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Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance.

Publication ,  Journal Article
Verkoczy, L; Diaz, M; Holl, TM; Ouyang, Y-B; Bouton-Verville, H; Alam, SM; Liao, H-X; Kelsoe, G; Haynes, BF
Published in: Proc Natl Acad Sci U S A
January 5, 2010

We previously reported that some of the rare broadly reactive, HIV-1 neutralizing antibodies are polyreactive, leading to the hypothesis that induction of these types of neutralizing antibody may be limited by immunologic tolerance. However, the notion that such antibodies are sufficiently autoreactive to trigger B cell tolerance is controversial. To test directly whether rare neutralizing HIV-1 antibodies can activate immunologic tolerance mechanisms, we generated a knock-in mouse in which the Ig heavy chain (HC) variable region rearrangement (V(H)DJ(H)) from the polyreactive and broadly neutralizing human monoclonal antibody 2F5 was targeted into the mouse Igh locus. In vitro, this insertion resulted in chimeric human/mouse 2F5 antibodies that were functionally similar to the human 2F5 antibody, including comparable reactivity to human and murine self-antigens. In vivo, the 2F5 V(H)DJ(H) insertion supported development of large- and small pre-B cells that expressed the chimeric human/mouse Igmu chain but not the production of immature B cells expressing membrane IgM. The developmental arrest exhibited in 2F5 V(H)DJ(H) knock-in mice is characteristic of other knock-in strains that express the Ig HC variable region of autoreactive antibodies and is consistent with the loss of immature B cells bearing 2F5 chimeric antibodies to central tolerance mechanisms. Moreover, homozygous 2F5 V(H)DJ(H) knock-in mice support reduced numbers of residual splenic B cells with low surface IgM density, severely diminished serum IgM levels, but normal to elevated quantities of serum IgGs that did not react with autoantigens. These features are consistent with elimination of 2F5 HC autoreactivity by additional negative selection mechanism(s) in the periphery.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 5, 2010

Volume

107

Issue

1

Start / End Page

181 / 186

Location

United States

Related Subject Headings

  • Spleen
  • Recombinant Fusion Proteins
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Immunoglobulin Variable Region
  • Immunoglobulin Heavy Chains
  • Immune Tolerance
  • Humans
  • HIV-1
 

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Verkoczy, L., Diaz, M., Holl, T. M., Ouyang, Y.-B., Bouton-Verville, H., Alam, S. M., … Haynes, B. F. (2010). Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci U S A, 107(1), 181–186. https://doi.org/10.1073/pnas.0912914107
Verkoczy, Laurent, Marilyn Diaz, T Matt Holl, Ying-Bin Ouyang, Hilary Bouton-Verville, S Munir Alam, Hua-Xin Liao, Garnett Kelsoe, and Barton F. Haynes. “Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance.Proc Natl Acad Sci U S A 107, no. 1 (January 5, 2010): 181–86. https://doi.org/10.1073/pnas.0912914107.
Verkoczy L, Diaz M, Holl TM, Ouyang Y-B, Bouton-Verville H, Alam SM, et al. Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):181–6.
Verkoczy, Laurent, et al. “Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance.Proc Natl Acad Sci U S A, vol. 107, no. 1, Jan. 2010, pp. 181–86. Pubmed, doi:10.1073/pnas.0912914107.
Verkoczy L, Diaz M, Holl TM, Ouyang Y-B, Bouton-Verville H, Alam SM, Liao H-X, Kelsoe G, Haynes BF. Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):181–186.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 5, 2010

Volume

107

Issue

1

Start / End Page

181 / 186

Location

United States

Related Subject Headings

  • Spleen
  • Recombinant Fusion Proteins
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Immunoglobulin Variable Region
  • Immunoglobulin Heavy Chains
  • Immune Tolerance
  • Humans
  • HIV-1