Virchow, R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre: Pionierarbeit der Zellpathologie und Gewebelehre im 19. Jahrhundert. (Good Press, 1858).
Dulbecco, R., Allen, R., Okada, S. & Bowman, M. Functional changes of intermediate filaments in fibroblastic cells revealed by a monoclonal antibody. Proc. Natl Acad. Sci. USA 80, 1915–1918 (1983).
Google Scholar
Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).
Google Scholar
Muhl, L. et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 11, 3953 (2020).
Google Scholar
Mor-Vaknin, N., Punturieri, A., Sitwala, K. & Markovitz, D. M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 5, 59–63 (2003).
Google Scholar
Li, R. et al. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. eLife 7, e36865 (2018).
Google Scholar
Chandrakanthan, V. et al. Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta. Nat. Cell Biol. 24, 1211–1225 (2022).
Google Scholar
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Google Scholar
Krishnamurty, A. T. et al. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148 (2022).
Google Scholar
Fan, D., Takawale, A., Lee, J. & Kassiri, Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5, 15 (2012).
Google Scholar
Friedrich, M. et al. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat. Med. 27, 1970–1981 (2021).
Google Scholar
Rivellese, F. et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat. Med. 28, 1256–1268 (2022).
Google Scholar
Zhang, F. et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature 623, 616–624 (2023).
Google Scholar
Kelly, T., Huang, Y., Simms, A. E. & Mazur, A. Fibroblast activation protein-ɑ: a key modulator of the microenvironment in multiple pathologies. Int. Rev. Cell Mol. Biol. 297, 83–116 (2012).
Google Scholar
Kiener, H. P. et al. Cadherin-11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 60, 1305–1310 (2009).
Google Scholar
Roberts, E. W. et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).
Google Scholar
Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).
Google Scholar
Malhotra, D. et al. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13, 499–510 (2012).
Google Scholar
Gravallese, E. M. & Firestein, G. S. Rheumatoid arthritis — common origins, divergent mechanisms. N. Engl. J. Med. 388, 529–542 (2023).
Google Scholar
Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. JAMA 320, 1360–1372 (2018).
Google Scholar
Smolen, J. S. & Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015).
Google Scholar
Smith, M. D. The normal synovium. Open Rheumatol. J. 5, 100–106 (2011).
Google Scholar
Hochberg, M. C. et al. Rheumatology (Elsevier, 2023).
Fletcher, A. L., Acton, S. E. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat. Rev. Immunol. 15, 350–361 (2015).
Google Scholar
Perez-Shibayama, C., Gil-Cruz, C. & Ludewig, B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunol. Rev. 289, 31–41 (2019).
Google Scholar
Li, L., Wu, J., Abdi, R., Jewell, C. M. & Bromberg, J. S. Lymph node fibroblastic reticular cells steer immune responses. Trends Immunol. 42, 723–734 (2021).
Google Scholar
Onder, L. & Ludewig, B. A fresh view on lymph node organogenesis. Trends Immunol. 39, 775–787 (2018).
Google Scholar
van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Google Scholar
Katakai, T. et al. Organizer-like reticular stromal cell layer common to adult secondary lymphoid organs. J. Immunol. 181, 6189–6200 (2008).
Google Scholar
Roozendaal, R. et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 30, 264–276 (2009).
Google Scholar
Cremasco, V. et al. B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat. Immunol. 15, 973–981 (2014).
Google Scholar
Tew, J. G. et al. Follicular dendritic cells and presentation of antigen and costimulatory signals to B cells. Immunol. Rev. 156, 39–52 (1997).
Google Scholar
Qin, D. et al. Fcγ receptor IIB on follicular dendritic cells regulates the B cell recall response. J. Immunol. 164, 6268–6275 (2000).
Google Scholar
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Google Scholar
Acton, SophieE. et al. Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 37, 276–289 (2012).
Google Scholar
Lee, J.-W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8, 181–190 (2007).
Google Scholar
Magnusson, F. C. et al. Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity. Gastroenterology 134, 1028–1037 (2008).
Google Scholar
Fletcher, A. L. et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 207, 689–697 (2010).
