B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies

Bhat, Premila; Radhakrishnan, Jai

doi:10.1038/sj.ki.5002663

Cited by 54 publications

(54 citation statements)

References 82 publications

(80 reference statements)

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“…1 Immunosuppressive therapy with cyclophosphamide or mycophenolate mofetil has been shown to improve the renal outcome of lupus nephritis considerably. 1,2 Although a mainstay of therapy, these treatments are associated with serious side effects. 1,2 Therefore, more specific therapeutic approaches to this systemic disease are being intensively evaluated.…”

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confidence: 99%

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Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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The B-cell survival factors APRIL and BLyS are important for B-cell maturation and activation and contribute to human autoimmune diseases. Interference with B-cell function by targeting these molecules is currently being investigated in large clinical trials for systemic lupus erythematosus. The local expression patterns of APRIL and BLyS have not been investigated in detail in kidneys with lupus nephritis. We studied the mRNA expression of APRIL, BLyS, and the corresponding receptors BCMA, TACI, and BAFF-R in microdissected human biopsies with proliferative lupus nephritis (n ¼ 25) and compared it with pretransplant biopsies of living donors (n ¼ 9). APRIL and BLyS mRNA levels were significantly higher in glomeruli of patients with proliferative lupus nephritis (12-and 30-fold, respectively). Tubulointerstitial expression of APRIL, BLyS, BCMA, and TACI was also significantly elevated. To localize the respective proteins in the kidney, APRIL, BLyS, and BAFF-R were studied by immunohistochemistry in renal biopsies with proliferative (n ¼ 21) or membranous (n ¼ 8) lupus nephritis. APRIL was prominently expressed in glomeruli with proliferative, but not membranous, lupus nephritis. The staining pattern was consistent with mesangial cells. A prominent accumulation of CD68-positive cells was present in glomeruli in association with APRIL expression. APRIL, BLyS, and BAFF-R were also expressed in interstitial inflammatory cell accumulation. This is the first study, which details local expression of APRIL and BLyS in glomeruli and tubulointerstitium of human proliferative lupus nephritis. This information might help define intrarenal effects of APRIL and BLyS inhibition in human lupus nephritis.

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confidence: 99%

“…1,2 Although a mainstay of therapy, these treatments are associated with serious side effects. 1,2 Therefore, more specific therapeutic approaches to this systemic disease are being intensively evaluated.…”

mentioning

confidence: 99%

Intrarenal production of B-cell survival factors in human lupus nephritis

et al. 2011

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“…The loss of B-cell tolerance is welldocumented to increase the incidence of SLE disease in mice and humans, and the effectiveness of anti-B-cell therapies in the treatment of SLE further demonstrates their crucial involvement (1)(2)(3). B cells can contribute to SLE by their ability to present antigens to autoreactive T cells, activate inflammatory responses by secretion of cytokines and chemokines, and, especially, secrete autoantibodies.…”

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confidence: 99%

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Savitsky

Yanai

Tamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Tolllike receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5 −/− mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the γ2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.autoimmunity | B lymphocytes | TLR signaling

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“…B cells play a significant role in the pathogenesis of autoimmune diseases including SLE (26). As new bioengineered monoclonal anti-B cell antibodies have been developed, there has been significant interest in the past decade in studying the effects of specific B cell-depleting agents for the treatment of SLE.…”

Section: Lupus Nephritismentioning

confidence: 99%

Novel B Cell Therapeutic Targets in Transplantation and Immune-Mediated Glomerular Diseases

Vincenti

Cohen

Appel

2010

Clinical Journal of the American Society of Nephrology

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B cells and antibodies play an important role in the alloresponse to renal grafts as well as in immune-mediated glomerular diseases. In transplantation, greater recognition and improved diagnosis of antibody-mediated rejection have been a catalyst to the introduction of newer drugs and regimens that target B cells, plasma cells, and donor-specific antibodies to improve the outcome associated with antibody-mediated rejection. In immune-mediated renal disease, novel and more selective B cell therapies are gradually modifying the traditional therapeutic approach that consists of steroids and other immunosuppressants. A new era of selective and more effective immunosuppression agents that target the humoral response is finally emerging in transplantation and renal diseases.Clin J Am Soc Nephrol 5: 142-151, 2010. doi: 10.2215/CJN.04580709 B cells and antibodies play a critical role both in the alloresponse after renal transplantation and in immune-mediated glomerular diseases. In transplantation, B cells, in addition to their role in the humoral response to alloantigens, act as efficient antigen-presenting cells and thus participate in the activation of T cells (1). The development of more sensitive solid phase-based serologic assays for detecting anti-HLA antibodies and the routine use of C4d (a complement fragment considered a marker of antibody deposition) staining in kidney biopsies have led to better recognition of the importance of both acute and chronic antibody-mediated rejection on graft outcome (2,3). The role of B cells in generating and perpetuating alloantibody production has provided the rationale for the use of anti-B cell therapies in desensitization of highly sensitized patients, decreasing the titer of donor-specific antibodies (DSA) and reversing acute antibody-mediated rejection after transplantation (4).In glomerular diseases that are suspected to be mediated by B cells and antibodies, novel and more selective targeting of B cells is gradually altering the traditional therapeutic approach that consists of steroids and other immunosuppressive drugs (Table 1). In this review, we summarize clinical trials in renal transplantation and immune-mediated glomerular diseases using novel therapies that target B cells and antibodies. Novel Anti-B Cell TherapiesThe anti-B cell agent most frequently used, albeit off-label, in renal transplantation and in glomerular diseases is rituximab. Rituximab, a chimeric monoclonal antibody (mAb) that is approved for use in B cell lymphoma and rheumatoid arthritis, binds to the CD20 receptor of B cells and depletes them through complement-dependent cytotoxicity, antibody-dependent cytotoxicity, and stimulation of B cell apoptosis (4,5). B cell depletion with rituximab may persist for Ն6 mo and is followed by a repopulation of B cells that are deficient of the CD27 receptor, a marker for memory B cells. Repopulation of naive B cells and the persistence of normal Ig levels impart to rituximab both its efficacy and safety (5). For decreasing the potential immunogenicity tha...

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B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies

Cited by 54 publications

References 82 publications

Intrarenal production of B-cell survival factors in human lupus nephritis

Intrarenal production of B-cell survival factors in human lupus nephritis

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Novel B Cell Therapeutic Targets in Transplantation and Immune-Mediated Glomerular Diseases

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