B cell receptor signaling-based index as a biomarker for the loss of peripheral immune tolerance in autoreactive B cells in rheumatoid arthritis.

Taras Lyubchenko,Gary O Zerbe,Oliver Frey

doi:10.1371/journal.pone.0102128

Taras Lyubchenko, Gary O Zerbe + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0102128

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Abstract

This study examines the loss of peripherally induced B cell immune tolerance in Rheumatoid arthritis (RA) and establishes a novel signaling-based measure of activation in a subset of autoreactive B cells - the Induced tolerance status index (ITSI). Naturally occurring naïve autoreactive B cells can escape the “classical” tolerogenic mechanisms of clonal deletion and receptor editing, but remain peripherally tolerized through B cell receptor (BCR) signaling inhibition (postdevelopmental “receptor tuning” or anergy). ITSI is a statistical index that numerically determines the level of homology between activation patterns of BCR signaling intermediaries in B cells that are either tolerized or activated by auto antigen exposure, and thus quantifies the level of peripheral immune tolerance. The index is based on the logistic regression analysis of phosphorylation levels in a panel of BCR signaling proteins. Our results demonstrate a new approach to identifying autoreactive B cells based on their BCR signaling features.

Highlights

We recently reported about changes in B cell antigen receptor signaling profiles associated with the loss of postdevelopmentally induced peripheral immune tolerance in a subset of autoreactive B cells in patients with Rheumatoid arthritis [1,2]
Phosphorylation levels of B cell antigen receptor (BCR) signal transduction proteins were measured with BD Phosflow assay in CD19+CD272IgD+IgMlow/2 BND cells as described in [2]; cells were stimulated with anti-BCR (polyclonal goat F(ab9)2 anti-human Ig(H+L) purchased from Southern Biotech) in vitro for 10 min and baseline and phospho-response amplitude levels of individual BCR signal transduction proteins were compared between Rheumatoid arthritis (RA) patients and healthy controls [2]
According to the central hypothesis of our study (Figure 1), in healthy individuals, autoreactive BND cells that have escaped the mechanisms of central tolerance maintain the peripheral immune tolerance (PIT) to ubiquitous autoantigens through continuous receptor tuning and BCR signaling inhibition, and our results demonstrate that this tolerogenic mechanism is compromised in RA

Summary

Introduction

We recently reported about changes in B cell antigen receptor signaling profiles associated with the loss of postdevelopmentally induced peripheral immune tolerance (anergy) in a subset of autoreactive B cells in patients with Rheumatoid arthritis [1,2]. This follow-up study further examines the loss of B cell immune tolerance in RA and proposes a novel BCR signaling-based measure of autoimmune activation in the autoreactive B cell subset - the Induced Tolerance Status Index (ITSI). The loss of B cell immune tolerance has been recognized as an important factor in the onset of RA [7,8,13]

Results

Discussion

Conclusion