NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy.

Chimeric antigen receptor (CAR) T-cell therapy was envisioned as a mechanism to re-direct effector T-cells to eliminate tumor cells. CARs are composed of the variable region of an antibody that binds a native cancer antigen coupled to the signaling domain of a TCR and co-stimulatory molecules. Its success and approval by the U.S. Food and Drug Administration for the treatment of B-cell malignancies revolutionized the immunotherapy field, leading to extensive research on its possible application for other cancer types. In this review, we will focus on the evolution of CAR-T cell therapy outlining current technologies as well as major obstacles for its wide application. We will highlight achievements, the efforts to increase efficacy and to evolve into an off-the-shelf treatment, and as a possible future treatment for non-cancer related diseases.

The only current curative treatment for chronic lymphocytic leukemia (CLL) is allogenic hematopoietic stem cell transplantation. Chimeric antigen receptor treatment targeting CD19 for CLL achieved some complete responses, suggesting the need for alternative or combinational therapies to achieve a more robust response. In this work, we evaluated CAR-T cells specific for Siglec-6, an antigen expressed in CLL, as a novel CAR-T cell treatment for CLL. We found that detection of SIGLEC6 mRNA and Siglec-6 protein is highly restricted to placenta and immune cells in other tissues and it is not expressed in hematopoietic stem cells. We generated CAR-T cells specific for Siglec-6 based on the sequence of the fully human anti-Siglec-6 antibody (JML1), which was identified in a CLL patient that was cured after allo-hematopoietic stem cell transplantation (alloHSCT), and observed that it specifically targeted CLL cells in vitro and in a xenograft mouse model. Interestingly, a short hinge region increased the activity of CAR-T cells to target cells expressing higher Siglec-6 levels but similarly targeted CLL cells expressing lower Siglec-6 levels in vitro and in vivo. Our results identify a novel CAR-T cell therapy for CLL and establish Siglec-6 as a possible target for immunotherapy.

Dysregulation of autophagy has been implicated in the development of various disease indications including autoimmune diseases. Here we identified hitherto unsuspected molecular alterations of autophagy occurring at an early stage of the macroautophagy pathway in the salivary glands and spleen of NOD.H-2h4 mice that develop a primary Sjögren's-like syndrome. In this study we investigated the capacity of phosphopeptide P140 to correct immune alteration in NOD.H-2h4 mice and the effect on neogenesis of tertiary lymphoid structures in salivary glands, which is hallmark characteristic of SS. Phosphopeptide P140 known to lower excessive autophagy processes, rescued sick NOD.H-2h4 mice from some autophagy defects and significantly reduced formation of tertiary lymphoid structures in salivary glands. Mechanistically, the frequency of activated CD44high/CD62Llow CD4+ T cell populations was significantly decreased and this reduction was correlated with an increased number of CD44low/CD62Lhigh resting T cells. The CD8 T cell compartment was not affected. P140 down-regulated the maturation and differentiation of B cells into plasma cells, and decreased IgG and autoantibody secretion. It had no effect on germinal centers B cells (B220+ FAS+GL-7+) that are an important compound of the B cell humoral immune response. Together with previous data generated in MRL/lpr mice that develop some features of Sjögren's syndrome associated to other inflammatory and autoimmune defects, our present findings strongly reinforce the potential of autophagy modulators, such as P140, for treating patients with Sjögren's syndrome.

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

CD40/CD40L interactions play a critical role in immunity and autoimmunity. In this study, we sought to understand the requirement for CD40 signaling in the programmed cell death-1 (PD-1) checkpoint and CD28 costimulatory pathways important for maintenance of peripheral tolerance. Blocking either pathway can result in loss of self-tolerance and development of autoimmunity. We found that primary Sjögren’s syndrome (pSS) and autoimmune thyroid diseases (ATDs) that develop spontaneously in CD28-deficient IFN-γ−/− NOD.H-2h4 (CD28−/−) mice required CD40 signaling. Specifically, blockade of CD40L with the anti-CD40L mAb, MR1, inhibited autoantibody production and inflammation in thyroid and salivary gland target tissues. Unexpectedly, however, ATD and pSS in PD-1–deficient IFN-γ−/− NOD.H-2h4 (PD-1−/−) mice developed independently of CD40/CD40L interactions. Treatment with MR1 had no effect and even exacerbated disease development in pSS and ATD, respectively. Most interesting, anti-thyroglobulin and pSS-associated autoantibodies were increased following anti-CD40L treatment, even though MR1 effectively inhibited the spontaneous splenic germinal centers that form in PD-1–deficient mice. Importantly, blockade of the PD-1 pathway by administration of anti–PD-1 mAb in CD28−/− mice recapitulated the PD-1−/− phenotype, significantly impacting the ability of MR1 to suppress ATD and pSS in these mice. These results indicate that there can be different pathways and requirements to autoimmune pathogenesis depending on the availability of specific checkpoint and costimulatory receptors, and an intact PD-1 pathway is apparently required for inhibition of autoimmunity by anti-CD40L.

