Cutting edge: The silent chemokine receptor D6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis

Abstract D6, a promiscuous nonsignaling chemokine binding molecule expressed on the lymphatic endothelium, internalizes and degrades CC chemokines, and D6−/− mice demonstrated increased cutaneous inflammation following topical phorbol ester or CFA injection. We report that D6−/− mice were unexpectedly resistant to the induction of experimental autoimmune encephalomyelitis due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35–55 in CFA, D6−/− mice showed reduced spinal cord inflammation and demyelination with lower incidence and severity of experimental autoimmune encephalomyelitis attacks as compared with D6+/+ littermates. In adoptive transfer studies, MOG-primed D6+/− T cells equally mediated disease in D6+/+ or D6−/− mice, whereas cells from D6−/− mice transferred disease poorly to D6+/− recipients. Lymph node cells from MOG-primed D6−/− mice showed weak proliferative responses and made reduced IFN-γ but normal IL-5. CD11c+ dendritic cells accumulated abnormally in cutaneous immunization sites of D6−/− mice. Surprisingly, D6, a “silent” chemokine receptor, supports immune response generation.</jats:p

Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders

International audienceWith an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre-and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age-and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD