Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire

Rowland, Sarah L.; Tuttle, Kathryn D.; Torres, Raul M.; Pelanda, Roberta

doi:10.1007/s12026-012-8366-7

Cited by 21 publications

(24 citation statements)

References 98 publications

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“…Interestingly, diminished BM hematopoietic progenitor populations during infection are frequently accompanied by the development of extramedullary hematopoiesis in the spleen and liver (31, 33, 107), which may open niches and resources for the process of granulopoiesis and myelopoiesis. Additionally, the basis for and biological impact of the infection-induced blockade of B cell development in the BM remains unclear (108). In the context of infection, the presence of microbial antigens in the BM while B cells are undergoing selection could lead to the development of B cells that are tolerant to pathogen antigens or even to the deletion of pathogen-specific B cells.…”

Section: Discussionmentioning

confidence: 99%

Infection-Induced Changes in Hematopoiesis

Zaretsky

Engiles²,

Hunter

2014

The Journal of Immunology

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The bone marrow is an important site for the interrelated processes of hematopoiesis, granulopoiesis, erythropoiesis and lymphopoiesis. A wide variety of microbial challenges are associated with profound changes in this compartment that impact on hematopoietic differentiation and mobilization of a variety of cell types. This article reviews some of the key pathways that control BM homeostasis, the infectious and inflammatory processes that affect the BM, and how addressing the knowledge gaps in this area has the potential to widen our comprehension of immune homeostasis.

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Section: Discussionmentioning

confidence: 99%

Infection-Induced Changes in Hematopoiesis

Zaretsky

Engiles²,

Hunter

2014

The Journal of Immunology

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“…Antigen binding is thought to cause the elbow to bend, affecting the initiation of signaling (25,26). However, precisely how bending relates to signaling remains unclear; indeed, the mechanism of signaling itself remains uncertain, with competing proposals disagreeing over whether aggregation or disaggregation of BCRs at the B-cell surface is required (27)(28)(29). Although our findings do not distinguish between these alternatives, it is possible that differences in conformational flexibility afforded by looser or tighter elbow joints could have an impact on signaling by affecting aggregation, disaggregation, or cross-linking.…”

Section: Discussionmentioning

confidence: 99%

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Kaplinsky

Sun

et al. 2014

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

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Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (V H )-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in V H gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use V H genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential V H gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.immunomics | principal component analysis | development T he mature antibody repertoire is shaped by selective forces that influence B-cell survival (1). Comparison of immature and mature B-cell subsets has shown that selection acts specifically on complementarity determining region 3 (CDR3) of the antibody heavy-chain molecule, an antigen-binding region that is a key determinant of antigen specificity (2). On average, mature B-cell subsets express antibodies that have shorter and more negatively charged CDR3s, which is the result of selection against autoreactive and polyreactive B cells (3,4).Each recombined antibody heavy-chain gene is composed of a variable (V H ), diversity (D), and joining (J H ) gene segment. Because the CDR3 region spans the V H -D-J H joint, investigators have asked whether selection might favor B cells whose antibodies use specific V H , D, or J H gene segments. Selection in favor of specific gene segments during B-cell maturation might help to explain the observed maturation-associated changes in CDR3 length and charge, and might suggest a preference for "hard-wired" antigen specificities. Evidence against selection would suggest that differences in CDR3 result exclusively from the nontemplated addition and deletion of nucleotides at the V H -D and D-J H junctions, and therefore that the death of B cells with counterselected CDR3s during maturation is simply the evolutionary cost (3) of maintaining this mechanism of generating antibody diversity.Nearly two decades ago, a low-throughput sequencing study in mice suggested that specific V H gene segments were used at different frequencies by pre-B cells (in which heavy-chain recombination has been completed) and mature B cells in the spleen (5). This observation was interpreted as selection for hard-wired specificities. However, the statistical robustness of this observation was limited by the small number of recombined genes that were sequenced, and although subsequent investigations have detected differences in V H use between pre-B and upstream pro-B cells, they have failed to confirm such differences between pre-B and...

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“…The use of rat IgH C regions should ensure efficient physiological interaction of the translocus-encoded membrane Ig with those endogenous components of the B cell Ag receptor (CD79A and CD79B) and other host Ag receptor-associated molecules that are necessary for efficient B cell activation. The use of rat IgH C regions will also allow physiological interaction with the various host Fc receptors implicated in immune response regulation (49,50).…”

Section: Discussionmentioning

confidence: 99%

High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

Osborn

Avis

et al. 2013

The Journal of Immunology

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Mice transgenic for human Ig loci are an invaluable resource for the production of human Abs. However, such mice often do not yield human mAbs as effectively as conventional mice yield mouse mAbs. Suboptimal efficacy in delivery of human Abs might reflect imperfect interaction between the human membrane IgH chains and the mouse cellular signaling machinery. To obviate this problem, in this study we generated a humanized rat strain (OmniRat) carrying a chimeric human/rat IgH locus (comprising 22 human VHs, all human D and JH segments in natural configuration linked to the rat CH locus) together with fully human IgL loci (12 Vκs linked to Jκ-Cκ and 16 Vλs linked to Jλ-Cλ). The endogenous Ig loci were silenced using designer zinc finger nucleases. Breeding to homozygosity resulted in a novel transgenic rat line exclusively producing chimeric Abs with human idiotypes. B cell recovery was indistinguishable from wild-type animals, and human V(D)J transcripts were highly diverse. Following immunization, the OmniRat strain performed as efficiently as did normal rats in yielding high-affinity serum IgG. mAbs, comprising fully human variable regions with subnanomolar Ag affinity and carrying extensive somatic mutations, are readily obtainable, similarly to conventional mAbs from normal rats.

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Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire

Cited by 21 publications

References 98 publications

Infection-Induced Changes in Hematopoiesis

Infection-Induced Changes in Hematopoiesis

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

High-Affinity IgG Antibodies Develop Naturally in Ig-Knockout Rats Carrying Germline Human IgH/Igκ/Igλ Loci Bearing the Rat CH Region

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