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1.
Autoimmun Rev ; 20(2): 102730, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33338593

RESUMO

Systemic sclerosis (SSc) is considered one of the most challenging and difficult to treat among rheumatic disorders, due to its severity, multiorgan manifestation and different outcomes. It manifests fibrosis in different organs, mostly in skin and lungs. The skin fibrosis expression is considered the first sign of the disease and usually it is followed by internal organ fibrosis. An aberrant immune system activation seems to relate to the expression of the disease, but even environmental influences and dysregulation of many molecules signalling pathways are involved in the development of the disease. Current therapies are limited and characterized by multiple side effects: systemic route is the elective administration route, which decreases patient adherence to the therapy, as they are often already bothered by pain and disfigurement. Treatments available are organ-based, originally indicated for other conditions and there is no therapy available to reduce the fibroblast population size within existing fibrotic lesions. Disease-modifying therapies or immunomodulatory agents that are highly effective in other rheumatic diseases have shown disappointing results in SSc. There are thus no standardized and effective treatments for this disease, and there are even unanswered questions related to the insurgence of the pathology and all the mechanisms involved. An ideal approach could be considered "targeted therapy" that will be an increasingly attainable objective insofar as our understanding of the disease improves. The advantages in identifying the molecule and the signalling pathways involved in the pathology have helped to find some novel compounds for the therapy of scleroderma fibrosis or following innovative uses for already-approved drugs, corroborated by many clinical studies.


Assuntos
Esclerodermia Localizada , Escleroderma Sistêmico , Fibroblastos , Fibrose , Humanos , Esclerodermia Localizada/patologia , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Pele/patologia
2.
J Am Acad Orthop Surg ; 28(16): e686-e695, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32769717

RESUMO

Scleroderma is derived from Latin meaning hard skin. It is an uncommon, noninflammatory connective tissue disorder characterized by increased fibrosis of the skin and in certain variants, multiple other organ systems. Scleroderma involves a spectrum of pathologic changes and anatomic involvement. It can be divided into localized and systemic scleroderma. Hand involvement is common and can include calcium deposits within the soft tissues, digital ischemia, and joint contracture. Nonsurgical management consists of lifestyle modifications, biofeedback, therapy for digital stiffness/contracture, and various pharmacologic medications. When nonsurgical measures are unsuccessful, certain surgical options may be indicated, each with their inherent advantages and pitfalls. Patients with scleroderma who are undergoing surgical intervention pose unique difficulties because of their poorly vascularized tissue and deficient soft-tissue envelopes, thus increasing their susceptibility to wound healing complications and infection. Some subgroups of patients are frequently systemically ill, and specific perioperative measures should be considered to reduce their surgical risk. The spectrum of hand manifestations seen in patients with scleroderma will be reviewed with the focus on evaluation and management.


Assuntos
Mãos , Procedimentos Ortopédicos/métodos , Esclerodermia Localizada/cirurgia , Escleroderma Sistêmico/cirurgia , Calcinose , Mãos/patologia , Mãos/cirurgia , Humanos , Comunicação Interdisciplinar , Equipe de Assistência ao Paciente , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/patologia , Esclerodermia Localizada/terapia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia
3.
Clin Dermatol ; 38(2): 235-249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32513403

RESUMO

Sclerodermalike syndromes (SLSs) comprise diseases with mucin deposition (eg, scleromyxedema, scleredema), with eosinophilia (eg, eosinophilic fasciitis), metabolic or biochemical abnormalities (eg, nephrogenic systemic fibrosis), or endocrine disorders (eg, POEMS syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal lymphoproliferative disorder, and hypothyroidism). Chronic graft-versus-host disease may also show sclerodermalike skin changes. Inherited progeria syndromes with early aging (eg, Werner syndrome) and a heterogeneous group of hereditary disorders with either skin thickening (eg, stiff skin syndrome) or atrophy and tightening (eg, acrogeria) can also imitate classic systemic sclerosis (SSc). In addition, SLSs can be provoked by several drugs, chemicals, or even physical injury (eg, trauma, vibration stress, radiation). In SLSs, the distribution of skin involvement seems to be atypical compared with SSc. The acral skin involvement is usually missing, and lack of Raynaud phenomenon, scleroderma-specific antinuclear antibodies, the absence of scleroderma capillary pattern, and internal organ manifestations indicate the presence of an SLS. Skin involvement is sometimes nodular, and the underlying tissues can also be affected. For the differential diagnosis, a skin biopsy of the deeper layers including fascia and muscle is required. Histology does not always allow differentiation between SSc and SLSs; therefore, the diagnosis is often based on the distribution, quality of cutaneous involvement, and other accompanying clinical features.


