A Fail-safe Mechanism for Negative Selection of Isotype-switched B Cell Precursors Is Regulated by the Fas/FasL Pathway

Seagal, Jane; Edry, Efrat; Zohar, Keren; Leider, Nira; Benny, Ofra; Machluf, Marcelle; Melamed, Doron

doi:10.1084/jem.20030357

Cited by 35 publications

(45 citation statements)

References 53 publications

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“…Another mechanism of negative selection is apoptosis, mediated via Fas/ Fas ligand interaction. We have recently shown that the Fas pathway is important for blocking the development of autoimmune isotype-switched B cell precursors in the BM [54,61]. Since stimulation with CpG DNA protects B cells against Fas-mediated apoptosis by downregulating Fas expression [62], it may allow isotypeswitched B cell precursors to escape this deletion and to construct an autoimmune repertoire.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, most of the antibodies produced by BM B cells are low-affinity and nonpathogenic IgM isotype [3]. However, studies have shown that developing B cells can undergo somatic hypermutation and class switch recombination [54,55], which suggests a mechanism by which high-affinity effector antibody can be generated. (iii) An alternative possibility is that activation occurs outside the BM.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody-forming plasma cells were detected by ELISPOT assay, as described previously [54]. In brief, BM culture cells, stimulated with CpG DNA for 48-72 h, were washed and recultured for 14-16 h on the top of membranes coated with anti-j and anti-k antibodies (Southern Biotechnology Associates).…”

Section: Elispotmentioning

confidence: 99%

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CpG DNA stimulates autoreactive immature B cells in the bone marrow

2007

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Polyclonal activation of developing B cells is an injurious process, because most of these cells are nontolerant and express autoreactive receptors. CpG DNA is a polyclonal activator of mature B cells, but its effect on developing B cells is unclear. We tested whether developing, nontolerant B cells are responsive to mitogenic stimulation by CpG DNA and whether such a stimulus can interfere with the establishment of central tolerance. We found that developing B cells express Toll-like receptor 9 and undergo a polyclonal response to CpG DNA stimulation, as revealed by proliferation and differentiation to antibody-producing cells. In vitro and ex vivo experiments revealed that stimulation with CpG DNA protects immature B cells from negative selection imposed by apoptosis and receptor editing and results in the production of autoantibodies. Finally, we found that in vivo administration of CpG DNA activates immature B cells in the bone marrow and suppresses the expression of recombinationactivating genes in a mouse model of central tolerance and receptor editing. These results suggest that mitogenic signals provided by CpG DNA stimulate nontolerant immature B cells in the bone marrow and have the potential to interfere with central tolerance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CpG DNA stimulates autoreactive immature B cells in the bone marrow

2007

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“…Alternatively, IgG/IgA-secreting CD19 high CD45R Ϫ/low spleen cells could be a physiological correlate of the distinct developmental pathway to IgG-and IgA-switched B cells described in Ig-deficient mice, which is established at the level of B cell precursors and is T independent (43,44). Although not induced by intentional immunization, the IgG/IgA production of the CD19 high CD45R Ϫ/low B cells might be the result of regular microbial encounters (45), particularly, intestinal bacteria, but these cells also contributed importantly to the early postnatal IgG production, which is known to be developmentally controlled and (foreign) Ag independent (46).…”

Section: Cd45rmentioning

confidence: 99%

A Population of CD19highCD45R−/lowCD21low B Lymphocytes Poised for Spontaneous Secretion of IgG and IgA Antibodies

Andrés

Cortegano

Serrano

et al. 2007

The Journal of Immunology

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Ab responses to selected Ags are produced by discrete B cell populations whose presence and functional relevance vary along the ontogeny. The earliest B lineage-restricted precursors in gestational day 11 mouse embryos display the CD19+CD45R/B220− phenotype. Phenotypically identical cells persist throughout gestation and in postnatal life, in parallel to the later-arising, CD19+CD45R+ B cells. Very early after birth, the CD19+CD45R− B cell subset included high frequencies of spontaneously Ig-secreting cells. In the adult spleen, a small subset of CD19highCD45R−/lowIgM+/−IgD−CD21/Cr2−/low cells, which was detected in perifollicular areas, displayed genetic and phenotypical traits of highly differentiated B cells, and was enriched in IgG- and IgA-secreting plasma cells. In vitro differentiation and in vivo adoptive transfer experiments of multipotent hemopoietic progenitors revealed that these CD19highCD45R−/low B cells were preferentially regenerated by embryo-, but not by adult bone marrow-, derived progenitors, except when the latter were inoculated into newborn mice. Both the early ontogenical emergence and the natural production of serum Igs, are shared features of this CD19highCD45R−/low B cell population with innate-like B lymphocytes such as B1 and marginal zone B cells, and suggest that the new population might be related to that category.

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“…Serum IgG is also present in CD40/CD40L-deficient mice (38) and in patients with X-linked hyper-IgM syndrome (39). CSR can occur in responses to thymusindependent Ags (40) and TLR ligands (18,41) and during B cell lymphogenesis independently of T cells (42,43). Furthermore, both CSR and somatic hypermutation can occur outside of germinal centers (44).…”

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Antibody Repertoire Development in Fetal and Neonatal Piglets. XVII. IgG Subclass Transcription Revisited with Emphasis on New IgG3

Butler

Wertz

2006

The Journal of Immunology

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Fetal piglets offer an in vivo model for determining whether Ag-independent IgG subclass transcription proceeds in a manner that differs from subclass transcription in pigs exposed to environmental Ags and TLR ligands. Our data from ≃12,000 Cγ clones from >60 piglets provide the first report on the relative usage of all known porcine Cγ genes in fetal and young pigs. Studies revealed that among the six Cγ genes, allelic variants of IgG1 comprised 50–80% of the repertoire, and IgG2 alleles comprised <10% in nearly all tissues. However, relative transcription of allelic variants of IgG1 randomly deviate from the 1:1 ratio expected in heterozygotes. Most surprising was the finding that IgG3 accounted for half of all Cγ transcripts in the ileal Peyer’s patches (IPPs) and mesenteric lymph nodes but on average only ≃5% of the clones from the thymus, tonsil, spleen, peripheral blood, and bone marrow of newborns. Lymphoid tissues from late term fetuses revealed a similar expression pattern. Except for IgG3 in the IPPs and mesenteric lymph nodes, no stochastic pattern of Cγ expression during development was seen in animals from mid-gestation through 5 mo. The age and tissue dependence of IgG3 transcription paralleled the developmental persistence of the IPP, and its near disappearance corresponds to the diversification of the preimmune VDJ repertoire in young piglets. We hypothesize that long-hinged porcine IgG3 may be important in preadaptive responses to T cell-independent Ags similar to those described for its murine namesake.

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A Fail-safe Mechanism for Negative Selection of Isotype-switched B Cell Precursors Is Regulated by the Fas/FasL Pathway

Cited by 35 publications

References 53 publications

CpG DNA stimulates autoreactive immature B cells in the bone marrow

CpG DNA stimulates autoreactive immature B cells in the bone marrow

A Population of CD19highCD45R−/lowCD21low B Lymphocytes Poised for Spontaneous Secretion of IgG and IgA Antibodies

Antibody Repertoire Development in Fetal and Neonatal Piglets. XVII. IgG Subclass Transcription Revisited with Emphasis on New IgG3

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