Google Scholar
Baptista, A. P. et al. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. eLife 3, e04433 (2014).
Google Scholar
Lukacs-Kornek, V. et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat. Immunol. 12, 1096–1104 (2011).
Google Scholar
Siegert, S. et al. Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS ONE 6, e27618 (2011).
Google Scholar
Pinchuk, I. V. et al. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. Gastroenterology 135, 1228–1237 (2008).
Google Scholar
Owens, B. M. et al. CD90+ stromal cells are non-professional innate immune effectors of the human colonic mucosa. Front. Immunol. 4, 307 (2013).
Google Scholar
Das, A. et al. Follicular dendritic cell activation by TLR ligands promotes autoreactive B cell responses. Immunity 46, 106–119 (2017).
Google Scholar
Zeng, Q. et al. Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses. Cell Metab. 35, 837–854 e838 (2023).
Google Scholar
Karouzakis, E. et al. Molecular characterization of human lymph node stromal cells during the earliest phases of rheumatoid arthritis. Front. Immunol. 10, 1863 (2019).
Google Scholar
Mellors, R. C., Heimer, R., Corcos, J. & Korngold, L. Cellular origin of rheumatoid factor. J. Exp. Med. 110, 875–886 (1959).
Google Scholar
Nosanchuk, J. S. & Schintzier, B. Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis. A clinicopathologic study. Cancer 24, 343–354 (1969).
Google Scholar
Shapira, Y., Weinberger, A. & Wysenbeek, A. J. Lymphadenopathy in systemic lupus erythematosus. Prevalence and relation to disease manifestations. Clin. Rheumatol. 15, 335–338 (1996).
Google Scholar
Cook, M. The size and histological appearances of mesenteric lymph nodes in Crohn’s disease. Gut 13, 970 (1972).
Google Scholar
Nguyen, H. N. et al. Autocrine loop involving IL-6 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity 46, 220–232 (2017).
Google Scholar
West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).
Google Scholar
Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928–942 (2019).
Google Scholar
Ivashkiv, L. B. Cytokine expression and cell activation in inflammatory arthritis. Adv. Immunol. 63, 337–376 (1996).
Google Scholar
Sponheim, J. et al. Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am. J. Pathol. 177, 2804–2815 (2010).
Google Scholar
Boots, A. M., Wimmers-Bertens, A. J. & Rijnders, A. W. Antigen-presenting capacity of rheumatoid synovial fibroblasts. Immunology 82, 268–274 (1994).
Google Scholar
Tran, C. N. et al. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes. Arthritis Rheum. 56, 1497–1506 (2007).
Google Scholar
Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628–636 (2008).
Google Scholar
Öhlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).
Google Scholar
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
Google Scholar
Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of 100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).
Google Scholar
Kerdidani, D. et al. Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts. J. Exp. Med. 219, e20210815 (2022).
Google Scholar
DeLeon-Pennell, K. Y., Barker, T. H. & Lindsey, M. L. Fibroblasts: the arbiters of extracellular matrix remodeling. Matrix Biol. 91–92, 1–7 (2020).
Google Scholar
Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).
Google Scholar
Valencia, X. et al. Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J. Exp. Med. 200, 1673–1679 (2004).
Google Scholar
Eckes, B. et al. Mechanical tension and integrin ɑ2β1 regulate fibroblast functions. J. Investig. Dermatol. Symp. Proc. 11, 66–72 (2006).
Google Scholar
Li, B. & Wang, J. H. Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J. Tissue Viability 20, 108–120 (2011).
Google Scholar
Levick, J. R. & McDonald, J. N. Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann. Rheum. Dis. 54, 417–423 (1995).
Google Scholar
Gretz, J. E., Anderson, A. O. & Shaw, S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156, 11–24 (1997).
Google Scholar
Astarita, J. L. et al. The CLEC-2–podoplanin axis controls fibroblastic reticular cell contractility and lymph node microarchitecture. Nat. Immunol. 16, 75–84 (2015).
Google Scholar
Desmouliere, A., Chaponnier, C. & Gabbiani, G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 13, 7–12 (2005).
Google Scholar
Distler, J. H. W. et al. Shared and distinct mechanisms of fibrosis. Nat. Rev. Rheumatol. 15, 705–730 (2019).
