Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire

Cyster, Jason G.; Hartley, Samantha; Goodnow, Christopher C.

doi:10.1038/371389a0

Cited by 516 publications

(446 citation statements)

References 43 publications

Supporting

Mentioning

420

Contrasting

Unclassified

Order By: Relevance

Section: Resultsmentioning

confidence: 99%

“…Under these conditions, self-reactive B lymphocytes would not only be exposed to higher concentrations of Ag, but also to an environment where they must compete with non-autoreactive B lymphocytes for survival factors (e.g. BAFF) and physiological niches [19][20][21].To examine B-lymphocyte tolerance to b-cell Ag within an environment where self-reactive clones comprise only a minor fraction of the total repertoire, NOD.insHEL and B6.insHEL mice as well as their non-Tg littermates were lethally irradiated and reconstituted with a mixture of BM cells from IgHEL-Tg and non-Tg donors of the same genetic background. Chimeras reconstituted with IgHEL to non-Tg BM ratios of 7:3 and 1:1 for B6 and NOD background mice, respectively, had equivalent proportions of HEL-specific B lymphocytes (mostly ranging between 10 and 20%) in BM, spleen and PLN 6 wk post-reconstitution, irrespective of whether recipients expressed insHEL or were non-Tg ( Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

et al. 2010

View full text Add to dashboard Cite

Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to b-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).Key words: Anergy . B lymphocytes . Self-tolerance . Transgenic mice . Type 1 diabetes Supporting Information available online Introduction B lymphocytes make important contributions to pancreatic b-cell pathogenesis in the NOD mouse model of type 1 diabetes (T1D): first, through secretion of auto-Ab which enhance capture of auto-Ag by DC and NK cells; second, and more importantly, through their action as efficient APC capable of activating and expanding b-cell-reactive CD4 1 T cells [1]. Both pathogenic functions depend on the production of self-reactive Ig by B lymphocytes [2,3], indicating that defective B-lymphocyte self-tolerance is a mechanism that contributes to susceptibility to this disease. Several lines of evidence also point to a pathogenic role for B lymphocytes in human T1D. For example, a recently completed clinical trial has demonstrated that treatment of newly diagnosed T1D patients with the B lymphocyte depleting Ab Rituximab resulted in markedly improved preservation of b-cell function [4]. Furthermore, the fact that the presence and spectrum of b-cell-specific auto-Ab have predictive value in determining T1D susceptibility is consistent with the impairment of B-lymphocyte tolerance in patients developing disease [5]. Studies of models in which BCR Tg specific for natural or neo-self-Ag are expressed in the germ-line of non-autoimmune prone mouse strains have revealed a range of self-tolerance mechanisms in the B-lymphocyte compartment [6]. Which of these mechanisms operate in particular situations is determined by the avidity of the Tg BCR for its cognate self-Ag, i.e. a combination of Ag valency, concentration and receptor affinity [7]. Self-reactive B lymphocytes that encounter cognate Ag with high avidity modify their specificity b...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

et al. 2010

View full text Add to dashboard Cite

show abstract

“…3,4 Additionally, increased levels of serum BAFF have been detected in patients with autoimmune disorders including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, Wegener granulomatosis, and adult MG. 4,8,[20][21][22] Thus, BAFF appears to protect autoreactive B cells from apoptosis and contribute to the development of autoimmune diseases. 9,23,24 On the other hand, circulating BAFF kinetics have not been reported in childhood-onset MG. In the present study, serum BAFF levels were significantly higher before IST in children with ocular MG than in controls; these decreased after IST.…”

Section: Discussionmentioning

confidence: 99%

An Increase in Circulating B Cell–Activating Factor in Childhood-Onset Ocular Myasthenia Gravis

Motobayashi

Inaba

Nishimura

et al. 2015

Pediatric Neurology

View full text Add to dashboard Cite

Myasthenia gravis is a B cellemediated autoimmune disorder. The pathophysiology of childhoodonset ocular myasthenia gravis remains unclear. We investigated serum B celleactivating factor levels and other immunological parameters in child patients with ocular myasthenia gravis. METHODS: Blood samples were obtained from 9 children with ocular myasthenia gravis and 20 age-matched controls. We assayed serum concentrations of B celleactivating factor, anti-acetylcholine receptor antibody titers, 7 types of cytokines (interleukins-2, -4, -6, -10, and -17A; interferon-g; tumor necrosis factor-a) as well as the percentages of peripheral blood CD4þ, CD8þ, and CD19þ cells. RESULTS: Serum B celleactivating factor levels were significantly higher before immunosuppressive therapy in patients with childhood-onset ocular myasthenia gravis than in controls and decreased after immunosuppressive therapy. A significant positive correlation was observed between serum B celleactivating factor levels and anti-acetylcholine receptor antibody titers in patients with myasthenia gravis. Serum B celleactivating factor concentrations did not correlate with the percentages of CD4þ, CD8þ, and CD19þ cells or the CD4þ/CD8þ ratio. No significant differences were observed in the levels of the 7 different types of cytokines examined, including interleukin-17A, between preimmunosuppressive therapy myasthenia gravis patients and controls. CONCLUSIONS: Circulating B celleactivating factor may play a key role in the pathophysiology of childhood-onset ocular myasthenia gravis.

show abstract

“…Thus, comparisons of turnover rates in mixtures of BCR Tg and non-Tg cells revealed that a mature B cell's lifespan is not absolute, but instead depends on the clonotypic identities of co-existing competitors. Cyster et al showed similar specificity-based competition as cells navigate TR stages [17]. In these studies, B cells bearing an autoreactive BCR transgene persisted in the absence of competition, but were excluded from splenic follicles and died rapidly when competing with B cells of normal receptor diversity.…”

Section: B Cells Undergo Both Negative and Positive Selection As Theymentioning

confidence: 91%

BAFF and the plasticity of peripheral B cell tolerance

Stadanlick

Cancro

2008

Current Opinion in Immunology

View full text Add to dashboard Cite

BAFF and its receptors play a crucial role in peripheral B cell selection and survival, by dictating the set point for mature primary B cell numbers and adjusting thresholds for specificity-based selection during transitional differentiation. The notion that selective stringency can be varied on the basis of homeostatic demands reveals a previously unappreciated degree of plasticity in B cell tolerance, and suggests a paradigm that unites peripheral negative and positive selection with the maintenance of mature B cell numbers. Moreover, it implies a developmentally regulated coupling of BCR and BAFF receptors at the transitional stages and beyond.

show abstract

Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire

Cited by 516 publications

References 43 publications

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

Enhanced responsiveness to T‐cell help causes loss of B‐lymphocyte tolerance to a β‐cell neo‐self‐antigen in type 1 diabetes prone NOD mice

An Increase in Circulating B Cell–Activating Factor in Childhood-Onset Ocular Myasthenia Gravis

BAFF and the plasticity of peripheral B cell tolerance

Contact Info

Product

Resources

About