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Research ArticleCell biology
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10.1172/jci.insight.152886
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Delgado-Arévalo, C. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Calvet-Mirabent, M.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Triguero-Martínez, A. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Vázquez de Luis, E. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Benguría-Filippini, A.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Largo, R.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Calzada-Fraile, D.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Popova, O. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Sánchez-Cerrillo, I. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Tsukalov, I.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Moreno-Vellisca, R.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by de la Fuente, H. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Herrero-Beaumont, G. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Ramiro, A. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Sánchez-Madrid, F. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by Castañeda, S. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Dopazo, A.
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1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Find articles by González Álvaro, I. in: JCI | PubMed | Google Scholar
1Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
2Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
3Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.
4Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain.
5CIBER Cardiovascular, Madrid, Spain.
6Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain.
7Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain.
8CIBER Infectious Diseases, Madrid, Spain.
Address correspondence to: Enrique Martin-Gayo, Universidad Autónoma de Madrid, Immunology Unit, Hospital de la Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain. Email: enrique.martin@uam.es.
Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
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Martin-Gayo, E.
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Authorship note: CDA, MCM, and ATM contributed equally to this work. IGA and EMG are co–senior authors.
Published October 4, 2022 - More info
Published in Volume 7, Issue 22 on November 22, 2022
AbstractThe individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.
Graphical Abstract
Introduction
Rheumatoid arthritis (RA) pathogenesis is a multifactorial process that involves the crosstalk between multiple adaptive and innate immune cell subsets leading to chronic synovitis and the progressive destruction of joint cartilage and bone tissue. Altered adaptive immune responses in patients with active RA disease mediated by autoantibody-producing B cells (1–3), Th1 and Th17 CD4+ T cells (4, 5), and activated cytotoxic CD8+ T cells (6) have been well characterized. However, less is known about the contribution of specific innate cell populations to perpetuate chronic inflammation and the induction of pathogenic CD4+ T cells able to produce both IL-17 and IFN-γ (known as Th1/Th17 cells), a T cell subset that is enriched in synovial fluid (SF) of patients with RA (7) and has been linked to severity of multiple autoimmune disorders (8–10). In this regard, deregulation of myeloid cells such as monocytes (Mo) and DC can lead to the development of autoimmunity (11, 12). However, the heterogeneity of Mo and DC lineages has made difficult to fully understand the contribution of individual cell subsets to RA pathology. Several studies have reported alterations in Mo subset phenotype and function in the peripheral blood (PB) and SF from patients with RA (13–15), along with their participation in the erosion of juxta-articular bone (14, 16). In contrast, less is known about the contribution of different subtypes of DC to RA immunopathology (17).
DC can be divided into 2 main subgroups, conventional DC (cDC) and plasmacytoid DC (pDC), with different functional specializations (18, 19). pDC physiologically mediate type I IFN responses in the context of viral infections (20) but have also been involved in autoimmune disorders, such as systemic lupus erythematosus and psoriasis (20). In addition, pDC appear to play a tolerogenic role on RA joint inflammation (21, 22). In contrast, cDC can be subdivided into CD141+ and CD1c+ cDC with differential abilities to efficiently activate CD8+ and CD4+ T cell responses, respectively (23, 24). Frequencies of both CD141+ and CD1c+ cDC have been reported to be reduced in the PB and enriched in the SF of patients with RA. Moreover, CD141+ and CD1c+ cDC in SF of RA individuals can induce IFN-γ+ and TNF-α+ CD4+ T cell (22, 25) or IL-17 secretion by T cells in vitro (26) in individual studies. However, potential differences in functional capacities of both cDC subsets and in Mo from patients with RA to induce pathogenic IL-17+IFN-γ+ T cells have not been directly addressed. In addition, the molecular mechanisms specifically affecting phenotypical and functional properties of CD1c+ cDC in patients with RA and the functional implications of these alterations have not been characterized. Previous genome-wide association studies (GWAS) identified genetic variations related to class II-HLA, TNF-α, Fc-receptor (FcR), toll-like receptor (TLR), and nucleic acid sensing pathways that are associated with increased risk of developing RA (27–30). Several studies have also suggested that recognition of endogenous DNA and RNA as DAMPs by nucleic-acid sensors might induce innate responses that contribute to the development of autoimmunity, including RA (31). In addition, activation of alternative innate pathways such as the NLRP3 inflammasome has been proposed as a pathogenic activation mechanism of Mo in RA (32, 33). However, it is unknown whether common or different innate sensors may differentially mediate pathogenic activation of CD1c+ cDC and other myeloid cells in RA. In fact, the most accepted treatments nowadays are based on the blockade of inflammatory cytokines or their receptors, which are not always effective (34, 35). Therefore, it is critical to identify innate sensors that might be specifically mediating pathogenic activation in different myeloid subsets in RA, in order to design more targeted and effective therapies.
The objective of our study was to specifically investigate the contribution of CD1c+ cDC to chronic disease perpetuation and the mechanism of pathogenic activation of these cells in RA. Our phenotypical, transcriptional, and functional analysis identified CD64 and CCR2 as markers of activated migratory CD1c+ cDC enriched in the inflamed joint from patients with RA, which are selectively restored in the PB after treatment initiation and reduction of clinical severity. In addition, CD1c+ cDC from the SF of patients with RA are characterized by preferential expression of IL-1β, IL-8, and CCL3 and by higher functional abilities to induce pathogenic IL-17+IFN-γ+ T cell responses in vitro compared with other synovial myeloid subsets. Interestingly, inflammatory and functional RA-like properties could be induced in vitro on CD1c+ cDC by incubation with dsDNA-IgG complexes. Remarkably, we have identified the NLRC4 as a sensor required for FcγR-mediated detection of dsDNA-IgG complexes, thereby inducing Caspase 1–dependent inflammasome activation of CD1c+ cDC subset. Collectively, our translational study provides evidence of active contribution of CD1c+ cDC to RA disease progression and identifies therapeutic target candidates that might be useful for targeted therapies for RA.
