Checkpoints that control B cell development

Melchers, Fritz

doi:10.1172/jci78083

Cited by 241 publications

(262 citation statements)

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“…1D). This ratio likely reflects a dynamic differentiation process in which pro-B cells with two nonproductive rearrangements are negatively selected and those with a productive rearrangement on one allele are positively selected (12). Due in large part to feedback mechanisms from productive V(D)J H rearrangements during pro-B-cell development, ∼40% of splenic B cells displayed V H DJ H rearrangements on both alleles (one productive and one nonproductive) and the remaining 60% had one productive V H DJ H and one DJ H rearrangement (5).…”

Section: Resultsmentioning

confidence: 99%

“…V H -to-DJ H rearrangement is also regulated to generate diverse utilization of the 100s of upstream V H s. Although proximal V H s, notably the most proximal V H (V H 81X), are somewhat overused in pro-B V(D)J rearrangements, the sequestering of the D H s and J H s in a separate chromosomal domain from that of the V H s (8,9), coupled with the phenomenon of locus contraction (10,11), allows even the most distal V H s to be used. Subsequently, the somewhat biased primary V H repertoire in pro-B cells is subjected to cellular selection mechanisms to generate a more normalized primary repertoire in newly generated B cells (12).…”

Section: Significancementioning

confidence: 99%

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Highly sensitive and unbiased approach for elucidating antibody repertoires

Lin

et al. 2016

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

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Developing B lymphocytes undergo V(D)J recombination to assemble germ-line V, D, and J gene segments into exons that encode the antigen-binding variable region of Ig heavy (H) and light (L) chains. IgH and IgL chains associate to form the B-cell receptor (BCR), which, upon antigen binding, activates B cells to secrete BCR as an antibody. Each of the huge number of clonally independent B cells expresses a unique set of IgH and IgL variable regions. The ability of V(D)J recombination to generate vast primary B-cell repertoires results from a combinatorial assortment of large numbers of different V, D, and J segments, coupled with diversification of the junctions between them to generate the complementary determining region 3 (CDR3) for antigen contact. Approaches to evaluate in depth the content of primary antibody repertoires and, ultimately, to study how they are further molded by secondary mutation and affinity maturation processes are of great importance to the B-cell development, vaccine, and antibody fields. We now describe an unbiased, sensitive, and readily accessible assay, referred to as high-throughput genome-wide translocation sequencing-adapted repertoire sequencing (HTGTS-Repseq), to quantify antibody repertoires. HTGTS-Rep-seq quantitatively identifies the vast majority of IgH and IgL V(D)J exons, including their unique CDR3 sequences, from progenitor and mature mouse B lineage cells via the use of specific J primers. HTGTS-Rep-seq also accurately quantifies DJ H intermediates and V(D)J exons in either productive or nonproductive configurations. HTGTS-Rep-seq should be useful for studies of human samples, including clonal B-cell expansions, and also for following antibody affinity maturation processes. 1). In this process, the V, D, and J coding ends are generated as covalent hairpins that must be opened and that are often further processed, before being joined by classical nonhomologous end joining (2). Processing of V, D, J coding ends can involve generation of deletions or insertions of nucleotides at the junction regions (2), including the frequent de novo addition of nucleotides by the terminal deoxynucleotidyl transferase component of the V(D)J recombination process (3). Notably the V(D)J junctional region encodes a major antigen contact region of the antibody variable region, known as complementarity determining region 3 (CDR3), and thus these junctional diversification processes make a huge contribution to antibody diversity.The mouse IgH locus spans 2.7 megabases (Mb). There are 100s of V H s in the several megabase distal portion of the IgH, with the number varying substantially in certain mouse strains (4). The V H s lie ∼100 kb upstream from a 50-kb region containing 13 D H s, which is followed several kilobases downstream by a 2-kb region containing four J H s. The IgH constant region (C H ) exons lie downstream of the J H s. After assembly of a V H DJ H exon, transcription initiates upstream of the V H and terminates downstream of the C H exons, with V(D)J and C H portions being fused...

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Highly sensitive and unbiased approach for elucidating antibody repertoires

Lin

et al. 2016

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

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“…As part of their developmental process, B cells exit the bone marrow at the immature/transitional stage after having successfully completed the rearrangement of both heavy and light chain immunoglobulin (germline) genes to form a fully functional B-cell receptor (BCR). This process involves several checkpoints, designed to evaluate fitness and to eliminate B cells with self-reactive BCRs (reviewed in (2)). In the periphery, immature/transitional B cells develop into naive B cells following further selection, likely in the spleen, a process that is accompanied by a number of distinct phenotypic changes.…”

Section: Populations Of Human B Cells and Their Relevance To Hiv Infementioning

confidence: 99%

B‐cell responses to HIV infection

Moir

Fauci

2017

Immunological Reviews

146

153

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Summary The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV.

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“…B-cells develop in the bone marrow where they pass through a number of checkpoints to become immune-competent cells, ready to pass into the populations of B1 cells in the lung and epithelia, and into conventional B2 cells, or marginal zone B cells, in the spleen [19]. From studies of c-Abl deficient mice, a marked reducing effect on development of early, non-mature B-cells was observed [16,20], suggesting that Arg cannot make up for the effects of c-Abl deficiency in developing B-cells.…”

Section: The Role For Abl Kinases In B-cell Activationmentioning

confidence: 99%

B-cells and Inflammation in the Absence of the Abelson Related Gene (Arg)

Andersson¹,

Jacobsen²

2016

J Clin Cell Immunol

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The Abelson non-receptor tyrosine kinases, c-Abl and Arg, are important regulators of cellular processes in cancer, inflammation, infection, and neuronal dynamics. Recent research on the role for these kinases in processes involving interactions with the cytoskeleton or signaling molecules, may lead to further insight into the pathogenesis of a variety of disorders, including chronic inflammatory diseases. In a mouse model for multiple sclerosis, we recently reported that Arg deficient mice develop T-cell mediated autoimmune neuro-inflammation with the same severity as littermate controls, but display a different B-cell phenotype upon immunization. Here we comment on these results and discuss the role for Arg in B-cell activation and homeostasis.

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Checkpoints that control B cell development

Abstract: R e v i e w S e R i e S : A u t o i m m u n i t y2 2 0 5

Cited by 241 publications

References 100 publications

Highly sensitive and unbiased approach for elucidating antibody repertoires

Highly sensitive and unbiased approach for elucidating antibody repertoires

B‐cell responses to HIV infection

B-cells and Inflammation in the Absence of the Abelson Related Gene (Arg)

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