Search

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular abnormalities, and immune dysfunction, with no definitive cure. Patients with progressive pulmonary fibrosis face a high mortality risk, underscoring the urgent need for effective treatments. Although fibroblasts are recognized as key drivers of fibrosis, the precise molecular mechanisms remain poorly understood. In this study, we employ single-cell RNA sequencing to explore the role of fibroblasts in pulmonary fibrosis. Using a mouse model induced by subcutaneous bleomycin administration, we identify two distinct fibroblast subpopulations: nephronectin-positive (NPNT) and peptidase inhibitor 16-positive cells(PI16). NPNT-positive fibroblasts, located around the alveoli, exhibit increased extracellular matrix expression following bleomycin treatment. To further understand pulmonary fibrosis, subcutaneous and intratracheal bleomycin-induced mouse models are compared. A comparative gene expression analysis reveals shared and unique features between the models, highlighting the complexity of the fibrotic process. These findings offer valuable insights into the molecular mechanisms of SSc-associated pulmonary fibrosis and may inform the development of therapies targeting specific fibroblast subpopulations or pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Katsuto Tamai is a scientific founder of and received research funding from StemRIM. Katsuto Tamai and Takashi Shimbo are StemRIM stockholders. Yuya Ouchi, Tomomi Kitayama, Sho Yamazaki and Kastuto Tamai are employees of StemRIM., (Copyright © 2024. Published by Elsevier Inc.)

Objective: SSc is a connective tissue disease with multisystem disorder induced by the inflammation and fibrosis following T and B cell abnormalities. Follicular helper CD4+ T (TFH) cells play a crucial role in the formation of germinal centres and specialize in interacting to aid B cell differentiation. We aimed to investigate TFH cells and their subsets to evaluate their involvement with B cell alteration in SSc., Method: Circulating TFH cells (cTFH), B cells and their subsets were assessed by flow cytometry. The concentration of serum cytokines was measured by cytokine array assay. Immunohistochemistry and IF were performed to evaluate the migration of TFH cells in SSc skin lesions., Results: The proportion of cTFH cells did not differ from controls, but their subsets were imbalanced in SSc patients. The frequency of TFH 1 was increased and correlated with ACA titre, serum IgM or CRP levels of patients, and cytokine concentrations of IL-21 and IL-6 that induce B cell differentiation in SSc. cTFH cells from SSc showed activated phenotype with expressing higher cytokine levels compared with controls. The frequency of TFH 17 was also increased, but was not correlated with a high level of Th17 cytokines in patients' sera. Furthermore, infiltration of TFH cells was found in skin lesion of SSc patients., Conclusion: We here describe an imbalance of cTFH toward TFH 1 that may induce B cell alteration through IL-21 and IL-6 pathways and promote inflammation, contributing to the pathogenesis of SSc disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Sarcoidosis and systemic sclerosis (SSc) are both multisystem disorders of unknown etiology. Some cases having both sarcoidosis and SSc have been reported previously. The present study was to investigate clinical features in sarcoidosis patients who possessed SSc-specific autoantibody. The pathophysiology of each disease, including shared pathways leading to the development of both conditions, is reviewed in addition to previous reports of patients with concomitant SSc and sarcoidosis. SSc-specific autoantibodies including anticentromere antibody (ACA), anti-topoisomerase I antibody, anti-RNA polymerase III antibody and anti-U1RNP antibody were examined in sarcoidosis patients. Complete medical histories, clinical examinations and laboratory tests were conducted for all patients. For reviewing previously published reports, all cases were retrieved through a PubMed search. ACA was most frequently observed in sarcoidosis patients. Plaques and papules were the most frequent as the cutaneous sarcoidosis lesions. Soluble interleukin-2 receptor was elevated in most of the cases (6/8, 75%), and thymus and activation-regulated chemokine (TARC) was elevated in all cases (6/6, 100%). Together with our two cases (cases 1 and 3), a review of previously reported cases of sarcoidosis patients concomitant with SSc showed high frequency of ACA and plaques as cutaneous lesions. We suppose that TARC may play some roles in the production of SSc-specific autoantibodies and development of concomitance with SSc in sarcoidosis, although the mechanisms remain unknown., (© 2019 Japanese Dermatological Association.)

Systemic sclerosis (SSc)-related autoantibodies are useful tools in identifying clinically homogenous subsets of patients and predicting their prognosis. In this report, we described five SSc patients with anti-centriole antibodies. All five patients were females and had digital ulcers/gangrene. Four of five (80%) patients had pulmonary arterial hypertension (PAH). None of the five patients had active pulmonary fibrosis or developed renal crisis. Anti-centriole antibodies may be a marker for PAH and digital ulcers/gangrene.

