RESUMO
Type I interferon (IFN-I) signaling has been shown to be upregulated in systemic sclerosis (SSc). Dysregulated B-cell functions, including antigen presentation, as well as antibody and cytokine production, all of which may be affected by IFN-I signaling, play an important role in the pathogenesis of the disease. We investigated the IFN-I signature in 71 patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and 33 healthy controls (HCs). Activation via Toll-like receptors (TLRs) can influence the IFN-I signaling cascade; thus, we analyzed the effects of the TLR homologue CD180 ligation on the IFN-I signature in B cells. CD180 stimulation augmented the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in dcSSc B cells (p = 0.0123). The expression of IFN-I receptor (IFNAR1) in non-switched memory B cells producing natural autoantibodies was elevated in dcSSc (p = 0.0109), which was enhanced following anti-CD180 antibody treatment (p = 0.0125). Autoantibodies to IFN-Is (IFN-alpha and omega) correlated (dcSSc p = 0.0003, HC p = 0.0192) and were present at similar levels in B cells from dcSSc and HC, suggesting their regulatory role as natural autoantibodies. It can be concluded that factors other than IFN-alpha may contribute to the elevated IFN-I signature of dcSSc B cells, and one possible candidate is B-cell activation via CD180.
Assuntos
Antígenos CD , Autoanticorpos , Linfócitos B , Interferon Tipo I , Humanos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Pessoa de Meia-Idade , Feminino , Masculino , Autoanticorpos/imunologia , Antígenos CD/metabolismo , Adulto , Interferon Tipo I/metabolismo , Fator de Transcrição STAT1/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Receptor de Interferon alfa e beta/genética , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/metabolismo , Idoso , Regulação para Cima , Transdução de SinaisAssuntos
Autoanticorpos , Predisposição Genética para Doença , Haplótipos , Linhagem , Esclerodermia Difusa , Humanos , Autoanticorpos/sangue , Esclerodermia Difusa/genética , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/sangue , Feminino , Fenótipo , Masculino , Proteína Inibidora do Complemento C1/genética , Fatores de Risco , Adulto , Mutação , Pessoa de Meia-Idade , Antígenos HLA/genética , Antígenos HLA/imunologiaRESUMO
The contributions of anti-Topoisomerase 1 (Top1) autoantibodies to the pathophysiology of diffuse cutaneous systemic sclerosis (dcSSc), the most aggressive scleroderma subtype, are unknown. Top1 catalyzes DNA relaxation and unwinding in cell nuclei, a site previously considered inaccessible to antibodies. The discovery of autoantibodies in systemic lupus erythematosus that penetrate nuclei and inhibit DNA repair raised the possibility that nuclear-penetrating autoantibodies contribute to mechanisms of autoimmunity. Here we show that an anti-Top1 autoantibody produced by a single B cell clone from a patient with dcSSc penetrates live cells and localizes into nuclei. Functionally, the autoantibody inhibits formation of the Top1 cleavage complex necessary for DNA nicking, which distinguishes it from cytotoxic camptothecin Top1 inhibitors used in cancer therapy that trap the cleavage complex rather than preventing its formation. Discovery of a patient-derived cell-penetrating scleroderma anti-Top1 autoantibody that inhibits Top1 cleavage complex formation supports the hypothesis that anti-Top1 autoantibodies contribute to cellular dysfunction in dcSSc and offers a valuable antibody reagent resource for future studies on anti-Top1 autoantibody contributions to scleroderma pathophysiology.
