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Abstract Number: 922

Role Of B Cells and/Or Autoantibodies In Pulmonary Manifestations Of Inflammatory Arthritis

Lisa K. Peterson1, Jeremy Sokolove2, Paul Jedlicka3, Lauren J. Lahey4, William H. Robinson5 and Leonard L. Dragone6, 1Pediatrics, National Jewish Health, Denver, CO, 2VA Palo Alto Healthcare System and Stanford University, Palo Alto, CA, 3Pathology, University of Colorado Denver, Aurora, CO, 4Medicine, VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, 5VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, 6Dept of Pediatrics, National Jewish Health, Denver, CO

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: autoantibodies, autoantigens and rheumatoid arthritis (RA), B cell targeting, Lung Disease

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Session Information

Session Title: B cells in Human and Animal Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: RA is a systemic condition affecting approximately 1% of the general population leading to progressive arthritis and extra-articular manifestations (ExRA), including interstitial lung disease (RA-ILD). RA-ILD is a major cause of morbidity and mortality due to its progression despite the use of therapies that effectively treat arthritis. These observations suggest that the articular and RA-ILD manifestations may have overlapping but unique features related to their pathogenesis, which could be identified and specific therapies started if biomarkers for RA-ILD were available. A significant obstacle to advancing our ability to predict the development of RA-ILD is the limited availability of relevant experimental mouse models that have a predictable kinetics of developing RA-ILD.

Methods: To enable mechanistic and biomarker studies, we created a mouse disease model based on SKG mice which develop inflammatory arthritis as well as ExRA manifestations upon zymosan exposure. Our model utilizes Double SKG Src-Like adaptor protein (SLAP)-Knockout mice (DSSKO) that are arthritis-resistant to the disease trigger (zymosan), yet develop progressive lung inflammation with histologic features of the clinical manifestations of RA-ILD that occurs with predictable kinetics. To examine the contributions of lymphocytes to the pulmonary manifestations associated with inflammatory arthritis using adoptive transfer and antibody-mediated cell depletion.

To identify autoantibodies associated with autoimmune lung disease in zymosan-treated DSSKO mice we performed arthritis autoantigen arrays on a well-characterized cohort of DSSKO mice with lung disease but without arthritis and SKG mice with arthritis but without lung disease. As a complement to this approach, generated B cell hybridomas and screened them against lung tissue lysates by ELISA and western blot. Specific autoantigens were then identified using mass spectrometry.

Results:

Transfer of CD4+ T cells from DSSKO mice into RAG2-/- mice induced arthritis in the absence of the lung disease. Thus, CD4+ T cells are not sufficient to induce lung disease. In contrast, B cell depletion studies using an anti-CD20 monoclonal antibody eliminated lung disease in DSSKO mice, implicating B cells and/or autoantibodies in lung disease pathogenesis. In addition, DSSKO mice developed distinct profiles of anti-citrullinated antibodies compared to arthritis-prone (SKG) controls. DSSKO mice developed autoantibodies to several citrullinated antigens previously detected in the serum of humans with RA, though the exact relationship to RA-ILD pathogenesis is unknown. 

Conclusion: B cells and/or autoantibodies are required for autoimmune lung disease in zymosan-treated DSSKO mice. DSSKO mice developed a distinct profile of autoantibodies to antigens that have been detected in the serum of humans with RA, but the relationship to RA-ILD pathogenesis is unknown. Therefore, identification of autoantibodies that develop during lung disease in DSSKO mice may reveal new biomarkers for RA-ILD. Identified autoantibodies could potentially also be used to determine their contribution to disease pathogenesis.


Disclosure:

L. K. Peterson,
None;

J. Sokolove,
None;

P. Jedlicka,
None;

L. J. Lahey,
None;

W. H. Robinson,
None;

L. L. Dragone,
None.

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