RESUMO
OBJECTIVE: To investigate the epigenetic footprint of idiopathic inflammatory myopathies (IIM) through characterization of circulating extracellular vesicles (EVs) and the expression of EV-derived small non-coding RNAs (sncRNAs). METHODS: In this cross-sectional study, EVs were isolated by size-exclusion chromatography from plasma of patients with IIM and age- and sex-matched healthy donors (HD). EV-derived sncRNAs were sequenced and quantified using Next-Generation Sequencing (NGS). Following quality control and normalization, filtered count reads were used for differential microRNA (miRNA) and piwi-interacting RNA (piRNA) expression analyses. Putative gene targets enriched for pathways implicated in IIM were analyzed. Patients' clinical and laboratory characteristics at the time of sampling were recorded. RESULTS: Forty-seven IIM patients and 45 HD were enrolled. MiR-486-5p (p < 0.01), miR-122-5p, miR-192-5p, and miR-32-5p were significantly upregulated (p < 0.05 for all), while miR-142-3p (p < 0.001), miR-141-3p (p < 0.01), let-7a-5p (p < 0.05) and miR-3613-5p (p < 0.05) downregulated in EVs from IIM patients versus HD. MiR-486-5p was associated with raised muscle enzymes levels. Several target genes of up/downregulated miRNAs in IIM participate in inflammation, necroptosis, interferon and immune signaling. Six piRNAs were significantly dysregulated in IIM EVs versus HD (p < 0.05). Within IIM, miR-335-5p was selectively upregulated and miR-27a-5p downregulated in dermatomyositis (n = 21, p < 0.01). Finally, plasma EV levels were significantly increased in cancer-associated myositis (CAM, n = 12) versus non-CAM IIM (n = 35, p = 0.02) and HD (p < 0.01). EVs cargo in CAM was significantly enriched of let-7f-5p and depleted of miR-143-3p. CONCLUSION: Through an unbiased screening of EV-derived sncRNAs, we characterize miRNAs and piRNAs in the EVs cargo as potential biomarkers and modifiers of diverse IIM phenotypes.
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Biomarcadores , Vesículas Extracelulares , MicroRNAs , Miosite , Pequeno RNA não Traduzido , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Feminino , Masculino , Pessoa de Meia-Idade , Miosite/genética , Miosite/sangue , Miosite/diagnóstico , Miosite/imunologia , Estudos Transversais , MicroRNAs/genética , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/sangue , Adulto , Idoso , Sequenciamento de Nucleotídeos em Larga Escala , Perfilação da Expressão GênicaRESUMO
PURPOSE OF REVIEW: Idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune disorders characterized by muscle weakness and inflammation. MicroRNAs (miRNAs) are the main class of small noncoding RNAs regulating a wide range of physiological and pathological processes and play a role in mediating autoimmunity and inflammation. In this review, we summarize the latest knowledge on the role of miRNAs in systemic autoimmune diseases with particular focus on IIMs. RECENT FINDINGS: Study on miRNA expression in IIMs is helping in understanding the pathogenetic basis of the disease at a tissue and systemic level. Several miRNAs, even with a muscle-specific expression (myomiRs), have been shown to be involved in immune and nonimmune mechanisms of myofiber damage. MiRNAs modulate and orchestrate the local inflammatory infiltrate and could be used as potential biomarkers as they correlate with disease activity and response to therapy. SUMMARY: IIMs comprise different clinical phenotypes and still little is known about the molecular signature of each subset. Further research about miRNA profiling will provide additional insights in the disease characterization with an expected impact on the therapeutic strategies.
