B Lymphocytes: Development, Tolerance, and Their Role in Autoimmunity—Focus on Systemic Lupus Erythematosus

Tobón, Gabriel J.; Izquierdo, Jorge Hernán; Cañas, Carlos A.

doi:10.1155/2013/827254

Cited by 64 publications

(54 citation statements)

References 126 publications

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“…Bone marrow is crucial for myelopoiesis and B cell generation, and is associated with maturation of T lymphocytes to a lesser degree [28,29]. In CLP-induced sepsis, there is a significant decline of the percentage of Grl + -myeloid cells in the bone marrow, accounting for four-fifth of the decrease in viable cells yield in the marrow.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model

Zhao¹,

Alam²,

Liu³

et al. 2015

CMM

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Abstract:Background: Seven isoforms of histone deacetylase Class III have been reported -Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand-puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model. Methods:Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 μM) for 6 hours.Results: AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262).Conclusion: Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated "cytokine storm", coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model

Zhao¹,

Alam²,

Liu³

et al. 2015

CMM

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“…Abnormal B cell activation contributes to SLE pathogenesis through both antibody-dependent and independent fashions [1, 54, 79–81]. In addition to the impaired B cell survival, B cell-specific deletion of PKK also resulted in significant reduction of activated CD4 + T cells in Sle mice (Figure 5), and PKK-deficient Sle B cells fail to efficiently up-regulate the critical T cell-costimulatory molecules CD80 and CD86 in response to BCR stimulation (Figure 6C).…”

Section: Discussionmentioning

confidence: 99%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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“…Repeat renal biopsies, had they been done, might have demonstrated histological remission at 1 year which we have suggested may precede biochemical remission which can take a long time as suggested by these data. What is clinically important is that despite the failure of these two rituximab randomised controlled trials to achieve their primary endpoint, many clinicians continue to use rituximab in daily practice, based on their personal experience, the large case series and registry data, and the long-term outcome data in the LUNAR trial [1,14,25]. This contrasts with the clinical reality for belimumab, where despite the positive trial data there has been relatively slow uptake of use of this drug in lupus, possibly because of difficulty in knowing which patients would benefit most and due to the lack of data on use in LN.…”

Section: Rituximab In Lnmentioning

confidence: 99%

“…B cells play a pivotal role in the development and maintenance of autoimmune disease [1]. Systematic lupus erythematosus (SLE) is a prototypic autoimmune disorder associated with a diverse array of pathogenic autoantibodies directed towards cytoplasmic and nuclear cell compartments.…”

Section: Introductionmentioning

confidence: 99%

Rituximab in Systemic Lupus Erythematosus and Lupus Nephritis

Beckwith

Lightstone²

2014

Nephron Clin Pract

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Treatment options for systemic lupus erythematosus (SLE) and lupus nephritis (LN) have high associated morbidity and mortality. Side effects, particularly from long-term corticosteroid usage, limit patient adherence, with subsequent impacts on treatment efficacy. In addition, a subset of patients with SLE/LN fails to respond to current standard immunotherapy. There is an urgent need to develop steroid-sparing treatment regimens as well as novel therapies for the management of refractory disease. Rituximab is a chimeric mouse/human monoclonal antibody directed against the B cell CD20 receptor. It has been used in the treatment of non-Hodgkin's lymphoma for over 30 years and has an excellent safety profile. Recent work has demonstrated a role for B cell depletion therapy in the management of autoimmune disease, and the efficacy of rituximab in many observational studies in SLE and LN has been noted. Unfortunately, two large randomised controlled trials evaluating rituximab for the treatment of renal and non-renal lupus failed to meet their primary endpoints. Reasons for this have been discussed extensively within the medical community with a general consensus that trial design (steroid use, trial size and endpoints used) was the principal reason for the failures. Despite the lack of trial evidence, clinical experience means many physicians firmly believe in the value of rituximab in SLE/LN treatment and have continued to use it in their clinical practice. Recent work has demonstrated the efficacy of rituximab as a steroid-sparing agent and as an alternative therapeutic option for refractory SLE/LN. There are two further rituximab randomised controlled trials planned/started in LN - one using a steroid-minimising regimen with rituximab for induction and one evaluating rituximab for LN refractory to 6 months standard of care treatment. Rituximab remains a problematic drug in lupus and LN - it is a biologically plausible agent with a huge amount of supportive anecdotal clinical data. Yet the completed trials have been negative to date despite clinical experience strongly suggesting efficacy. It is hoped that the two new trials will determine the role for rituximab, at least in LN.

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B Lymphocytes: Development, Tolerance, and Their Role in Autoimmunity—Focus on Systemic Lupus Erythematosus

Cited by 64 publications

References 126 publications

Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model

Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model

PKK deficiency in B cells prevents lupus development in Sle lupus mice

Rituximab in Systemic Lupus Erythematosus and Lupus Nephritis

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