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Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.

Publication ,  Journal Article
Clark, AG; Buckley, ES; Foster, MH
Published in: Eur J Immunol
March 2018

Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice. Herein we report that the tolerance defect is revealed by TLR7 and TLR9 as well as TLR4 ligands, with additive effect, and is partially reversed by Mek inhibition. Gene expression analysis reveals significant differences in transcription of multiple TLR pathway genes and ptpn22 in stimulated NZB compared to B6 B cells. Additionally, the defect is detected in Ig transgenic NZB F1 hybrid strains (NZBxNZW)F1 and (B6xNZB)F1. These results implicate an inherited defect wherein NZB anergic B cells maintain coordinated TLR/BCR signaling that permits autoantibody production. Agents targeting these pathways may have therapeutic benefit in the subset of lupus patients that manifest similar defects in B-cell regulation.

Duke Scholars

Published In

Eur J Immunol

DOI

EISSN

1521-4141

Publication Date

March 2018

Volume

48

Issue

3

Start / End Page

492 / 497

Location

Germany

Related Subject Headings

  • Toll-Like Receptors
  • Toll-Like Receptor 9
  • Toll-Like Receptor 7
  • Toll-Like Receptor 4
  • Mice, Transgenic
  • Mice, Inbred NZB
  • Mice
  • Membrane Glycoproteins
  • Male
  • MAP Kinase Signaling System
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Clark, A. G., Buckley, E. S., & Foster, M. H. (2018). Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice. Eur J Immunol, 48(3), 492–497. https://doi.org/10.1002/eji.201747287
Clark, Amy G., Elizabeth S. Buckley, and Mary H. Foster. “Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.Eur J Immunol 48, no. 3 (March 2018): 492–97. https://doi.org/10.1002/eji.201747287.
Clark, Amy G., et al. “Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.Eur J Immunol, vol. 48, no. 3, Mar. 2018, pp. 492–97. Pubmed, doi:10.1002/eji.201747287.
Journal cover image

Published In

Eur J Immunol

DOI

EISSN

1521-4141

Publication Date

March 2018

Volume

48

Issue

3

Start / End Page

492 / 497

Location

Germany

Related Subject Headings

  • Toll-Like Receptors
  • Toll-Like Receptor 9
  • Toll-Like Receptor 7
  • Toll-Like Receptor 4
  • Mice, Transgenic
  • Mice, Inbred NZB
  • Mice
  • Membrane Glycoproteins
  • Male
  • MAP Kinase Signaling System