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Doenças Autoimunes , MicroRNAs , Miosite , Humanos , MicroRNAs/genética , Autoimunidade , Inflamação/genéticaRESUMO
There is still a need for an efficient method for the isolation of extracellular vesicles (EVs) from human blood that provides a reliable yield with acceptable purity. Blood is a source of circulating EVs, but soluble proteins and lipoproteins hamper their concentration, isolation, and detection. This study aims to investigate the efficiency of EV isolation and characterization methods not defined as "gold standard". EVs were isolated from human platelet-free plasma (PFP) of patients and healthy donors through size-exclusion chromatography (SEC) combined with ultrafiltration (UF). Then, EVs were characterized using transmission electron microscopy (TEM), imaging flow cytometry (IFC), and nanoparticle tracking analysis (NTA). TEM images showed intact and roundish nanoparticles in pure samples. IFC analysis detected a prevalence of CD63+ EVs compared to CD9+, CD81+, and CD11c+ EVs. NTA confirmed the presence of small EVs with a concentration of ~1010 EVs/mL that were comparable when stratifying the subjects by baseline demographics; conversely, concentration differed according to the health status across healthy donors and patients affected with autoimmune diseases (130 subjects in total, with 65 healthy donors and 65 idiopathic inflammatory myopathy (IIM) patients). Altogether, our data show that a combined EV isolation method, i.e., SEC followed by UF, is a reliable approach to isolate intact EVs with a significant yield from complex fluids, which might characterize disease conditions early.
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Cromatografia em Gel , Vesículas Extracelulares , Ultrafiltração , Humanos , Cromatografia em Gel/métodos , Vesículas Extracelulares/química , Lipoproteínas/metabolismo , Microscopia Eletrônica de Transmissão , Ultrafiltração/métodos , SangueRESUMO
Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110-0.2300) vs. 0.0000 (0.0000-0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125-17.9400) vs. 0.0000 (0.0000-0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Adulto , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Interleucina-18 , Interleucina-10 , Interleucina-17 , Citocinas , BiomarcadoresRESUMO
PURPOSE OF REVIEW: This review summarizes the recent developments about anti-MDA5 antibody positive dermatomyositis with a focus on its pathogenesis, clinical features and treatment options of rapidly progressive interstitial lung disease, its most ominous complication. RECENT FINDINGS: Anti-MDA5+ dermatomyositis has a heterogeneous clinical spectrum with different patient subsets exhibiting widely different outcomes; severe acute interstitial lung disease is the main factor impacting prognosis. The pathogenetic role of anti-MDA5 antibodies is an active area of investigation. SUMMARY: Anti-MDA5+ dermatomyositis has a wider spectrum of manifestations than previously thought. A high index of suspicion is needed not to miss atypical presentations. In the setting of acute interstitial lung involvement, once a confident diagnosis is made, an aggressive approach with early combined immunosuppression affords the best chances of survival.
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Dermatomiosite , Doenças Pulmonares Intersticiais , Autoanticorpos , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Humanos , Helicase IFIH1 Induzida por Interferon , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/terapia , PrognósticoRESUMO
PURPOSE OF REVIEW: This is a comprehensive review of the current knowledge on predominant immune cell phenotypes involved in idiopathic inflammatory myopathies (IIM). RECENT FINDINGS: Major circulating immune cell subpopulations described in IIM encompass the lymphocyte compartment. An unbalance in T cell subsets seems to consistently affect the peripheral and muscle compartment, with a predominance of CD4+ T and B cells in dermatomyositis, CD8+ T cells in polymyositis/inclusion body myositis (IBM) and novel findings highlighting novel proinflammatory T subsets, that is, CD8+Tbet+ and CD28- T cells across different IIM subsets. On the other hand, an impairment in Treg cells number and function has been described especially across polymyositis/dermatomyositis and IBM. Total T follicular helper (Tfh) cells, increased in immune-mediated necrotizing myopathy, skewed toward Tfh2 and Tfh17 in dermatomyositis, polymyositis, and juvenile dermatomyositis. B cell compartment is more rarely described in IIM, yet an unbalance in this pool is as well likely. Evidence of plasma cells increased in polymyositis, dermatomyositis, IBM, and Bregs decreased in dermatomyositis have been reported. Perturbations in the memory and naïve subsets are common in dermatomyositis/polymyositis and antisynthetase syndrome. SUMMARY: Protean immune cell abnormalities characterize different IIM subsets, reflecting the complexity of these autoimmune conditions. A deeper understanding of B-cell and T-cell immunophenotyping may promote early diagnosis and identification of new potential therapeutic targets.
