Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-α/βR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25 + Foxp3 + regulatory T (T reg ) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-γ and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T reg cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.cMet (HGF receptor) | experimental autoimmune encephalitis | immune tolerance | multiple sclerosis | neuroprotection

IntroductionMicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that regulate mRNAs by binding to their 3Ј untranslated (3ЈUTR) regions. 1,2 More than 9000 miRNAs have been identified in more than 100 species. Most miRNA genes are transcribed by RNA polymerase II into primary miRNA transcripts that are processed in the nucleus by a complex containing the RNase III endonuclease Drosha. 1 The resulting precursor miRNAs are transported to the cytoplasm, where the mature miRNAs are excised by a complex containing the endonuclease Dicer. 1 Mature miRNAs are incorporated into the RNA-induced silencing complex, which binds to the 3ЈUTRs of target mRNAs, inducing their degradation and/or repressing their translation. Posttranscriptional regulation of gene expression by miRNAs is critical for a wide range of physiologic and pathologic processes, including cell proliferation, apoptosis, differentiation, morphogenesis, development, and oncogenesis. [1][2][3][4] Several miRNAs play pivotal roles in the immune system. 5-7 MicroRNA-155 (miR155) has emerged as a particularly prominent player in innate and adaptive immune responses. 5,7 miR155 is derived from an exon of the B-cell integration cluster (BIC) gene, which was identified as a common integration site of avian leucosis virus in chicken B-cell lymphomas. 8,9 BIC is a non-protein-coding gene for which the only known function is the production of miR155. Subsequent studies revealed that miR155 expression is deregulated in diverse cancers. 10,11 The molecular mechanisms underlying the oncogenic role of miR155 remain unclear. miR155 expression is induced during the activation of T cells, B cells, monocytes, macrophages, and dendritic cells (DCs), suggesting that it plays multiple roles in the immune system. 5 In agreement with this, the immune system of miR155-deficient mice is compromised by defects in several cell types. 12,13 Activated T cells from miR155 Ϫ/Ϫ mice exhibit a bias toward Th2 differentiation and express elevated levels of IL4, IL5, and IL10. This was attributed to the fact that miR155 targets the mRNA coding for c-Maf, a transcription factor implicated in IL-4 expression and Th2 differentiation. 12 The B-cell compartment in miR155 Ϫ/Ϫ mice exhibits defects in germinal center development and in the generation of efficient antibody responses. miR155 is critical for affinity maturation because the generation of plasma cells produces high-affinity isotype-switched antibodies and the development of memory B cells. [12][13][14] The B-cell defects in miR155 Ϫ/Ϫ mice result at least in part from miR155 repressing the expression of the transcription factor PU.1 14 and activation-induced cytidine deaminase. 15,16 Lastly, bone marrow-derived DCs (BM-DCs) from miR155 Ϫ/Ϫ mice are impaired in their ability to activate T cells. 12 We recently reported that the induction of miR155 expression in human monocyte-derived DCs (Mo-DCs) exposed to the TLR4 ligand lipopolysaccharide (LPS) leads to modulation of the IL1 signal transduction pathway. 17 Another study foun...

Here, we show that a lupus-suppressing locus is caused by a nonsense mutation of the filamentous actin-inhibiting Coronin-1A gene. This mutation was associated with developmental and functional alterations in T cells including reduced migration, survival, activation, and Ca2+ flux. T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected. By transfer of T cells, it was shown that suppression of autoimmunity could be accounted for by the presence of the Coro1a(Lmb3) mutation in T cells. Our results demonstrate that Coronin-1A is required for the development of systemic lupus and identify actin-cytoskeleton regulatory proteins as potential targets for modulating autoimmune diseases.

The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.