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
BackgroundInterleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA).MethodsIL-40 expression was determined i...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.745523/full |
| _version_ | 1819140105686745088 |
|---|---|
| author | Adela Navrátilová Adela Navrátilová Lucie Andrés Cerezo Lucie Andrés Cerezo Hana Hulejová Viktor Bečvář Michal Tomčík Michal Tomčík Martin Komarc David Veigl Dana Tegzová Dana Tegzová Jakub Závada Jakub Závada Marta Olejárová Marta Olejárová Karel Pavelka Karel Pavelka Jiří Vencovský Jiří Vencovský Ladislav Šenolt Ladislav Šenolt |
| author_facet | Adela Navrátilová Adela Navrátilová Lucie Andrés Cerezo Lucie Andrés Cerezo Hana Hulejová Viktor Bečvář Michal Tomčík Michal Tomčík Martin Komarc David Veigl Dana Tegzová Dana Tegzová Jakub Závada Jakub Závada Marta Olejárová Marta Olejárová Karel Pavelka Karel Pavelka Jiří Vencovský Jiří Vencovský Ladislav Šenolt Ladislav Šenolt |
| author_sort | Adela Navrátilová |
| collection | DOAJ |
| description | BackgroundInterleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA).MethodsIL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined.ResultsIL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p<0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (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 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 disease activity score 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 neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p<0.0001) and neutrophil elastase (p<0.0001). Synovial fibroblasts exposed to 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.ConclusionsWe show the up-regulation of IL-40 in RA and its decrease following B cell depleting 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. |
| first_indexed | 2024-12-22T11:33:16Z |
| format | Article |
| id | doaj.art-897554b968044773b38c65bc7efe3f6c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T11:33:16Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-897554b968044773b38c65bc7efe3f6c2022-12-21T18:27:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-10-011210.3389/fimmu.2021.745523745523IL-40: A New B Cell-Associated Cytokine Up-Regulated in Rheumatoid Arthritis Decreases Following the Rituximab Therapy and Correlates With Disease Activity, Autoantibodies, and NETosisAdela Navrátilová0Adela Navrátilová1Lucie Andrés Cerezo2Lucie Andrés Cerezo3Hana Hulejová4Viktor Bečvář5Michal Tomčík6Michal Tomčík7Martin Komarc8David Veigl9Dana Tegzová10Dana Tegzová11Jakub Závada12Jakub Závada13Marta Olejárová14Marta Olejárová15Karel Pavelka16Karel Pavelka17Jiří Vencovský18Jiří Vencovský19Ladislav Šenolt20Ladislav Šenolt21Department of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Methodology, Faculty of Physical Education and Sport, Charles University, Prague, CzechiaFirst Orthopaedic Clinic, 1st Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Experimental Rheumatology, Institute of Rheumatology, Prague, CzechiaDepartment of Rheumatology, First Faculty of Medicine, Charles University, Prague, CzechiaBackgroundInterleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA).MethodsIL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined.ResultsIL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p<0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (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 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 disease activity score 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 neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p<0.0001) and neutrophil elastase (p<0.0001). Synovial fibroblasts exposed to 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.ConclusionsWe show the up-regulation of IL-40 in RA and its decrease following B cell depleting 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.745523/fullinterleukin-40rheumatoid arthritisautoantibodiesdisease activityB cellsNETosis |
| spellingShingle | Adela Navrátilová Adela Navrátilová Lucie Andrés Cerezo Lucie Andrés Cerezo Hana Hulejová Viktor Bečvář Michal Tomčík Michal Tomčík Martin Komarc David Veigl Dana Tegzová Dana Tegzová Jakub Závada Jakub Závada Marta Olejárová Marta Olejárová Karel Pavelka Karel Pavelka Jiří Vencovský Jiří Vencovský Ladislav Šenolt Ladislav Šenolt 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 Frontiers in Immunology interleukin-40 rheumatoid arthritis autoantibodies disease activity B cells NETosis |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | interleukin-40 rheumatoid arthritis autoantibodies disease activity B cells NETosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.745523/full |
| work_keys_str_mv | AT adelanavratilova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT adelanavratilova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT lucieandrescerezo il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT lucieandrescerezo il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT hanahulejova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT viktorbecvar il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT michaltomcik il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT michaltomcik il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT martinkomarc il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT davidveigl il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT danategzova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT danategzova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT jakubzavada il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT jakubzavada il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT martaolejarova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT martaolejarova il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT karelpavelka il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT karelpavelka il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT jirivencovsky il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT jirivencovsky il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT ladislavsenolt il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis AT ladislavsenolt il40anewbcellassociatedcytokineupregulatedinrheumatoidarthritisdecreasesfollowingtherituximabtherapyandcorrelateswithdiseaseactivityautoantibodiesandnetosis |