SLAP deficiency decreases dsDNA autoantibody production.
Ontology highlight
ABSTRACT:
SUBMITTER: Peterson LK
PROVIDER: S-EPMC4053206 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
Publications
SLAP deficiency decreases dsDNA autoantibody production.
Peterson Lisa K LK Pennington Luke F LF Shaw Laura A LA Brown Meredith M Treacy Eric C EC Friend Samantha F SF Hatlevik Øyvind Ø Rubtsova Kira K Rubtsov Anatoly V AV Dragone Leonard L LL
Clinical immunology (Orlando, Fla.) 20131231 2
Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-pept ...[more]
Similar Datasets
Project description:Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n?=?811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n?=?906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p?=?2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p?=?2.4E-04), with p(heterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
| S-EPMC3048371 | biostudies-literature
Project description:CD47, a self-recognition marker, plays an important role in both innate and adaptive immune responses. To explore the potential role of CD47 in activation of autoreactive T and B cells and the production of autoantibodies in autoimmune disease, especially systemic lupus erythematosus (SLE), we have generated CD47 knockout Fas(lpr) (CD47(-/-) -Fas(lpr) ) mice and examined histopathological changes in the kidneys, cumulative survival rates, proteinuria, extent of splenomegaly and autoantibodies, serum chemistry and immunological parameters. In comparison with Fas(lpr) mice, CD47(-/-) -Fas(lpr) mice exhibit a prolonged lifespan and delayed autoimmune nephritis, including glomerular cell proliferation, basement membrane thickening, acute tubular atrophy and vacuolization. CD47(-/-) -Fas(lpr) mice have lower levels of proteinuria, associated with reduced deposition of complement C3 and C1q, and IgG but not IgM in the glomeruli, compared to age-matched Fas(lpr) mice. Serum levels of antinuclear antibodies and anti-double-stranded DNA antibodies are significantly lower in CD47(-/-) -Fas(lpr) than in Fas(lpr) mice. CD47(-/-) -Fas(lpr) mice also display less pronounced splenomegaly than Fas(lpr) mice. The mechanistic studies further suggest that CD47 deficiency impairs the antigenic challenge-induced production of IgG but not IgM, and that this effect is associated with reduction of T follicular cells and impairment of germinal centre development in lymphoid tissues. In conclusion, our results demonstrate that CD47 deficiency ameliorates lupus nephritis in Fas(lpr) mice via suppression of IgG autoantibody production.
| S-EPMC4607582 | biostudies-literature
Project description:Reactive oxygen species are involved in the aging process and diseases. Despite the important role of Cu/Zn SOD (superoxide dismutase) encoded by SOD1, SOD1-/- mice appear to grow normally under conventional breeding conditions. In the present paper we report on a novel finding showing a distinct connection between oxidative stress in erythrocytes and the production of autoantibodies against erythrocytes in SOD1-/- mice. Evidence is presented to show that SOD1 is primarily required for maintaining erythrocyte lifespan by suppressing oxidative stress. A SOD1 deficiency led to an increased erythrocyte vulnerability by the oxidative modification of proteins and lipids, resulting in anaemia and compensatory activation of erythropoiesis. The continuous destruction of oxidized erythrocytes appears to induce the formation of autoantibodies against certain erythrocyte components, e.g. carbonic anhydrase II, and the immune complex is deposited in the glomeruli. The administration of an antioxidant, N-acetylcysteine, suppressed erythrocyte oxidation, ameliorated the anaemia, and inhibited the production of autoantibodies. These data imply that a high level of oxidative stress in erythrocytes increases the production of autoantibodies, possibly leading to an autoimmune response, and that the intake of antioxidants would prevent certain autoimmune responses by maintaining an appropriate redox balance in erythrocytes.