Assuntos
Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia , Pele/patologia , Biópsia/métodos , Diagnóstico Diferencial , Humanos , Escleroderma Sistêmico/etiologia , Síndrome
4.
Ann Rheum Dis ; 79(9): 1227-1233, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32482644

RESUMO

OBJECTIVES: Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc). METHODS: Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α. RESULTS: The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFß), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFß and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFß receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis. CONCLUSION: PGC-1α is upregulated in SSc and promotes autophagy to foster TGFß-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.


Assuntos
Autofagia/genética , Fibroblastos/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Animais , Bleomicina/farmacologia , Western Blotting , Colágeno/biossíntese , Modelos Animais de Doenças , Fibrose , Imunofluorescência , Humanos , Camundongos , Reação em Cadeia da Polimerase , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
5.
Autoimmun Rev ; 19(8): 102583, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32553611

RESUMO

Systemic sclerosis (SSc) is a rare chronic disease of unknown etiology characterized by vascular abnormalities and fibrosis involving the skin and internal organs, especially the gastrointestinal tract, lung, heart and kidneys. Although the disease was historically stratified according to the extent of skin involvement, more recent approaches place more emphasis on patterns and extent of internal organ involvement. Despite numerous clinical trials, disease-modifying treatment options are still limited resulting in persistent poor quality of life and high mortality. This review provides an overview of autoantibodies in SSc and novel approaches to stratify the disease into clinically actionable subsets.


Assuntos
Autoanticorpos , Escleroderma Sistêmico , Autoanticorpos/sangue , Autoanticorpos/imunologia , Humanos , Qualidade de Vida , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia
6.
Adv Exp Med Biol ; 1253: 375-403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445102

RESUMO

Scleroderma (systemic sclerosis; SSc) is a complex and highly heterogeneous multisystem rheumatic disease characterized by vascular abnormality, immunologic derangement, and excessive deposition of extracellular matrix (ECM) proteins. To date, the etiology of this life-threatening disorder remains not fully clear. More and more studies show epigenetic modifications play a vital role. The aberrant epigenetic status of certain molecules such as Fli-1, BMPRII, NRP1, CD70, CD40L, CD11A, FOXP3, KLF5, DKK1, SFRP1, and so on contributes to the pathogenesis of progressive vasculopathy, autoimmune dysfunction, and tissue fibrosis in SSc. Meanwhile, numerous miRNAs including miR-21, miR-29a, miR-196a, miR-202-3p, miR-150, miR-let-7a, and others are involved in the process. In addition, the abnormal epigenetic biomarker levels of CD11a, Foxp3, HDAC2, miR-30b, miR-142-3p, miR-150, miR-5196 in SSc are closely correlated with disease severity. In this chapter, we not only review new advancements on the epigenetic mechanisms involved in the pathogenesis of SSc and potential epigenetic biomarkers, but also discuss the therapeutic potential of epigenetic targeting therapeutics such as DNA methylation inhibitors, histone acetylase inhibitors, and miRNA replacement.


Assuntos
Epigênese Genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/terapia , Biomarcadores , Humanos , MicroRNAs , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia
8.
Dermatol Online J ; 26(2)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239898

RESUMO

A 60-year old man developed skin hardening and edema on his extremities. Although he had been treated with oral prednisolone at another hospital, skin stiffness relapsed during tapering of prednisolone. At the initial visit to our department, physical examination showed skin hardening of the extremities and also symmetric erythematous macules on the back. Histological examination revealed fasciitis on the forearm and morphea on the back. Eosinophilic fasciitis is occasionally associated with morphea. However, cases of concurrent eosinophilic fasciitis and generalized morphea are rare. In the present case, CD34 was differentially expressed in both lesions, suggesting eosinophilic fasciitis and morphea are separate diseases with different origin of mesenchymal cells.


Assuntos
Eosinofilia/complicações , Fasciite/complicações , Escleroderma Sistêmico/complicações , Adulto , Idoso , Antígenos CD34/metabolismo , Eosinofilia/tratamento farmacológico , Eosinofilia/patologia , Fasciite/tratamento farmacológico , Fasciite/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia
9.
Lancet Respir Med ; 8(3): 304-320, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32113575