Background: Systemic sclerosis (SSc) is a systemic inflammatory and fibrotic disease characterized by activation of circulating T lymphocytes., Objective: To determine phenotypic abnormalities of γ/δ T cells and whether γ/δ T cells influence fibroblasts activation in SSc patients., Methods: Number and proportion of peripheral γ/δ T lymphocytes, and their expressions of cell surface molecules were evaluated by flow cytometry. Isolated γ/δ T cells were cocultured with fibroblast, and mRNA expressions of proalpha1(I) collagen and proalpha2(I) collagen (COL1A2) of fibroblasts were analyzed by real time RT-PCR. γ/δ T cell infiltrations in the skin were examined histopathologically., Results: No significant difference in number and proportion of γ/δ T cells was observed in SSc patients compared to healthy controls (HCs). Geometric mean fluorescence intensity (GMFI) of CD16 and CD69 on γ/δ T cells was significantly increased in patients with diffuse cutaneous SSc (dcSSc) compared to HCs. CD62L expression was significantly decreased in patients with dcSSc compared to HCs. The percentage of CD69 positive γ/δ T cells was significantly higher in patients with SSc than HCs. COL1A2 mRNA expression was significantly higher in fibroblasts cocultured with γ/δ T cells from SSc than that from HCs in cell contact independent manner. Additionally, γ/δ T cell infiltrations were observed in SSc patients' skin., Conclusion: Our results suggest that γ/δ T cells showed activated phenotype in SSc and suggest that SSc γ/δ T cells may play an important role on fibrotic process by upregulation of COL1A2 mRNA expression in fibroblasts., (Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to determine the prevalence of anti-CCP antibodies (anti-CCP Abs) and to assess associations between the presence of anti-CCP Ab and arthritis or arthralgia in SSc patients., Methods: Serum samples were obtained from 146 SSc patients. Anti-CCP Ab, anti-agalactosyl (AG) IgG Ab, IgM-RF, IgG-RF and MMP-3 were determined, respectively., Results: The presence of anti-CCP Ab was found in 18/146 (12%) patients with SSc. Elevated levels of anti-AG IgG Abs, IgM- and IgG-RFs were observed in 50/146 (34%), 17/146 (12%) and 4/146 (3%), respectively. Serum anti-CCP Ab levels were significantly elevated in SSc-RA overlap patients compared with SSc patients with or without arthralgia (P < 0.05 or P < 0.001, respectively). Serum MMP-3 levels did not correlate with the presence of arthritis or arthralgia but were significantly associated with modified Rodnan total skin thickness score. In SSc-RA overlap patients, 10/11 (91%) patients were positive for two or more RA-related Abs., Conclusions: The serum titre of anti-CCP Ab is higher in SSc-RA overlap patients than in SSc patients with or without arthralgia. The finding of high titres of anti-CCP Abs and the elevated levels combinatory with other RA-related Abs may help to define the diagnosis of SSc-RA overlap. MMP-3 might be a better marker to assess skin involvement rather than joint involvement in SSc patients.

Objective: To assess red blood cell velocity in finger nail-fold capillaries using video capillaroscopy in patients with SSc and other collagen diseases., Methods: This study included 127 patients with SSc as well as patients with SLE (n = 33), DM/PM (n = 21), RA (n = 13) and APS (n = 12), and 20 healthy subjects. Red blood cell velocity was evaluated using frame-to-frame determination of the position of capillary plasma gaps., Results: The mean red blood cell velocity was significantly decreased in patients with SSc compared to healthy controls (63.0% reduction) and patients with other conditions. Mean blood velocity was similar between patients with dcSSc and lcSSc. Importantly, even SSc patients with normal or non-specific nail-fold video capillaroscopic (NVC) patterns or a scleroderma early NVC pattern exhibited a significantly lower red blood cell velocity compared to healthy controls (51.7 and 61.4% reduction, respectively) or patients with other conditions, despite normal or mild capillary changes. Patients with the scleroderma active and late NVC pattern showed a more decreased blood velocity (65.5 and 66.2% reduction, respectively). This reduced blood velocity was significantly associated with NVC findings, including capillary ramification and capillary loss. Although remarkably reduced velocity was observed in SSc patients with intractable digital ulcers (72.1% reduction), it was significantly improved by lipo-prostaglandin E(1) (lipo-PGE(1)) infusion., Conclusion: Our results suggest that reduced blood velocity is a hallmark of SSc. Furthermore, measurement of red blood cell velocity may be useful in evaluating therapeutic effects on microcirculation.