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Abstract Number: 2578

Monoclonal IgG Antibodies (ACPAs) From Synovial Fluid B Cells of Rheumatoid Arthritis Patients – Antigen-Driven Affinity Maturation and Cross Reactivity

Khaled Amara1, Johanna Steen2, Fiona Murray2, Henner Morbach3, Blanca Fernandez-Rodriguez4, Vijay Balasingh2, Marianne Engström2, Omri Snir2, Lena Israelsson5, Anca Catrina2, Hedda Wardemann6, Davide Corti4, Eric Meffre Sr.3, Lars Klareskog7 and Vivianne Malmström8, 1Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden., Stockholm, Sweden, 2Department of Medicine, Rheumatology unit, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, 3Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 4Institute for Research in Biomedicine, Bellinzona, Switzerland, 5Medicine, Rheumatology unit, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, 6Max Planck Research Group Molecular Immunology, Max Planck Institute for Infection Biology, Berlin, Germany, 7Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 8Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: autoantibodies, B cells, citrulline, monoclonal antibodies and rheumatoid arthritis (RA)

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Session Information

Title: B-cell Biology and Targets in Autoimmune Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose: Antibodies targeting citrullinated proteins (ACPA) are commonly found in patients with Rheumatoid Arthritis (RA), strongly associate with distinct HLA-DR alleles and predict a more aggressive disease course as compared to seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II driven T-cell help remain unclarified. In this study we have assessed the specificity and the immunoglobulin gene characteristics of B cells derived from RA synovial fluid of RA by utilizing a method that allows in vitro production of monoclonal antibodies derived from single human memory B cells.

Methods: Recombinant monoclonal antibodies (n=204) were generated from single flow cytometry purified synovial CD19+IgG+ B cells from active RA patients (n=5). Antigen specificity and affinity were determined by ELISA and Biacore respectively. Frozen tissue sections from active RA synovial inflammation were evaluated by immunohistochemistry for presence of citrullinated antigens using the generated recombinant antibodies.

Results: Our results demonstrate that approximately 25% of synovial IgG-expressing B-cells are specific for citrullinated autoantigens in ACPA-positive RA patients, while such antibodies were not found in seronegative patients. These citrulline-reactive antibodies did not react with the unmodified arginine peptides. Surprisingly, several antibodies displayed cross reactivity to several citrullinated antigens but with variable binding affinities. Overall, KD values ranged from 1.35 X 10-06 – 5.94 X 10-10 for CEP-1, from 3.84 X 10-05 – 3.1 X 10-09 for cit-fib, and from 2.8 X 10-06 – 1.05 X 10-10 for cit-vim. Positive staining has been observed in biopsies of two RA patients. On the molecular level, striking differences were found between the monoclonal recognizing citrullinated antigens and those that did not. Based on DNA sequences, we could demonstrate that the citrulline-specific antibodies displayed fewer overall mutations but, yet displayed more replacement mutations in their CDRs regions as compared to the citrulline-negative clones. Interestingly, the reversion of citrulline-specific antibodies to their germline sequences led to a loss of reactivity to all the autoantigens.

Conclusion: A role for active antigen selection of the citrulline-reactive synovial B-cells was supported by the strong bias towards amino acid replacement mutations in ACPA+ antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences. The observed cross reactivity suggests that multiple antigens could participate in driving these clones.


Disclosure:

K. Amara,
None;

J. Steen,
None;

F. Murray,
None;

H. Morbach,
None;

B. Fernandez-Rodriguez,
None;

V. Balasingh,
None;

M. Engström,
None;

O. Snir,
None;

L. Israelsson,
None;

A. Catrina,
None;

H. Wardemann,
None;

D. Corti,
None;

E. Meffre Sr.,
None;

L. Klareskog,
None;

V. Malmström,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/monoclonal-igg-antibodies-acpas-from-synovial-fluid-b-cells-of-rheumatoid-arthritis-patients-antigen-driven-affinity-maturation-and-cross-reactivity/

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