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1.
Autoimmun Rev ; 19(9): 102602, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32659476

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is a lethal complication affecting 8-15% of patients. Screening tests such as echocardiography and pulmonary function tests allow for triaging patients for diagnosis by right heart catheterization. Understanding risk factors of SSc-PAH could help differentiate high-risk patients. METHODS: A systematic review was conducted to determine associations with SSc-PAH, including clinical/disease characteristics, antibodies, labs and biomarkers. The frequencies of publications featuring each risk/association were reported. RESULTS: Among 2654 articles, 984 duplicates and 1578 irrelevant articles were removed, leaving 92 articles for manual screening. After excluding 55 papers with small sample sizes, publications from identical cohorts, not English language, or PAH not ascertained by RHC, 37 articles were eligible. A total of 43 factors for SSc-PAH were identified within seven categories. Several associations were due to PAH and risk factors such as dynpnea, right heart failure, and short 6-minute walk distance. Patient characteristics (14), pulmonary physiology (6), antibody profiles (6) and genetics/epigenetics (6) had the most numerous and diverse factors, while biomarkers (4) and other labs (2) features were infrequent. Low carbon monoxide (DLCO) (6), older age (4), longer disease duration (4), positive anticentromere antibodies (ACA) (4), telangiectasias (4), high brain natriuretic peptide (4) were frequent associations. CONCLUSIONS: Risk factors for SSc-PAH such as ACA, older age, longer disease duration limited cutaneous SSc subset and presence of ILD may enrich screening programs. Genes and other antibody profiles are inconsistent and requires further validation.


Assuntos
Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Envelhecimento , Humanos , Peptídeo Natriurético Encefálico , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/imunologia , Fatores de Risco , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia
2.
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
3.
Ann Rheum Dis ; 79(6): 724-726, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32349982

RESUMO

Due to the frequent presence of interstitial lung disease and widespread use of immunosuppressive treatment, systemic sclerosis (SSc) patients may be considered at risk for a more severe disease course and higher mortality when they develop Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) virus infection. Therefore, with World Scleroderma Foundation endorsement, experts from different specialties including rheumatology, virology and clinical immunology gathered virtually to answer to the main practical clinical questions regarding SARS-CoV-2 infection coming from both patients and physicians. This preliminary advice is aligned with other national and international recommendations, adapted for SSc patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/virologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/virologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , /virologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia
5.
Int Heart J ; 61(2): 413-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32224603

RESUMO

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.


Assuntos
Anticorpos Antinucleares/imunologia , Centríolos/imunologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Vasodilatadores/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Bosentana/uso terapêutico , Cateterismo Cardíaco , Quimioterapia Combinada , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Feminino , Volume Expiratório Forçado , Humanos , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Hipertensão Arterial Pulmonar/diagnóstico por imagem , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Capacidade de Difusão Pulmonar , Pirimidinas/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Sulfonamidas/uso terapêutico , Tadalafila/uso terapêutico , Tomografia Computadorizada por Raios X
6.
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
7.
Arthritis Rheumatol ; 72(7): 1160-1169, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32134204

RESUMO

OBJECTIVE: Genome-wide gene expression studies implicate macrophages as mediators of fibrosis in systemic sclerosis (SSc), but little is known about how these cells contribute to fibrotic activation in SSc. We undertook this study to characterize the activation profile of SSc monocyte-derived macrophages and assessed their interaction with SSc fibroblasts. METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) were obtained from whole blood from SSc patients (n = 24) and age- and sex-matched healthy controls (n = 12). Monocytes were cultured with autologous or allogeneic plasma to differentiate cells into macrophages. For reciprocal activation studies, macrophages were cocultured with fibroblasts using Transwell plates. RESULTS: The gene expression signature associated with blood-derived human SSc macrophages was enriched in SSc skin in an independent cohort and correlated with skin fibrosis. SSc macrophages expressed surface markers associated with activation and released CCL2, interleukin-6, and transforming growth factor ß under basal conditions (n = 8) (P < 0.05). Differentiation of healthy donor monocytes in plasma from SSc patients conferred the immunophenotype of SSc macrophages (n = 13) (P < 0.05). Transwell experiments demonstrated that coculture of SSc macrophages with SSc fibroblasts induced fibroblast activation (n = 3) (P < 0.05). CONCLUSION: These data demonstrate that the activation profile of SSc macrophages is profibrotic. SSc macrophages are activated under basal conditions and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These findings also suggest that activation of SSc macrophages arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in SSc and suggest that therapeutic targeting of these cells may be beneficial in ameliorating disease in SSc patients.