RESUMO

Systemic sclerosis is an autoimmune connective tissue disease, which is characterised by immune dysregulation and progressive fibrosis that typically affects the skin, with variable internal organ involvement. It is a rare condition that affects mostly young and middle-aged women, resulting in disproportionate morbidity and mortality. Currently, interstitial lung disease is the most common cause of death among patients with systemic sclerosis, with a prevalence of up to 30% and a 10-year mortality of up to 40%. Interstitial lung disease is more common among African Americans and in people with the diffuse cutaneous form of systemic sclerosis or anti-topoisomerase 1 antibodies. Systemic sclerosis-associated interstitial lung disease most commonly presents with dyspnoea, cough, and a non-specific interstitial pneumonia pattern on CT scan, with a minority of cases fulfilling the criteria for usual interstitial pneumonia. The standard therapy has traditionally been combinations of immunosuppressants, particularly mycophenolate mofetil or cyclophosphamide. These immunosuppressants can be supplemented by targeted biological and antifibrotic therapies, whereas autologous haematopoietic stem-cell transplantation and lung transplantation are reserved for refractory cases.


Assuntos
Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/terapia , Masculino , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia
10.
Autoimmun Rev ; 19(5): 102515, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173517

RESUMO

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.


Assuntos
Medicina de Precisão , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Autoanticorpos/imunologia , Biomarcadores/análise , Feminino , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia
11.
Ann Rheum Dis ; 79(4): 507-517, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32041748

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). METHODS: Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. RESULTS: SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. CONCLUSIONS: Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fibroblastos/metabolismo , MicroRNAs/metabolismo , Miofibroblastos/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Notch/metabolismo , Escleroderma Sistêmico/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Epigênese Genética , Fibrose , Código das Histonas , Humanos , Indóis/farmacologia , Fenótipo , Piridonas/farmacologia , Receptores Notch/antagonistas & inibidores , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Transdução de Sinais , Pele/citologia , Pele/metabolismo , Pele/patologia
12.
Surg Pathol Clin ; 13(1): 165-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32005430

RESUMO

Patients with connective tissue diseases may have pulmonary involvement, including interstitial lung disease. Various patterns of interstitial lung disease have been classically described in certain connective tissue diseases. It is now recognized that there is significant overlap between patterns of interstitial lung disease observed in the various connective tissue diseases. Differentiating idiopathic from connective tissue disease-related interstitial lung disease is challenging but of clinical importance. New concepts in the diagnosis of connective tissue disease related interstitial lung disease may prove useful in making the diagnosis.


Assuntos
Doenças do Tecido Conjuntivo/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Doenças do Tecido Conjuntivo/patologia , Dermatomiosite/diagnóstico , Dermatomiosite/patologia , Diagnóstico Diferencial , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/patologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença Mista do Tecido Conjuntivo/patologia , Polimiosite/diagnóstico , Polimiosite/patologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia
13.
Clin Immunol ; 213: 108364, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32087329

RESUMO

OBJECTIVES: To evaluate expansion of CD21low B cells and their role in B cell homeostasis, apoptosis, clinical manifestations and serum vascular endothelial growth factor (VEGF) in systemic sclerosis (SSc). MATERIALS AND METHODS: B-cells subpopulations and apoptosis have been assessed in 74 SSc patients and 20 healthy donors. Renal Doppler ultrasound, echocardiography, pulmonary function test and VEGF were performed. RESULTS: SSc patients with expanded CD21low B cells (SSc-CD21low) show a distinct B cell profile with increased memory B cells compared to patients without CD21low B cells (SSc-CD21+). Renal resistive index, systolic pulmonary arterial pressure and FVC/DLCO ratio were significantly higher in SSc-CD21low group than SSc-CD21+, DLCO was lower in SSc-CD21low group than SSc-CD21+. We found a positive linear correlation between CD21low and sPAP, RI and FVC/DLCO ratio whereas a negative correlation was observed between CD21low and DLCO and VEGF levels. CONCLUSIONS: CD21low B cells are increased in SSc patients with visceral vascular manifestations.


Assuntos
Subpopulações de Linfócitos B/imunologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Doenças Vasculares/etiologia , Idoso , Feminino , Cardiopatias/etiologia , Humanos , Nefropatias/etiologia , Pneumopatias/etiologia , Masculino , Pessoa de Meia-Idade , Receptores de Complemento 3d/imunologia , Escleroderma Sistêmico/patologia , Fator A de Crescimento do Endotélio Vascular/sangue
14.
Arthritis Res Ther ; 22(1): 30, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070422

