ANALYSIS OF THE MURINE ANTIBODY REPERTOIRE

Summary

Principal Investigator: GARNETT H KELSOE
Abstract: .o. The murine antibody repertoire experiences a series of expansions and contractions that coincide with specific stages of B-cell development arid differentiation. The initial repertoire of antibody specificities generated by V(D)J recombination is reduced during B-cell maturation by the effects of immunological tolerance mechanism acting on immature and transitional B cells. The purging of autoreactivity from developmentally immature B cell compartments it is thought to be accomplished by at least three mechanisms: cional deletion by apoptosis, inactivation by energy, and receptor editing, the induction of secondary V(D)J gene rearrangements to replace self- reactive receptors. Receptor editing is believed to be the premiere mechanism for B-cell tolerance. Questions remain, however, regarding how the process of receptor editing acts and whether experimental evidence for receptor editing reflects the induction of genetic changes in autoimmune B cells or selection for variants that spontaneously undergo secondary rearrangements. We shall investigate the tolerizing contractions of the B-cell repertoire with particular reference to: 1) the signals and developmental stages of B cells that initiatelsupport receptor editing;2) the role of self-antigens in the induction of regulated RAG 1/2 expression and rearrangement, and;3) the selection criteria that might determine clonal tolerance/selection during B-cell maturation in viva. Qom cap mop axiom 0-c 0opccc woo'- t00 0co -td
Funding Period: ----------------1989 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells
    Yoshihiro Ueda
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 178:3593-601. 2007
  2. pmc Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro B cells
    Marco Davila
    Department of Immunology, Duke University, Durham, NC 27710, USA
    J Exp Med 204:3195-208. 2007
  3. ncbi Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice
    David J DiLillo
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 180:361-71. 2008
  4. pmc The human fetal lymphocyte lineage: identification by CD27 and LIN28B expression in B cell progenitors
    Laurie McWilliams
    2 DUMC, Durham, NC 27710 M K, E mail
    J Leukoc Biol 94:991-1001. 2013
  5. pmc Identification of a tissue-specific, C/EBPβ-dependent pathway of differentiation for murine peritoneal macrophages
    Derek W Cain
    Department of Immunology, Duke University, Durham, NC 27710
    J Immunol 191:4665-75. 2013
  6. pmc Effects of acute and chronic inflammation on B-cell development and differentiation
    Derek Cain
    Department of Immunology, Duke University, Durham, North Carolina 27710, USA
    J Invest Dermatol 129:266-77. 2009
  7. pmc IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia
    Yoshihiro Ueda
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 182:6477-84. 2009
  8. pmc Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells
    Anne E Lieberman
    Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
    BMC Immunol 10:37. 2009
  9. pmc Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome
    Masayuki Kuraoka
    Department of Immunology, Duke University, Durham, NC 27710, USA
    J Immunol 183:3237-48. 2009
  10. pmc Stromal cell independent B cell development in vitro: generation and recovery of autoreactive clones
    T Matt Holl
    Department of Immunology, DUMC 3010, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol Methods 354:53-67. 2010

Scientific Experts

  • GARNETT H KELSOE
  • Anne E Lieberman
  • Yoshihiro Ueda
  • Derek W Cain
  • Masayuki Kuraoka
  • Dongmei Liao
  • T Matt Holl
  • Huaiyong Chen
  • Derek Cain
  • Kaiyong Yang
  • Laurie McWilliams
  • Gregory D Sempowski
  • Mandy Womble
  • Eda K Holl
  • Motonari Kondo
  • David J DiLillo
  • Marco Davila
  • Anjali Patel
  • Serina Floyd
  • Kuei Ying Su
  • M Anthony Moody
  • Matthew J Kan
  • Emily G O'Koren
  • Xiaoe Liang
  • Michael D Gunn
  • Kristen Hopper
  • Joshua Amos
  • SUSHMITA JHA
  • BRIAN P O'CONNOR
  • Jenny P Y Ting
  • Albert G Zimmermann
  • Pilar B Snowden
  • Alexander E Reynolds
  • Kelly E Roney
  • Ian McLeod
  • CHRISTIAN RAETZ
  • Ziqiang Guan
  • Pilar Snowden
  • Barton F Haynes
  • Marc C Levesque
  • Sallie D Allgood
  • Junji Uchida
  • Karen M Haas
  • Yasuhito Hamaguchi
  • Thomas F Tedder
  • Emily Heikamp
  • Feifei Liu
  • Lindsay G Cowell

