RESUMEN
OBJECTIVES: Retroperitoneal fibrosis (RPF) is mostly idiopathic (iRPF); however, it can be secondary to drugs, malignancies, infections, or, as recently recognised, can be part of the IgG4-related diseases. The aim of our study was i) to describe the presenting clinical/laboratory/imaging features and treatment modalities used in patients with iRPF and ii) to evaluate factors potentially associated with disease relapse. METHODS: The medical records of patients diagnosed with iRPF and followed in four tertiary medical units in Athens, Greece from 2000 to 2018 were retrospectively evaluated. RESULTS: Sixty-seven patients with iRPF were included in the study. Seventy-three per cent were males, with a mean age at diagnosis 56.0±9.2 years. Low-back pain (63%) and constitutional symptoms (57%) were the commonest presenting symptoms. Elevated acute-phase reactants (78%), anaemia (43%) and impaired renal function (41%) were the most common laboratory findings. Serum IgG4 at diagnosis was evaluated in 36/67 patients and 36% of them had elevated levels (mean 297.7±166.3mg/dL). Diagnosis was mainly based on abdominal CT and/or MRI. Clinical/laboratory/radiological presentation did not differ between patients with elevated and normal serum IgG4 levels. Steroids were used as first-line treatment in 98%. Relapse occurred in 28.6% after a mean of 43.1±31.8 months. Relapse did not associate to initial clinical/imaging findings or to any treatment used, however patients with increased serum IgG4 had a significantly higher relapse rate (75% vs. 25%, p=0.005). CONCLUSIONS: Relapse occurred in one-fifth of patients independently of the initial clinical/radiographic presentation or treatment used. iRPF patients with baseline elevated serum IgG4 levels have a higher relapse rate.
Asunto(s)
Fibrosis Retroperitoneal , Proteínas de Fase Aguda , Enfermedad Crónica , Femenino , Grecia , Humanos , Inmunoglobulina G , Masculino , Recurrencia , Fibrosis Retroperitoneal/diagnóstico por imagen , Fibrosis Retroperitoneal/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Primary Sjögren's syndrome (SS) is characterized by chronic periductal inflammatory infiltrates in the salivary glands. Several previous studies have indicated that the ductal epithelia of SS patients play a pro-inflammatory role and manifest an intrinsically activated status, as demonstrated in cultured non-neoplastic ductal salivary gland epithelial cell (SGEC) lines. Herein, we investigated the activation of inflammasomes in the salivary epithelia of SS patients and non-SS controls, using salivary biopsy tissues and SGEC lines. The ductal epithelial cells of SS patients were found to display significant activation of the AIM2 (absent in melanoma-2) inflammasome. Such activation occurred in a cell-autonomous manner, as it was illustrated by the constitutively high expression of AIM2 activation-related genes, the presence of cytoplasmic ASC specks and the increased spontaneous IL-1ß production observed in patients' SGEC lines. Since AIM2 activation is known to occur in response to cytoplasmic DNA, we further searched for the presence of undegraded extranuclear DNA in the SGEC lines and SG tissues of patients and controls. This investigation revealed marked cytoplasmic accumulations of damaged genomic DNA that co-localized with AIM2 in the specimens of SS patients (but not controls). The SGEC lines and the ductal tissues of SS patients were also found to manifest impaired DNase1 expression and activity, which possibly denotes defective cytoplasmic DNA degradation in patients' cells and AIM2 triggering thereof. In corroboration, DNase1-silencing in normal SGEC was shown to lead to high AIM2-related gene expression and IL-1ß production. Our findings indicate that the cell-intrinsic activation status of ductal epithelia in SS patients owes to persistent epithelial AIM2 activation by aberrant cytoplasmic DNA build-up.
