here is increasing evidence that SARS-CoV-2 not only affects the respiratory tract but also impacts the CNS, resulting in neurological symptoms such as loss of smell and taste, headache , fatigue, nausea and vomiting in more than one-third of individuals with COVID-19 (refs. 1,2). Moreover, acute cerebrovascular disease and impaired consciousness have been reported 3. While Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

SUMMARY B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has so far been associated primarily with interleukin (IL)-10 because B cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens1,2. Here, we identify IL-35-producing B cells as novel 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 strikingly improved resistance to infection with the intracellular bacterial pathogen Salmonella typhimurium, as shown by their superior containment of the bacterial growth and their prolonged survival both after primary infection, and upon secondary challenge after vaccination, 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 enhanced stimulatory function of B cells as antigen-presenting cells (APC). During Salmonella infection IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM+CD138hiTACI+CXCR4+CD1dintTim1int plasma cells expressing the transcription factor Blimp1. During EAE CD138+ plasma cells were also the major source of B cell-derived IL-35 and IL-10. Collectively, our data unravel the importance of IL-35-producing B cells in regulation of immunity, and highlight IL-35 production by B cells as a novel therapeutic target for autoimmune and infectious diseases. More generally, this study emphasizes 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.

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are a mainstay therapeutic approach for IBD. However, up to 40% of patients are non-responsive to anti-TNF agents, and identifying alternative therapeutic targets is a priority. Here we show that expression of the cytokine Oncostatin M (OSM) and its receptor (OSMR) is increased in the inflamed intestine of IBD patients compared to healthy controls, and correlates closely with histopathological disease severity. OSMR is expressed in non-hematopoietic, non-epithelial intestinal stromal cells, which respond to OSM by producing various pro-inflammatory molecules including interleukin-6 (IL-6), the leukocyte adhesion factor ICAM-1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, high pre-treatment OSM expression is strongly associated with failure of anti-TNF therapy based on analysis of over 200 IBD patients, including two cohorts from phase 3 clinical trials of infliximab and golimumab. OSM is thus a potential biomarker and therapeutic target for IBD, with particular relevance for anti-TNF resistant patients.