Search

Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3 + regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes -derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Autoantibodies directed against nuclear antigens often arise in autoimmune disease associated with the failure to clear apoptotic cells in a swift and timely manner. Nucleic acids present in apoptotic cells and in membranous microparticles derived thereof exert adjuvant activity in the immune response to apoptosis. The scope of this review is to provide an overview on the current knowledge on B cell responses to apoptotic cells and membranous microparticles. Although physiological B cell responses to apoptotic cells result in the release of IL-10 by B cells and immunosuppression, pathological responses lead to autoantibody formation. Toll-like receptors specific for nucleic acids are engaged in both types of responses. In this review we delineate the functional impact of nucleic acids on B cell responses in the context of apoptosis.

Plasmacytoid dendritic cells (pDC) exert contradictory roles: they represent major players in the pathogenesis of type I interferon-mediated autoimmunity but contribute to tolerance in the transplant setting. In this study we describe pDC as cellular enhancers of B cell-derived IL-10 production, a mechanism recently described as relevant in maintaining peripheral tolerance. Our data demonstrate that in human peripheral blood pDC augment IL-10 production in B cells in response to TLR7 and -9 ligands. They further show that pDC themselves produce IL-10 in response to TLR stimulation, most prominently after triggering of TLR7. Additionally, the data indicate that the positive regulatory effect of pDC on IL-10 production is not due to type I interferon production or other soluble factors. We conclude that pDC/B cell contact is essential for B cell-mediated immune suppression.

In contrast to nec, the apo is not accompanied by local inflammation. The immunosuppressive effects of apo cells have been repeatedly reported and a dysregulation of apo is discussed to play a major role in the pathogenesis of autoimmune disorders. The intracellular executioners of apo are the cysteine-aspartic acid proteases, also known as caspases that cleave a variety of intracellular substrates and mediate the morphological changes observed during apo. The association of autoimmune diseases with defects in caspase function indicates the necessity for functional integrity of caspases in the apo cell death machinery. Here, we describe that cells undergoing apo in presence of the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone stimulated MPhi to secrete proinflammatory cytokines. These findings indicate that caspase signalling is of central importance for silent and non- or anti-inflammatory cell death.

Human plasmacytoid dendritic cells (PDC) are blood dendritic cell antigen 2 (BDCA2) and blood dendritic cell antigen 4 (BDCA4) positive leukocytes that do not express common lineage markers. They have been described as proinflammatory innate immune cells and are the major source of alphaIFN in the human body. PDC-derived secretion of type I IFNs upon triggering of nucleic acid-sensing toll-like receptors (TLR) primes immune cells to rapidly respond to microbial stimuli and promotes a Th1 response. Here, we report that human PDC express CD36 and CD61 (beta3 integrin), both involved in uptake of apoptotic cells and in induction of tolerance. Freshly isolated PDC and PDC within human blood leukocytes constitutively express IL-10. Thus, PDC may possess a so far neglected role in propagation of immune tolerance.