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Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Inflamasomas/metabolismo , Síndrome de Sjögren/etiología , Biomarcadores , Biopsia , Citocinas/metabolismo , Células Epiteliales/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Glándulas Salivales/metabolismo , Síndrome de Sjögren/patologíaRESUMEN
Sjögren's syndrome (SS) patients manifest high cell-free DNA (cf-DNA) levels in serum, associated with impaired DNaseI activity. Undegraded DNA may accumulate in tissues and act as an inflammasome-activating signal. Herein, we investigated the occurrence of aberrant DNA build-up in various biologic compartments of SS patients and its correlation with the activity of NLRP3 and AIM2 inflammasomes. For this purpose, we evaluated sera, PBMC, circulating monocytes and salivary glands (SG) from different SS patient subgroups and controls. We found that SS patients at high risk for lymphoma and those with established lymphoma display high serum cf-DNA levels, substantial extranuclear DNA accumulations in PBMC and SG tissues, a unique NLRP3 inflammasome gene signature in PBMC, and significantly increased serum IL-18 and ASC levels. In these patients, the circulating monocytes manifested NLRP3 inflammasome activation and increased response to NLRP3 stimuli, whereas SG-infiltrating macrophages exhibited signs of NLRP3 activation and pyroptosis. Cell-free nucleic acids isolated from patients' sera competently primed the activation of both NLRP3 and AIM2 inflammasomes in healthy monocytes. SS patients also manifested diminished DNaseI activity in serum and DNaseII expression in PBMC, which inversely correlated with indices of inflammasome activation. DNaseII gene-silencing in healthy monocytes led to cytoplasmic DNA deposition and activation of inflammasome-related genes and of caspase1. Our data reveal the occurrence of systemic NLRP3 inflammasome activation in severe SS, which is associated with widespread extranuclear accumulations of inflammagenic DNA and impaired DNA degradation. These findings can provide novel biomarkers and new therapeutic targets for the management of SS patients with adverse outcomes.
Asunto(s)
Biomarcadores/sangre , Ácidos Nucleicos Libres de Células/sangre , Inflamasomas/metabolismo , Leucocitos Mononucleares/inmunología , Linfoma/inmunología , Glándulas Salivales/inmunología , Síndrome de Sjögren/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Muerte Celular , Ácidos Nucleicos Libres de Células/inmunología , Células Cultivadas , Degradación Necrótica del ADN , Fragmentación del ADN , Progresión de la Enfermedad , Endodesoxirribonucleasas/genética , Endodesoxirribonucleasas/metabolismo , Femenino , Humanos , Interleucina-18/metabolismo , Linfoma/diagnóstico , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Riesgo , Síndrome de Sjögren/diagnóstico , Adulto JovenRESUMEN
Sjögren's syndrome (SS) patients manifest inflammation in the salivary glands (SG) and evidence of persistent intrinsic activation of ductal SG epithelial cells (SGEC), demonstrable in non-neoplastic SGEC lines derived from patients (SS-SGEC). The peroxisome-proliferator-activated receptor-γ (PPARγ) mediates important anti-inflammatory activities in epithelial cells. Herein, the comparative analysis of SG biopsies and SGEC lines obtained from SS patients and controls had revealed constitutively reduced PPARγ expression, transcriptional activity and anti-inflammatory function in the ductal epithelia of SS patients that were associated with cell-autonomously activated NF-κB and IL-1ß pathways. Transcriptome profiling analysis revealed several differentially expressed proinflammatory and metabolism-related gene sets in SS-SGEC lines. These aberrations largely correlated with the severity of histopathologic lesions, the disease activity and the occurrence of adverse manifestations in SS patients studied, a fact which corroborates the key role of the persistently-activated epithelia in the pathogenesis of both local and systemic features of this disease. The treatment of control SGEC lines with PPARγ agonists was found to diminish the NF-κB activation and apoptosis induced by proinflammatory agents. In addition, the in-vitro application of PPARγ agonists and pharmacologic inhibitors of IL-1ß and NF-κB had significant beneficial effects on SS-SGEC lines, such as the restoration of PPARγ functions and the reduction of their intrinsic activation, a fact which may advocate the future clinical study of the above agents as therapeutic modalities for SS.