Google Scholar
Zeisberg, M. & Kalluri, R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 304, C216–C225 (2013).
Google Scholar
Tolboom, T. C. et al. Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann. Rheum. Dis. 61, 975–980 (2002).
Google Scholar
Tunyogi-Csapo, M. et al. Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption. Arthritis Rheum. 58, 2397–2408 (2008).
Google Scholar
Gregorieff, A. et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129, 626–638 (2005).
Google Scholar
McCarthy, N. et al. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26, 391–402.e395 (2020).
Google Scholar
Brugger, M. D., Valenta, T., Fazilaty, H., Hausmann, G. & Basler, K. Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis. PLoS Biol. 18, e3001032 (2020).
Google Scholar
Liu, Y. et al. Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state. Dev. Cell 57, 1758–1775.e1757 (2022).
Google Scholar
Wei, K. et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 582, 259–264 (2020).
Google Scholar
Rinn, J. L. et al. A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev. 22, 303–307 (2008).
Google Scholar
Frank-Bertoncelj, M. et al. Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions. Nat. Commun. 8, 14852 (2017).
Google Scholar
Knosp, W. M., Scott, V., Bachinger, H. P. & Stadler, H. S. HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis. Development 131, 4581–4592 (2004).
Google Scholar
Dieu-Nosjean, M. C., Goc, J., Giraldo, N. A., Sautes-Fridman, C. & Fridman, W. H. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).
Google Scholar
Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 477 (2016).
Google Scholar
Nayar, S. et al. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc. Natl Acad. Sci. USA 116, 13490–13497 (2019).
Google Scholar
Manzo, A. et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur. J. Immunol. 35, 1347–1359 (2005).
Google Scholar
Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).
Google Scholar
Kobayashi, I. & Ziff, M. Electron microscopic studies of the cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum. 18, 475–483 (1975).
Google Scholar
Kuhn, C. & McDonald, J. A. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am. J. Pathol. 138, 1257–1265 (1991).
Google Scholar
Rodriguez, A. B. et al. Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36, 109422 (2021).
Google Scholar
Zhang, Y. et al. CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis. Cancer Cell 42, 1370–1385.e9 (2024).
Google Scholar
Yang, C. Y. et al. Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes. Proc. Natl Acad. Sci. USA 111, E109–E118 (2014).
Google Scholar
Hecker, L., Jagirdar, R., Jin, T. & Thannickal, V. J. Reversible differentiation of myofibroblasts by MyoD. Exp. Cell Res. 317, 1914–1921 (2011).
Google Scholar
Garrison, G. et al. Reversal of myofibroblast differentiation by prostaglandin E2. Am. J. Respir. Cell Mol. Biol. 48, 550–558 (2013).
Google Scholar
Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).
Google Scholar
Filer, A. & Buckley, C. D. et al. in Rheumatology (ed. Hochberg, M. C.) 1–7 (Elsevier, 2023).
Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).
Google Scholar
Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).
Google Scholar
Donlin, L. T. et al. Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue. Arthritis Res. Ther. 20, 139 (2018).
Google Scholar
Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).
Google Scholar
Armaka, M. et al. Single-cell multimodal analysis identifies common regulatory programs in synovial fibroblasts of rheumatoid arthritis patients and modeled TNF-driven arthritis. Genome Med. 14, 78 (2022).
Google Scholar
Mueller, A. A. et al. Wnt signaling drives stromal inflammation in inflammatory arthritis. Preprint at bioRxiv https://doi.org/10.1101/2025.01.06.631510 (2025).
MacLauchlan, S. et al. Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res. Ther. 19, 166 (2017).
Google Scholar
Lewis, M. J. et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 28, 2455–2470.e2455 (2019).
Google Scholar
Faust, H. J. et al. Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis. Nat. Commun. 15, 9859 (2024).
Google Scholar
Rauber, S. et al. CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis. Nat. Immunol. 25, 682–692 (2024).
Google Scholar
Korsunsky, I. et al. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 3, 481–518.e14 (2022).
Google Scholar
Tian, L., Chen, F. & Macosko, E. Z. The expanding vistas of spatial transcriptomics. Nat. Biotechnol. 41, 773–782 (2023).
