Baff Binds to the Tumor Necrosis Factor Receptor–Like Molecule B Cell Maturation Antigen and Is Important for Maintaining the Peripheral B Cell Population

Thompson, Jeffrey S.; Schneider, Pascal; Kalled, Susan L.; Wang, Lichun; Lefèvre, Eric A.; Cachero, Teresa G.; Mackay, Fabienne; Bixler, Sarah A.; Zafari, Mohammad; Liu, Zhongying; Woodcock, Stephen A.; Qian, Fang; Batten, Marcel; Madry, Christine; Richard, Yolande; Benjamin, Christopher D.; Browning, Jeffrey L.; Tsapis, Andréas; Tschopp, Jürg; Ambrose, Christine

doi:10.1084/jem.192.1.129

Cited by 362 publications

(289 citation statements)

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“…Assessments were performed at baseline and weeks 2 (study day 8 in this study), 4,8,12,16,20, and 26 (the treatment period). An additional followup assessment was carried out 13 weeks after the final dose of the study drug was administered (week 38).…”

Section: Methodsmentioning

confidence: 99%

“…APRIL promotes B cell and plasma cell activation and survival and plays important roles in immunoglobulin class switching and antigen presentation (9)(10)(11). BLyS promotes B cell survival and maturation (12)(13)(14)(15). APRIL and BLyS form homotrimers and heterotrimers, which can be present at elevated levels in the serum of patients with autoimmune diseases including RA, Sjögren's syndrome, and systemic lupus erythematosus (SLE) (16)(17)(18).…”

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confidence: 99%

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Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Genovese¹,

Kinnman²,

Bourdonnaye³

et al. 2011

Arthritis & Rheumatism

115

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Objective. To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.Methods. The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. Results.No statistically significant differences were observed in the efficacy end points at week 26 (P ‫؍‬ 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.Conclusion. This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Genovese¹,

Kinnman²,

Bourdonnaye³

et al. 2011

Arthritis & Rheumatism

115

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“…[1][2][3][4][5] BLyS is a potent B cell co-stimulator, and promotes B cell differentiation, proliferation and survival. 1,2,[6][7][8][9][10] In BLyS deficient mice, the number of B cells, serum IgG and IgM levels were decreased, and B cell development was blocked at the transitional T1 stage. 11 BLyS and a proliferation-inducing ligand (APRIL) bind to B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), 4,12,13 which belong to the tumor necrosis factor receptor superfamily and are mainly expressed in B cells.…”

Section: Introductionmentioning

confidence: 99%

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

et al. 2002

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Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in humans and in animal models. This study was conducted to screen for polymorphisms of human BLYS, and to examine whether they are involved in the genetic susceptibility to human SLE and RA. A systematic polymorphism screening was performed in the coding region, 5 0 and 3 0 untranslated regions, and promoter region of human BLYS. Association of the detected polymorphisms with SLE and RA was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy individuals, using the case-control approach. Four single nucleotide polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare nonsynonymous substitution (Ala105Thr) in the coding region were detected. The BLYS SNPs were found to form three common haplotypes. Significant association with the susceptibility to SLE or RA was not observed. However, a tendency for the increase of À871T/T genotype was observed in SLE patients with anti-Sm antibody (P ¼ 0.082). BLYS mRNA level was significantly elevated in the monocytes from individuals carrying À871T (P ¼ 0.010). In addition, although statistically not significant, 105Thr allele was slightly increased in patients with RA compared with controls (P ¼ 0.058). Characterizing the functional and clinical significance of these new SNPs requires further study.

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“…BAFF plays a vital role in B cell survival (11)(12)(13)(14)(15)(16)(17). BAFF-deficient mice display substantial (albeit incomplete) reductions in mature B cells and in baseline serum Ig levels and Ig responses to T cell-dependent and T cell-independent antigens (18)(19)(20).…”

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confidence: 99%

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

Stohl¹,

Xu²,

Kim³

et al. 2005

Arthritis & Rheumatism

Self Cite

104

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Objective. To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis.Methods. We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology.Results Conclusion. BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.Renal involvement in patients with systemic lupus erythematosus (SLE) is clinically apparent in ϳ50% of cases and leads to considerable morbidity. The vast majority of SLE patients with renal involvement develop increased proteinuria, sometimes to degrees great enough to adversely affect systemic fluid balance and hemodynamics (nephrotic syndrome). Glomerular disease is widely believed to be the major contributor to this increased proteinuria. Indeed, the World Health Organization (WHO) classification of lupus nephritis focuses almost entirely on glomerular lesions, with little attention to tubular, interstitial, or vascular lesions. Accordingly, factors which promote glomerular disease in SLE may be vital to the pathogenesis of lupus nephritis.

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Baff Binds to the Tumor Necrosis Factor Receptor–Like Molecule B Cell Maturation Antigen and Is Important for Maintaining the Peripheral B Cell Population

Cited by 362 publications

References 26 publications

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

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