ResultsFrequencies of CD64+CD1c+ cDC in the blood are restored in treated patients with RA with reduced disease activity. Proportions of CD1c+ and CD141+ cDC, and to a lower extent pDC, were markedly reduced in the PB of 31 patients with RA recruited prior to initiating treatment and compared with 30 healthy controls (HC) including 13 age- and sex-matched individuals (Supplemental Figure 1, A and B, and Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.152886DS1), in line with previous studies (25). In contrast, frequencies of classical (C), transitional (T), and nonclassical (NC) Mo were not significantly different between these 2 cohorts (Supplemental Figure 1B). Of these populations, T-Mo and both CD1c+ and CD141+ cDC subsets were more significantly enriched in SF from patients with RA obtained during flares despite they were receiving treatment (Supplemental Figure 1B and Supplemental Table 2). We next analyzed the evolution of proportions of circulating cDC and Mo subsets in n = 14 patients with RA in a longitudinal follow-up study after treatment for either 1 or 2 years (Supplemental Table 3). We observed that, in treated patients with RA experiencing improvement of clinical values over time, such as lower number of swollen joints and lower disease activity assessed by DAS28-ESR score (Figure 1A), proportions of circulating CD1c+ cDC were more significantly recovered (nominal P = 0.0067; FDR-corrected P = 0.0335) (Figure 1B). Proportions of CD1c+ cDC were not significantly associated with age on the RA and HC cohorts (Supplemental Figure 1C). In contrast, frequencies of circulating Mo and CD141+ cDC were not significantly affected in these treated individuals (Supplemental Figure 1D). Therefore, CD1c+ cDC might be differentially altered in patients with RA. A phenotypical analysis of circulating myeloid subsets showed a nonsignificant trend to increased expression of CD40 on cDC (Figure 1C). However, expression of CD40 was significantly upregulated in CD1c+ cDC from SF, and it also tended to be increased in CD141+ cDC from this location (Figure 1C). In addition, we also identified a trend of increased CD86 levels in circulating CD1c+ and CD141+ cDC and NC-Mo, and this increase was not observed in pDC or in SF Mo subsets from patients with RA (Supplemental Figure 2, A–C). Remarkably, PB and SF CD1c+ — but not CD141+ cDC — showed significantly higher expression of CD64 (Figure 1C). Proportions of CD64+ cells in CD1c+ cDC were not significantly associated with higher disease activity (Supplemental Figure 2D). Interestingly, CD64 expression levels tended to remain upregulated in CD1c+ cDC even in treated patients with RA (Figure 1D). In contrast, CD64 expression was basally the highest in C-Mo but did not significantly increase in circulating cells. On the other hand, CD64 was significantly elevated on T- and NC-Mo from SF (Supplemental Figure 2B), in agreement with previous studies (36). In addition, no alterations in expression of alternative FcRs such as CD16 on CD1c+ cDC, CD141+ cDC, or Mo were detected, while pDC displayed a mild increase in patients with RA (Figure 1C and Supplemental Figure 2, A and B). Therefore, differential maturation programs might be taking place in CD1c+ cDC compared with CD141+ cDC and Mo. Together, our data indicate that CD1c+ cDC from RA individuals are preferentially restored after treatment initiation and are characterized by the differential expression of the cell surface marker CD64, suggesting a significant contribution of this DC subset to the perpetuation of RA pathology.
Figure 1Alterations in frequencies and expression of CD64 in DC subsets present in peripheral blood and synovial fluid from patients with RA. (A and B) Analysis of DAS28-ESR and number of swollen joint count (SJC) (A) or proportions of CD1c+ cDC (B) in blood samples from n = 31 patients with RA collected at the first visit (untreated baseline) and after 1 or 2 years of treatment. Statistical significance was calculated using a 2-tailed matched-pairs Wilcoxon test. (C) Proportions of CD40 (left), CD64 (center), and CD16 (right) on gated CD1c+ cDC (upper plots) and CD141+ cDC (lower plots) from the blood of healthy controls (HC, n = 28) and untreated patients with RA (n = 31) and SF from treated patients with RA (n = 12). Statistical significance was calculated using a Kruskal-Wallis test with Dunn’s correction. (D) Proportions of CD64+ cells within circulating CD1c+ cDC from the blood of n = 19 HC and n = 14 patients with RA at baseline and 1–2 years after treatment initiation. Statistical significance was calculated using a 2-tailed Mann Whitney U test.
Specific transcriptional profiles of innate activation in CD1c+ cDC in patients with RA. Next, differential transcriptional patterns of circulating CD1c+ and CD141+ cDC and Mo from the PB of n = 4 patients with RA and n = 4 HC were characterized. Principal component analysis (PCA) of detected genes suggests that each cell subset in RA was transcriptionally different from its corresponding HC (Supplemental Figure 3). A comparative gene expression analysis considering FDR-corrected significant P values and changes in log2 fold change of expression ov
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