Google Scholar
Lake, B. B. et al. An atlas of healthy and injured cell states and niches in the human kidney. Nature 619, 585–594 (2023).
Google Scholar
Wu, H. et al. High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing. Nat. Commun. 15, 1396 (2024).
Google Scholar
Madissoon, E. et al. A spatially resolved atlas of the human lung characterizes a gland-associated immune niche. Nat. Genet. 55, 66–77 (2023).
Google Scholar
Vannan, A. et al. Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis. Nat. Genet. 57, 647–658 (2025).
Google Scholar
Fawkner-Corbett, D. et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810–826.e823 (2021).
Google Scholar
Qi, J. et al. Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nat. Commun. 13, 1742 (2022).
Google Scholar
Reis Nisa, P. et al. Spatial programming of fibroblasts promotes resolution of tissue inflammation through immune cell exclusion. Preprint at bioRxiv https://doi.org/10.1101/2024.09.20.614064 (2024).
Periyakoil, P. K. et al. Deep topic modeling of spatial transcriptomics in the rheumatoid arthritis synovium identifies distinct classes of ectopic lymphoid structures. Preprint at bioRxiv https://doi.org/10.1101/2025.01.08.631928 (2025).
Bhamidipati, K. et al. Spatial patterning of fibroblast TGFβ signaling underlies treatment resistance in rheumatoid arthritis. Preprint at bioRxiv https://doi.org/10.1101/2025.03.14.642821 (2025).
Vickovic, S. et al. Three-dimensional spatial transcriptomics uncovers cell type localizations in the human rheumatoid arthritis synovium. Commun. Biol. 5, 129 (2022).
Google Scholar
Smith, M. H. et al. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis. Nat. Immunol. 24, 1200–1210 (2023).
Google Scholar
Zheng, L. et al. ITGA5+ synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis. Ann. Rheum. Dis. 84, 232–252 (2025).
Google Scholar
Zhao, S. et al. Effect of JAK inhibition on the induction of proinflammatory HLA–DR+CD90+ rheumatoid arthritis synovial fibroblasts by interferon-γ. Arthritis Rheumatol. 74, 441–452 (2022).
Google Scholar
Seibl, R. et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am. J. Pathol. 162, 1221–1227 (2003).
Google Scholar
Kim, K. W. et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol. Lett. 110, 54–64 (2007).
Google Scholar
Goh, F. G. & Midwood, K. S. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology 51, 7–23 (2012).
Google Scholar
Chabaud, M., Fossiez, F., Taupin, J. L. & Miossec, P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J. Immunol. 161, 409–414 (1998).
Google Scholar
Zrioual, S. et al. Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J. Immunol. 182, 3112–3120 (2009).
Google Scholar
Slowikowski, K. et al. CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts. Proc. Natl Acad. Sci. USA 117, 5532–5541 (2020).
Google Scholar
Hartupee, J., Liu, C., Novotny, M., Li, X. & Hamilton, T. IL-17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 4135–4141 (2007).
Google Scholar
MacNaul, K. L., Chartrain, N., Lark, M., Tocci, M. J. & Hutchinson, N. I. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-1 and tumor necrosis factor-ɑ on stromelysin expression. J. Biol. Chem. 265, 17238–17245 (1990).
Google Scholar
Ainola, M. M. et al. Pannus invasion and cartilage degradation in rheumatoid arthritis: involvement of MMP-3 and interleukin-1β. Clin. Exp. Rheumatol. 23, 644–650 (2005).
Google Scholar
Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110–115 (2017).
Google Scholar
Kuo, D. et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci. Transl. Med. 11, eaau8587 (2019).
Google Scholar
Yan, M. et al. ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nat. Immunol. 23, 1330–1341 (2022).
Google Scholar
Nguyen, H. N. et al. Leukemia inhibitory factor (LIF) receptor amplifies pathogenic activation of fibroblasts in lung fibrosis. Proc. Natl Acad. Sci. USA 121, e2401899121 (2024).
Google Scholar
Xiao, Y. & MacRae, I. J. Toward a comprehensive view of microRNA biology. Mol. Cell 75, 666–668 (2019).
