The regulation of autoreactive B cells during innate immune responses (original) (raw)
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Dendritic Cell and Macrophage-Mediated Tolerance in Lupus-Prone Mice
During infection, immune cells respond to polyclonal activators, like bacterial and viral antigens, through innate immune responses. Therefore, mechanisms to regulate the activation of autoreactive B cells during polyclonal activation are necessary to prevent autoimmunity. Previous studies into the mechanisms of B cell tolerance have focused on B cell Receptor (BCR)-mediated regulation of autoreactive or chronically antigen-experienced B cells. However, the regulation of chronically antigen-experienced B cells during polyclonal activation is less understood. We recently identified a novel mechanism of tolerance wherein DCs and MΦs repress Ig secretion by autoreactive B cells. Polyclonal activators through Toll-like Receptors (TLRs) induce DCs and MΦs to secrete soluble factors (IL-6, sCD40L, and TNFα) that differentially regulate naïve and chronically antigen-experienced B cells. IL-6, sCD40L, and TNFα selectively repress chronically stimulated autoreactive B cells while having no e...
Defective in Repressing Immunoglobulin Dendritic Cells from Lupus-Prone Mice Are
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Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. We recently showed that during innate immune responses, secretion of IL-6 by dendritic cells (DCs) maintained autoreactive B cells in an unresponsive state. In this study, we describe that TLR4-activated DCs from lupus-prone mice are defective in repressing autoantibody secretion, coincident with diminished IL-6 secretion. Reduced secretion of IL-6 by MRL/lpr DCs reflected diminished synthesis and failure to sustain IL-6 mRNA production. This occurred coincident with lack of NF-B and AP-1 DNA binding and failure to sustain IB␣ phosphorylation. Analysis of individual mice showed that some animals partially repressed Ig secretion despite reduced levels of IL-6. This suggests that in addition to IL-6, DCs secrete other soluble factor(s) that regulate autoreactive B cells. Collectively, the data show that MRL/lpr mice are defective in DC/IL-6-mediated tolerance, but that some individuals maintain the ability to repress autoantibody secretion by an alternative mechanism.
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The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) mice results in the secretion of autoantibodies. TC dendritic cells (DCs) enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6) control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1(+) cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1(+) cells in the marginal zone correlated with a Type I Interferon (IFN) signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administ...
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Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand (CD40L) as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and nontransgenic B cells but not by transiently stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus-prone MRL/lpr mice. Compared with C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing immunoglobulin secreti...
Dysfunctional B cells in systemic lupus erythematosus
Autoimmunity Reviews, 2004
The classical view of B cells in the biology of autoimmune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing antibodies (Ab) is far from being complete. Indeed, studies over the last decade suggest that B cells have extraordinarily diverse functions within the immune system other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating dentritic cells (DC) and T cell subsets function through cytokine production, and in activation of T cells. Receptor editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune diseases, including systemic lupus erythematosus (SLE), highlight their pivotal function. Transgenic (Tg) animal models have shown that sensitivity of B cells to B cell Ag receptor (BCR) cross-linking is correlated to autoimmunity. Indeed, negative signaling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domain-containing protein tyrosine phosphatase-1 (SHP-1) has also been documented. In fact, we have now reached a newer area whereby B cells returned as an important contributor to autoimmune disorders. D
Autoimmunity, 2010
It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high circulating autoantibody titers and immunecomplex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through costimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells.
Do follicular dendritic cells regulate lupus-specific B cells?
Molecular Immunology, 2014
The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies.
Immunologic Research
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by increased autoantibody production that leads to multiple tissue injuries. Dendritic cells (DCs) are important orchestrators of immune responses and key components in fine-tuning the balance between tolerance and immunity. However, their role in autoimmune disorders such as SLE remains uncertain. We analyzed the contribution of DCs in triggering SLE by adoptively transferring splenic DCs from aged autoimmune [NZB×NZW]F1 (BWF1) mice to young healthy BWF1 mice. We observed that the transfer of DCs from autoimmune mice to pre-autoimmune mice induced high autoantibody titers in the serum of recipient mice. Moreover, autoimmune DCs from aged BWF1 mice were crucial for the expansion and differentiation of plasmablasts and CD5 + B cells or B1-like cells in the peripheral blood, and spleen of recipient BWF1 mice, a phenomenon that is observed in autoimmune BWF1 mice. On the other hand, DCs from aged BWF1 mice participated in the expansion and differentiation of DCs and IFN-γ-producing T cells. These results reveal that DCs from autoimmune BWF1 mice exhibit functional and phenotypic characteristics that allow them to trigger B cell hyperactivation, as well as DC and T cell expansion and differentiation, thereby promoting an exacerbated humoral response in lupus-prone mice.
Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases
Autoimmunity Reviews, 2015
Dendritic cells (DCs) play a key role in the activation of the immune response against pathogens, as well as in the modulation of peripheral tolerance to self-antigens (Ags). Furthermore, an imbalance in the activating/inhibitory receptors expressed on the surface of DCs has been linked to increased susceptibility to develop autoimmune diseases underscoring their immunogenicity potential. It has been described that modulation of activating or inhibitory molecules expressed by DCs, such as CD86, TLRs, PDL-1 and FcγRs, can define the immunogenic phenotype. On the other hand, T cell tolerance can be achieved by tolerogenic DCs, which have the capacity of blocking undesired autoimmune responses in several experimental models, mainly by inducing T cell anergy, expansion of regulatory T cells and limiting B cell responses. Due to the lack of specific therapies to treat autoimmune disorders and the tolerogenic capacity of DCs shown in experimental autoimmune disease models, autologous tolDCs are a potential therapeutic strategy for fine-tuning the immune system and reestablishing tolerance in human autoimmune diseases. New advances in the role of DCs in systemic lupus erythematosus (SLE) pathogenesis and the identification of pathogenic self-Ags may favor the development of novel tolDC based therapies with a major clinical impact. In this review, we discuss recent data relative to the role of DCs in systemic autoimmune pathogenesis and their use as a therapy to restore tolerance.
2009
DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds) double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigennaïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies.