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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-b-cells-andor-autoantibodies-in-pulmonary-manifestations-of-inflammatory-arthritis/