Assuntos
Autoanticorpos , Núcleo Celular , DNA Topoisomerases Tipo I , DNA Topoisomerases Tipo I/imunologia , DNA Topoisomerases Tipo I/metabolismo , Humanos , Autoanticorpos/imunologia , Núcleo Celular/metabolismo , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/tratamento farmacológicoAssuntos
Miosite , Esclerodermia Difusa , Humanos , Miosite/imunologia , Miosite/diagnóstico , Miosite/patologia , Miosite/complicações , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/complicações , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/patologia , Feminino , Autoanticorpos/sangue , Autoanticorpos/imunologia , Pessoa de Meia-Idade , Neurônios Motores/patologia , Neurônios Motores/imunologia , Síndrome , MasculinoRESUMO
OBJECTIVE: In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin. METHODS: We analyzed the transcriptomes of 2,465 myeloid cells from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single-cell RNA sequencing. Monocyte-derived dendritic cells (mo-DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin-1 (FCN-1). RESULTS: A t-distributed stochastic neighbor embedding analysis of single-cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc-specific myeloid cell clusters. One SSc-associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc-associated myeloid population highly expressed monocyte markers FCN-1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo-DCs. Mo-DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors. CONCLUSION: Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll-like receptors and highly up-regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc.
Assuntos
Células Dendríticas/imunologia , Lectinas/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Receptores de IgG/imunologia , Esclerodermia Difusa/imunologia , Humanos , Lectinas/biossíntese , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores de IgG/biossíntese , Índice de Gravidade de Doença , FicolinasRESUMO
Disease-associated, high-affinity pathological autoantibody production is a well-described consequence of immune dysregulation affecting B cells in systemic sclerosis (SSc), including the distribution of B-cell subsets. We have previously shown that the increased relative frequency of CD19+CD27+IgD- switched memory B cells is associated with the severe form of SSc. This study sought to analyze memory B cell subsets using an extended range of markers for further subdivision based on CD19, IgD, CD27, CD38 and CD95 phenotype, to define relationship between the alterations of memory B cell subsets and the clinical features of SSc. Peripheral blood samples were obtained from 21 SSc patients, including 14 diffuse (dcSSc) and 7 limited (lcSSc) cutaneous SSc patients, with disease duration of 2.7 ( ± 1.6) years. After purification of CD19+ B cells, multiparametric flow cytometry was performed and the frequencies of CD19+IgD-CD27-CD38+ double negative (DN) 1, CD19+IgDloCD27+CD38+ unswitched, CD19+IgD-CD27+CD38+CD95- resting switched and CD19+IgD-CD27+CD38-CD95+ activated switched memory (ASM) B cells were determined, and correlated with clinical features of SSc. The dcSSc patients had a higher frequency of ASM B cells (p = 0.028) compared to lcSSc patients. The percentage of ASM B cells was elevated in anti-Scl-70 (anti-topoisomerase I) antibody positive patients compared to negative patients (p = 0.016). Additionally, the frequency of ASM B cells was also increased in patients with pulmonary fibrosis (p = 0.003) suggesting that patients with severe form of SSc have higher ASM B cell ratios. Furthermore, the ratio of DN1 B cells was decreased (p = 0.029), while the level of anti-citrate synthase IgG natural autoantibody was elevated (p = 0.028) in patients with active disease. Our observations on the increase of ASM B cells in dcSSc and in patients with pulmonary fibrosis may point to the association of this alteration with the severe form of the disease. Functionally the correlation of ASM B cells as effector memory-plasma cell precursors with anti-topoisomerase I antibody positivity could reflect their contribution to pathological autoantibody production, whereas the decrease of memory precursor DN B cells and the increase of anti-citrate synthase IgG autoantibody may have potential significance in the assessment of disease activity.
Assuntos
Linfócitos B/imunologia , Memória Imunológica , Fibrose Pulmonar/imunologia , Esclerodermia Difusa/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Autoanticorpos/sangue , Linfócitos B/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/sangue , Fibrose Pulmonar/diagnóstico , Esclerodermia Difusa/sangue , Esclerodermia Difusa/diagnóstico , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/diagnósticoRESUMO
OBJECTIVES: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities. RESULTS: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis. CONCLUSIONS: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms.
