Unmethylated CpG‐containing DNA plays a critical role in immunity via the augmentation of Th1 but suppression of Th2 T cell responses. We describe here that CpG motifs also redirect isotype ...production by murine B cells to "Th1‐like" Ig isotypes (IgG2a, IgG2b, and IgG3) while suppressing Th2 isotypes (IgG1 and IgE). Using genetically mutant B cells, we find that the IgG2a, IgG2b and IgG3 isotypes are transcriptionally regulated via the promotion of class‐switching, in a manner critically dependent upon TLR9 and MyD88. Thus, CpG DNA redirects Ig isotype production by regulating the specificity of class‐switch recombination.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The IgG2a Ig subclass plays a critical role in the pathogenesis of humoral autoimmunity and protection against pathogens. The T‐box transcription factor T‐bet has been implicated as a critical ...mediator of class‐switch recombination (CSR) to IgG2a, but its relative importance to this process in various immune contexts remains incompletely defined. We report here that, surprisingly, T‐bet is selectively required for IgG2a class switching in response to T‐independent, but not T‐dependent, stimuli. Specifically, T‐dependent signaling through CD40, in contrast to T‐independent signaling via lipopolysaccharide, can bypass a requirement for T‐bet in IgG2a germline transcription and subsequent isotype switching. In contrast, T‐bet‐deficient B cells undergo class switching to other IgG isotypes at least as well as wild‐type counterparts. Thus, T‐bet is a class‐specific regulator of IgG CSR and represents a unique regulator of B cell differentiation by participating in a T‐independent, but not a T‐dependent, activation pathway. T‐bet‐deficient B cells therefore represent a novel paradigm by which to investigate the regulation of humoral immune responses.
This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-gamma. B cells produce IFN-gamma in response to ...IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN-gamma-producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-gammaR and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-gammaR-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-gamma, indicating that additional transcriptional activators must be coupled to the IFN-gammaR in B cells. Finally, we show that although IL-12/IL-18 or IFN-gamma-producing Th1 cells are required to initiate transcription of the IFN-gamma gene in B cells, sustained expression of IFN-gamma and T-bet by B cells is dependent on an IFN-gamma/IFN-gammaR/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN-gamma-producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.
NFAT transcription factors play critical roles in gene transcription during immune responses. To investigate further the two most prominent NFAT family members, NFATc1 and NFATc2, we generated mice ...bearing lymphoid systems devoid of both. Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions, including Th cytokine production, surface effector molecule expression, and cytolytic activity. Nevertheless, doubly deficient B cells were hyperactivated, as evidenced by extremely elevated serum IgG1 and IgE, as well as plasma cell expansion and infiltration of end organs. Thus, in T cells, NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation, while in B cells, NFATs regulate both normal homeostasis and differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, ...and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.
Forkhead transcription factors play key roles in the regulation of immune responses. Here, we identify a role for one member of this family, Foxj1, in the regulation of T cell activation and ...autoreactivity. Foxj1 deficiency resulted in multiorgan systemic inflammation, exaggerated Th1 cytokine production, and T cell proliferation in autologous mixed lymphocyte reactions. Foxj1 suppressed NF-κB transcription activity in vitro, and Foxj1-deficient T cells possessed increased NF-κB activity in vivo, correlating with the ability of Foxj1 to regulate IκB proteins, particularly IκBβ. Thus, Foxj1 likely modulates inflammatory reactions and prevents autoimmunity by antagonizing proinflammatory transcriptional activities. These results suggest a potentially general role for forkhead genes in the enforcement of lymphocyte quiescence.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
7.
SH2D1A regulates T-dependent humoral autoimmunity Hron, Jonathan D; Caplan, Liron; Gerth, Andrea J ...