Assuntos
Fibroblastos/metabolismo , Macrófagos/imunologia , Escleroderma Sistêmico/genética , Pele/metabolismo , Adulto , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Diferenciação Celular , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Técnicas de Cocultura , Feminino , Fibrose/genética , Fibrose/imunologia , Fibrose/metabolismo , Antígenos HLA-DR/imunologia , Humanos , Imunofenotipagem , Interleucina-6/genética , Interleucina-6/imunologia , Lectinas Tipo C/imunologia , Leucócitos Mononucleares , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Lectinas de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Monócitos/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/imunologia , Receptores de Superfície Celular/imunologia , Fator de Transcrição STAT3/metabolismo , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Pele/patologia , Transcriptoma , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
8.
Rheumatology (Oxford) ; 59(6): 1218-1225, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32025734

RESUMO

Sjögren's syndrome (SjS) accompanied by other systemic autoimmune rheumatic connective tissue diseases has historically been termed 'secondary' in contrast to 'primary' SjS as a standalone entity. However, it is a matter of a long-standing debate whether the prefixes 'primary' and 'secondary', including a temporal component, are obsolete in the terminology of SjS. We review the history and the pathophysiological, chronological, genetic, histological and clinical data underlying the concept of 'secondary' SjS. There are important unintended consequences of the nomenclature; notably 'secondary' SjS has been much less researched and is often excluded from clinical trials. We argue for further research, a change in terminology and more stringent classification. Further we highlight possible opportunities for trials in SjS and other systemic autoimmune diseases that might contribute to an advance in care for all patients with SjS.


Assuntos
Artrite Reumatoide/complicações , Autoimunidade , Lúpus Eritematoso Sistêmico/complicações , Escleroderma Sistêmico/complicações , Síndrome de Sjogren/complicações , Artrite Reumatoide/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Síndrome de Sjogren/imunologia
9.
Isr Med Assoc J ; 22(2): 104-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043328

RESUMO

BACKGROUND: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials. OBJECTIVES: To report the first Israeli experience with HSCT for progressive SSc and review the current literature. METHODS: Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages. RESULTS: Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded. CONCLUSIONS: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.


Assuntos
Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Adulto , Autoanticorpos/sangue , Autoanticorpos/classificação , Criança , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Israel/epidemiologia , Pulmão/patologia , Monitorização Fisiológica/métodos , Avaliação de Processos e Resultados em Cuidados de Saúde , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/terapia , Pele/patologia , Transplante Autólogo
10.
Arthritis Res Ther ; 22(1): 32, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32085768

RESUMO

BACKGROUND: Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). METHODS: Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and ß4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. RESULTS: In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for ß4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). CONCLUSIONS: This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.


Assuntos
Autoanticorpos/imunologia , Gastroenteropatias/imunologia , Receptores Nicotínicos/imunologia , Escleroderma Sistêmico/complicações , Idoso , Autoanticorpos/sangue , Autoantígenos/imunologia , Estudos Transversais , Feminino , Motilidade Gastrointestinal/fisiologia , Humanos , Imunoprecipitação/métodos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia
11.
Int J Mol Sci ; 21(4)2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32079137

RESUMO

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Gânglios Autônomos/fisiopatologia , Receptores Colinérgicos/imunologia , Doenças Reumáticas/fisiopatologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Sistema Nervoso Autônomo/imunologia , Sistema Nervoso Autônomo/fisiopatologia , Gânglios Autônomos/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Doenças Reumáticas/imunologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/fisiopatologia
12.
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
13.
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
14.
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
15.
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
17.
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
18.
Clin Rheumatol ; 39(1): 5-8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31376088

RESUMO

Lower urinary tract symptoms (LUTS) have long been overlooked in systemic sclerosis (SSc). However, they are out of proportion of what would be expected based on age, sex, and presence of usual risk factors. Thus, there must be specific scleroderma-related mechanisms to result in LUTS. Fibrosis, nervous involvement (notably, dysautonomia), early signs of menopauses, and functional restriction play certainly a role, but available evidence shows inconsistent results. Thus, these factors are not sufficient to explain all aspect of LUTS in SSc. In vitro experiments point out a promising alternative mechanism, already observed in other rheumatologic diseases: an antibody-mediated etiology. However, more research is needed to better understand the pathophysiology of LUTS in SSc and develop specific treatment.