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Dermatomiosite , Miosite de Corpos de Inclusão , Miosite , Polimiosite , Dermatomiosite/diagnóstico , Humanos , Imunofenotipagem , Polimiosite/diagnósticoRESUMO
OBJECTIVE: To investigate prevalence of anti-Pentraxin 3 (PTX3) antibodies in sera of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. METHODS: Anti-PTX3 and PTX3 levels were analysed by enzyme-linked immunosorbent assays in sera from unselected patients with AAV and compared with patients with systemic lupus erythematosus (SLE, n = 130), other connective tissue diseases (CTDs, n = 97) and matched healthy controls (n = 97). Optical density (OD) cut-off for positive anti-PTX3 antibodies was determined by ROC curve analysis and set as 0.234. Indirect immunofluorescence (IIF) on fixed human granulocytes was used to analyze the fluorescence pattern of anti-PTX3 antibodies. Liquid-phase inhibition tests were conducted to assess potential interferences. RESULTS: We included 101 AAV patients (females 58%, median age 60[51-69] years) affected either with granulomatosis with polyangiitis (GPA, n = 51), microscopic polyangiitis (MPA, n = 12) or eosinophilic granulomatosis with polyangiitis (EGPA, n = 38). Anti-PTX3 antibodies were detected in 29.7% AAV patients, being significantly higher than in healthy controls (p < 0.001) and CTDs (p = 0.030) but lower than in SLE (p = 0.004). Anti-PTX3 antibody prevalence was 44.7% in EGPA, 25% in MPA and 19% in GPA (p = 0.034). Among ANCA negative patients, 35.7% displayed positive anti-PTX3 antibodies. Anti-PTX3 were associated with a lower prevalence of systemic (p = 0.002), ear-nose-throat (p = 0.006) and renal manifestations (p = 0.016). Anti-PTX3 antibodies were characterized by a specific IIF pattern on fixed granulocytes. PTX3 serum levels resulted lower in AAV than healthy controls (p < 0.001). PTX3 inhibited anti-PTX3 binding in a dose-dependent manner. CONCLUSIONS: Anti-PTX3 autoantibodies appear a promising novel biomarker of AAV, especially EGPA.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Autoanticorpos/sangue , Biomarcadores/sangue , Granuloma Eosinófilo/diagnóstico , Granulomatose com Poliangiite/diagnóstico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Ensaio de Imunoadsorção Enzimática , Granuloma Eosinófilo/imunologia , Feminino , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos SoroepidemiológicosRESUMO
PURPOSE OF REVIEW: This review encompasses the main novelties regarding nonimmune mechanisms implicated in the pathogenesis of idiopathic inflammatory myopathies (IIM). RECENT FINDINGS: In recent years, growing data support a role for endoplasmic-reticulum (ER) stress as a propagator of muscular damage, together with the release of interferon type I and reactive oxygen species in hypoxemic muscle fibers. Other studies evaluating the relationship between autophagy and Toll-like receptors (TLRs) in IIM subtypes have shown increased TLR3 and TLR4 expression in fibers of IIM patients and colocalization with LC3, an autophagy marker, submitting autophagy as a likely player in IIM pathogenesis. Most novel evidences concern the potential role of denervation of the neuromuscular junction in IIM, possibly connected to hyperexpression of MHC-I, and trafficking of extracellular vesicles, which may represent a connection between nonimmune and immune-mediated mechanisms of muscle inflammation and damage. SUMMARY: Nonimmune mechanisms contribute to the pathogenesis of IIM, likely cooperating with immune-mediated inflammation. Consistent data were released for ER stress, autophagy, mitochondrial dysfunction and hypoxia; in addition to, neuromuscular denervation and extracellular vesicles have been proposed as thoughtful links between muscle inflammation, damage and atrophy. Further understanding of nonimmune abnormalities and potential reversible pathways is needed to improve the management of IIM.
