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I24 Innate and adaptive immunity in host-microbiota mutualism
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Abstract / Cytokine 59 (2012) 491–496
I22 Regulatory B cells in healthy and in patients with sle C. Mauri, Medicine, University College London, London, United Kingdom Recent advances have demonstrated the existence of an IL-10-producing B cell subset with regulatory capacity named (Bregs). In mice, Bregs have been shown to restrain the severity of autoimmune disorders and contribute to the development of infection and cancer. In humans, CD19+CD24hiCD38hiC D1dhiB cells have been ascribed with regulatory function. We have shown that this B cell subset inhibits the activation of T helper (Th)1 and Th17 responses whilst supporting the differentiation of FoxP3+ Tregs. We have shown that, in addition to regulating the differentiation of CD4+ T cells, Bregs are essential for the maintenance of CD1d-restricted invariant natural killer T (iNKT) cells in healthy individuals but fail to exert the same effect in SLE patients. iNKT cells play a potent immune-regulatory role functioning in both innate and adaptive immunity. Defective B cell-mediated stimulation of iNKT cells in SLE was associated with rapid CD1d recycling leading to reduced CD1d surface expression on B cells from SLE patients, a defect that could be recapitulated in B cells from healthy individuals after simultaneous stimulation with interferon-a (IFN-a) and anti-immunoglobulin (Ig). iNKT cell homeostasis was restored in SLE patients responding to B cell depletion therapy, upon normalization of CD1d levels in repopulated CD19+CD24hiCD38hiC D1dhi Bregs.
I24 Innate and adaptive immunity in host-microbiota mutualism A. Macpherson, Visceral Surgery and Medicine, Gastroenterology, University Hospital Inselspital, Bern, Switzerland The mammalian intestine harbours one of the most dense microbial communities on the planet. Experiments that compare germ-free and colonised mice show that the mucosal immune system is highly adapted to the presence of the commensal microbiota. To induce mucosal immune responses to commensal intestinal bacteria, small numbers of commensals are sampled by dendritic cells (DC) at the epithelial surface. These locally induce IgA B cells through T-dependent and T-independent pathways, but they do not penetrate beyond the mesenteric lymph nodes to reach systemic secondary lymphoid structures. Experiments where colonisation of the intestine has been uncoupled from mucosal immune induction with live commensals show that the resulting response is very long-lived unless another response is induced by stimulation with a different commensal microbe. Adaptive immunity in pathogen-free experimental mice is normally ignorant of intestinal commensals. Nevertheless, there is a threshold set by innate immunity, which can strengthen the epithelial barrier and allow clearance of small numbers of commensals that escape the permeability barrier or are released by ,commensal loaded’ DC. Defective innate clearance is compensated functionally by increased systemic adaptive responses to intestinal commensals, showing a continuum between innate and adaptive immunity.
Disclosure of interest: None declared. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.312 http://dx.doi.org/10.1016/j.cyto.2012.06.314
I23 Atacicept: Phase 2 development candidate for the therapy of systemic autoimmune syndrome H. Hess, Immunology, Merck KGAA, Darmstadt, Germany Atacicept is a novel immunomodulator with B cell targeting properties and currently the advanced clinical development. The primary disease indication for atacicept is SLE, a systemic autoimmune disease with a major involvement of B cells in its etiopathogenesis. Atacicept is a fusion protein comprised of the extracellular domain of the TNF receptor superfamiliy member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) and the Fc portion of human IgG1. TACI is expressed on mature B lymphocytes and first detectable on T1 transitional B cells. Expression increases in marginal zone B cells and is finally down-regulated at the plasma cell stage. Two other TNF homologs, BLyS (B lymphocyte stimulator, a.k.a. ‘‘BAFF”, or B cell activating factor of the TNF family) and APRIL (A proliferation-inducing ligand), bind with high affinity and specificity to TACI. BLyS enhances the survival and proliferation of transitional B cells. Aside from direct effects on B cells, BLyS and APRIL as well as homo and hetero oligomers are part of the fascinating complexity of immune cell regulation that we are just teetering on the brink of understanding. Despite a well-defined scientific rationale and convincing pre-clinical efficacy profiles, clinical development of atacicept in various indications has passed turbulent times. This presentation is a synopsis of B cell survival factors in health and disease and describing clinical development paths of a molecule that significantly impacts on B cells homeostasis and perhaps beyond. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.313
I25 Intracellular metabolic pathways control immune tolerance G. Matarese, Medicine, Salerno University, Salerno, Italy The field that links immunity and metabolism is rapidly expanding. Apparently non-immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation suggesting that metabolic alterations can be induced by or be consequence of an altered self-immune tolerance. In this context, a key role is played by signalling systems acting as metabolic ‘‘sensors” linking energy/nutritional status to regulatory T (Treg) cell functions such s the adipose tissue derived hormone, leptin. We propose that a dynamic/oscillatory activity of intracellular metabolism might represent a shift in understanding the molecular mechanisms governing Treg cell tolerance. In particular, the decision between Treg cell proliferation and hyporesponsiveness arises from their ability to probe the extracellular milieu and, modulating the metabolic intracellular signalling, to determine different qualitative and quantitative functional outcomes. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.315
Abstract / Cytokine 59 (2012) 491–496
I22 Regulatory B cells in healthy and in patients with sle C. Mauri, Medicine, University College London, London, United Kingdom Recent advances have demonstrated the existence of an IL-10-producing B cell subset with regulatory capacity named (Bregs). In mice, Bregs have been shown to restrain the severity of autoimmune disorders and contribute to the development of infection and cancer. In humans, CD19+CD24hiCD38hiC D1dhiB cells have been ascribed with regulatory function. We have shown that this B cell subset inhibits the activation of T helper (Th)1 and Th17 responses whilst supporting the differentiation of FoxP3+ Tregs. We have shown that, in addition to regulating the differentiation of CD4+ T cells, Bregs are essential for the maintenance of CD1d-restricted invariant natural killer T (iNKT) cells in healthy individuals but fail to exert the same effect in SLE patients. iNKT cells play a potent immune-regulatory role functioning in both innate and adaptive immunity. Defective B cell-mediated stimulation of iNKT cells in SLE was associated with rapid CD1d recycling leading to reduced CD1d surface expression on B cells from SLE patients, a defect that could be recapitulated in B cells from healthy individuals after simultaneous stimulation with interferon-a (IFN-a) and anti-immunoglobulin (Ig). iNKT cell homeostasis was restored in SLE patients responding to B cell depletion therapy, upon normalization of CD1d levels in repopulated CD19+CD24hiCD38hiC D1dhi Bregs.
