Match!

Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development

Published on Sep 15, 2001in Journal of Clinical Investigation12.282
· DOI :10.1172/JCI13051
Eric Meffre34
Estimated H-index: 34
,
Michèle Milili19
Estimated H-index: 19
+ 3 AuthorsClaudine Schiff27
Estimated H-index: 27
Abstract
Developing B cells must pass a series of checkpoints that are regulated by membrane-bound Igμ through the Igα-Igβ signal transducers. To determine how Igμ expression affects B cell development and Ab selection in humans we analyzed Ig gene rearrangements in pro-B cells from two patients who are unable to produce Igμ proteins. We find that Igμ expression does not affect VH, D, or JH segment usage and is not required for human Igκ and Igλ recombination or expression. However, the heavy and light chains found in pro-B cells differed from those in peripheral B cells in that they showed unusually long CDR3s. In addition, the Igκ repertoire in Igμ-deficient pro-B cells was skewed to downstream Jκs and upstream Vκs, consistent with persistent secondary V(D)J rearrangements. Thus, Igμ expression is not required for secondary V(D)J recombination in pro-B cells. However, B cell receptor expression shapes the Ab repertoire in humans and is essential for selection against Ab’s with long CDR3s.
  • References (83)
  • Citations (106)
📖 Papers frequently viewed together
1,422 Citations
200541.06Science
13 Authors (Barton F. Haynes, ..., S. Munir Alam)
598 Citations
152 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References83
Newest
#1Eric C. B. Milner (UW: University of Washington)H-Index: 24
#2Wendy O. Hufnagle (UW: University of Washington)H-Index: 4
Last. Catherine Alexander (UW: University of Washington)H-Index: 1
view all 5 authors...
47 CitationsSource
#1Rafael CasellasH-Index: 37
#2Tien-An Yang ShihH-Index: 3
Last. Michel C. NussenzweigH-Index: 136
view all 7 authors...
Receptor editing, clonal deletion, and anergy are the mechanisms by which B cells maintain tolerance to self antigens. To determine the extent to which receptor editing shapes the normal antibody repertoire, we generated an immunoglobulin κ polymorphism that facilitates the detection of editing of immunoglobulin light chains in vivo. We found that B cells are targeted for editing during a 2-hour delay in development at the pre-BII cell stage, and that about 25% of all antibody molecules are prod...
297 CitationsSource
#1Cornelia MundtH-Index: 7
#2Steve LicenceH-Index: 10
Last. I MÃ¥rtenssonH-Index: 21
view all 5 authors...
The pre-B cell receptor consists of immunoglobulin (Ig) μ heavy chains and surrogate light chain, i.e., the VpreB and λ5 proteins. To analyze the role of the two VpreB proteins, mice lacking the VpreB1 and VpreB2 genes were generated. VpreB1−/−VpreB2−/− mice were impaired in their B cell development at the transition from pre-BI to large pre-BII cells. Pre-BII cells did not expand by proliferation, consequently 40-fold less small pre-BII and immature B cells were found in bone marrow, and the ge...
96 CitationsSource
#1Amy ReichlinH-Index: 7
#2Yun HuH-Index: 3
Last. Michel C. NussenzweigH-Index: 136
view all 8 authors...
The B cell receptor (BCR) regulates B cell development and function through immunoglobulin (Ig)α and Igβ, a pair of membrane-bound Ig superfamily proteins, each of which contains a single cytoplasmic immunoreceptor tyrosine activation motif (ITAM). To determine the function of Igβ, we produced mice that carry a deletion of the cytoplasmic domain of Igβ (IgβΔC mice) and compared them to mice that carry a similar mutation in Igα (MB1ΔC, herein referred to as IgαΔC mice). IgβΔC mice differ from Igα...
109 CitationsSource
#1Claudine Schiff (HHMI: Howard Hughes Medical Institute)H-Index: 1
#2Bénédicte Lemmers (HHMI: Howard Hughes Medical Institute)H-Index: 2
Last. Eric Meffre (HHMI: Howard Hughes Medical Institute)H-Index: 19
view all 5 authors...
Since the initial report of X-linked agammaglobulinemia by Bruton, numerous autosomal primary immune deficiencies affecting early B-cell differentiation have been described in humans. The identification of these autosomal mutations has been facilitated by phenotype comparison with knockout mice. In mice, defects in B-cell development have been observed after disruption of genes encoding transcription factors, the interleukin-7 pathways as well as structural or signaling components of the pre-B-c...
23 CitationsSource
#1H Schroederjr (UAB: University of Alabama at Birmingham)H-Index: 43
#2Perry M. Kirkham (UAB: University of Alabama at Birmingham)H-Index: 11
It is becoming more apparent that some B cells do not carry the same antigen receptors throughout their life. B cells that have edited their receptors have now been found in humans as rare cells that accumulate in arthritic joints.
6 CitationsSource
#1Eric Meffre (Rockefeller University)H-Index: 19
#2Eric Davis (NIH: National Institutes of Health)H-Index: 4
Last. Michel C. Nussenzweig (Rockefeller University)H-Index: 136
view all 8 authors...
