Molecular dissection of human b-cell tolerance - insights from primary immunodeficiencies

Henner Morbach,Jessica Rojas,Mary Conley,Jean-Nicolas Schickel,Greta Meyers,Eric Meffre,Sergei Rudchenko,Charlotte Cunningham-Rundles,Ismail Reisli,Jose Franco,Yen-Shing Ng,Laurence Menard

doi:10.1186/1546-0096-12-s1-p40

Abstract

Objectives The aim was to further dissect the BCR and TLR signaling pathways involved in the establishement of central B-cell tolerance in humans. In detail, we aimed to analyze the role of CD19 in mediating central B-cell tolerance in humans. CD19 is a co-receptor expressed on B cells and is involved in the amplification of B-cell responses; its expression is decreased in patients with systemic lupus erythematosus (SLE), suggesting that proper CD19 expression may normally prevent autoimmunity. Additionally, CD19-deficient patients suffering from an antibody deficiency are also prone to develop systemic autoimmune diseases resembling SLE. Methods To test the function of the central B-cell tolerance checkpoint in humans, we analyzed by ELISA and immunofluorescence tests the reactivity of recombinant antibodies cloned from single transitional B cells from individuals carrying CD19 mutations. Additionally, we analyzed alterations in TLR and BCR signaling pathways in CD19-deficient human B cells using flow cytometry and immunoblotting.

Highlights

B cells play a central role in the pathogenesis of many autoimmune diseases
We could show that alterations in B-cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways result in defective central B-cell tolerance
CD19 is a co-receptor expressed on B cells and is involved in the amplification of B-cell responses; its expression is decreased in patients with systemic lupus erythematosus (SLE), suggesting that proper CD19 expression may normally prevent autoimmunity

Summary

Introduction

B cells play a central role in the pathogenesis of many autoimmune diseases. Understanding the mechanisms that regulate B-cell tolerance in humans is important for the development of new therapeutic strategies. Patients with monogenic diseases provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. We could show that alterations in B-cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways result in defective central B-cell tolerance

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