Abstract Objectives Displaying immunosuppressive and trophic properties, mesenchymal stem/stromal cells (MSC) are being evaluated as promising therapeutic options in a variety of autoimmune and ...degenerative diseases. Although benefits may be expected in systemic sclerosis (SSc), a rare autoimmune disease with fibrosis-related mortality, MSC have yet to be evaluated in this specific condition. While autologous approaches could be inappropriate because of functional alterations in MSC from patients, the objective of the present study was to evaluate allogeneic and xenogeneic MSC in the HOCl-induced model of diffuse SSc. We also questioned the source of human MSC and compared bone marrow- (hBM-MSC) and adipose-derived MSC (hASC). Methods HOCl-challenged BALB/c mice received intravenous injection of BM-MSC from syngeneic BALB/c or allogeneic C57BL/6 mice, and xenogeneic hBM-MSC or hASC (3 donors each). Skin thickness was measured during the experiment. At euthanasia, histology, immunostaining, collagen determination and RT-qPCR were performed in skin and lungs. Results Xenogeneic hBM-MSC were as effective as allogeneic or syngeneic BM-MSC in decreasing skin thickness, expression of Col1 , Col3 , α-Sma transcripts, and collagen content in skin and lungs. This anti-fibrotic effect was not associated with MSC migration to injured skin or with long-term MSC survival. Interestingly, compared with hBM-MSC, hASC were significantly more efficient in reducing skin fibrosis, which was related to a stronger reduction of TNFα , IL1 β, and enhanced ratio of Mmp1/Timp1 in skin and lung tissues. Conclusions Using primary cells isolated from 3 murine and 6 human individuals, this preclinical study demonstrated similar therapeutic effects using allogeneic or xenogeneic BM-MSC while ASC exerted potent anti-inflammatory and remodeling properties. This sets the proof-of-concept prompting to evaluate the therapeutic efficacy of allogeneic ASC in SSc patients.
Background Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Pathologic conversion of regulatory T (Treg) cells into inflammatory ...cytokine–producing cells is thought to be an important step in the progression of autoimmunity, but whether loss of normal Treg cell function contributes to SSc is unknown. Objective We sought to determine whether Treg cells in the blood and skin of patients with SSc acquired abnormal production of effector cytokines. Methods Peripheral blood and skin biopsy specimens were collected from control subjects and patients with limited or diffuse SSc. Flow cytometry was used to evaluate expression of cell-surface proteins and the cytokine production profile of forkhead box protein 3–positive Treg cells compared with forkhead box protein 3–negative conventional T cells. Results Treg cells in the blood of patients with SSc had a normal phenotype and did not produce T-effector cytokines. In contrast, Treg cells from skin affected by SSc produced significant amounts of IL-4 and IL-13. Although Treg cells in the blood of patients with SSc did not make TH 2 cytokines, they contained a significantly higher proportion of skin-homing cells expressing TH 2 cell–associated chemokine receptors. Evidence that IL-33 caused the differentiation of skin Treg cells into TH 2-like cells, combined with high tissue-localized expression of this cytokine in patients with SSc and expression of the ST2 chain of the IL-33 receptor on skin-localized Treg cells, suggests that IL-33 might be an important stimulator of tissue-localized loss of normal Treg cell function. Conclusion These data are the first evidence for the presence of TH 2-like Treg cells in human autoimmunity and show that Treg cell plasticity can be tissue specific. Localized dysfunction of Treg cells is a previously unknown factor that might contribute to fibrosis in patients with SSc.
Systemic sclerosis (SSc) is an autoimmune disease which is characterized by vasculopathy, tissue fibrosis and activation of the innate and adaptive immune system. Clinical features of the disease ...consists of skin thickening and internal organ involvement. Due to the heterogeneous nature of the disease it is difficult to predict disease progression and complications. Despite the discovery of novel autoantibodies associated with SSc, there is an unmet need for biomarkers for diagnosis, disease progression and response to treatment. To date, the use of single (surrogate) biomarkers for these purposes has been unsuccessful. Combining multiple biomarkers in to predictive panels or ultimately algorithms could be more precise.
Given the limited therapeutic options and poor prognosis of many SSc patients, a better understanding of the immune-pathofysiological profiles might aid to an adjusted therapeutic approach. Therefore, we set out to explore immunological fingerprints in various clinically defined forms of SSc. We used multilayer profiling to identify unique immune profiles underlying distinct autoantibody signatures. These immune profiles could fill the unmet need for prognosis and response to therapy in SSc. Here, we present 3 pathophysiological fingerprints in SSc based on the expression of circulating antibodies, vascular markers and immunomodulatory mediators.
