Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding V(H)81X-expressing B cells.

Ola Grimsholm,Susanna Cardell,Alessandra De Riva,Ulf Yrlid,Haixia Chen,Inga-Lill Mårtensson,Dongfeng Chen,Berglind Bergmann,Sofia Andersson,Giljun Park,Weicheng Ren,Alessandro Camponeschi,Inger Gjertsson,Nina Höök,Angelina I Bernardi,Anneli Strömberg

doi:10.1038/ncomms8077

Abstract

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V(H)81X from both pools.

Highlights

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive B-cell receptors (BCRs)
The absence of surrogate light (SL) chain allows the development of self-reactive naive B cells, which is sufficient to drive the spontaneous formation of persistent autoreactive T-cell-independent and -dependent (Td) germinal centre (GC)
Peripheral tolerance appears maintained by selection thresholds on the GC B cells entering into the memory B-cell and plasma cell pools

Summary

Introduction

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. At the pro-Bcell stage early in B-cell development VDJH recombination leads to expression of an antibody m-heavy (mH) chain This assembles with the invariant surrogate light (SL) chain, encoded by VpreB and l5, and the signalling molecules Iga/b forming a pre-BCR16,17, where association with the SL chain serves as a quality control of mH chains. The SLC À / À mouse is a unique model in which to investigate B-cell tolerance mechanisms without the complexity of multiple genetic loci being involved, as in multigenic autoimmune diseases As they express a diverse antibody repertoire and on a lupus-resistant background, this model allows the changes in the BCR repertoire imposed by tolerance mechanisms to be uncovered not possible with monoclonal Ig transgenic mice. Peripheral tolerance appears maintained by selection thresholds on GC B cells entering the memory B-cell and plasma cell pools

Methods

Results

Conclusion