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Estresse do Retículo Endoplasmático/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Miosite/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Autofagia/fisiologia , Humanos , Fibras Musculares Esqueléticas/patologia , Miosite/patologia , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Pentraxin3 (PTX3) is an emerging player in lupus nephritis (LN). Anti-PTX3 antibodies showed to delay LN occurrence in vivo. AIM: To evaluate renal changes following immunization with PTX3 in a murine model of LN. MATERIALS AND METHODS: Twenty-two lupus-prone New Zealand Black/White (NZB/W)F1 mice were divided into two groups (n = 11) and subcutaneously injected with human recombinant (hr)PTX3 100 µg or phosphate buffer saline (PBS) 200 µl, three times 3 weeks apart, starting before development of proteinuria. Five mice from each group were scheduled for sacrifice at week 22 and 6 from each group at week 29. Renal lesions included electron-dense deposits (EDD), glomerular deposition of IgG, complement and PTX3 as markers of renal inflammation. They were evaluated by immunofluorescence (IF), confocal and immunoelectron microscopy (IEM). Validated semiquantitative scores were used when available to score renal lesions. Chi-squared test with Fisher exact test was used for comparison. RESULTS: Nineteen out of 22 mice were sacrificed as scheduled. Only hrPTX3-immunized mice developed anti-PTX3 antibodies. Compared to PBS-injected mice, they displayed a dramatic decrease in glomerular deposits of IgG, C1q and PTX3, as well as in the amount of EDD (p = 0.006) and podocyte effacement (p = 0.043). Importantly, PTX3 was pinpointed inside the EDD and co-localized with nuclear material. CONCLUSIONS: Immunization with PTX3 prevented progression from the preclinical to the clinical stage of LN, inciting anti-PTX3 antibodies and preventing renal PTX3 deposition. PTX3 is a novel component of EDD, submitting it as one initiating autoantigen in LN and as potential target for early treatment.
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Formação de Anticorpos/imunologia , Complexo Antígeno-Anticorpo/ultraestrutura , Proteína C-Reativa/metabolismo , Glomérulos Renais/ultraestrutura , Nefrite Lúpica/imunologia , Componente Amiloide P Sérico/metabolismo , Animais , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Proteínas do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Resistência à Doença , Feminino , Humanos , Imunização , Glomérulos Renais/metabolismo , Camundongos , Camundongos Endogâmicos , Microscopia Eletrônica , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/imunologiaRESUMO
PURPOSE OF REVIEW: Lung involvement is a distinctive feature of antisynthetase syndrome (ASS) and it is considered a basic disease-classifying criterion. In this review, we go over clinical features, radiological patterns, prognostic factors, pathogenesis and treatment of lung involvement in ASS patients, focusing on the clinical differences linked to the different antibody specificities known so far. RECENT FINDINGS: The lung is the most common extramuscular organ involved in ASS and has the greatest impact on patient prognosis. The pulmonary disease-defining manifestation in ASS is interstitial lung disease (ILD), yet a proportion of patients also develop pulmonary arterial hypertension and, less frequently, obstructive bronchiolitis or acute respiratory failure according to drivers not yet fully understood but likely associated with the underlying autoantibody pattern. Clinical presentation of pulmonary involvement can range from milder forms to a rapidly progressive disease which may lead to chronic lung damage if misdiagnosed and not properly treated. SUMMARY: The knowledge of risk factors associated with progressive or refractory lung damage is important to identify and properly treat patients with the poorest prognosis. For those with a disease not responsive to conventional therapy the efficacy of other therapeutic option is under evaluation.
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Autoimunidade , Doenças Pulmonares Intersticiais/etiologia , Miosite/complicações , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Pessoa de Meia-Idade , Miosite/imunologia , Prognóstico , RadioisótoposRESUMO
PURPOSE OF REVIEW: The aim of this study was to provide the most recent evidence on clinical utility of myositis-specific autoantibodies (MSAs) in the management of patients with myositis. RECENT FINDINGS: In the last few years, several evidences have emerged on the clinical and pathogenetic role of established and novel MSA. Antisynthetase antibodies represent a reliable biomarker for pulmonary involvement also in patients with connective tissue diseases other than myositis. Antisignal recognition particle and antihydroxy-3-methylglutaryl coenzyme A reductase autoantibodies are able to induce complement-dependent muscle damage. Dermatomyositis-specific antibodies are useful indicators of clinical diversity. The pivotal role of antitranscription intermediary factor 1γ autoimmune response in adult-age paraneoplastic dermatomyositis has been further asserted. AnticN1A and antifour-and-a-half LIM protein 1 antibodies are newly conceived myositis-related antibody specificities, which can contribute to patients' stratification into more homogeneous groups. SUMMARY: Distinct autoantibody-associated clinical phenotypes can be predicted by extended MSA testing in serum. Standardization and validation of MSA laboratory detection methods is strongly recommended for better supporting myositis diagnosis, management and prognosis definition.