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a severe and highly heterogeneous disease. The modified Rodnan skin score (mRSS) is a widely used tool for the assessment of the extent and degree of skin thickness. This study aimed to identify the classes of patients with early similar skin thickening trajectories without any a priori assumptions and study their associations with organ involvement and survival. METHODS: From the French SSc national cohort, patients with a disease duration of less than 2 years at inclusion and with at least 2 mRSS available within the first 4 years of follow-up were enrolled. Classes of patients with similar mRSS trajectories were identified based on a latent class mixed model. The clinical characteristics and survival rate were compared between the obtained classes. RESULTS: A total of 198 patients fulfilled the inclusion criteria, with a total of 641 mRSS available. The median disease duration and follow-up were 0.8 (interquartile range 0.4; 1.2) and 6.3 (3.8; 8.9) years, respectively. Individual trajectories of mRSS were highly heterogeneous between patients. Models with 1-6 latent classes of trajectories were sequentially assessed, and the 5-class model represented the best fit to data. Each class was characterized by a unique global trajectory of mRSS. The median disease duration did not differ significantly between classes. Baseline organ involvement was more frequent in classes with significant change over time (classes 2-5) than in class 1 (low baseline mRSS without significant change over time). Using Cox regression, we observed a progressively increasing risk of death from classes 1 to 5. CONCLUSIONS: Early identification of clinical phenotype based on skin thickening trajectories could predict morbi-mortality in SSc. This study suggested that mRSS trajectories characterization might be pivotal for clinical practice and future trial designs.


Assuntos
Escleroderma Sistêmico/classificação , Escleroderma Sistêmico/patologia , Pele/patologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/mortalidade
15.
Clin Exp Immunol ; 201(1): 14-24, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32048277

RESUMO

Toll-like receptors (TLRs) are evolutionarily conserved receptors essential for the host defence against pathogens. Both immune and non-immune cells can express TLRs, although at different levels. Systemic sclerosis (SSc) is a chronic disease in which autoimmunity, dysregulated profibrotic mediator release and activation of fibroblasts lead to dysregulated collagen deposition and fibrosis. There is now increasing knowledge that the innate immune system and, in particular, TLRs take a part in SSc pathogenesis. The list of endogenous ligands that can stimulate TLRs in SSc is growing: these ligands represent specific danger-associated molecular patterns (DAMPs), involved either in the initiation or the perpetuation of inflammation, and in the release of factors that sustain the fibrotic process or directly stimulate the cells that produce collagen and the endothelial cells. This review reports evidences concerning TLR signalling involvement in SSc. We report the new DAMPs, as well as the TLR-linked pathways involved in disease, with emphasis on type I interferon signature in SSc, the role of plasmacytoid dendritic cells (pDCs) and platelets. The dissection of the contribution of all these pathways to disease, and their correlation with the disease status, as well as their values as prognostic tools, can help to plan timely intervention and design new drugs for more appropriate therapeutic strategies.


Assuntos
Plaquetas/imunologia , Células Dendríticas/imunologia , Plasmócitos/imunologia , Escleroderma Sistêmico/imunologia , Receptores Toll-Like/imunologia , Animais , Plaquetas/patologia , Células Dendríticas/patologia , Humanos , Plasmócitos/patologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/patologia
16.
Autoimmun Rev ; 19(4): 102494, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062031

RESUMO

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease which is characterised by autoimmunity, widespread tissue fibrosis of the skin and internal organs, and vasculopathic alterations. SSc is more common in women but has a more severe expression of disease including internal organ-based complications and higher mortality in men. The extant literature shows that although important pathophysiological sex differences are present in SSc, behavioural differences (e.g. higher smoking rates in men) and occupational exposures may contribute to poorer outcomes in men with SSc. The higher death male death rate in the general population and greater prevalence of lung fibrosis are likely the key factors responsible for excess mortality found in men. Other important factors include (but are not limited to) a greater prevalence of the disease subset, delayed time to diagnosis, and higher disease activity in early disease in men. SSc carries a significant burden of disease-related morbidity; however, no qualitative studies to date have focussed on gender differences in SSc. The purpose of this review is to provide a comprehensive overview of gender differences in SSc including (but not limited to) epidemiology, pathophysiology, clinical expression of disease, mortality, SSc in transgender individuals, and psychosocial aspects of disease.