Google Scholar
Trenkmann, M. et al. Tumor necrosis factor α-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling. Arthritis Rheum. 65, 916–927 (2013).
Google Scholar
Stanczyk, J. et al. Altered expression of microRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001–1009 (2008).
Google Scholar
Nakasa, T. et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58, 1284–1292 (2008).
Google Scholar
Long, L. et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. J. Immunol. Res. 2013, 296139 (2013).
Saferding, V. et al. MicroRNA-146a governs fibroblast activation and joint pathology in arthritis. J. Autoimmun. 82, 74–84 (2017).
Google Scholar
Churov, A. V., Oleinik, E. K. & Knip, M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun. Rev. 14, 1029–1037 (2015).
Google Scholar
Iborra, M., Bernuzzi, F., Invernizzi, P. & Danese, S. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun. Rev. 11, 305–314 (2012).
Google Scholar
O’Reilly, S. MicroRNAs in fibrosis: opportunities and challenges. Arthritis Res. Ther. 18, 11 (2016).
Google Scholar
Aprelikova, O. & Green, J. E. MicroRNA regulation in cancer-associated fibroblasts. Cancer Immunol. Immunother. 61, 231–237 (2012).
Google Scholar
Eckes, B. et al. Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol. 19, 325–332 (2000).
Google Scholar
Janmey, P. A., Fletcher, D. A. & Reinhart-King, C. A. Stiffness sensing by cells. Physiol. Rev. 100, 695–724 (2020).
Google Scholar
Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).
Google Scholar
Chang, S. K. et al. Cadherin-11 regulates fibroblast inflammation. Proc. Natl Acad. Sci. USA 108, 8402–8407 (2011).
Google Scholar
Vandooren, B. et al. Tumor necrosis factor ɑ drives cadherin 11 expression in rheumatoid inflammation. Arthritis Rheum. 58, 3051–3062 (2008).
Google Scholar
Schneider, D. J. et al. Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-β production and epithelial to mesenchymal transition. FASEB J. 26, 503–512 (2012).
Google Scholar
Wu, M. et al. Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol. 66, 1010–1021 (2014).
Google Scholar
Schroer, A. K. et al. Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction. JCI Insight 4, e131545 (2019).
Google Scholar
Stanford, S. M. et al. Receptor protein tyrosine phosphatase α–mediated enhancement of rheumatoid synovial fibroblast signaling and promotion of arthritis in mice. Arthritis Rheumatol. 68, 359–369 (2016).
Google Scholar
Sendo, S. et al. Clustering of phosphatase RPTPɑ promotes Src signaling and the arthritogenic action of synovial fibroblasts. Sci. Signal. 16, eabn8668 (2023).
Google Scholar
Lo, C.-M., Wang, H.-B., Dembo, M. & Wang, Y.-l. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79, 144–152 (2000).
Google Scholar
Gu, Z. et al. Soft matrix is a natural stimulator for cellular invasiveness. Mol. Biol. Cell 25, 457–469 (2014).
Google Scholar
Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L344–L357 (2015).
Google Scholar
Southern, B. D. et al. Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. J. Biol. Chem. 291, 6083–6095 (2016).
Google Scholar
Cambré, I. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun. 9, 4613 (2018).
Google Scholar
Müller-Ladner, U. et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol. 149, 1607–1615 (1996).
Google Scholar
Bartok, B. & Firestein, G. S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev. 233, 233–255 (2010).
Google Scholar
Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 5, 40 (2013).
Google Scholar
Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009).
Google Scholar
Orange, D. E. et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N. Engl. J. Med. 383, 218–228 (2020).
Google Scholar
Nile, C. J., Read, R. C., Akil, M., Duff, G. W. & Wilson, A. G. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 58, 2686–2693 (2008).
Google Scholar
Karouzakis, E. et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes. Immun. 12, 643–652 (2011).
Google Scholar
Nakano, K., Whitaker, J. W., Boyle, D. L., Wang, W. & Firestein, G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72, 110–117 (2013).
Google Scholar
de la Rica, L. et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J. Autoimmun. 41, 6–16 (2013).
