B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus

J A Goeken; T Layer; S Fleenor; M Laccheo; P Lenert

doi:10.1177/0961203310371157

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B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus

Journal article

Peer reviewed

B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus

J A Goeken, T Layer, S Fleenor, M Laccheo and P Lenert

Lupus, Vol.19(11), pp.1290-1301

10/2010

DOI: 10.1177/0961203310371157

PMID: 20605877

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Abstract

The capacity to make secondary structures significantly affects the ability of Toll-like receptor 9 (TLR9) agonists and antagonists to either induce or block TLR9-dependent activation in B cells. However, it has a minor impact on TLR9-induced activation in interferon alpha (IFNα)-producing dendritic cells. Based on the ability of inhibitory oligodeoxynucleotides to form predictable secondary structures, we have classified TLR9-antagonists into Class R ('restricted', palindromic) and Class B ('broadly reactive', linear) oligodeoxynucleotides. In non-autoreactive B cells, Class R oligodeoxynucleotides are at least 10-fold less potent TLR9-inhibitors. We wanted to determine whether engagement of the B-cell receptor for antigen could overcome this restriction. Here we show that in non-autoreactive mouse B cells, B-cell receptor for antigen engagement increased the potency of Class R oligodeoxynucleotides for TLR9 activation at least 10-fold, making it equal in potency to linear oligodeoxynucleotides. However, this enhanced potency was selective for TLR9-induced B-cell cycling and apoptosis protection while TLR9-induced IL-6, an event that strongly depends on signaling via late endosomes, still required 10 times more Class R oligodeoxynucleotides. Thus, pathway-specific effects of Class R oligodeoxynucleotides for TLR9/B-cell receptor for antigen co-stimulated B cells may have therapeutic advantages over non-selective targeting of B cells, a strategy that may be seen as a potential therapy for human systemic lupus erythematosus.

Cell Cycle

Oligodeoxyribonucleotides - immunology

Toll-Like Receptor 9 - antagonists & inhibitors

Humans

Oligodeoxyribonucleotides - chemistry

Toll-Like Receptor 9 - genetics

Immunoglobulin M - immunology

Receptors, Antigen, B-Cell - immunology

Toll-Like Receptor 9 - agonists

Mice, Knockout

Toll-Like Receptor 9 - immunology

B-Lymphocytes - drug effects

Autoantibodies - immunology

Lymphocyte Activation - immunology

Animals

B-Lymphocytes - immunology

Lymphocyte Activation - drug effects

Oligodeoxyribonucleotides - genetics

Lupus Erythematosus, Systemic - immunology

Mice

Nucleic Acid Conformation

Oligodeoxyribonucleotides - pharmacology

Details

Title: Subtitle: B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus
Creators: J A Goeken - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
T Layer
S Fleenor
M Laccheo
P Lenert
Resource Type: Journal article
Publication Details: Lupus, Vol.19(11), pp.1290-1301
DOI: 10.1177/0961203310371157
PMID: 20605877
ISSN: 0961-2033
eISSN: 1477-0962
Grant note: AI047374 / NIAID NIH HHS AI064736 / NIAID NIH HHS
Language: English
Date published: 10/2010
Academic Unit: Pathology; Immunology; Internal Medicine
Record Identifier: 9984094708602771

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