IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

International audienceB lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease

A case for B cells in the pathogenesis of Sjögren's syndrome

T cells have long occupied central stage of the debate on the type of lymphocytes involved in the pathogenesis of Sjögren's syndrome (SS). The relevance of B cells has, however, been emphasized over the past five years, and new insights into their ftinctions, revealed. Hence, it has become apparent that B cells accomplish various tastes. For example, beyond the paradigm that T lymphocytes maintain strict control over B cells, the latter cells are now acknowledged to solicit their own help from the former cells, release a flurry of cytokines, and act as antigen-presenting cells. Furthermore, increased levels of the B cell activating factor (BAFF) may be responsible for qualitative anomalies found in SS such as high numbers of circulating Bm2/Bm2' cells, and accumulation of transitional type 2 and marginal zone-like B cells in salivary glands. BAFF is also associated with functional abnormalities of B cells in SS, such as increased expression of CD19, which decreases the required strength generated by antigen receptor binding for transmitting its signal. SS may thus be conceived as a model for B cell-induced autoimmunity. Since this brings novel prospects for the treatment of the disease, it is no surprise that B cell ablative-treatment has proven to be relatively efficacious in SS.SCOPUS: sh.jinfo:eu-repo/semantics/publishe

TLR2 is one of the endothelial receptors for beta 2-glycoprotein I.

International audienceDuring the antiphospholipid syndrome, beta2-gpI interacts with phospholipids on endothelial cell (EC) surface to allow the binding of autoantibodies. However, induced-pathogenic intracellular signals suggest that beta2-gpI associates also with a receptor that is still not clearly identified. TLR2 and TLR4 have long been suspected, yet interactions between TLRs and beta2-gpI have never been unequivocally proven. The aim of the study was to identify the TLR directly involved in the binding of beta2-gpI on EC surface. beta2-gpI was not synthesized and secreted by ECs in vitro, but rather taken up from FCS. This uptake occurred through association with TLR2 and TLR4 which partitioned together in the lipid rafts of ECs. After coimmunoprecipitation, mass-spectrometry identification of peptides demonstrated that TLR2, but not TLR4, was implicated in the beta2-gpI retention. These results were further confirmed by plasmon resonance-based studies. Finally, siRNA were used to obtain TLR2-deficient ECs that lost their ability to bind biotinylated beta2-gpI and to trigger downstream phosphorylation of kinases and activation of NFkappaB. TLR4 may upregulate TLR2 expression, thereby contributing to beta2-gpI uptake. However, our data demonstrate that direct binding of beta2-gpI on EC surface occurs through direct interaction with TLR2. Furthermore, signaling for anti-beta2-gpI may be envisioned as a multiprotein complex concentrated in lipid rafts on the EC membrane

New ELISA for B cell-activating factor.

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BAFF, a new target for intravenous immunoglobulin in autoimmunity and cancer.

International audienceIntravenous immunoglobulin (IVIg) has been used to treat autoimmune diseases and lymphoid malignancies with some therapeutic effect. In both these pathological conditions, there is an overproduction of BAFF (for "B-cell-activating factor of the TNF family"), and APRIL (for "a proliferation-inducing ligand"). The presence of antibodies (Abs) with BAFF and APRIL specificities in IVIg preparations was investigated by enzyme-linked immunosorbent assay, and Western Blot analysis. Apoptosis was measured by the annexin-V binding method, and confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique. Nonglycosylated recombinant BAFF, glycosylated affinity-purified BAFF, and recombinant APRIL (but not TNFalpha), were recognized by certain IgG in IVIg, and their F(ab')(2) fragments. Steric hindrance prevented the antiapoptotic effects of BAFF on B-lymphocytes. This work documents the presence of anti-BAFF and anti-APRIL Abs in IVIg. These can functionally neutralize the role of BAFF in B-cell survival. These anti-BAFF IgG might amend deleterious effects of BAFF in B-cell-mediated autoimmune diseases

Ectopic germinal centers are rare in Sjogren's syndrome salivary glands and do not exclude autoreactive B cells.

International audienceThis study reports on the characterization of B cells of germinal center (GC)-like structures infiltrating the salivary glands (SGs) of patients with Sjögren's syndrome. Eight two-color combinations were devised to characterize the phenotype of these B cells in 11 SG specimens selected from biopsies obtained from 40 Sjögren's syndrome patients and three normal tonsils. The 9G4 mAb, which recognizes V4.34-encoded autoAbs, enabled us to identify autoreactive B cells. Quantitative RT-PCR was used to determine the level of mRNAs for activation-induced cytidine deaminase (AICDA), repressors and transcription factors. CD20(+)IgD(-)CD38(+)CD21(+)CD24(-) B cells, similar to those identified in tonsil GCs, were seen in the SGs of four patients and, and since they expressed AICDA, they were termed "real GCs". CD20(+)IgD(+)CD38(-)CD21(+)CD24(+) B cells, seen in aggregates from the remaining seven samples, were characteristically type 2 transitional B cells and marginal zone-type B cells. They lacked AICDA mRNAs and were termed "aggregates". Real GCs from SGs contained mRNAs for Pax-5 and Bcl-6, like tonsil GC cells, whereas aggregates contained mRNAs for Notch-2, Blimp-1, IRF-4, and BR3, similar to marginal zone B cells. Further experimental data in support of this dichotomy included the restriction of CXCR5 expression to real GC cells, while sphingosine 1-phosphate receptor 1 was expressed only in aggregates. In contrast, both types of B cell clusters expressed the idiotype recognized by the 9G4 mAb. Our data indicate that, in SGs, a minority of B cell clusters represent genuine GC cells, while the majority manifest features of being type 2 transitional B cells and marginal zone cells. Interestingly, both types of B cell aggregates include autoreactive B cells