Google Scholar
Araki, Y. et al. Histone methylation and STAT-3 differentially regulate interleukin-6-induced matrix metalloproteinase gene activation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 68, 1111–1123 (2016).
Google Scholar
Lee, A. et al. Tumor necrosis factor ɑ induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 65, 928–938 (2013).
Google Scholar
Loh, C. et al. TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis. Ann. Rheum. Dis. 78, 1205–1214 (2019).
Google Scholar
Sohn, C. et al. Prolonged tumor necrosis factor alpha primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 67, 86–95 (2015).
Google Scholar
Friščić, J. et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 54, 1002–1021.e10 (2021).
Google Scholar
Weinand, K. et al. The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis. Nat. Commun. 15, 4650 (2024).
Google Scholar
Ai, R. et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat. Commun. 9, 1921 (2018).
Google Scholar
Ai, R. et al. DNA methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980 (2015).
Google Scholar
Karouzakis, E. et al. Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci. Rep. 8, 7370 (2018).
Google Scholar
Ai, R. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat. Commun. 7, 11849 (2016).
Google Scholar
Hammaker, D. et al. Joint location–specific JAK-STAT signaling in rheumatoid arthritis fibroblast-like synoviocytes. ACR Open Rheumatol. 1, 640–648 (2019).
Google Scholar
Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit. Nat. Rev. Drug. Discov. 17, 197–223 (2018).
Google Scholar
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).
Google Scholar
van de Donk, N. & Zweegman, S. T-cell-engaging bispecific antibodies in cancer. Lancet 402, 142–158 (2023).
Google Scholar
Fenis, A., Demaria, O., Gauthier, L., Vivier, E. & Narni-Mancinelli, E. New immune cell engagers for cancer immunotherapy. Nat. Rev. Immunol. 24, 471–486 (2024).
Google Scholar
Busek, P., Mateu, R., Zubal, M., Kotackova, L. & Sedo, A. Targeting fibroblast activation protein in cancer — prospects and caveats. Front. Biosci. 23, 1933–1968 (2018).
Google Scholar
Xin, L. et al. Fibroblast activation protein-ɑ as a target in the bench-to-bedside diagnosis and treatment of tumors: a narrative review. Front. Oncol. 11, 648187 (2021).
Google Scholar
Scott, A. M. et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).
Google Scholar
McConathy, J. et al. 671P LuMIERE: a phase I/II study evaluating safety, dosimetry, and preliminary activity of [177Lu]Lu-FAP-2286 in patients with advanced solid tumors. Ann. Oncol. 35, S526 (2024).
Google Scholar
Shahvali, S., Rahiman, N., Jaafari, M. R. & Arabi, L. Targeting fibroblast activation protein (FAP): advances in CAR-T cell, antibody, and vaccine in cancer immunotherapy. Drug. Deliv. Transl. Res. 13, 2041–2056 (2023).
Google Scholar
Chai, X. P. et al. Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-ɑ. Acta Pharmacol. Sin. 39, 415–424 (2018).
Google Scholar
Cui, X. Y. et al. Covalent targeted radioligands potentiate radionuclide therapy. Nature 630, 206–213 (2024).
Google Scholar
Loureiro, L. R. et al. Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment. J. Exp. Clin. Cancer Res. 42, 341 (2023).
Google Scholar
de Sostoa, J. et al. Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J. Immunother. Cancer 7, 19 (2019).
Google Scholar
Hiltbrunner, S. et al. Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial. Ann. Oncol. 32, 120–121 (2021).
Google Scholar
Bocci, M. et al. In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment. J. Control. Rel. 367, 779–790 (2024).
Google Scholar
Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019).
Google Scholar
Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).
Google Scholar
Dorst, D. N. et al. Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy. Rheumatology 61, 2999–3009 (2022).
Google Scholar
Mori, Y. et al. FAPI PET: fibroblast activation protein inhibitor use in oncologic and nononcologic disease. Radiology 306, e220749 (2023).
Google Scholar
Chavula, T., To, S. & Agarwal, S. K. Cadherin-11 and its role in tissue fibrosis. Cell Tissues Organs 212, 293–303 (2023).