Detail Information

Publications15

  1. pmc T-independent activation-induced cytidine deaminase expression, class-switch recombination, and antibody production by immature/transitional 1 B cells
    Yoshihiro Ueda
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 178:3593-601. 2007
    ..We propose that inflammation-induced extramedullary lymphopoiesis represents a specialized mechanism for innate Ab responses to microbial pathogens...
  2. pmc Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro B cells
    Marco Davila
    Department of Immunology, Duke University, Durham, NC 27710, USA
    J Exp Med 204:3195-208. 2007
    ..Conservation of cRSs distal from the 3' end of V(H) gene segments suggests a function for these cryptic signals other than V(H) gene replacement...
  3. ncbi Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice
    David J DiLillo
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 180:361-71. 2008
    ..Thereby, depleting mature and memory B cells does not have a dramatic negative effect on preexisting Ab levels...
  4. pmc The human fetal lymphocyte lineage: identification by CD27 and LIN28B expression in B cell progenitors
    Laurie McWilliams
    2 DUMC, Durham, NC 27710 M K, E mail
    J Leukoc Biol 94:991-1001. 2013
    ..Our observations suggest that CD27 expression during B cell development identifies a physiologic state or lineage for human B cell development distinct from the memory B cell compartment. ..
  5. pmc Identification of a tissue-specific, C/EBPβ-dependent pathway of differentiation for murine peritoneal macrophages
    Derek W Cain
    Department of Immunology, Duke University, Durham, NC 27710
    J Immunol 191:4665-75. 2013
    ..We conclude that C/EBPβ plays an intrinsic, tissue-restricted role in the generation of resident macrophages. ..
  6. pmc Effects of acute and chronic inflammation on B-cell development and differentiation
    Derek Cain
    Department of Immunology, Duke University, Durham, North Carolina 27710, USA
    J Invest Dermatol 129:266-77. 2009
    ..In this Perspective, we review inflammation's effects on central and extramedullary B lymphopoiesis and discuss the potential consequences of peripheral B-cell development in the context of systemic autoimmune diseases...
  7. pmc IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia
    Yoshihiro Ueda
    Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol 182:6477-84. 2009
    ..Thus, IL-1 plays a necessary, but indirect, role in the support of alum-induced neutrophilias by expanding both pluripotent and myeloid progenitor compartments to accelerate granulopoiesis...
  8. pmc Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells
    Anne E Lieberman
    Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
    BMC Immunol 10:37. 2009
    ..These results are inconsistent with a model of cRS cleavage during autoreactivity-induced VH gene replacement...
  9. pmc Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome
    Masayuki Kuraoka
    Department of Immunology, Duke University, Durham, NC 27710, USA
    J Immunol 183:3237-48. 2009
    ....
  10. pmc Stromal cell independent B cell development in vitro: generation and recovery of autoreactive clones
    T Matt Holl
    Department of Immunology, DUMC 3010, Duke University Medical Center, Durham, NC 27710, USA
    J Immunol Methods 354:53-67. 2010
    ..Furthermore, serum IgG autoantibody exceeded that present in autoimmune, C4(-/-) animals following the reconstitution of RAG1(-/-) mice with IgM+ CD cells derived from BL/6 mice...
  11. pmc Distinct granuloma responses in C57BL/6J and BALB/cByJ mice in response to pristane
    Huaiyong Chen
    Department of Immunology, Duke University Medical Center, Durham, NC, USA
    Int J Exp Pathol 91:460-71. 2010
    ..These observations suggest that the recruitment of inflammatory leucocytes under the direction of chemokines differentiates the patterns of granuloma responses to pristane in C57BL/6J and BALB/cByJ mice...
  12. pmc Genetic regulation of pristane-induced oil granuloma responses
    Huaiyong Chen
    Department of Immunology, Duke University Medical Center, Durham, NC, USA
    Int J Exp Pathol 91:472-83. 2010
    ..Interestingly, IL-6(-/-) mice had intact MG formation; however, SG organization was impaired. These studies provide insight into granulomateous pathology induced by non-infectious substances for example, biomedical sutures...
  13. pmc Plexin-D1 is a novel regulator of germinal centers and humoral immune responses
    Eda K Holl
    Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
    J Immunol 186:5603-11. 2011
    ..These data show a new role for immune plexins in the GC reaction and generation of immunologic memory...
  14. pmc Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism
    Derek W Cain
    Department of Immunology, Duke University, Durham, North Carolina, United States of America
    PLoS ONE 6:e19957. 2011
    ..We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis...
  15. pmc Activation-induced cytidine deaminase mediates central tolerance in B cells
    Masayuki Kuraoka
    Department of Immunology, Duke University, Durham, NC 27710, USA
    Proc Natl Acad Sci U S A 108:11560-5. 2011
    ..Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow...