The Yin and Yang of IL-17 in Systemic Sclerosis

Wei, Lanxuan; Abraham, David; Ong, Voon H

doi:10.3389/fimmu.2022.885609

Cited by 23 publications

(23 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding is of general interest since Th17 cells appear to play important roles in many autoimmune diseases (57, 58). In SSc, several studies indicate key roles of Th17 cells in disease pathogenesis, but the mechanism by which these cells operate have still not been fully worked out (59)(60)(61). Regarding SSc-PAH, data are limited, but there is one study indicating Th17 polarization by flow cytometry of lymphocytes from PAH patients (62).…”

Section: B Amentioning

confidence: 99%

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

et al. 2022

View full text Add to dashboard Cite

IntroductionSystemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21.Materials and methodsTo investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS).ResultsBy IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail.ConclusionThis study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.

show abstract

Section: B Amentioning

confidence: 99%

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Among the six members of the IL-17 cytokine family (IL-17A-F), IL-17A is the pioneer cytokine mostly studied in Th17 immunopathogenesis of SSc. 58,59 Th17 cells predominantly secrete IL-17A and IL-17F, but their response is skewed toward the IL-17A pathway than the IL-17F pathway. 59 Nakashima et al first observed no increase in IL-17F levels in the sera of patients with SSc.…”

Section: Il-17amentioning

confidence: 99%

“…58,59 Th17 cells predominantly secrete IL-17A and IL-17F, but their response is skewed toward the IL-17A pathway than the IL-17F pathway. 59 Nakashima et al first observed no increase in IL-17F levels in the sera of patients with SSc. However, a proportional increase in the IL-17F population with disease duration and severity has also been reported.…”

Section: Il-17amentioning

confidence: 99%

“…Some contradictory studies indicating no difference or lower level of IL-17A in the sera of patients with SSc exist. 59 However, it is thought to be involved in the production of profibrotic or proinflammatory cytokines and to enhance fibroblast proliferation. Moreover, its elevation is associated with disease onset and activity, modified Rodnan skin score, lung severity, telangiectasia, and pitting scars.…”

Section: Il-17amentioning

confidence: 99%

“…Other anti-IL-17 drugs, such as ixekizumab and secukinumab, are also being studied for SSc treatment. 59 Given that IL-17A signaling inhibits fibrogenic processes via the downregulation of CTGF and collagen synthesis, 36,66 it may represent an attractive target in SSC treatment.…”

Section: Il-17amentioning

confidence: 99%

See 2 more Smart Citations

Targeting cytokines and potentiality of JAK–STAT inhibition in systemic sclerosis

Aung

Hamaguchi

Matsushita

2022

J Cutaneous Imm & Allergy

View full text Add to dashboard Cite

Systemic sclerosis (SSc) or scleroderma is an autoimmune disease of unknown etiology, the treatment of which has garnered increased research interest. Associated symptoms range from localized or diffused skin tightening to multiple organ failure, including the lungs, kidneys, heart, and gastrointestinal tract, with considerable morbidity and mortality. Given that several cytokines contribute to the immune pathogenesis of SSc, efforts have been made toward the development of treatments targeting these cytokines to control disease progression. Indeed, anti‐cytokine therapy has emerged as a new therapeutic intervention. Recently, the Janus kinase signal transducer and activator of transcription (JAK–STAT) pathway has been investigated as a novel candidate for the fibrogenic pathology of SSc. However, a comprehensive scientific review of the targeted therapy for SSc has been hampered by the rarity and heterogeneous nature of the disease. In this review, we provide an overview of cytokines involved in the innate and adaptive immune pathogenesis of SSc based on recent scientific data. In particular, we focus on targeted anti‐cytokine therapy and the emerging role of the JAK–STAT inhibitor, a prospective therapeutic agent for the reversal of disease pathogenesis.

show abstract

Serum IL-17 and TNFα as prognostic biomarkers in systemic sclerosis patients: a prospective study

Kosałka-Węgiel,

Lichołai,

Pacholczak-Madej

et al. 2023

Rheumatol Int

View full text Add to dashboard Cite

Recent reports have demonstrated that endothelial injury is critical in the pathogenesis of systemic sclerosis (SSc) and is associated with increased levels of circulating inflammatory biomarkers. This study aims to analyze the serum concentrations of selected cytokines and evaluate their relationship with SSc clinics and the long-term course of the disease. This study included 43 SSc patients and 24 matched healthy controls. In both groups, we measured serum levels of inflammatory cytokines related to the inflammatory response, such as tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-4, IL-6, IL-10, and IL-17, and fibroblast activation protein (FAP). Additionally, in SSc patients, we evaluated the presence of four single nucleotide polymorphisms (SNPs) located in the promotor region of the TNFA gene, namely rs361525, rs1800629, rs1799964, and rs1799724, which might be related to increased TNFα concentrations. The main aim consisted of associating inflammatory cytokines with (1) clinical disease characteristics and (2) longitudinal observation of survival and cancer prevalence. SSc patients were characterized by a 17% increase in serum TNFα. There was no other difference in serum cytokines between the studied groups and diffuse vs. limited SSc patients. As expected, evaluated serum cytokines correlated with inflammatory biomarkers (e.g., IL-6 and C-reactive protein). Interestingly, patients with higher IL-17 had decreased left ventricle ejection fraction. During the median 5-year follow-up, we recorded four cases of neoplastic diseases (lung cancer in two cases, squamous cell carcinoma of unknown origin, and breast cancer with concomitant multiple myeloma) and nine deaths. The causes of death included lung cancer (n = 2), renal crisis (n = 1), multiple-organ failure (n = 1), and unknown reasons in five cases. Surprisingly, higher TNFα was associated with an increased cancer prevalence, while elevated IL-17 with death risk in the follow-up. Furthermore, the AG rs361525 genotype referred to higher TNFα levels than GG carriers. Both AG rs361525 and CT rs1799964 genotypes were associated with increased cancer risk. Higher serum concentrations of TNFα characterize the SSc patients, with the highest values associated with cancer. On the other hand, increased IL-17 in peripheral blood might predict poor SSc prognosis. Further research is needed to validate these findings.

show abstract

The Yin and Yang of IL-17 in Systemic Sclerosis

Cited by 23 publications

References 52 publications

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

Targeting cytokines and potentiality of JAK–STAT inhibition in systemic sclerosis

Serum IL-17 and TNFα as prognostic biomarkers in systemic sclerosis patients: a prospective study

Contact Info

Product

Resources

About