Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.

Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88 -/-mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88 -/-mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4-/-and TLR9 -/-mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4 -/-mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9 -/-mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOGinduced EAE.

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.

EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17-and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-a/b secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE.In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.Key words: Autoimmunity . DC . EAE/MS . T cells . Type I IFN Supporting Information available online IntroductionEAE is an animal model for the human autoimmune demyelinating disease MS [1]. The pathological changes in the CNS during EAE are very similar to MS with perivascular infiltrates of T cells, B cells and macrophages [2]. Murine EAE is induced by injection of myelin autoantigens such as myelin oligodendrocyte glycoprotein (MOG) in CFA containing killed Mycobacterium tuberculosis and pertussis toxin. EAE was previously thought to be a purely IL-12-driven Th1-mediated autoimmune disease [3].However Langrish et al. demonstrated that proinflammatory IL-17-producing Th17 cells mediate EAE [4]. Murine-naïve CD4 CD251 6]. Recently it wasshown that different epitopes of MOG predominately induce a Th1 or Th17 response, which influences the lesion distribution and clinical symptoms of EAE and suggests a promoting role for both Th17 and Th1 cells in MOG-induced EAE [7]. DC are key actors when an adaptive immune response is initiated [8]. There are two major DC subsets in mice, which are characterized by differential expression of cell surface markers [9] . pDC also have a powerful ability to modify the adaptive immune response, e.g. T-cell differentiation [11,12]. The expression of costimulatory molecules differs between mDC and pDC, e.g. maturation leads to upregulation of B7 molecules on mDC, but downregulation of these molecules on pDC [13,14]. Moreover, mDC and pDC differ in their expression of TLR and response to TLR ligation. TLR7 and TLR9 ligation results in type I IFN production in pDC because of constitutive expression of IFN regulatory factor-7, whereas ligation of these receptors leads to IL-12 production in mDC [15,16]. We have previously shown that TLR9 a...