Basophils contribute to pristane-induced Lupus-like nephritis model (original) (raw)
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PloS one, 2016
Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly usefu...
Basophils and Systemic Lupus Erythematosus in Murine Models and Human Patients
Biology
Basophils are the rarest cell population in the blood. Even though basophils are known to participate in some allergic reactions and immune responses to parasitic infections, their immunological role is still largely elusive. Recent evidence has suggested that in some murine models of systemic lupus erythematosus and lupus-like nephritis, basophils may also be implicated in autoimmunity processes by promoting autoantibody production and tissue injury. We conducted a systematic search to collect the available evidence on basophils’ potential immunomodulatory role in autoimmunity and, particularly, systemic lupus erythematosus. We identified several articles investigating basophils’ role in murine models of lupus (n = 3) and in patients affected with systemic lupus erythematosus (n = 8). Even though the alteration of the “adaptive” immune response is considered the main immunopathological event in systemic lupus erythematosus, the contribution from the mechanisms of “innate” immunity ...
Arthritis and Rheumatism, 2008
ObjectiveThe detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-like receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model.The detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-like receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model.MethodsSerum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7–deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry.Serum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7–deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry.ResultsWe found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas anti–double-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7–deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis.We found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas anti–double-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7–deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis.ConclusionTLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.TLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.
Frontiers in Immunology
Tissue-specific mouse models are essential tools to decipher the role of each cell compartment and/or their expressed genes in the pathophysiology of diseases. Here, we describe a new knock-in mouse model allowing expression of both the fluorescent protein tdTomato and the CRE recombinase selectively in the basophil compartment under the control of the Mcpt8 gene. These “CT-M8” mice did not show any abnormalities in their peripheral distribution of major immune cell populations nor their basophil function. CT-M8 mice allowed the identification of basophils by immunofluorescence and flow cytometry and basophil-specific Cre-mediated floxed gene deletion. Breeding of our CT-M8 mice with the ROSA26flox-stop-DTA mice led to the generation of basophil-deficient mice with no detectable abnormalities in other cell compartments. These mice were then used to document basophil involvement in systemic lupus erythematosus (SLE) pathophysiology since we previously reported by transient depletion ...
Basophils and Autoreactive IgE in the Pathogenesis of Systemic Lupus Erythematosus
Current Allergy and Asthma Reports, 2011
A hallmark of this disease, like for other autoimmune diseases, is the presence of large amounts of autoantibodies. As such SLE is considered to be a B cell disease perpetuated by the expansion of autoreactive T and B cells. The T cells involved have long been considered to be Th1 and Th17 cells as these potent pro-inflammatory cells can be found in the tissues of SLE patients.
Basophils, IgE, and Autoantibody-Mediated Kidney Disease
The Journal of Immunology, 2011
Basophils are of interest in immunology due to their ability to produce a Th2-signature cytokine, IL-4, following activation. A new understanding of the role of basophils in immunity shows novel functions at a cellular level through which basophils influence adaptive immunity. This review summarizes new advances in basophil biology and discusses new roles for basophils in human disease, especially in the mediation of the pathogenesis of lupus nephritis. Recently, basophils have been shown to contribute to self-reactive Ab production in systemic lupus erythematosus and may enhance pre-existing loss of B cell tolerance, suggesting that basophils, IL-4, and IgE mediate the pathogenesis of lupus nephritis by promoting the Th2 environment and activating autoreactive B cells. In addition to envisaging exciting therapeutic prospects, these novel findings open the way for the study of basophils in other autoimmune and renal diseases.
Kidney International, 2003
Background. There is strong evidence that Th1 cytokines are essential for disease in murine models of lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-␥ (IFN-␥) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of lupus, although its precise role remains unclear. We investigated the role of IL-12 for lupus-like disease induced by pristane. IL-12p35deficient (Ϫ/Ϫ) and control (ϩ/ϩ) BALB/c mice were treated with pristane or phosphate-buffered saline (PBS).
Frontiers in Immunology
Systemic lupus erythematosus is a complex autoimmune disease during which patients develop autoantibodies raised against nuclear antigens. During the course of the disease, by accumulating in secondary lymphoid organs (SLOs), basophils support autoreactive plasma cells to amplify autoantibody production. We have recently shown that murine lupus-like disease could be controlled by 10 days of oral treatment with a combination of prostaglandin D2 (PGD2) receptor (PTGDR) antagonists through the inhibition of basophil activation and recruitment to SLOs. Importantly, inhibiting solely PTGDR-1 or PTGDR-2 was ineffective, and the development of lupus-like disease could only be dampened by using antagonists for both PTGDR-1 and PTGDR-2. Here, we aimed at establishing a proof of concept that a clinically relevant bispecific antagonist of PTGDR-1 and PTGDR-2 could be efficient to treat murine lupus-like nephritis. Diseased Lyn-deficient female mice received treatment with AMG853 (vidupiprant, ...