I24 Innate and adaptive immunity in host-microbiota mutualism A. Macpherson, Visceral Surgery and Medicine, Gastroenterology, University Hospital Inselspital, Bern, Switzerland The mammalian intestine harbours one of the most dense microbial communities on the planet. Experiments that compare germ-free and colonised mice show that the mucosal immune system is highly adapted to the presence of the commensal microbiota. To induce mucosal immune responses to commensal intestinal bacteria, small numbers of commensals are sampled by dendritic cells (DC) at the epithelial surface. These locally induce IgA B cells through T-dependent and T-independent pathways, but they do not penetrate beyond the mesenteric lymph nodes to reach systemic secondary lymphoid structures. Experiments where colonisation of the intestine has been uncoupled from mucosal immune induction with live commensals show that the resulting response is very long-lived unless another response is induced by stimulation with a different commensal microbe. Adaptive immunity in pathogen-free experimental mice is normally ignorant of intestinal commensals. Nevertheless, there is a threshold set by innate immunity, which can strengthen the epithelial barrier and allow clearance of small numbers of commensals that escape the permeability barrier or are released by ,commensal loaded’ DC. Defective innate clearance is compensated functionally by increased systemic adaptive responses to intestinal commensals, showing a continuum between innate and adaptive immunity.
Disclosure of interest: None declared. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.312 http://dx.doi.org/10.1016/j.cyto.2012.06.314
I23 Atacicept: Phase 2 development candidate for the therapy of systemic autoimmune syndrome H. Hess, Immunology, Merck KGAA, Darmstadt, Germany Atacicept is a novel immunomodulator with B cell targeting properties and currently the advanced clinical development. The primary disease indication for atacicept is SLE, a systemic autoimmune disease with a major involvement of B cells in its etiopathogenesis. Atacicept is a fusion protein comprised of the extracellular domain of the TNF receptor superfamiliy member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) and the Fc portion of human IgG1. TACI is expressed on mature B lymphocytes and first detectable on T1 transitional B cells. Expression increases in marginal zone B cells and is finally down-regulated at the plasma cell stage. Two other TNF homologs, BLyS (B lymphocyte stimulator, a.k.a. ‘‘BAFF”, or B cell activating factor of the TNF family) and APRIL (A proliferation-inducing ligand), bind with high affinity and specificity to TACI. BLyS enhances the survival and proliferation of transitional B cells. Aside from direct effects on B cells, BLyS and APRIL as well as homo and hetero oligomers are part of the fascinating complexity of immune cell regulation that we are just teetering on the brink of understanding. Despite a well-defined scientific rationale and convincing pre-clinical efficacy profiles, clinical development of atacicept in various indications has passed turbulent times. This presentation is a synopsis of B cell survival factors in health and disease and describing clinical development paths of a molecule that significantly impacts on B cells homeostasis and perhaps beyond. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.313
I25 Intracellular metabolic pathways control immune tolerance G. Matarese, Medicine, Salerno University, Salerno, Italy The field that links immunity and metabolism is rapidly expanding. Apparently non-immunological disorders such as obesity and type 2 diabetes have been linked to immune dysregulation suggesting that metabolic alterations can be induced by or be consequence of an altered self-immune tolerance. In this context, a key role is played by signalling systems acting as metabolic ‘‘sensors” linking energy/nutritional status to regulatory T (Treg) cell functions such s the adipose tissue derived hormone, leptin. We propose that a dynamic/oscillatory activity of intracellular metabolism might represent a shift in understanding the molecular mechanisms governing Treg cell tolerance. In particular, the decision between Treg cell proliferation and hyporesponsiveness arises from their ability to probe the extracellular milieu and, modulating the metabolic intracellular signalling, to determine different qualitative and quantitative functional outcomes. Disclosure of interest: None declared. http://dx.doi.org/10.1016/j.cyto.2012.06.315