Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures

Hill, David; Ward, Amy; Nicholson, Lindsay B.; Jones, Gareth Wyn

doi:10.1016/j.cyto.2021.155650

Cited by 6 publications

(8 citation statements)

References 223 publications

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“…Interaction analysis showed that rituximab responders had a greater decrease in genes encoding for serum amyloid proteins, Ig chains, the citrullination enzyme PADI2 and transcriptional regulator RORgamma. In tocilizumab responders, a greater reduction in pro-lymphoid follicle development genes was observed in keeping with the important role of IL-6 as a B cell growth factor driving in situ ectopic lymphoid structure development within inflamed tissues 38 .…”

Section: Discussionsupporting

confidence: 60%

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Rivellese

Surace

Goldmann

et al. 2022

Nat Med

137

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Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

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Section: Discussionsupporting

confidence: 60%

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Rivellese

Surace

Goldmann

et al. 2022

Nat Med

137

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“…Among TLS-promoting factors, IL-6 can promote TLS development in Th17 cells containing podophyllol. Meanwhile, IL-27 can limit the size and function of TLS by controlling the multiplication of Th17 cells (35,39). Th17 cells and Th17 cytokines, such as IL-17 and IL-22, also contribute to the occurrence and development of TLS (40)(41)(42)(43).…”

Section: Tls Formationmentioning

confidence: 99%

“…With continuous inflammatory stimulation, the TLSs mature. At this time, T- and B-cell compartmentalization occurs; CD21 + FDC networks appear at the TLS center and gradually form a functional GC ( 35 ). Of note, although LTIs are extremely important for SLO development in most areas of the human body, the latest evidence shows that TLS can still be formed in the absence of LTIs ( 36 ).…”

Section: Background Of Tlsmentioning

confidence: 99%

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

et al. 2022

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Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.

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“…It is known that ELS represents a structure of lymphocyte clusters in non-lymphoid tissues, primarily consisting of B cells, T cells, and DCs. ELS is closely related to both cellular immunity and humoral immunity ( 67 ). The synovial membrane pathological feature in approximately 40% of RA patients is follicular synovitis with ELS ( 76 ).…”

Section: Cross Talk Between Il-27 Signaling and Ra Pathologiesmentioning

confidence: 99%

“…Pdp + Th17 cells contribute to ELS formation ( 77 – 79 ). Of note, IL-27 regulates the formation and development of ELS ( 67 ). A previous study also found that in RA patients and adjuvant-induced arthritis (AIA) mice, IL-27 signaling inhibits Pdp + Th17 cells, which is linked to ELS formation ( 68 ).…”

Section: Cross Talk Between Il-27 Signaling and Ra Pathologiesmentioning

confidence: 99%

Interleukin 27 Signaling in Rheumatoid Arthritis Patients: Good or Evil?

Liang

Chen

et al. 2022

Front. Immunol.

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The occurrence and development of rheumatoid arthritis (RA) is regulated by numerous cytokines. Interleukin 27 (IL-27) is a soluble cytokine that exerts biological effects by regulating the Janus tyrosine kinase (JAK)/signal transducer and activator of the transcription (STAT) signaling pathway via the IL-27 receptor. IL-27 is known for its pleiotropic roles in modulating inflammatory responses. Previous studies found that IL-27 levels are elevated in RA blood, synovial fluid, and rheumatoid nodules. Cellular and animal experiments indicated that IL-27 exerts multiple regulatory functions in RA patients via different mechanisms. IL-27 inhibits ectopic-like structure (ELS) formation and CD4+ T helper type 2 (Th2) cell, CD4+ T helper type 17 (Th17) cell, and osteoclast differentiation in RA, contributing to alleviating RA. However, IL-27 promotes Th1 cell differentiation, which may exacerbate RA synovitis. Moreover, IL-27 also acts on RA synovial fibroblasts (RA-FLSs) and regulatory T cells (Tregs), but some of its functions are unclear. There is currently insufficient evidence to determine whether IL-27 promotes or relieves RA. Targeting IL-27 signaling in RA treatment should be deliberate based on current knowledge.

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Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures

Cited by 6 publications

References 223 publications

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

Interleukin 27 Signaling in Rheumatoid Arthritis Patients: Good or Evil?

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