mice), and there are a number of suppression modalities (IL-10, TGF-beta, expression of proapoptotic membrane molecules) that vary across Breg subtypes. The Breg subtypes may be homologous to the Treg subtypes (Br1 cells expressing IL-10, Br3 cells expressing TGF-beta, and B-Foxp3 cells), although the Br1 subtype seems to predominate. Nevertheless, differences with Treg cells may exist: Breg activation may chiefly involve the toll-like receptors rather than the antigen receptor; and Bregs act earlier, facilitating the recruitment of Tregs then disappearing once the Tregs become operational. Bregs make a major contribution to autoimmune disorders associated with several forms of immune deficiency, as well as to the absence of transplant rejection when there is a strong B cell response. Breg deficiencies have been reported in lupus, and the disappointing effects in this disease of treatments designed to inhibit the B cell response may be related to further Breg impairment. In several animal models, Breg stimulation is effective in correcting a variety of autoimmune disorders, most notably those initiated in the mucous membranes. Research into the interactions between the gut microbiota and Bregs holds considerable promise.