The term ‘sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes ...according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first‐ and advanced‐line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.
Abstract Systemic sclerosis (SSc) is a chronic immune disorder of unknown origin, dominated by excessive fibrosis responsible for cutaneous and pulmonary fibrosis, and by vascular endothelial ...dysfunction at the origin of skin ischemia, renal and pulmonary artery lesions. Renal and pulmonary complications are mainly responsible for the severity of the disease. Recent advances led to a better understanding of pathological mechanisms and a more accurate classification of patients according to clinical and biological (auto-antibodies) phenotype. Recent trials provided interesting data on different therapeutic strategies, depending on organ involvement. These data are of particular importance in such disease, still characterized by increased mortality and morbidity rates. In this review, we aim to synthetize recent advances in diagnosis and prognosis leading to better classification of SSc patients, and in therapeutic management.
Objective
To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis–associated Raynaud's ...phenomenon (SSc‐RP) episodes than placebo.
Methods
This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial in patients with SSc‐RP assessed the effect of 50‐unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between‐group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank‐sum test.
Results
The intent‐to‐treat analysis included 46 BTA‐treated patients and 44 placebo recipients. At 4 weeks after assigned treatment injections, the median number of daily RP episodes decreased comparably in the BTA and placebo groups (median change –1 episode/day interquartile range (IQR) –1.5, 0 episodes/day and –1 episode/day IQR –2.5, 0 episodes/day, respectively) (P = 0.77 versus placebo). Moreover, change in Raynaud's Condition Score, quality of life assessed by Health Assessment Questionnaire disability index, and hand function assessed by shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Cochin Hand Function Scale from baseline to follow‐up weeks 4, 12, and 24 did not differ significantly between groups. The BTA group experienced transient hand muscle weakness significantly more frequently (P = 0.003).
Conclusion
Neither the primary nor secondary end points were reached, and our results do not support any beneficial effect of palmar BTA injections to treat SSc‐RP.
Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to ...antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.
Cellular and molecular mechanisms in fibrosis Dees, Clara; Chakraborty, Debomita; Distler, Jörg H. W.
Experimental dermatology,
January 2021, 2021-01-00, 20210101, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The activation of fibroblasts is required for physiological tissue remodelling such as wound healing. However, when the regulatory mechanisms are disrupted and fibroblasts remain persistently ...activated, the progressive deposition of extracellular matrix proteins leads to tissue fibrosis, which results in dysfunction or even loss of function of the affected organ. Although fibrosis has been recognized as a major cause of morbidity and mortality in modern societies, there are only few treatment options available that directly disrupt the release of extracellular matrix from fibroblasts. Intensive research in recent years, however, identified several pathways as core fibrotic mechanisms that are shared across different fibrotic diseases and organs. We discuss herein selection of those core pathways, especially downstream of the profibrotic TGF‐β pathway, which are druggable and which may be transferable from bench to bedside.
Objective
Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly ...impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti‐ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction.
Methods
Serum from a patient with SSc with GI dysfunction but without defined SSc‐associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on‐bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry.
Results
We identified gephyrin as a novel SSc autoantigen. Anti‐gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti‐gephyrin antibody–positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15%, P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti‐gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00; P = 0.001) and severe distention and bloating (0.03 vs 0.004; P = 0.010). Severe constipation was associated with anti‐gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility.
Conclusion
Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti‐gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.
Type 2 innate lymphoid cells (ILC2s), a recently identified population of lymphoid cells lacking lineage-specific receptors, promote type 2 immunity and tissue remodelling. However, the contributive ...role of ILC2s in the pathogenesis of systemic sclerosis (SSc) is unknown. We aimed to evaluate the levels and correlations with fibrotic manifestations in SSc.
69 patients with SSc and 47 healthy controls were included. Blood samples and skin sections were analysed by flow cytometry and immunohistochemically by staining two complementary panels of markers.
Dermal and circulating ILC2s were significantly elevated in patients with SSc compared with controls. Dermal, but not circulating ILC2s were activated. Stratification of the SSc population in patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) demonstrated increased levels of ILC2s in both subgroups with significantly higher frequencies in dcSSc compared with lcSSc. Moreover, dermal and circulating ILC2 counts correlated closely with the modified Rodnan skin score and with the presence of pulmonary fibrosis.
ILC2 counts are elevated in patients with SSc and correlate with the extent of skin fibrosis and the presence of interstitial lung disease providing compelling evidence for profibrotic effect of ILC2s in SSc.
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