Assuntos
Anticorpos Antinucleares/imunologia , DNA Topoisomerases Tipo I/imunologia , RNA Polimerase III/imunologia , Esclerodermia Difusa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Ácido Hialurônico/sangue , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Estudos Prospectivos , Proteômica , Esclerodermia Difusa/sangue , Esclerodermia Difusa/tratamento farmacológico , Inibidor Tecidual de Metaloproteinase-1/sangue , Transcriptoma , Adulto JovemRESUMO
OBJECTIVES: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time. METHODS: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model. RESULTS: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693. CONCLUSIONS: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc.
Assuntos
Esclerodermia Difusa/genética , Esclerodermia Limitada/genética , Adulto , Idoso , Anticorpos Antinucleares/imunologia , Artrite Reumatoide/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , DNA Topoisomerases/imunologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/imunologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Síndrome de Sjogren/genética , População BrancaRESUMO
OBJECTIVE: The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer. METHODS: A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35 S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups. RESULTS: Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009). CONCLUSION: SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.
Assuntos
Autoanticorpos/imunologia , Neoplasias/epidemiologia , Ribonuclease P/imunologia , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/imunologia , Adulto , Proteínas Reguladoras de Apoptose/imunologia , Autoantígenos/imunologia , Feminino , Humanos , Pneumopatias/imunologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Ribonucleoproteínas/imunologia , Esclerodermia Difusa/epidemiologia , Esclerodermia Difusa/fisiopatologia , Esclerodermia Limitada/epidemiologia , Esclerodermia Limitada/fisiopatologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologiaRESUMO
INTRODUCTION: Systemic sclerosis (SSc) is a multi-dimensional connective tissue disease of unknown etiology. Given the immense clinical complexity of SSc, the treatment of this condition is not standardized and considerable heterogeneity exists in SSc management approaches. The purpose of this article is to highlight novel therapeutic strategies and new medications under development for the treatment of systemic sclerosis (SSc). AREAS COVERED: Herein, the authors focus primarily on recently completed clinical trials and phase 3 and 4 clinical trials of therapeutic agents that show promise in SSc. This review is organized by the clinical complications that occur in SSc, for which novel treatment strategies are under study. EXPERT OPINION: Combining therapies to address the individual manifestations of SSc is a cornerstone to the comprehensive management of this condition. Therapeutic strategies must take into account the organs involved, the level of disease activity in each area, and the disease stage. Controlling the complex biological network, progressive vasculopathy and fibrosis, as well as manifestations of end-organ dysfunction are all critical considerations when determining the best treatment approach for SSc.
Assuntos
Drogas em Investigação/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Autoanticorpos/sangue , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Drogas em Investigação/administração & dosagem , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/imunologia , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Esclerodermia Difusa/complicações , Esclerodermia Difusa/tratamento farmacológico , Esclerodermia Difusa/imunologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Resultado do TratamentoRESUMO
You are consulted to evaluate a 56-year-old woman with known Raynaud's phenomenon, finger swelling of several; months' duration, and new hypertension with a blood pressure of 160/100 mm/Hg. She also reports progressive shortness of breath. Physical examination reveals telangiectasias, sclerodactyly, and proximal skin sclerosis (thick shiny skin on the chest and upper arms), and bibasilar crackles are found on chest examination. Laboratory tests reveal evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevation of the serum creatinine level (previously normal), and chest computed tomography shows evidence of ground-glass opacification in both lower lung fields.