A growing body of evidence suggests that when B cells are chronically stimulated, a phenotypically unique subset expands. Data suggest that this atypical population contains B cell receptor (BCR) specificities capable of binding the antigen, or sets of antigens that initiated the expansion of these cells. These B cells have been given various names, including double negative B cells, atypical memory B cells, tissue-like memory B cells, or age associated B cells (ABCs). However, on close inspection these reports described B cell subsets that closely resemble B cells we refer to as CD11c+ B cells that often express T-bet. Here we will review the human studies that describe atypical memory B cells and compare and contrast their phenotype and suggested function in health and disease.

Sjögren’s syndrome (SS) is the second most common rheumatic autoimmune disease with a broad spectrum of clinical and serological manifestations and no approved biologics. To better understand the pathogenesis of SS and explore potential soluble biomarkers and therapeutic targets, sera from 109 SS and 50 healthy controls (HC) were examined. Comprehensive profiling was performed using autoantigen and proteomic arrays (UTSW, 95 autoAb’s; RBM’s, 165 proteins; and SOMAscan, 1129 protein). Data showed that autoAb’s against U1sn-RNP-BB’, U1sn-RNP-C and Ribo phaspho protein P1 significantly increased in SS compared to HC (Fold change >1.5 and FDR <0.05) that positively correlate with FOCUS disease score (FDR<0.05). RBM and SOMAscan was highly consistent and detected 123 unique proteins up-or down-regulated in SS compared to HC. Strikingly, 71 were interferon-regulated proteins, with IP10 correlating best with FOCUS score (r=0.65). Pathway and network analysis also confirmed strong activation of type I interferon signaling. Type I interferon signature genes were also observed in salivary gland of the NOD.H-2h4 mice, a model that closely resembles human SS. Additional proteins dysregulated in SS patent sera include the TNF signaling, antimicrobial proteins A2M and B2M, and multiple SLAMF family members, which may shed light on disease mechanisms and novel therapeutic strategies.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease that affects exocrine glands resulting in severe dryness of mucosal surfaces, primarily the mouth and eyes. Female, but not male NOD.H-2h4 mice develop pSS-like manifestations in aged mice. Previously, we have shown that pSS disease that arise in these mice is driven by early peripheral dysregulation that manifests as spontaneous germinal centers (sGC) that are dependent on CD40/CD40L interactions (Mahmoud, T et al., Sci Transl Med 2016). We now examined if other key immune pathways also play a role in pathogenesis of pSS. We found that NOD.H-2h4 mice deficient in either CD28/IFNg or PD1/IFNg developed exacerbated pSS manifestations, compared to the NOD.H-2h4 wild type (WT) mice. As in the WT mice, a single treatment with anti-CD40L mAb in CD28/IFNg−/− mice diminished both sGC and salivary gland tertiary lymphoid structures (TLS). Unexpectedly, however, the aggressive disease noted in PD1/IFNg−/− animals was not similarly inhibited by treatment with anti-CD40L mAb. While anti-CD40L dissolved the sGC, it had no effect on the TLS that develop in the salivary glands of these PD1/IFNg−/− mice. The different results following anti-CD40L mAb treatment in CD28/IFNg−/−vs. PD1/IFNg−/− mice is likely not due to lack of functional Tregs in CD28/IFNg−/− mice, as while transient depletion of Tregs in PD1/IFNg−/− mice resulted increased salivary gland TLS, anti-CD40L still had minimal impact on disease.

Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1(+)CD11c(+)CD122(+)MHC class II+. These cells share characteristics with the NK cell lineage and with cells previously described as IFN-producing killer dendritic cells: 1) they depend on IL-15 and express E4BP4; 2) they are cytotoxic and produce type I and type II IFN upon activation; and 3) they are efficient APCs both through MHC class II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR-15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. Alternatively, low expression of miR-150, miR-181, and miR-744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells.

Several mouse models of SLE, including FcgRIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IKDCs or pre-mNKs in other systems and identified as NK1.1+CD11c+CD122+MHC-II+. These cells belong to the NK cell lineage because they depend on IL15 and express E4BP4. Functionally they are cytotoxic, produce type I and type II interferons upon activation and they are efficient antigen presenting cells both through MHC-II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. Transferring 4 million atypical NKs purified from spleens of SLE-prone mice into WT induces a 2-week-long wave of inflammatory cytokines in the serum, a sustained increase in T cell activation and follicular helper cells for the following months, and a progressive expansion of dendritic cells, monocytes and granulocytes. Furthermore IL15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine producing/antigen-presenting cells that affect the priming and progression of systemic autoimmune disease.