Immunoglobulin gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy or receptor editing normally silence B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene “knock-ins”. However, it has been difficult to identify cells that have edited receptors in unmanipulated mice and humans. To try to identify such cells we isolated and characterized B cells that coexp...
106 CitationsSource
Abstract Seventy percent of peripheral immature conventional (B2) B cells fail to develop into mature B cells. The nature of this cell loss has not been characterized; the process that governs which immature B cells develop into long-lived peripheral B cells could be either stochastic or selective. Here, we demonstrate that this step is in fact selective, in that the fate of an immature B cell is highly dependent on its Ig receptor specificity. A significant skewing of the B cell receptor repert...
148 CitationsSource
Mutations in Btk, μ heavy chain, or the surrogate light chain account for 85–90% of patients with early onset hypogammaglobulinemia and absent B cells. The nature of the defect in the remaining patients is unknown. We screened 25 such patients for mutations in genes encoding components of the pre–B-cell receptor (pre-BCR) complex. A 2-year-old girl was found to have a homozygous splice defect in Igα, a transmembrane protein that forms part of the Igα/Igβ signal-transduction module of the pre-BCR...
163 CitationsSource
#1Tamotsu Yamagami (BII: Basel Institute for Immunology)H-Index: 20
#2Edwin ten Boekel (BII: Basel Institute for Immunology)H-Index: 12
Last. Fritz Melchers (BII: Basel Institute for Immunology)H-Index: 72
view all 6 authors...
Abstract Single cell PCR assays have been further developed that detect over 80% of all VκJκ, VκRS, and VλJλ rearrangements at efficiencies between 70% and 90%. These IgL chain gene rearrangement assays were used with small pre-BII cells that develop in comparably high numbers in the bone marrow of wild-type, Cκ-deficient, and JCκ-deficient homozygous and heterozygous mice. In all of these mice, only 15%–25% of all small pre-BII cells carry VλJλ rearrangements. These results confirm that λL chai...
32 CitationsSource
Cited By106
Newest
#1Ming Tian (Harvard University)H-Index: 17
#2Kelly McGovern (Harvard University)H-Index: 1
Last. Nicole Manfredonia (Harvard University)
view all 15 authors...
HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1–infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models ...
Source
#1Akihiro Hoshino (Tokyo Medical and Dental University)H-Index: 9
#2Akira Nishimura (Tokyo Medical and Dental University)H-Index: 1
Last. Taizo Wada (Kanazawa University)H-Index: 14
view all 14 authors...
1 CitationsSource
#1Todd BradleyH-Index: 13
Last. Robert Parks (Duke University)H-Index: 36
view all 30 authors...
Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX4...
1 CitationsSource
#1Ming Tian (Boston Children's Hospital)H-Index: 17
#2Kelly McGovern (Boston Children's Hospital)
Last. Frederick W. Alt (Boston Children's Hospital)H-Index: 157
view all 15 authors...
HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1 infected individuals, bnAbs evolve from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar process of antibody maturation. One way to test vaccination strategies is to immunize mouse models that express human bnAb precursors. Such immunization experiments can assess whether the vaccine can convert precursor antibody into bn...
Source
#1Nitya S. Ramadoss (Stanford University)H-Index: 7
#2William A. Robinson (Stanford University)H-Index: 79
B cells can assume protective or pathogenic roles in immune-mediated diseases (IMDs). Analysis of the B cell receptor (BCR) repertoires in six IMDs provides insights into the diversity of B cell repertoires across diseases as well as into potential pathological mechanisms and the effects of different treatments.
Source
#1Marjolein WentinkH-Index: 8
#2Tomas KalinaH-Index: 22
Last. M.E.L. van der BurgH-Index: 59
view all 11 authors...
B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Appropriate signalling via this pre-BCR complex is followed by rearrangement of the Ig light chain genes, resulting in the format...
Source
#1Kevin S. Cashman (Emory University)H-Index: 3
#2Scott A. Jenks (Emory University)H-Index: 12
Last. Iñaki Sanz (Emory University)H-Index: 6
view all 9 authors...
The maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess. Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical i...
Source
#1Joel Finney (Duke University)H-Index: 2
#2Akiko Watanabe (Duke University)H-Index: 7
Last. Masayuki Kuraoka (Duke University)H-Index: 12
view all 4 authors...
Source
#1Ho-Chang Kuo (CGU: Chang Gung University)H-Index: 26
#2Cheng-Tsung Pan (NCTU: National Chiao Tung University)H-Index: 1
Last. Lien-Hung Huang (CGU: Chang Gung University)H-Index: 3
view all 7 authors...
Source
#1Rachael Bashford-Rogers (University of Cambridge)H-Index: 7
#2L Bergamaschi (University of Cambridge)H-Index: 1
Last. Kenneth G. C. Smith (University of Cambridge)H-Index: 66
view all 12 authors...
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the ‘BCR repertoire’. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus er...
5 CitationsSource