Background/Purpose: Interleukin 40 (IL-40) is recently identified B cell – associated cytokine implicated in humoral immune responses and in B cell development and homeostasis. As B cells play a pivotal role in autoimmunity, we aimed to investigate the function of IL-40 in rheumatoid arthritis (RA).

Methods: IL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum and synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and in healthy controls (HC, n=50). All patients met the ACR-EULAR criteria of the particular disease (1,2,3). We also assessed the changes of IL-40 levels in RA patients following the B-cell depletion therapy by rituximab (n=33) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines and markers of NETosis. The effect of IL-40 on synovial fibroblasts was determined.

Results: We observed increased expression of IL-40 in the RA synovial tissue compared to OA, particularly in synovial lining cells and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA compared to OA patients (p< 0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA or SLE patients (p< 0.0001 for all) and decreased after 16 and 24 weeks (p< 0.01 and p< 0.01) following rituximab treatment. No significant effect of adalimumab on serum IL-40 was observed. IL-40 levels in RA patients correlated with rheumatoid factor-IgM and anti-cyclic citrullinated peptides (anti-CCP) in the serum (p< 0.0001 and p< 0.01), as well as in the synovial fluid (p< 0.0001 and p< 0.001). Synovial fluid IL-40 was also associated with DAS28 (p< 0.05), synovial fluid leukocyte count (p< 0.01), neutrophil attractants IL-8 (p< 0.01), MIP-1α (p< 0.01), and markers of NETosis such as proteinase 3 (p< 0.0001) and neutrophil elastase (p< 0.0001). RA synovial fibroblasts exposed to recombinant IL-40 increased the secretion of IL-8 (p< 0.01), MCP-1 (p< 0.05) and MMP-13 (p< 0.01) compared to the unstimulated cells.

Conclusion: We show the up-regulation of IL-40 in RA and its decrease following B-cell depletion therapy. The association of IL-40 with autoantibodies, chemokines and markers of NETosis may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 in synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.

References:
(1) Aletaha D, Neogi T, Silman AJ, et al., 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81. (2) Aringer M. EULAR/ACR classification criteria for SLE. Semin Arthritis Rheum. 2019 Dec;49(3S):S14-S17. (3) Zhang W, Doherty M, Peat G, et al. EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis. Ann Rheum Dis. 2010;69:483–9.

Acknowledgement:
Supported by AZV-NU21-05-00276, MHCR 023728, SVV 260 523 and BBMRI-CZ LM2018125

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-40-a-new-b-cell-associated-cytokine-up-regulated-in-rheumatoid-arthritis-decreases-following-the-rituximab-therapy-and-correlates-with-disease-activity-autoantibodies-and-netosis/