The Journal of experimental medicine,
2004-Jul-19, 2004-07-19, 20040719, Volume:
200, Issue:
2
Journal Article
Peer reviewed
Open access
The signaling lymphocytic activation molecule (SLAM)/CD150 family includes a family of chromosome 1-encoded cell surface molecules with costimulatory functions mediated in part by the adaptor protein ...SH2D1A (SLAM-associated protein, SAP). Deficiency in SH2D1A protects mice from an experimental model of lupus, including the development of hypergammaglobulinemia, autoantibodies including anti-double stranded DNA, and renal disease. This protection did not reflect grossly defective T or B cell function per se because SH2D1A-deficient mice were susceptible to experimental autoimmune encephalomyelitis, a T cell-dependent disease, and they were capable of mounting normal T-independent antigen-specific immunoglobulin responses. Instead, T-dependent antibody responses were impaired in SH2D1A-deficient mice, reflecting defective germinal center formation. These findings demonstrate a specific role for the SLAM-SH2D1A system in the regulation of T-dependent humoral immune responses, implicating members of the CD150-SH2D1A family as targets in the pathogenesis and therapy of antibody-mediated autoimmune and allergic diseases.
Abstract
To study the role of the direct and indirect pathways in achieving tolerance, we used genetically altered mouse strains in two ways: 1) MHC class II-deficient mice were used as donors of ...skin and cardiac grafts to eliminate the direct CD4+ T cell response, and 2) B6 II−4+ mice, which are MHC class II-deficient mice expressing an MHC class II transgene only on thymic epithelium, were used as recipients of normal grafts. These mice cannot mount an indirect response. Eliminating the indirect pathway actually made it more difficult to achieve prolonged allograft survival when we used costimulatory blockade than when both pathways were available. Costimulatory blockade was ineffective even when CD4+ T cells from normal animals were transferred into recipients that lacked MHC class II molecules. These results suggest that an active CD4+ response through the indirect pathway is necessary for costimulatory blockade to be effective in prolonging allograft survival.
Implantable Defibrillator Lead Failure. Introduction: Patients with implantable cardioverter defibrillators (ICD) critically depend on correct functioning of their system. The aim of this study was ...to determine the incidence and clinical presentation of transvenous ICD lead failures during long‐term follow‐up.
Methods and Results: The study group consisted of 261 consecutive patients who received Medtronic right ventricular polyurethane transvenous leads (models 6884, 6966, 6936) between 1990 and 1998 as part of an abdominal
(n = 70)
or pectoral
(n = 191)
ICD system. During mean follow‐up of
4.0 ± 2.6 years
, 31 patients (12%) developed a lead‐related sensing failure with oversensing of artifacts. All failures except two were compatible with an insulation defect and occurred late after ICD placement (
6.0 ± 1.8 years
after implant). Lead survival decreased from 98% at 4‐year follow‐up to only 62% at 8‐year follow‐up. Lead survival was not related to patient age, sex, venous lead implantation route, or device implantation site. In 26 (87%) of 31 patients, a sensing defect resulted in inappropriate detection of ventricular fibrillation and subsequent delivery of
3 ± 3
(range 1–11) inappropriate shocks in 19 (61%) of 31 patients. Device interrogation showed artifacts classified as nonsustained ventricular tachycardia in 21 patients,
40 ± 43 days
before clinically relevant failure of the system. One patient with a subclavian crush syndrome required resuscitation because of undersensing of true ventricular fibrillation.
Conclusion: Transvenous polyurethane ICD leads showed a high rate of lead insulation failure late after implantation with frequent inappropriate shock deliveries. Close follow‐up is mandatory in patients with these leads. Automated device control features with patient alert function integrated into new devices may contribute to early detection of lead failure.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 (DKO). DKO mice exhibit increased lymphoproliferation, decreased ...activation-induced cell death, and impaired induction of FasL. The transcription factors Egr2 and Egr3 are potent activators of FasL expression. Here we find that Egr2 and Egr3 are NFAT target genes. Activation of FasL occurs via the NFAT-dependent induction of Egr3, as demonstrated by the ability of exogenously provided NFATp to restore Egr-dependent FasL promoter activity in DKO lymph node cells. Further, Egr3 expression is enriched in Th1 cells, suggesting a molecular basis for the known preferential expression of FasL in the Th1 versus Th2 subset.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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