Several mouse models of systemic lupus erythematosus, including FcγRIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IFN-producing killer DCs or pre-mature NKs in other systems. In this study, we show that atypical NKs purified from spleens of systemic lupus erythematosus-prone mice, and identified as NK1.1(+)CD11c(+)CD122(+)MHC-II(+), induce persistent autoimmune disease in an IFN-I- and CD40L-dependent manner when transferred to wild-type mice. A single transfer of 4 × 10(6) NK1.1(+) cells from TLR7tg into wild-type induces a 2-wk-long wave of inflammatory cytokines in the serum; a sustained increase in T cell activation and follicular helper cells for the following months; and a progressive expansion of dendritic cells, monocytes, and granulocytes. Furthermore, IL-15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine-producing/APCs that affect the priming and progression of systemic autoimmune disease.

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single proinflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could be explained by the widespread gene expression dysregulation known as “genomic storm” in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this storm. Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate, but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some proinflammatory molecules, complement components and endogenous “danger” signals. The improved survival in endotoxemia was associated with serum levels of proinflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes.

Event Abstract Back to Event Passive immunotherapy with modified intravenous immunoglobulins (IVIg) improves survival in experimental sepsis by attenuating inflammatory and coagulation pathways Tchavdar L. Vassilev1* 1 Bulgarian Academy of Sciences, Bulgaria T. Vassilev1, I. Djoumerska-Alexieva1, J. Dimitrov2, L. Roumenina2, E. Voynova1, I. Nina Ivanovska1, K. Srini2; 1Stefan Angelov Institute of Microbiology, Sofia, Bulgaria, 2INSERM Unit 872, Paris, France. The exposure of some IgG antibodies to ferrous ions is known to enhance their polyspecificity that includes the ability to bind at least one pro-inflammatory cytokine (J.Biol.Chem.2006:281,439). Sepsis is a medical disaster that responds poorly to available drugs including intravenous immunoglobulin (IVIg) preparations. IVIg, pre-exposed in vitro to Fe(II) ions was used for passive immunotherapy of mice with sepsis induced by the injection of LPS, of live E.coli, of zymosan or by the CLP technique. A single dose of 50 to 250 mg/kg of the modified immunoglobulin preparation, but not of the native, commercially available IVIg significantly increased survival in all sepsis models. The mechanisms of the protective activity of modified IVIg were studied in LPS sepsis. Its therapeutic effect was not due to a more efficient LPS neutralization and was still present when administered 6 hours after LPS. In the treated animals the serum levels of pro-inflammatory cytokines were decreased, IL10 levels were increased, the coagulation abnormality was overcome and the complement exhaustion was prevented. The exposure to Fe(II) ions induced structural changes in the IgG molecules as demonstrated by fluorescent spectroscopy, kinetic and thermodynamic analyses. These changes did not result in their denaturation as the modified preparations still met the strict Pharmacopoeia requirements for IVIg. We suggest that modified IVIg with additionally enhanced polyspecificity, induced by a brief exposure to pro-oxidative ferrous ions, has a clinical potential in sepsis and other variants of the SIRS syndrome (post-traumatic, in avian flu, etc.). Acknowledgements This work was supported by the Bulgarian and Swiss National Science Funds, the Pasteur Institute (Paris) and the NATO Science for Peace Program. Keywords: passive immunotherapy, Systemic Inflammatory Response Syndrome, Sepsis, IVIgG, Experimental models Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Vassilev TL (2013). Passive immunotherapy with modified intravenous immunoglobulins (IVIg) improves survival in experimental sepsis by attenuating inflammatory and coagulation pathways. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00698 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Tchavdar L Vassilev, Bulgarian Academy of Sciences, Sofia, Bulgaria, vassilev@microbio.bas.bg Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tchavdar L Vassilev Google Tchavdar L Vassilev Google Scholar Tchavdar L Vassilev PubMed Tchavdar L Vassilev Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2(k/k) protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH(-/-) mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity.

Interferon-producing killer dendritic cells (IKDC) are a recently discovered innate cell subset that shares morphological and functional characteristics of NK and DC cells. The aim of this study is to investigate the role of IKDCs in terms of initiating autoimmune disease. We found that these cells are expanded in mice with multiple copies of the TLR7 gene and that the number of these cells correlates with disease activity. Expansion of this population is due to their cell intrinsic sensitivity to TLR7 stimulation. IKDCs are dependent of IL15, produce high levels of IFN type I and type II after stimulation with a TLR7 agonist, are capable of MHC class II antigen presentation, and can cross-present antigen to CD8 cells. Adoptive transfer of IKDC to wild type mice causes activation of naïve T cells, expansion of inflammatory monocyte populations and IFN-dependent CD8 activation. IKDC adoptive transfer also induces elevated inflammatory cytokine and IgG levels in the serum. We found that IFN type I and CD40/CD40L interactions are essential for the inflammatory effect of these cells. Taken together these results uncover a potential role for this cell populaiton in the development of autoimmune pathologies.