| S-EPMC1798435 | biostudies-literature
Project description:The inflammatory cytokine macrophage migration-inhibitory factor (MIF) promotes atherosclerosis via lesional monocyte and T-cell recruitment. B cells have emerged as important components in atherogenesis, but the interaction between MIF and B cells in atherogenesis is unknown. Here, we investigated the atherosclerotic phenotype of Mif-gene deletion in Apoe-/- mice. Apoe-/- Mif-/- mice fed a Western diet exhibited strongly reduced atherosclerotic lesions in brachiocephalic artery (BC) and abdominal aorta compared with controls. This phenotype was accompanied by reduced circulating B cells. Flow cytometry revealed a B-cell developmental defect with increased premature and immature B-cell counts in bone marrow (BM) of Apoe-/- Mif-/- mice and diminished B-cell numbers in spleen. This finding was linked with a decreased expression of Baff-R and differentiation-driving transcription factors at the immature B-cell stage, whereas peritoneal B cells exhibited unchanged CD80 and CD86 expression but vastly decreased CD9 and elevated CD23 levels, indicating that the developmental block favors the generation of immature, egressing, and reactive B cells. Mif deficiency did not affect absolute B-cell numbers in the vessel wall but favored a relative increase of B cells in the atheroprone BC region and the appearance of periadventitial B-cell-rich clusters. Of note, Mif-/- mice exhibited a significant increase in oxidized low-density lipoprotein (oxLDL)-specific antibodies after the injection of oxLDL, indicating that Mif deficiency is associated with higher sensitivity of B cells against natural-occurring antigens such as oxLDL. Importantly, Apoe-/- mice adoptively transplanted with Apoe-/-Mif-/- BM showed reduced peripheral B cells compared with Apoe-/- BM transplantation but no atheroprotection in the BC; also, whereas there was a selective increase in atheroprotective IgM-anti-oxLDL-antibodies in global Mif deficiency, BM-specific Mif deficiency also led to elevated proatherogenic anti-oxLDL-IgG. Together, these findings reveal a novel link between MIF and B cells in atherogenesis. Protection from atherosclerosis by Mif deficiency is associated with enhanced B-cell hypersensitivity, which in global but not BM-restricted Mif deficiency favors an atheroprotective autoantibody profile in atherosclerotic mice. Targeting MIF may induce protective B-cell responses in atherosclerosis.-Schmitz, C., Noels, H., El Bounkari, O., Straussfeld, E., Megens, R. T. A., Sternkopf, M., Alampour-Rajabi, S., Krammer, C., Tilstam, P. V., Gerdes, N., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.
| S-EPMC6207164 | biostudies-literature
Project description:Many studies have demonstrated that anti-dsDNA IgG is closely associated with lupus nephritis. Recently, it was found that activation of the fibroblast growth factor-inducible 14 (Fn14) signaling pathway damages glomerular filtration barrier in MRL/lpr lupus-prone mice. However, MRL/lpr mice have high titers of serum autoantibodies other than anti-dsDNA IgG. The aim of this study was to further explore the effect of Fn14 deficiency on anti-dsDNA IgG-induced glomerular damage in severe combined immunodeficiency (SCID) mice that have no endogenous IgG. Fn14 deficiency was generated in SCID mice. The murine hybridoma cells producing control IgG or anti-dsDNA IgG were intraperitoneally injected into mice. In two weeks, the urine, serum, and kidney tissue samples were harvested from mice at sacrifice. It showed that the injection of anti-dsDNA IgG, but not control IgG hybridoma cells, induced proteinuria and glomerular damage in SCID mice. Between the wild-type (WT) and knockout (KO) mice injected with anti-dsDNA IgG hybridoma cells, the latter showed a decrease in both proteinuria and glomerular IgG deposition. The histopathological changes, inflammatory cell infiltration, and proinflammatory cytokine production were also attenuated in the kidneys of the Fn14-KO mice upon anti-dsDNA IgG injection. Therefore, Fn14 deficiency effectively protects SCID mice from anti-dsDNA IgG-induced glomerular damage.
| S-EPMC6311848 | biostudies-literature
Project description:Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.
| S-EPMC9241489 | biostudies-literature
Project description:To test if manipulating TCR complex-mediated signaling (TCR signaling) could treat autoimmune disease, we generated the double SKG Src-like adapter protein (SLAP) knockout (DSSKO) mouse model. The SKG mutation in ZAP70 and SLAP have opposing functions on the regulation of TCR signaling. The combination of these two mutations alters TCR signaling in the context of a defined genetic background, uniform environmental conditions, and a well-characterized signaling disruption. In contrast to SKG mice, DSSKO mice do not develop zymosan-induced chronic autoimmune arthritis. This arthritis prevention is not due to significant alterations in thymocyte development or repertoire selection but instead enhanced numbers of regulatory T cells (Tregs) and decreased numbers of Th17 cells skewing the ratio of Tregs to autoreactive effector T cells. Treg depletion and/or functional blockade led to the development of arthritis in DSSKO mice. In vitro suppression of effector T cell proliferation was also enhanced, demonstrating that DSSKO mice have increased numbers of Tregs with increased function. Understanding how TCR signals influence development, expansion, and function of Tregs in DSSKO mice could advance our ability to manipulate Treg biology to treat ultimately autoimmune disease.
