Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases

Cheema, Gurtej S.; Roschke, Viktor; Hilbert, David M.; Stohl, William

doi:10.1002/1529-0131(200106)44:6<1313::aid-art223>3.0.co;2-s

Cited by 739 publications

(527 citation statements)

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“…It has been reported that serum BLyS protein level is more strongly correlated with autoantibodies such as anti-DNA and rheumatoid factor than with total immunoglobulin level. 24 Our present observation may support the role for BLyS in the production of autoantibodies. In addition, a patient with SLE with severe, recurrent sialoadenitis was found to be homozygous for À871T allele (data not shown).…”

Section: Discussionsupporting

confidence: 83%

“…4,11,22 Recently, increase of BLyS level was also reported in the serum or synovial fluid of human SLE, RA and Sjö gren's syndrome. [23][24][25] Serum BLyS level was shown to be correlated with those of anti-dsDNA antibody and rheumatoid factor (RF), 24 although another study failed to show correlation with RF or with anti-Ro, anti-La with BLyS. 25 Moreover, genome-wide screening results suggested linkage of 13q32, where the gene coding for BLyS is located, with human SLE.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 83%

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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“…Thus, it has been shown that mice over-expressing BAFF develop a lupus-like disease [72,[78][79][80]. Moreover, elevated BAFF serum levels have been found in patients with autoimmune diseases in which B cells play an important role [81,82]. Studies aimed at elucidating the mechanisms by which over expression of BAFF can result in loss of B-cell tolerance showed that BAFF over expression does not interfere with the central tolerance program in the bone marrow but rather prevents autoreactive B cells being anergized in the periphery [83].…”

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confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

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B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which autoreactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation.Key words: B cells . Negative selection . Positive selection . Receptor editing . Tolerance Introduction B-cell development, as it takes place in the bone marrow and spleen, can be subdivided into various stages based on the expression of different cell-surface and intra-cellular markers, the cell cycle profile and the rearrangement status of the cell's Ig-heavy (IgH) and Ig-light (IgL) chains [1][2][3][4]. In Fig. 1, the different stages of B-cell development in the bone marrow and spleen and the most important cell-surface markers by which different subpopulations can be distinguished are depicted. Moreover, the stages in which censoring for auto-reactivity takes place are shown in gray.The earliest B-lineage cell type found in the bone marrow is the pro/pre-BI cell. This cell type is characterized by the expression of CD19 and CD117 (c-kit) and the IgH chain loci are in a rearranged D-J configuration [4][5][6]. Under physiological conditions, these cells are already committed to the B-cell lineage. However, their commitment can be reversed by the ablation of the B-cell identity gene Pax5 [7][8][9]. Pro/pre-BI cells are the direct precursors of large pre-BII cells, which have lost CD117 expression and gained the expression of CD25 [3]. At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins . Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16]. These findings will be discussed in the section Large pre-BII cells.Pre-BCR signaling down-modulates transcription of the surrogate light chain genes , and thereby extinguishes its own expression. Upon down-modulation of surface pre-BCR expression, cells stop proliferating and enter the small pre-BII compartment [3]. At this developmental stage, [18][19][20]. It is at this stage of development that, for the first time, cells are censored for t...

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“…Cross-sectional and longitudinal studies have documented increased circulating levels of BAFF in as many as 50% of SLE patients. At the population level, circulating levels of BAFF correlate with circulating levels of anti-double-stranded DNA (anti-dsDNA) antibodies (23)(24)(25) and with clinical disease activity (26).…”

mentioning

confidence: 99%

“…Many patients with rheumatoid arthritis and Sjögren's syndrome also harbor elevated circulating levels of BAFF (23,24,27,28). Indeed, elevated circulating levels of BAFF do not necessarily result in autoimmune disease.…”

mentioning

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

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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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Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases

Cited by 739 publications

References 29 publications

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

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

Tolerance checkpoints in B‐cell development: Johnny B good

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

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