Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of T(H)2 cells and CD4+CD25+FoxP3+ regulatory T cells (T(reg)) independent of antigen specificity. Type II monocyte-induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed T(H)17 cell development and promoted both T(H)2 differentiation and expansion of T(reg) cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity.

Antigen presentation, but not antibody secretion, by B cells drives CNS autoimmunity induced by immunization with human MOG.

Objective Clinical studies indicate that anti-CD20 B cell depletion may be an effective multiple sclerosis therapy. We investigated mechanisms of its immune modulation using two paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35–55, a model that does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen presenting cells (APC), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less CNS inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in EAE induced by MOG p35–55, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naïve B cells. In this EAE setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B cell depletion reduced the frequency of regulatory T cells, and increased the capacity of remaining APC to promote development of encephalitogenic T cells. Interpretation Our study highlights distinct roles for B cells in pathogenesis and regulation of CNS autoimmune disease. Clinical benefit from depletion of antigen-activated B cells may relate primarily to abrogation of proinflammatory B cell APC function. However, in certain clinical settings, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable.

A20 is an anti-inflammatory protein linked to multiple human diseases, however the mechanisms by which A20 prevents inflammatory disease are incompletely defined. We now find that A20 deficient T cells and fibroblasts are susceptible to caspase independent and RIPK3 dependent necroptosis. Global RIPK3 deficiency significantly rescues the survival of A20 deficient mice. A20 deficient cells exhibit exaggerated formation of RIPK1-RIPK3 complexes. RIPK3 undergoes physiological ubiquitination at lysine 5 (K5), and this ubiquitination event supports the formation of RIPK1-RIPK3 complexes. The catalytic cysteine of A20’s deubiquitinating motif is required for inhibiting RIPK3 ubiquitination and RIPK1-RIPK3 complex formation. These studies link A20 and RIPK3 ubiquitination to necroptotic cell death, and suggest new mechanisms by which A20 may prevent inflammatory disease.

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.