| S-EPMC3135266 | biostudies-literature
Project description:BackgroundPristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith (anti-Sm/RNP) and other lupus autoantibodies. The present study addressed how these autoantibody levels are maintained over time.MethodsLupus was induced in BALB/c mice using pristane. Naïve B cells, switched memory B cells, switched plasmablasts, and plasma cells were flow-sorted and total IgG and anti-U1A (RNP) autoantibodies were determined with ELISA.ResultsB cells with a switched "memory-like" (CD19(+)CD138(-)IgM(-)IgD(-)) (sMB) phenotype were increased in pristane-treated mice and expressed higher levels of Toll like receptor 7 (Tlr7) than cells with this phenotype from untreated mice. Flow-sorted sMB cells from pristane-treated mice did not secrete IgG spontaneously, but were hyper-responsive to both synthetic (R848) and natural (apoptotic cells) TLR7 ligands, resulting in increased IgG production in vitro. The flow-sorted sMB cells also could be driven by R848 to produce IgG anti-U1A autoantibodies. Production of IgG was strongly inhibited by both JSH-23 and SB203580, suggesting that the canonical NFκB and p38 MAPK pathways, respectively, contribute to the TLR7 ligand hyper-responsiveness of sMB from pristane-treated mice.ConclusionsThe switched memory B cell subset from pristane-treated mice is expanded and shows an increased propensity to undergo terminal (plasma cell) differentiation in response to synthetic and natural TLR7 ligands. The data suggest that the decreased clearance of apoptotic cells characteristic of pristane-treated mice might help maintain high serum levels of anti-RNP/Sm autoantibodies.
| S-EPMC4718029 | biostudies-literature
Project description:Erythropoietin (Epo), a hormone known to stimulate bone marrow erythrocyte production, is widely used to treat anemia in patients at risk for vascular disease. However, the effects of Epo on angiogenesis are not well defined. We studied the role of Epo in a mouse model of retinopathy characterized by oxygen-induced vascular loss followed by hypoxia-induced pathological neovascularization. Without treatment, local retinal Epo levels were suppressed during the vessel loss phase. Administration of exogenous Epo prevented both vessel dropout and subsequent hypoxia-induced neovascularization. Early use of Epo also protected against hypoxia-induced retinal neuron apoptosis. In contrast, retinal Epo mRNA levels were highly elevated during the retinopathy neovascular phase. Exogenous late Epo treatment did not protect the retina, but rather enhanced pathological neovascularization. Epo's early protective effect occurred through both systemic retinal recruitment of proangiogenic bone marrow-derived progenitor cells and activation of prosurvival NF-kappaB via Epo receptor activation on retinal vessels and neurons. Thus early retinal Epo suppression contributed to retinal vascular instability, and elevated Epo levels during the proliferation stage contributed to neovascularization and disease. Understanding the role of Epo in angiogenesis is critical to timing its intervention in patients with retinopathy or other diseases in which pathological angiogenesis plays a significant role.
| S-EPMC2213374 | biostudies-literature
Project description:HypothesisThe management of superior labrum anterior to posterior (SLAP) tears typically consists of either repair or biceps tenodesis (BT). While repair is more frequently recommended in younger patients, patients older than 40 years are often treated with BT. The purpose of this study is to determine whether there has been a change in utilization of these procedures over the past decade with respect to patient age as well as compare reoperation rates between the two procedures.MethodsThe Pearldiver database was queried to identify BT and SLAP repairs indicated for SLAP tears performed from 2010 to 2019. The primary outcome was utilization rate, stratified by age. A secondary outcome was 2-year shoulder reoperation rates. Trends were reported in terms of compounded annual growth rate. Outcome analysis was conducted using univariate and multivariable analysis.ResultsFrom 2010 to 2019, SLAP repair was the most common procedure performed for SLAP tears. Regardless of age, BT performed for SLAP tear had a significantly increased utilization rate; whereas, SLAP repair had a significantly decreased utilization rate. SLAP repair was more commonly performed in younger patients compared to BT. Following multivariable analysis, patients who underwent SLAP repair had significantly higher odds (odds ratio (OR): 1.453; 95% confidence interval (CI): 1.26-1.68; P < .001) of requiring an arthroscopic reoperation within 2 years when compared to those who underwent BT with no significant difference with respect to 2-year open reoperation.ConclusionAlthough SLAP repair is still more commonly used to treat SLAP tears than BT, especially for younger patients, the utilization of SLAP repair is decreasing while BT is increasing. The increased utilization of BT may be associated with lower rates of shoulder reoperation for problematic SLAP tears.
| S-EPMC9998736 | biostudies-literature