TLR7 agonism accelerates disease in a mouse model of primary Sjögren’s syndrome and drives expansion of age-associated B cells
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PROVIDER: PRJNA875471 | ENA |
REPOSITORIES: ENA
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Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that Myd88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which Myd88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, aged-associated B cells (ABCs) were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of the ABC subset in pSS.
2022-09-01 | GSE212467 | GEO
Project description:Systemic autoimmune diseases such as lupus and scleroderma are characterized by the loss of tolerance to nuclear antigens, but the mechanisms by which specific autoantibodies are selected are unclear. Here we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased towards nucleolar antigens due to a duplication of TLR genes in the pseudoautosomal region that makes them more responsive to TLR7 ligands and augments the Btk-dependent signaling pathway. These findings provide genetic evidence that naturally occurring differences in expression of TLR7 have a dramatic impact on antigen selection in autoimmunity. Follicular B cells were isolated from spleen of C57BL/6 male and C57BL/6.Yaa male. Four mice from each group using in this analysis were 2 months old. Dye swab labeled RNA had been done in one mice from each group.
2010-07-01 | E-GEOD-4445 | biostudies-arrayexpress
Project description:Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that MyD88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which MyD88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, T-bet+ B cells were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of T-bet-expressing B cells in pSS.
| S-EPMC9799719 | biostudies-literature
Project description:Kin competition accelerates experimental range expansion in an arthropod herbivore
| PRJNA415129 | ENA
Project description:Systemic autoimmune diseases such as lupus and scleroderma are characterized by the loss of tolerance to nuclear antigens, but the mechanisms by which specific autoantibodies are selected are unclear. Here we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased towards nucleolar antigens due to a duplication of TLR genes in the pseudoautosomal region that makes them more responsive to TLR7 ligands and augments the Btk-dependent signaling pathway. These findings provide genetic evidence that naturally occurring differences in expression of TLR7 have a dramatic impact on antigen selection in autoimmunity. Keywords: genetic modification, Yaa locus
2006-06-01 | GSE4445 | GEO
Project description:Primary Sjogren’s disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Prior studies by our group showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. To this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10 Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10 Tlr-DKO). The objective of this study was to determine if Tlr9 mediated sex-biased disease and whether this was dependent on the expression of Tlr7.
2025-07-23 | GSE292271 | GEO
Project description:The debilitating autoimmune disease Systemic Lupus Erythematosus (SLE) is closely associated with Toll-like receptor (TLR) 7 and type I interferon (IFN) activity in humans and in murine SLE-like disease. Two central manifestations of SLE affect the myeloid lineage of the immune system, myeloid expansion and anemia. Yet, whether these symptoms are linked and the role of TLR7 and/or type I IFN in these processes is unclear. Here we show that TLR7 signaling promotes cell-autonomous, phosphoinositide 3-kinase (PI3K)- and mammalian target of rapamycin (mTOR)-dependent macrophage development from the common myeloid progenitor (CMP). Strikingly, this TLR7-driven macrophage development requires and is enhanced by type I IFN. Genome-wide transcriptional profiling and functional studies demonstrated that TLR7 promoted the expression of Spic, the master regulator of splenic red pulp macrophages (RPM) and preferential development of hemophagocytic RPM-like cells from CMP in vitro. We found increased incidence of RPM-like cells in vivo in a mouse model of SLE caused by TLR7 overexpression, which correlated with decreased red blood cell (RBC) count and anemia. These findings demonstrate a mechanism by which TLR7 signaling promotes anemia that is of clinical significance in SLE, other rheumatological diseases and chronic viral infections. This work also identifies a previously unknown molecular pathway by which TLR signaling and type I IFN synergize to promote myeloid development from hematopoietic progenitors. CMP were sorted from the bone marrow of wild-type C57BL/6 mice, cultured with SCF+R848 or SCFr+MCSF, and CD11b+F4/80+ macrophages sorted after 5 days, n=3 per group
2016-07-01 | E-GEOD-70520 | biostudies-arrayexpress
Project description:Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.
| S-EPMC6967132 | biostudies-literature
Project description:Early T follicular helper cell activity accelerates HCV-specific B cell expansion
| PRJNA661324 | ENA
Project description:Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia. We developed a model of MDS using zebrafish using knockout of Rps14, the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals develop bone marrow failure with dysplastic features. We conducted an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7. We conducted RNA-seq analysis of both treated and untreated animals to define the mechanism of imiquimod in alleviating anaemia. We find imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation.
2021-03-12 | GSE168727 | GEO