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Autoanticorpos/imunologia , Autoimunidade/imunologia , Miosite/imunologia , Humanos , PrognósticoRESUMO
OBJECTIVE: To evaluate the prevalence, duration and effect on damage accrual of the 'Lupus Low Disease Activity State' (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE). METHODS: We studied 293 Caucasian patients with SLE during a 7-year follow-up period. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SELENA-SLEDAI physician global assessment (PGA), and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We considered the following definition of LLDAS: SLEDAI-2K ≤4 without major organ activity, no new disease activity, PGA (0-3)≤1, prednisone ≤7.5 mg/day and well-tolerated immunosuppressant dosages. The effect of LLDAS on SDI was evaluated by multivariate regression analysis. We also evaluated remission defined as clinical SLEDAI-2K=0 and prednisone ≤5 mg/day in patients treated with/without stable immunosuppressants and/or antimalarials. RESULTS: LLDAS lasting 1, 2, 3, 4 or ≥5 consecutive years was achieved by 33 (11.3%), 43 (14.7%), 39 (13.3%), 31 (10.6%) and 109 (37.2%) patients, respectively. Patients who spent at least two consecutive years in LLDAS had significantly less damage accrual compared with patients never in LLDAS (p=0.001), and they were significantly less likely to have an increase in SDI (OR 0.160, 95% CI 0.060 to 0.426, p<0.001). On average, 84% of patients in LLDAS also fulfilled the criteria for remission. CONCLUSIONS: LLDAS was associated with a decrease in damage progression in Caucasian patients with SLE. The majority of patients in LLDAS were in remission, which can largely contribute to the protective effect of LLDAS on damage accrual.
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Anti-Inflamatórios/uso terapêutico , Progressão da Doença , Lúpus Eritematoso Sistêmico/patologia , Prednisona/uso terapêutico , Índice de Gravidade de Doença , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , População BrancaRESUMO
OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.
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Artrite/epidemiologia , Miosite/epidemiologia , Adulto , Artrite/diagnóstico , Artrite/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/imunologia , Fenótipo , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Anti-p200 antibodies have been receiving growing interest in view of findings associating their presence to risk of fetal autoimmune congenital heart block (CHB). The study compares and evaluates the performance of two assays currently being used for their detection. METHODS: One hundred and sixteen pregnant women positive for anti-SSA/Ro52 antibodies were considered as the study population. Fifty women negative for anti-SSA/Ro52 antibodies were considered as the control population. Anti-p200 antibodies were analyzed using two home-made ELISA assays: one with biotinylated antigen and the other with free antigen. RESULTS: The specificity of the p200-free assay was significantly higher with respect to that of the p200-biotin assay (p=0.023). Both methods showed a high area under curve (AUC), thus, a good accuracy. There was a significant prevalence of anti-p200 antibodies when the p200-free assay was used to analyze the sera of the pregnant women with CHB fetuses (p=0.007). Cohen's κ and Spearman's ρ coefficients showed a good concordance (0.71) and a high correlation (0.93), respectively. CONCLUSIONS: The p200-free assay with respect to the biotin-based method was more specific in detecting p200 antibodies in women positive for anti-SSA/Ro52 antibodies. In addition, only the p200-free method significantly found p200 antibodies in patients with fetal CHB.
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Autoanticorpos/sangue , Epitopos/imunologia , Laboratórios/organização & administração , Ribonucleoproteínas/imunologia , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , HumanosRESUMO
AIM: To identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE). METHODS: We studied 293 Caucasian patients with SLE during 7-year follow-up. Disease activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1-5â mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis. RESULTS: Among patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (p<0.001).In multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2â years 0.228 (0.061 to 0.850); 3â years 0.116 (0.031 to 0.436); 4â years 0.118 (0.027 to 0.519) and ≥5â years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180â mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)). CONCLUSIONS: Two consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.
