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Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice

Academic Article
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Overview

authors

  • Ait-Azzouzene, D.
  • Kono, Dwight
  • Gonzalez-Quintial, R.
  • McHeyzer-Williams, L. J.
  • Lim, M.
  • Wickramarachchi, D.
  • Gerdes, T.
  • Gavin, Amanda
  • Skog, P.
  • McHeyzer-Williams, Michael G.
  • Nemazee, David
  • Theofilopoulos, Argyrios

publication date

  • July 2010

journal

  • Journal of Immunology  Journal

abstract

  • During a T cell-dependent Ab response, B cells undergo Ab class switching and V region hypermutation, with the latter process potentially rendering previously innocuous B cells autoreactive. Class switching and hypermutation are temporally and anatomically linked with both processes dependent on the enzyme, activation-induced deaminase, and occurring principally, but not exclusively, in germinal centers. To understand tolerance regulation at this stage, we generated a new transgenic mouse model expressing a membrane-tethered gamma2a-reactive superantigen (gamma2a-macroself Ag) and assessed the fate of emerging IgG2a-expressing B cells that have, following class switch, acquired self-reactivity of the Ag receptor to the macroself-Ag. In normal mice, self-reactive IgG2a-switched B cells were deleted, leading to the selective absence of IgG2a memory responses. These findings identify a novel negative selection mechanism for deleting mature B cells that acquire reactivity to self-Ag. This process was only partly dependent on the Bcl-2 pathway, but markedly inefficient in MRL-Fas(lpr) lupus mice, suggesting that defective apoptosis of isotype-switched autoreactive B cells is central to Fas mutation-associated systemic autoimmunity.

subject areas

  • Adoptive Transfer
  • Animals
  • Antigens, CD95
  • B-Lymphocytes
  • Cell Line
  • Female
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Immunoglobulin Class Switching
  • Immunoglobulin G
  • Lupus Erythematosus, Systemic
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen
  • Superantigens
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Identity

PubMed Central ID

  • PMC3641794

International Standard Serial Number (ISSN)

  • 0022-1767

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.1000698

PubMed ID

  • 20554953
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Additional Document Info

start page

  • 1015

end page

  • 1027

volume

  • 185

issue

  • 2

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