Google Scholar
Schett, G. et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat. Rev. Rheumatol. 20, 531–544 (2024).
Google Scholar
Chung, J. B., Brudno, J. N., Borie, D. & Kochenderfer, J. N. Chimeric antigen receptor T cell therapy for autoimmune disease. Nat. Rev. Immunol. 24, 830–845 (2024).
Google Scholar
Michaelson, J. S. & Baeuerle, P. A. CD19-directed T cell-engaging antibodies for the treatment of autoimmune disease. J. Exp. Med. 221, e20240499 (2024).
Google Scholar
Shah, K. et al. Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy? Clin. Exp. Immunol. 217, 15–30 (2024).
Google Scholar
Parayath, N. N., Stephan, S. B., Koehne, A. L., Nelson, P. S. & Stephan, M. T. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat. Commun. 11, 6080 (2020).
Google Scholar
Zhao, Y. et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053–9061 (2010).
Google Scholar
Bucci, L. et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat. Med. 30, 1593–1601 (2024).
Google Scholar
Hagen, M. et al. BCMA-targeted T-cell-engager therapy for autoimmune disease. N. Engl. J. Med. 391, 867–869 (2024).
Google Scholar
Alexander, T., Kronke, J., Cheng, Q., Keller, U. & Kronke, G. Teclistamab-induced remission in refractory systemic lupus erythematosus. N. Engl. J. Med. 391, 864–866 (2024).
Google Scholar
Heipertz, E. L. et al. Current perspectives on “off-the-shelf” allogeneic NK and CAR-NK cell therapies. Front. Immunol. 12, 732135 (2021).
Google Scholar
Younesi, F. S., Miller, A. E., Barker, T. H., Rossi, F. M. V. & Hinz, B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat. Rev. Mol. Cell Biol. 25, 617–638 (2024).
Google Scholar
Bhattacharya, M. & Ramachandran, P. Immunology of human fibrosis. Nat. Immunol. 24, 1423–1433 (2023).
Google Scholar
Zhao, M. et al. Targeting fibrosis, mechanisms and clinical trials. Signal. Transduct. Target. Ther. 7, 206 (2022).
Google Scholar
Klein, K. et al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 75, 422–429 (2016).
Google Scholar
Neidhart, M., Karouzakis, E., Jungel, A., Gay, R. E. & Gay, S. Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis. Arthritis Rheumatol. 66, 1723–1733 (2014).
Google Scholar
Kehrberg, R. J., Bhyravbhatla, N., Batra, S. K. & Kumar, S. Epigenetic regulation of cancer-associated fibroblast heterogeneity. Biochim. Biophys. Acta Rev. Cancer 1878, 188901 (2023).
Google Scholar
Ulukan, B., Sila Ozkaya, Y. & Zeybel, M. Advances in the epigenetics of fibroblast biology and fibrotic diseases. Curr. Opin. Pharmacol. 49, 102–109 (2019).
Google Scholar
Liu, Y. et al. Epigenetics as a versatile regulator of fibrosis. J. Transl. Med. 21, 164 (2023).
Google Scholar
Fearon, U., Hanlon, M. M., Wade, S. M. & Fletcher, J. M. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. Clin. Exp. Immunol. 197, 170–180 (2019).
Google Scholar
Hu, Z. et al. Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review. Front. Immunol. 15, 1250884 (2024).
Google Scholar
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Google Scholar
Zhang, F. et al. Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution. J. Hematol. Oncol. 17, 80 (2024).
Google Scholar
Hamanaka, R. B. & Mutlu, G. M. Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism. FEBS J. 288, 6331–6352 (2021).
Google Scholar
Wang, S., Liang, Y. & Dai, C. Metabolic regulation of fibroblast activation and proliferation during organ fibrosis. Kidney Dis. 8, 115–125 (2022).
Google Scholar
Noom, A., Sawitzki, B., Knaus, P. & Duda, G. N. A two-way street — cellular metabolism and myofibroblast contraction. NPJ Regen. Med. 9, 15 (2024).
Google Scholar
Takahashi, S. et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 19, 76 (2017).
Google Scholar
Song, G. et al. Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis. Arthritis Res. Ther. 21, 87 (2019).