Assuntos
Sintomas do Trato Urinário Inferior/etiologia , Esclerodermia Localizada/complicações , Escleroderma Sistêmico/complicações , Fibrose/etiologia , Humanos , Sintomas do Trato Urinário Inferior/fisiopatologia , Fatores de Risco , Esclerodermia Localizada/imunologia , Escleroderma Sistêmico/imunologia
19.
J Invest Dermatol ; 140(1): 103-112.e8, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276679

RESUMO

IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-ß-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines. Keratinocyte-conditioned media tilted the balance of col-I to matrix metalloproteinase-1 production by fibroblasts in favor of matrix metalloproteinase-1, significantly more so in healthy donors than in scleroderma, resulting in enhanced extracellular matrix turnover, further increased by IL-17A. In organotypic skin, transforming growth factor-ß induced an extensive pro-fibrotic gene signature, including the enhanced expression of several collagen genes associated with Wnt signaling. IL-17A strongly promoted the expression of pro-inflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-ß. In this model, at the protein level, IL-17A significantly decreased col-I production. Our data strongly support a pro-inflammatory and antifibrogenic activity of IL-17A in the context of keratinocyte-fibroblast interaction and in full skin. These data help in directing and interpreting targeted therapeutic approaches in scleroderma.


Assuntos
Fibroblastos/fisiologia , Inflamação/imunologia , Interleucina-17/metabolismo , Queratinócitos/fisiologia , Esclerodermia Localizada/imunologia , Escleroderma Sistêmico/imunologia , Pele/patologia , Células Cultivadas , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Fibrose , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Técnicas de Cultura de Órgãos , Pele/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt
20.
Scand J Rheumatol ; 49(2): 146-153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31538512

RESUMO

Objectives: Scleroderma is a connective tissue immune disease that features collagen overproduction and can be categorized into two subtypes, localized scleroderma (LSc) and systemic sclerosis (SSc). SSc is clinically classified into two subsets: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) SSc. The immunoglobulin G-galactosylation (IgG-Gal) ratio is abnormal in a number of immune diseases and has not been evaluated in SSc.Method: The study recruited 93 LSc patients, 298 SSc patients, and 436 healthy controls. N-glycans of purified IgG were obtained from plasma and detected by tandem mass spectrometry. The IgG-Gal ratio was measured by calculating the relative intensities of agalactosylated (G0), monogalactosyl (G1), and digalactosyl (G2) N-glycans according to the formula G0/(G1 + G2 × 2). Furthermore, we examined whether the IgG-Gal ratio differed between different subtypes of SSc.Results: The IgG-Gal ratio was significantly higher in SSc patients (1.139 ± 0.870) than in LSc patients (0.485 ± 0.280) and controls (0.395 ± 0.190). The IgG-Gal ratio successfully distinguished SSc patients from LSc and controls (area under the curve = 0.88 and 0.81, respectively). The IgG-Gal ratio was significantly higher in dcSSc patients than in lcSSc patients and increased along with increases in modified Rodnan skin score (p = 6.03 × 10-5, Pearson's coefficient = 0.26) and erythrocyte sedimentation rate (p = 2.95 × 10-10, Pearson's coefficient = 0.38).Conclusion: IgG-Gal ratios were abnormal in SSc patients and were associated with disease severity. The IgG-Gal ratio therefore shows potential as a biomarker for the diagnosis of SSc.


Assuntos
Galactose/metabolismo , Imunoglobulina G/metabolismo , Escleroderma Sistêmico/imunologia , Adulto , Sedimentação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerodermia Localizada/imunologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/metabolismo
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