Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin–IgG c... more Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin–IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG–oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-γ and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.
Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded ... more Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.
Journal of Environmental Planning and Management, 2010
Policies such as the US Healthy Forests Restoration Act (HFRA) mandate collaboration in planning ... more Policies such as the US Healthy Forests Restoration Act (HFRA) mandate collaboration in planning to create benefits such as social learning and shared understanding among partners. However, some question the ability of top-down policy to foster successful local collaboration. Through in-depth interviews and document analysis, this paper investigates social learning and transformative learning in three case studies of Community Wildfire Protection Planning (CWPP), a policy-mandated collaboration under HFRA. Not all CWPP groups engaged in social learning. Those that did learned most about organisational priorities and values through communicative learning. Few participants gained new skills or knowledge through instrumental learning. CWPP groups had to commit to learning, but the design of the collaborative-mandate influenced the type of learning that was most likely to occur. This research suggests a potential role for top-down policy in setting the structural context for learning at the local level, but also confirms the importance of collaborative context and process in fostering social learning.
In 2003, the Healthy Forests RestorationAct (HFRA) called for USA communities at risk of wildfire... more In 2003, the Healthy Forests RestorationAct (HFRA) called for USA communities at risk of wildfire to develop Community Wildfire Protection Plans (CWPPs) requiring local, state and federal actors to work together to address hazardous fuels reduction and mitigation efforts. CWPPs can provide the opportunity for local government to influence actions on adjacent public land, by establishing local boundaries of the wildland-urban interface (WUI), the area where urban lands meet or intermix with wildlands. The present paper explores local response to the HFRA and CWPPs in the eastern USA, specifically if and how communities are using the policy incentive to identify the WUI. We conducted document reviews of eastern CWPPs, as well as qualitative analysis of in-depth interviews with participants in four case studies. We found tremendous variation in local response to HFRA, with plans completed at multiple scales and using different planning templates. The WUI policy incentive was not used in all CWPPs, suggesting that the incentive is not as useful in the eastern USA, where public land is less dominant and the perceived fire risk is lower than in the West. Even so, many communities in the East completed CWPPs to improve their wildfire preparedness.
Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin–IgG c... more Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin–IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG–oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-γ and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.
Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded ... more Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.
Journal of Environmental Planning and Management, 2010
Policies such as the US Healthy Forests Restoration Act (HFRA) mandate collaboration in planning ... more Policies such as the US Healthy Forests Restoration Act (HFRA) mandate collaboration in planning to create benefits such as social learning and shared understanding among partners. However, some question the ability of top-down policy to foster successful local collaboration. Through in-depth interviews and document analysis, this paper investigates social learning and transformative learning in three case studies of Community Wildfire Protection Planning (CWPP), a policy-mandated collaboration under HFRA. Not all CWPP groups engaged in social learning. Those that did learned most about organisational priorities and values through communicative learning. Few participants gained new skills or knowledge through instrumental learning. CWPP groups had to commit to learning, but the design of the collaborative-mandate influenced the type of learning that was most likely to occur. This research suggests a potential role for top-down policy in setting the structural context for learning at the local level, but also confirms the importance of collaborative context and process in fostering social learning.
In 2003, the Healthy Forests RestorationAct (HFRA) called for USA communities at risk of wildfire... more In 2003, the Healthy Forests RestorationAct (HFRA) called for USA communities at risk of wildfire to develop Community Wildfire Protection Plans (CWPPs) requiring local, state and federal actors to work together to address hazardous fuels reduction and mitigation efforts. CWPPs can provide the opportunity for local government to influence actions on adjacent public land, by establishing local boundaries of the wildland-urban interface (WUI), the area where urban lands meet or intermix with wildlands. The present paper explores local response to the HFRA and CWPPs in the eastern USA, specifically if and how communities are using the policy incentive to identify the WUI. We conducted document reviews of eastern CWPPs, as well as qualitative analysis of in-depth interviews with participants in four case studies. We found tremendous variation in local response to HFRA, with plans completed at multiple scales and using different planning templates. The WUI policy incentive was not used in all CWPPs, suggesting that the incentive is not as useful in the eastern USA, where public land is less dominant and the perceived fire risk is lower than in the West. Even so, many communities in the East completed CWPPs to improve their wildfire preparedness.
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Papers by rachel Brummel