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Síndrome Antifosfolipídica/complicações , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Prednisona/administração & dosagem , Vasculite/complicações , População Branca , Adulto , Anti-Inflamatórios/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Prospectivos , Indução de Remissão , Índice de Gravidade de Doença , Exacerbação dos Sintomas , Fatores de Tempo , Adulto JovemRESUMO
Autoantibodies are key mediators in determining the clinical manifestations of systemic lupus erythematosus (SLE). The mechanisms by which antibodies may be harmful to self tissues encompass complement mediated inflammation, cell apoptosis and immune-complexes mediated damage, however the precise cooperation of antibodies in SLE have not been unravelled so far. Lupus nephritis (LN) is a protean feature of SLE resulting in wide variety of symptoms including asymptomatic proteinuria, mild renal disease until end-stage renal failure which are triggered by complex autoantibody interactions. Novel clues concerning development and self-maintenance of LN have come to light in recent times, pointing straight to a multistep inflammatory process which is incited by anti-chromatin antibodies, the best known being anti-DNA and anti-nucleosome antibodies, culminating in a self-maintaining inflammatory loop with spreading of glomerular inflammation. In the maintenance of the inflammatory process pro-inflammatory antibodies are involved, among which anti-C1q are thought to play a major role, whereas hindrance of the nephritic process could be actively mediated by protective autoantibodies. Despite being so relevant in occurrence of LN, nor anti-chromatin neither anti-C1q antibodies have been precisely characterized in terms of origin, antigen specificity and mechanisms of action. Moreover, novel autoantibodies are emerging in LN which can modify disease course, whereas the pathogenic value of a myriad of cross-reactive antibodies has been progressively challenged. The aim of this review is to give a comprehensive view of known and emerging autoantibody reactivities involved in renal inflammation and damage going over their origin, mechanisms of action and interactions in determining LN course.
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Autoanticorpos/imunologia , Nefrite Lúpica/imunologia , Anticorpos Antinucleares/imunologia , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Antígenos/imunologia , Complemento C1q/imunologia , Reações Cruzadas/imunologia , Humanos , Glomérulos Renais/imunologia , Nefrite Lúpica/metabolismo , Podócitos/imunologiaRESUMO
BACKGROUND: Anti-pentraxin 3 (PTX3) antibodies were associated with the absence of lupus glomerulonephritis in humans. AIM: To explore the effects of anti-PTX3 antibodies in New Zealand Black/White (NZB/NZW F1) mice and their inherent mechanisms of action. MATERIALS AND METHODS: 30 NZB/NZW F1 mice were subdivided into 3 groups of 10 mice each and subcutaneously injected with PTX3, alum and PBS (group 1), alum and PBS (group 2) or PBS alone (group 3), 3 times 3 weeks apart, before development of renal disease. Mice were followed until natural death. Histological analysis and immunohistochemistry were performed on harvested kidneys. Effects of anti-PTX3 antibodies on C1q binding to immobilized PTX3-anti-PTX3 immune complexes were evaluated in vitro using human SLE sera. Qualitative characterization of human IgG anti-PTX3 was performed. RESULTS: Only group 1 mice developed anti-PTX3 antibodies. Anti-dsDNA and anti-C1q antibodies appeared significantly later and at lower levels in group 1 mice vs. controls (p < 0.0001). Proteinuria-free and overall survival were significantly increased in group 1 mice vs. controls (p < 0.05 and p = 0.03, respectively). Histopathological analysis showed that glomerular and tubular PTX3 staining and renal lesions were increased in controls compared with immunized mice. Addition of human SLE sera positive for anti-PTX3 antibodies to C1q and fixed PTX3 interfered with C1q binding to PTX3-anti-PTX3 immune complexes. Qualitative characterization of human IgG anti-PTX3 showed an increased proportion of IgG4. CONCLUSIONS: Anti-PTX3 antibodies delay lupus-like nephritis and prolong survival of NZB/NZW F1 mice. In vitro observations suggest anti-PTX3 antibodies may dampen complement activation via their Fc fragment, likely hindering renal inflammation.