Google Scholar
Ahmed, S. et al. Dual inhibition of glycolysis and glutaminolysis for synergistic therapy of rheumatoid arthritis. Arthritis Res. Ther. 25, 176 (2023).
Google Scholar
Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).
Google Scholar
Koedderitzsch, K., Zezina, E., Li, L., Herrmann, M. & Biesemann, N. TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A. Sci. Rep. 11, 19385 (2021).
Google Scholar
Becker, L. M. et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31, 107701 (2020).
Google Scholar
Broz, M. T. et al. Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas. Nat. Commun. 15, 2498 (2024).
Google Scholar
Cho, S. J., Moon, J. S., Lee, C. M., Choi, A. M. & Stout-Delgado, H. W. Glucose transporter 1-dependent glycolysis is increased during aging-related lung fibrosis, and phloretin inhibits lung fibrosis. Am. J. Respir. Cell Mol. Biol. 56, 521–531 (2017).
Google Scholar
Yin, X. et al. Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β. Sci. Signal. 12, eaax4067 (2019).
Google Scholar
Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e21 (2021).
Google Scholar
Huynh, N. C.-N. et al. Oncostatin M-driven macrophage-fibroblast circuits as a drug target in autoimmune arthritis. Inflamm. Regen. 44, 36 (2024).
Google Scholar
Tsaltskan, V. & Firestein, G. S. Targeting fibroblast-like synoviocytes in rheumatoid arthritis. Curr. Opin. Pharmacol. 67, 102304 (2022).
Google Scholar
Finch, R. et al. Op0224 results of a phase 2 study of Rg6125, an anti-cadherin-11 monoclonal antibody, in rheumatoid arthritis patients with an inadequate response to anti-TNFalpha therapy. Ann. Rheum. Dis. 78, 189–189 (2019).
Google Scholar
Scheller, J., Grötzinger, J. & Rose‐John, S. Updating interleukin‐6 classic‐and trans‐signaling. Signal. Transduct. 6, 240–259 (2006).
Google Scholar
Choy, E. H. et al. Translating IL-6 biology into effective treatments. Nat. Rev. Rheumatol. 16, 335–345 (2020).
Google Scholar
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M. & Scheller, J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat. Rev. Immunol. 23, 666–681 (2023).
Google Scholar
Ruderman, E. M. Rheumatoid arthritis: IL-6 inhibition in RA-deja vu all over again? Nat. Rev. Rheumatol. 11, 321–322 (2015).
Google Scholar
Danese, S. et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut 68, 40–48 (2019).
Google Scholar
Haringman, J. J. et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 54, 2387–2392 (2006).
Google Scholar
Vergunst, C. E. et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 58, 1931–1939 (2008).
Google Scholar
Szekanecz, Z. & Koch, A. E. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 5–13 (2016).
Google Scholar
Cambier, S., Gouwy, M. & Proost, P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol. Immunol. 20, 217–251 (2023).
Google Scholar
Kurowska-Stolarska, M. & Alivernini, S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat. Rev. Rheumatol. 18, 384–397 (2022).
Google Scholar
Hitchon, C. A. & El-Gabalawy, H. S. The synovium in rheumatoid arthritis. Open Rheumatol. J. 5, 107–114 (2011).
Google Scholar
Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
Google Scholar
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Google Scholar
Firestein, G. S. & McInnes, I. B. Immunopathogenesis of rheumatoid arthritis. Immunity 46, 183–196 (2017).
Google Scholar
Snir, O. et al. Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63, 2873–2883 (2011).
Google Scholar
Moon, J. S. et al. Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis. Nat. Commun. 14, 319 (2023).
Google Scholar
Rao, D. A. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542, 110–114 (2017).
Google Scholar
Donado, C. A. et al. Granzyme K activates the entire complement cascade. Nature https://doi.org/10.1038/s41586-025-08713-9 (2025).
Google Scholar
Kongpachith, S. et al. Affinity maturation of the anti-citrullinated protein antibody paratope drives epitope spreading and polyreactivity in rheumatoid arthritis. Arthritis Rheumatol. 71, 507–517 (2019).
Google Scholar