Assuntos
Escleroderma Sistêmico , Caracteres Sexuais , Feminino , Fibrose , Humanos , Masculino , Morbidade , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia
17.
Phytomedicine ; 67: 153160, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31901889

RESUMO

BACKGROUND: Increasing evidence indicated that the cannabinoid receptors were involved in the pathogenesis of organ fibrogenesis. PURPOSE: The purpose of this study was to discover novel cannabinoid receptor 2 (CB2) agonist and assess the potential of CB2 activation in treating systemic sclerosis. METHODS: A gaussia princeps luciferase-based split luciferase complementation assay (SLCA) was developed for detection of the interaction between CB2 and ß-arrestin2. A library of 366 natural products was then screened as potential CB2 agonist using SLCA approach. Several GPCR functional assays, including HTRF-based cAMP assay and calcium mobilization were also utilized to evaluated CB2 activation. Bleomycin-induced experimental systemic sclerosis was used to assess the in vivo anti-fibrotic effects. Dermal thickness and collagen content were evaluated via H&E and sirius red staining. RESULTS: Celastrol was identified as a new agonist of CB2 by using SLCA. Furthermore, celastrol triggers several CB2-mediated downstream signaling pathways, including calcium mobilization, inhibition of cAMP accumulation, and receptor desensitization in a dose-dependent manner, and it has a moderate selectivity on CB1. In addition, celastrol exhibited the anti-inflammatory properties on lipopolysaccharide (LPS) treated murine Raw 264.7 macrophages and primary macrophages. Finally, we found that celastrol exerts anti-fibrotic effects in the bleomycin-induced systemic sclerosis mouse model accompanied by reduced inflammatory conditions. CONCLUSION: Taken together, celastrol is identified a novel selective CB2 agonist using a new developed arrestin-based SLCA, and CB2 activation by celastrol reduces the inflammatory response, and prevents the development of dermal fibrosis in bleomycin-induced systemic sclerosis mouse model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Receptor CB2 de Canabinoide/agonistas , Escleroderma Sistêmico/tratamento farmacológico , Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Arrestina/metabolismo , Bleomicina/toxicidade , Cálcio/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Fibrose , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Triterpenos/química
18.
Clin Exp Immunol ; 201(1): 25-33, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31970748

RESUMO

Systemic sclerosis (SSc) is a severe autoimmune fibrotic disease characterized by fibrosis, vasculopathy, and immune dysregulation. Dendritic cells (DCs) are the most potent antigen-presenting cells, specialized in pathogen sensing, with high capacity to shape the immune responses. The most recent technological advances have allowed the discovery of new DC subsets with potential implications in inflammatory conditions. Alterations of DC distribution in circulation and affected tissue as well as impaired DC function have been described in SSc patients, pointing towards a crucial role of these cells in SSc pathogenesis. In particular, recent studies have shown the importance of plasmacytoid DCs either by their high capacity to produce type I interferon or other inflammatory mediators implicated in SSc pathology, such as chemokine C-X-C motif ligand 4 (CXCL4). In-vivo models of SSc have been vital to clarify the implications of DCs in this disease, especially DCs depletion and specific gene knock-down studies. This review provides these new insights into the contribution of the different DCs subsets in the pathogenesis of SSc, as well as to the novel developments on DCs in in-vivo models of SSc and the potential use of DCs and their mediators as therapeutic targets.


Assuntos
Células Dendríticas/imunologia , Escleroderma Sistêmico/imunologia , Animais , Células Dendríticas/patologia , Modelos Animais de Doenças , Humanos , Fator Plaquetário 4/genética , Fator Plaquetário 4/imunologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia
19.
Clin Exp Immunol ; 201(1): 34-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31990046

RESUMO

Systemic sclerosis (SSc) is a complex, heterogeneous autoimmune connective tissue disease. Autologous hematopoietic stem-cell transplantation (AHSCT) has emerged as a valuable treatment option for rapidly progressive diffuse cutaneous SSc (dcSSc) patients, and thus far is the only treatment that has been shown to have a long-term clinical benefit. AHSCT is thought to reintroduce immune homeostasis through elimination of pathogenic self-reactive immune cells and reconstitution of a new, tolerant immune system. However, the mechanism of action underlying this reset to tolerance remains largely unknown. In this study we review the immune mechanisms underlying AHSCT for SSc, with a focus on the role of the innate immune cells, including monocytes and natural killer (NK) cells, in restoring immune balance after AHSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunidade Inata , Células Matadoras Naturais/imunologia , Monócitos/imunologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/terapia , Autoenxertos , Humanos , Células Matadoras Naturais/patologia , Monócitos/patologia , Escleroderma Sistêmico/patologia
20.
Annu Rev Med ; 71: 263-276, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986085

RESUMO

Interleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases-myofibroblast activation, parenchymal cell dysfunction, and inflammation-while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease.


Assuntos
Fibrose/imunologia , Inflamação/imunologia , Interleucina-11/imunologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Interleucina-11/metabolismo , Interleucina-11/fisiologia , Interleucina-6/imunologia , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Neoplasias/imunologia , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Proteínas Recombinantes , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/imunologia , Pele/metabolismo , Pele/patologia
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