Assuntos
Autoanticorpos/imunologia , Proteína C-Reativa/imunologia , Nefrite Lúpica/imunologia , Componente Amiloide P Sérico/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Biomarcadores , Biópsia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Ativação do Complemento/imunologia , Complemento C1q/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imuno-Histoquímica , Testes de Função Renal , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/metabolismo , Nefrite Lúpica/mortalidade , Camundongos , Camundongos Endogâmicos NZB , Substâncias Protetoras , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Fatores de TempoRESUMO
AIM: To assess the prevalence of prolonged remission in Caucasian patients affected with systemic lupus erythematosus (SLE) and its relationship with damage accrual. METHODS: Caucasian patients diagnosed with SLE between 1990 and 2009 and quarterly seen from 2009 to 2013 were included in the study. We defined remission as prolonged when lasting ≥5 consecutive years. Three levels of remission were defined using the SLE Disease Activity Index-2000 (SLEDAI-2K): complete remission: no disease activity in corticosteroid-free and immunosuppressant-free patients; clinical remission off corticosteroids: serologically active clinical quiescent (SACQ) disease in corticosteroid-free patients and clinical remission on corticosteroids: SACQ disease in patients taking prednisone 1-5â mg/day. Damage was measured by the SLICC/American College of Rheumatology Damage Index (SDI). RESULTS: 224 patients fulfilled inclusion criteria: 196 (87.5%) were women, mean±SD disease duration 11.2±6.8â years. During the 5-year follow-up, 16 patients (7.1%) achieved prolonged complete remission, 33 (14.7%) prolonged clinical remission off corticosteroids and 35 (15.6%) prolonged clinical remission on corticosteroids. At the multivariate analysis, vasculitis (OR 4.95), glomerulonephritis (OR 2.38) and haematological manifestations (OR 2.19) over the patients' disease course were associated with an unremitted disease. SDI increased more frequently in unremitted (72/140, 51.4%) than in remitted patients (22/84, 26.2%; p=0.001); SDI median increase was higher in unremitted than in remitted patients: 1 (0-3) vs 0 (0-2), respectively (p<0.001). At multivariate analysis, unremitted disease (OR 2.52) and high-dose corticosteroid intake (OR 2.35) were risk factors for damage accrual. CONCLUSIONS: Thirty-seven percent of our Caucasian patients achieved a prolonged remission, which was associated with a better outcome in terms of damage accrual.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , População Branca , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Prevalência , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
PURPOSE: The aim of the present study was to evaluate the in vivo immunomodulatory effects of an acute short-term estradiol (E(2)) increase on serum levels of B cell-activating factor (BAFF), immunoglobulins (Ig), anti-nuclear antibodies (ANA), and the peripheral B cell phenotype. METHODS: We conducted, at the Infertility Center of the University of Padua, a prospective case-control study on a cohort of infertile normo-responder women (group-A, 63 patients) undergoing controlled ovarian stimulation (COS) compared with an age-matched cohort of normo-ovulatory healthy women (group-B, 39 patients). Three serial blood sample assays were conducted in both groups, at T0, hypothalamic suppression; T1, ovulation induction; and T2, ßhCG test in group A, and at T0, 2nd day; T1, 14th day; and T2, 21st day of cycle in group B, and serum levels of E(2) and BAFF, BAFF/E(2) ratio, circulating IgM, IgG, and IgA, ANA titer, and peripheral B cell phenotype were measured. We compared group-A versus group-B in terms of absolute and E(2) normalized values of BAFF at baseline (T0) to verify for possible differences between healthy and infertile women, at T1 to verify for possible differences occurring after spontaneous ovulation versus COS, and at T2 to evaluate differences in serum BAFF levels between pregnant versus non-pregnant patients (considering only group-A) and between non-pregnant women after spontaneous versus COS cycles (group-B versus group-A). In group-A, we also evaluated IgM, IgG, IgA levels, ANA titer, and peripheral B cell phenotype at T0 versus T1 versus T2. RESULTS: With the exception of E(2) levels at T1 (as expected), no significant differences were found between the two groups for all outcome measures. In group-A, BAFF at T0 positively correlated with IgM levels; marginal zone CD19+/CD27+/IgD+ memory B cell compartment tended to be expanded at T1 when compared with T0. CONCLUSIONS: Despite several mechanistic and clinical studies supporting a stimulatory role of E(2) on autoimmunity, the acute increase of E(2) during COS for infertility treatment does not seem to have a major impact on the immune system.