Abstract Interferon-producing killer dendritic cells (IKDCs) share functional characteristics with NK cells and DCs. We investigated their role in the autoimmune disease developed by transgenic mice that overexpress TLR7 (TLR7tg). We determined that a cell population resembling IKDCs expands in TLR7tg mice through their intrinsic sensitivity to TLR7 stimulation. We confirmed that they are bona fide NK cells by their ability to kill cells lacking MHC I molecules in vitro. These cells were also able to present antigen to naïve T cells in in vitro assays. Adoptive transfer of IKDCs isolated from TLR7tg mice into wild type mice induced priming and activation of naïve T cells. In vitro stimulation with TLR7 agonists of IKDCs derived from TLR7tg resulted in the production of TNFa, MCP-1, IFNa and high levels of IL-10. We also tested the requirement of cytokines that are essential for NK cell development. We found that the expansion of IKDCs in TLR7tg mice was IL15 dependent but IL18 independent. We observed that lack of IL15 reduced many pro-inflammatory subsets (Ly6C+monocytes, granulocytes, DCs and memory T cells) and delayed the development of glomerulonephritis in TLR7tg mice. These results reveal expansion of IKDCs in autoimmune inflammatory conditions and suggest a dual role for these cells in both the priming of autoreactive T cells and the release of inflammatory cytokines.

A novel approach for the selective silencing of targeted autoreactive B lymphocytes is reviewed that mimics the physiological mechanisms for suppressing B cell activity. It is based on the use of bi- or tri-specific chimeric antibodies that cross-link BCRs with a pre-selected antigen-binding specificity with one or more inhibitory types of receptors on the surface of the same disease-associated B lymphocyte. The effect of these engineered antibodies was proved to be specific as they only suppressed the production of the targeted pathological antibodies while sparing those with other specificities. The administration of the chimeric molecules to lupus-prone MRL/lpr mice resulted in decreased levels of disease-associated IgG autoantibodies and of proteinuria, in the prevention of cutaneous lesions, in decreased sizes of the lymphoid organs and in prolonged survival. These results prove that it is indeed possible to selectively silence unwanted B lymphocytes as well as to significantly delay the natural course of a spontaneous antibody-mediated autoimmune disease.

IgG molecules are exposed on a regular basis to acidic conditions during immunoaffinity purification procedures, as well as during the production of some therapeutic immunoglobulin preparations. This exposure is known to induce in them an antigen-binding polyreactivity. The molecular mechanisms and the possible biological significance of this phenomenon remain, however, poorly understood. In addition to the previously reported ability of these modified IgG antibodies to interact with a large panel of self-antigens, enhanced binding to non-self-antigens (bacterial), an increased ability to engage in F(ab')(2)/F(ab')(2) (idiotype/anti-idiotype) interactions and an increased functional antigen-binding affinity are reported here. The newly acquired 'induced polyreactivity' of low-pH buffer-exposed IgG is related to structural changes in the immunoglobulin molecules, and is at least partly attributable to the enhanced role of the hydrophobic effect in their interactions with antigen. Our results suggest that data from many previous studies on monoclonal and polyclonal IgG antibodies purified by low-pH buffer elution from protein A or protein G immunoaffinity columns should be reconsidered, as the procedure itself may have dramatically affected their antigen-binding behavior and biological activity. Low-pH buffer-treated pooled therapeutic immunoglobulins acquire novel beneficial properties, as passive immunotherapy with the pH 4.0 buffer-exposed, but not with the native therapeutic intravenous immunoglobulin preparation, improves the survival of mice with bacterial lipopolysaccharide-induced septic shock.

B cells represent an important link between the adaptive and innate immune systems as they express both antigen-specific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self-specific cells are eliminated from the mature B-cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events but are also influenced by TLR-dependent signals from the innate immune system. Additionally, B-cell-intrinsic and extrinsic TLR signaling are critical for inflammatory events required for the clearance of microbial infections. Factors secreted by TLR-activated macrophages or dendritic cells directly influence the fate of protective and autoreactive B cells. Additionally, naive and memory B cells respond differentially to TLR ligands, as do different B-cell subsets. We review here recent literature describing intrinsic and extrinsic effects of TLR stimulation on the fate of B cells, with particular attention to autoimmune diseases.