This work was funded by grants number 18237 and 20089 from Arthritis Research UK (http://www.arthritisresearchuk.org) to MB and the William Harvey Research Foundation. EC was recipient of short-term travel fellowships from EMBO (ASTF 318-2010) and EFIS-IL

A Cappione 3rd

A Hansen

A Kessel

B Chang

B Mietzner

C Vitali

Costantino Pitzalis

DI Stott

E Meffre

E Theander

Elisa Corsiero

F Barone

F Takemoto

H Mouquet

H Tsuboi

H Wardemann

IS Lossos

J Pijpe

J Samuels

Jay Reddy

JC Edwards

JF Scheid

JG Routsias

L Dawson

L Le Pottier

M Bombardieri

M Tsuiji

Michele Bombardieri

N Haneji

Nurhan Sutcliffe

P Youinou

S Salomonsson

S Yurasov

T Rogosch

T Tiller

PLoS ONE

English

PubMed

Corsiero, E

Sutcliffe, N

Pitzalis, C

Bombardieri, M

Queen Mary Research Online

A checkpoint for autoreactivity in human IgM+ memory B cell development.

Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjogren’s syndrome.

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren’s syndrome.

Antimuscarinic antibodies in Sjogren’s syndrome: where are we, and where are we going?

Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren’s syndrome.

Autoimmune response and target autoantigens in Sjogren’s syndrome.

Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors.

B cells in Sjogren’s syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue.

B-cell targeting in rheumatoid arthritis and other autoimmune diseases.

B-cell tolerance checkpoints in health and autoimmunity.

Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome.

Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the AmericanEuropean Consensus Group.

Comparison of immunoglobulin heavy chain rearrangements between peripheral and glandular B cells in a patient with primary Sjogren’s syndrome.

Defective B cell tolerance checkpoints in systemic lupus erythematosus.

Differential regulation of self-reactivity discriminates between IgG+ human circulating memory B cells and bone marrow plasma cells.

Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren’s syndrome.

Ectopic germinal centers are rare in Sjogren’s syndrome salivary glands and do not exclude autoreactive B cells.

Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning.

Generation and functional analysis of monoclonal antibodies against the second extracellular loop of human M3 muscarinic acetylcholine receptor.

Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus.

Identification of alpha-fodrin as a candidate autoantigen in primary Sjogren’s syndrome.

Immunoglobulin analysis tool: a novel tool for the analysis of human and mouse heavy and light chain transcripts.

Impaired early B cell tolerance in patients with rheumatoid arthritis.

Induction of anti-carbonicanhydrase-II antibody causes renal tubular acidosis in a mouse model of Sjogren’s syndrome.

Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren’s syndrome.

Polyreactive antibodies in adaptive immune responses to viruses.

Polyreactive antibodies in adaptive immune responses to viruses. Cell Mol Life Sci.

Predominant autoantibody production by early human B cell precursors.

Rituximab treatment in patients with primary Sjogren’s syndrome: an open-label phase II study.

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement.

The inference of antigen selection on Ig genes.

What do we know about memory B cells in primary Sjogren’s syndrome?

Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome

Sjögren's syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27-IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD- memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naïve (n = 66) and memory (n = 48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells

Directory of Open Access Journals

Accumulation of self-reactive naïve and memory B cell reveals sequential defects in B cell tolerance checkpoints in Sjögren's syndrome.

<div>Sjögren’s syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27−IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD− memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naïve (n = 66) and memory (n = 48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells.</div

Elisa Corsiero (678486)

Nurhan Sutcliffe (678487)

Costantino Pitzalis (23531)

Michele Bombardieri (56532)

The Francis Crick Institute

Accumulation of Self-Reactive Naïve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjögren’s Syndrome

Crossref

Corsiero Elisa

Sutcliffe Nurhan

Pitzalis Costantino

Bombardieri Michele

Public Library of Science (PLOS)

file:///data/remote/core/dit/data/public_library_of_science/pdf/26d/ZnRwOi8vZnRwLm5jYmkubmxtLm5paC5nb3YvcHViL3BtYy9vYV9wYWNrYWdlLzIyLzdlL1BNQzQyNzUyMDYudGFyLmd6.pdf

Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome

Abstract

Similar works

Full text

Available Versions

Queen Mary Research Online

Directory of Open Access Journals

The Francis Crick Institute

Crossref

Public Library of Science (PLOS)