Assuntos
Anti-Hipertensivos/uso terapêutico , Antirreumáticos/uso terapêutico , Hipertensão/terapia , Doenças Pulmonares Intersticiais/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Insuficiência Renal/terapia , Esclerodermia Difusa/terapia , Esclerodermia Limitada/terapia , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Complemento C3/imunologia , Complemento C4/imunologia , Inativadores do Complemento/uso terapêutico , Ciclofosfamida/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Troca Plasmática , RNA Polimerase III/imunologia , Doença de Raynaud , Insuficiência Renal/etiologia , Insuficiência Renal/imunologia , Insuficiência Renal/patologia , Esclerodermia Difusa/complicações , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/complicações , Esclerodermia Limitada/diagnóstico , Esclerodermia Limitada/imunologia , Transplante de Células-Tronco , Tomografia Computadorizada por Raios X , Transplante Autólogo , Vasodilatadores/uso terapêuticoAssuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Miosite/diagnóstico , Esclerodermia Difusa/imunologia , Doença Aguda , Idoso , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , DNA Topoisomerases Tipo I , Progressão da Doença , Eletromiografia , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Miosite/complicações , Miosite/imunologia , Proteínas Nucleares/imunologia , Ribonucleoproteína Nuclear Pequena U1/imunologia , Esclerodermia Difusa/complicações , Tomografia Computadorizada por Raios XAssuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas do Sistema Complemento/metabolismo , Imunofenotipagem , Escleroderma Sistêmico/imunologia , Humanos , Esclerodermia Difusa/sangue , Esclerodermia Difusa/imunologia , Esclerodermia Difusa/patologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Células Th1/imunologiaRESUMO
OBJECTIVES: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease. METHODS: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated. RESULTS: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression. CONCLUSIONS: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.
Assuntos
Imunidade Adaptativa/genética , Imunidade Inata/genética , Esclerodermia Difusa/genética , Esclerodermia Difusa/imunologia , Adulto , Biomarcadores/análise , Biópsia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Sistema de Registros , Análise de Regressão , Esclerodermia Difusa/patologia , Análise de Sequência de RNA , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , TranscriptomaRESUMO
OBJECTIVE: To evaluate the frequency of anti-collagen type V in humans with early systemic sclerosis (SSc) compared to defined SSc patients and healthy controls, since collagen type V was shown to be overexpressed in early SSc patients' skin and there is no data concerning the presence of this antibody in early stages of human SSc. Experimental studies showed that animal models immunized with collagen type V developed a disease similar to human systemic sclerosis (SSc), with antibodies production, mainly in early stages post-immunization. METHODS: Eighty-one female SSc patients were included and divided into two groups: early-SSc (18 patients-EULAR Preliminary Criteria) and defined-SSc (63 patients-ACR Criteria 1980). The control group consisted of 19 healthy women age-matched to Early-SSc group. Anti-collagen type V was performed by ELISA. Data was analyzed by appropriate tests. RESULTS: The prevalence of anti-collagen type V in early-SSc, defined-SSc and control groups was respectively 33, 17 and 5% (p = 0.07). SSc patients with anti-collagen type V had shorter disease duration compared to those without this antibody (8.8 ± 5.1 vs. 14.7 ± 8.9, p = 0.006). Likewise, early-SSc patients with anti-collagen V also had a shorter disease duration than patients negative for this antibody (4.6 ± 2.2 vs. 9.7 ± 5.2, p = 0.04). No association with clinical subsets or scleroderma antibodies specificities was observed (p > 0.05). CONCLUSION: The production of anti-collagen type V in SSc seems to be an early event independent of other antibodies specificities. Further studies are necessary to determine if the underlying mechanism for this chronology involves a primary immune response to abnormal expression of collagen type V.
Assuntos
Anticorpos/análise , Colágeno Tipo V/imunologia , Esclerodermia Difusa/imunologia , Esclerodermia Limitada/imunologia , Adulto , Fatores Etários , Anticorpos Antinucleares/análise , Biomarcadores/análise , Estudos de Casos e Controles , Colágeno Tipo V/análise , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Esclerodermia Localizada/imunologiaRESUMO
BACKGROUND: Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival. METHODS: We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival. RESULTS: Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death. CONCLUSIONS: dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.
Assuntos
Autoanticorpos/sangue , Estradiol/sangue , Esclerodermia Difusa/sangue , Pele/patologia , Idoso , Autoanticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocárdio/imunologia , Miocárdio/patologia , Esclerodermia Difusa/imunologia , Pele/imunologiaRESUMO
Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.