New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention. HighlightsClinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.

GM-CSF is effective in the treatment of DSS colitis in a mechanism involving the 440c(+) pDC population.

IFN (2, 3). The crosslinking of 125I-IFNa to several human cell lines indicates that the IFNa/P receptor is a multiprotein complex, consisting of 95-, 115-, and 135-kDa subunits (3-5).Type I IFNs induce the transcription of specific early genes, the IFN-stimulated genes (ISGs), through the activation of the Jakl and Tyk2 protein-tyrosine kinases (PTKs) (6,7). PTK activation mediates the IFN-induced rapid tyrosine phosphorylation of the multiprotein latent cytosolic transcription factor ISGF3, which consequently translocates to the nucleus, where it interacts with conserved promoter elements in ISGs (8,9). This model of PTK activation resulting in the tyrosine phosphorylation of specific transcription factors and gene activation has been described for several cytokines (6,10,11) and serves as a paradigm for cytokine signaling. In contrast, the early events triggered by IFNa receptor occupancy and the functions of the various subunits are poorly characterized.A cDNA coding for one subunit (IFNaRl) of the human

Based on the reports of the activation of the transcription factor known as STAT3 (for signal transducers and activators of transcription) or APRF (for acute phase response factor) by various cytokines, we investigated the possible role of STAT3 in type I interferon (IFN) receptor signaling. We show that STAT3 undergoes IFNalpha-dependent tyrosine phosphorylation and IFNalpha treatment induces protein-DNA complexes that contain STAT3. In addition, STAT3 associates with the IFNAR-1 chain of the type I receptor in a tyrosine phosphorylation-dependent manner upon IFNalpha addition. The binding of STAT3 to the IFNAR-1 chain occurs through a direct interaction between the SH2 domain-containing portion of STAT3 and the tyrosine-phosphorylated IFNAR-1 chain. Furthermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation. This phosphorylation event is apparently mediated by protein kinase C, since it was blocked by low concentrations of the protein kinase inhibitor H-7. The biological relevance of IFN activation of STAT3 is further illustrated by the finding that STAT3 is not activated by IFN in a cell line resistant to the antiviral and antiproliferative actions of IFN alpha but in which other components of the JAK-STAT pathway are activated by IFNalpha.

Down-regulation of activated signaling receptors in response to their ligands plays a key role in restricting the extent and duration of the signaling. Mechanisms underlying down-regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown. Here we show that IFNAR1 interacts with the Homolog of Slimb (HOS) F-box protein in a phosphorylation-dependent manner, and that this interaction is promoted by interferon a (IFNa). IFNAR1 is ubiquitinated by the Skp1-Cullin1-HOS-Roc1 (SCF HOS ) ubiquitin ligase in vitro. HOS expression and activities are required for IFNa-stimulated ubiquitination of IFNAR1, endocytosis of the type I interferon receptor, down-regulation of IFNAR1 levels, and IFNAR1 proteolysis via the lysosomal pathway. Furthermore, modulations of HOS activities affect the extent of Stat1 phosphorylation and Stat-mediated transcriptional activities as well as the extent of antiproliferative effects of type I interferons. These ®ndings characterize SCF HOS as an E3 ubiquitin ligase that is essential for ubiquitination, proteolysis and down-regulation of IFNAR1, and implicate HOS in the regulation of cellular responses to IFNa.