Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2 k/k protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH −/− mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity.inflammation | SLE | T follicular helper cells

Soil moisture data from the Oklahoma Mesonet are widely used in research efforts spanning many disciplines within Earth sciences. These soil moisture estimates are derived by translating measurements of matric potential into volumetric water content through site- and depth-specific water retention curves. The objective of this research was to increase the accuracy of the Oklahoma Mesonet soil moisture data through improved estimates of the water retention curve parameters. A comprehensive field sampling and laboratory measurement effort was conducted that resulted in new measurements of the percent of sand, silt, and clay; bulk density; and volumetric water content at −33 and −1500 kPa. These inputs were provided to the Rosetta pedotransfer function, and parameters for the water retention curve and hydraulic conductivity functions were obtained. The resulting soil property database, MesoSoil, includes 13 soil physical properties for 545 individual soil layers across 117 Oklahoma Mesonet sites. The root-mean-square difference (RMSD) between the resulting soil moisture estimates and those obtained by direct sampling was reduced from 0.078 to 0.053 cm3 cm−3 by use of the new water retention curve parameters, a 32% improvement. A >0.15 cm3 cm−3 high bias on the dry end was also largely eliminated by using the new parameters. Reanalysis of prior studies that used Oklahoma Mesonet soil moisture data may be warranted given these improvements. No other large-scale soil moisture monitoring network has a comparable published soil property database or has undergone such comprehensive in situ validation.

Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.

Several mouse models of SLE, including FcγRIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IKDCs or pre-mNKs in other systems. Here we show that atypical NKs purified from spleens of SLE-prone mice, and identified as NK1.1+CD11c+CD122+MHC-II+, induce persistent autoimmune disease in an IFN-I and CD40L-dependent manner when transferred to WT mice. A single transfer of 4x106 NK1.1+ cells from TLR7tg into WT induces a 2-week-long wave of inflammatory cytokines in the serum, a sustained increase in T cell activation and follicular helper cells for the following months, and a progressive expansion of dendritic cells, monocytes and granulocytes. Furthermore IL15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine producing/antigen-presenting cells that affect the priming and progression of systemic autoimmune disease.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by increased production of autoantibodies, which commonly target nuclear antigens, and concomitant deposition of immune complexes that cause inflammation in tissues. SLE is often associated with increased systemic expression of type I interferons, in some cases due to dysregulation in nucleic acid-sensing innate pathways. There is strong genetic evidence for a link between cytoplasmic RNA sensing pathways (RIG-I/MDA5) and SLE, both in human patients and murine models, however questions still remain regarding pathway initiation, cell types involved and downstream effects. Here we show that MAVS, an essential adaptor for RIG-I/MDA5 signaling, is necessary for all symptoms of autoimmune disease that develop spontaneously in the lupus model FcγRIIB−/− mice. This effect was independent of type I interferon signaling, TLR7 expression or STING, all three factors that have been connected to autoimmunity. Mixed bone marrow reconstitution experiments showed reduced occurrence in autoimmune germinal centers and diminished autoantibody production by MAVS-deficient B cells. Thus, MAVS plays a B cell intrinsic role in autoreactive B cell activation that is independent of its anti-viral functions and independent of elevated type I interferon expression.

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Pathogenic infections are important environmental modifiers of autoimmune disease as they can alter the immune system in a way that either promotes or reduces autoimmune responses. We tested the effect of infection with vesicular stomatitis virus (VSV) on the FcγR2B−/− (R2) mouse strain that spontaneously develops lupus disease. Infecting FcγR2B−/− mice with live VSV reduces autoantibody levels and inflammatory pathology, and prolongs survival. We showed that VSV-mediated protection can be transferred in a CD8 cell adoptive transfer experiment. Legend screening for surface markers on CD8 T cells indicated that CD8 T cells from VSV infected mice express high level of markers linked to exhausted and regulatory phenotypes. After testing the transfer of various CD8 T cell subsets, we have identified CD8+CD122+NKG2D+ cells as mediator in VSV-induced Lupus amelioration. Preliminary analysis of RNA Sequencing data for gene expression profiles among various CD8 subsets, indicate that the protective cells express higher level of genes linked to memory phenotype. Our working hypothesis is that the viral infection may induce the expansion of long lived CD8 populations that regulate the humoral response.

FcγRIIB knock-out mice in B6 background develop a lupus like autoimmune disease. With the addition of the yaa (Y-chromosome autoimmune accelerator) gene, pathogenecity in these male mice is significantly enhanced and autoantibodies switch from nuclear to nucleolar specificity. High titer of λ-light chains immunoglobulin, and anti-RNA antibodies were found in R2-/-yaa serum. Also, R2-/-yaa serum selectively bound 5 major nuclear proteins compared to R2-/- serum. To characterize the autoantibodies produced by R2-/-yaa mice and the nucleolar antigens that react with these antibodies, we have produced hybridomas. Hybridoma H526 produced anti-nucleolar IgG2c-λ antibodies. The antibody binds RNA, a synthetic polyribonucleotide poly (GC)20 and a RNA-associated nucleolar protein, nucleolin. R2-/-yaa serum also found to cross-react with poly (GC)20, nucleolin and also with poly ADP-ribose (PAR). Simultaneous presence of nucleolin and PAR autoantibodies has been found to be associated with lupus. Further characterization of nucleolin modification and lupus development is in progress.