Asunto(s)
Epitelio/fisiología , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Glándulas Salivales/patología , Síndrome de Sjögren/inmunología , Apoptosis , Línea Celular , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/metabolismo , PPAR gamma/agonistas , Rosiglitazona/farmacología , Transducción de Señal , Análisis de Matrices TisularesRESUMEN
OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, devastating disease. Treat-to-target strategy (T2T) more than the usual care, reduces disease activity by using aggressively all therapeutic options. The aim of the study was to evaluate our hypothesis that T2T strategy using biologic disease-modifying anti-rheumatic drugs (bDMARDs), when needed, is also safer than the usual care characterised by delayed initiation of bDMARDs. METHODS: Disease activity was regularly measured by DAS-28 until the end of treatment with the first bDMARD. All adverse events (AEs) and their severity were recorded. Cox proportional-hazards models were performed examining the association of treatment groups, with the risk of first AE. RESULTS: There were 113 patients in T2T and 250 patients in usual care group. The likelihood (adjusted hazard ratio, HR) of achieving remission or LDA was 71% higher in the T2T group than in the usual care group, as it has been already shown by others. The novel finding of our work was that AEs, including cancers, were less frequent in the T2T group with the corresponding HRs being less than 0.50 for serious AEs, infections and serious infections (significant or marginally non-significant results). There were 15 new cancer cases in usual care and 1 in T2T group (IR 1.99 vs. 0.4, p=0.027). CONCLUSIONS: Treat-to-target treatment with bDMARDs offers a safer, rapid and better long-term outcome to patients with RA.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/administración & dosificación , Tiempo de Tratamiento , Adulto , Anciano , Antirreumáticos/efectos adversos , Artritis Reumatoide/diagnóstico , Productos Biológicos/efectos adversos , Distribución de Chi-Cuadrado , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: To directly assess the prevalence of inflammatory rheumatic disease under treatment with biologic disease modifying anti-rheumatic drugs (b-DMARDs) and compare treatment patterns between rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including psoriatic arthritis. METHODS: The obligatory country-wide prescription electronic database covering 10.223.000 Greek citizens (95.1% of the population, 99.5% Caucasian), all of whom with fully reinbursed access to b-DMARDs, was used to retrospectively capture all patients under b-DMARDs for RA/SpA between June 2014-May 2015. Age, gender and medications for RA/SpA and co-morbid classical cardiovascular risk factors (hypertension, dyslipidaemia, diabetes) were retrieved and analysed. RESULTS: A total of 9.824 RA (61.2±14.0 years, 79% women) and 9.279 SpA patients (51.4±13.1 years, 41% women) using pharmacy-dispensed prescriptions for b-DMARDs were identified (overall prevalence 0.19%). Tumour necrosis factor inhibitors were used in 73% and 99% of RA and SpA patients, respectively. B-DMARD monotherapy (RA: 18.71%, SpA: 52.11%), b-DMARD switching during 12 months (RA: 7.73%, SpA: 6.26%), and use of methotrexate (RA: 50.25%, SpA: 27.35%) and corticosteroids (RA: 55.8%, SpA: 23.63%) differed between the two patient subgroups. In both subgroups, women received more often than men methotrexate, leflunomide, hydroxychloroquine and corticosteroids, and less often b-DMARD monotherapy. After adjustments for age, gender and concomitant drugs, the probability for anti-hypertensive and lipid-lowering drug prescription was higher in SpA than RA [OR=1.41 (95%CI: 1.29-1.54) and 1.24 (1.14-1.36), respectively, p<0.001], whereas for anti-diabetics it was similar. CONCLUSIONS: In the first country-wide study that examines the characteristics of rheumatic disease patients under b-DMARD we show that their exact prevalence is 0.19%, with RA patients being older by 10 years, only slightly more numerous, and less likely to receive treatment for hypertension and dyslipidaemia than their demographically matched SpA counterparts. Longitudinal studies should assess the implications of these novel findings on the differential financial burden of rheumatic diseases, as well as on cardiovascular morbidity and mortality of these patients.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Espondiloartropatías/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Antihipertensivos/uso terapéutico , Artritis Reumatoide/epidemiología , Enfermedades Cardiovasculares/epidemiología , Comorbilidad , Bases de Datos Factuales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/epidemiología , Dislipidemias/tratamiento farmacológico , Dislipidemias/epidemiología , Femenino , Grecia/epidemiología , Humanos , Hidroxicloroquina/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Isoxazoles/uso terapéutico , Leflunamida , Modelos Logísticos , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/epidemiología , Factores de Riesgo , Espondiloartropatías/epidemiologíaRESUMEN
BACKGROUND: Data regarding the prevalence and clinical significance of asymptomatic bacteriuria (AB) in women with autoimmune rheumatic disease (ARD) are scarce. METHODS: In this prospective, case-control study, consecutive female outpatients with ARD were screened for AB. For each patient, demographics, type, duration, and treatment of underlying ARD, and risk factors for urinary tract infection (UTI), were recorded. Age-matched women with endocrine disease, without any autoimmune disease, not receiving immunosuppressive agents were used as controls. Subjects were followed up for 1 year for the development of symptomatic UTI. RESULTS: Two hundred sixty patients with ARD (mean age, 52.4 [standard deviation {SD}, 14.6] years) and 238 controls (mean age, 51.2 [SD, 16.5] years) were enrolled. The majority of patients with ARD (93.5%; 95% confidence interval [CI], 89.7%-95.9%) were receiving immunosuppressive agents. AB was detected in 24 patients with ARD (9.2%; 95% CI, 6.2%-13.4%) and in 22 controls (9.2%; 95% CI, 5.5%-12.9%) (P = 1.000). The most prevalent pathogen was Escherichia coli (16/24 [66%]). Independent predictors for AB among patients were diabetes (odds ratio [OR], 6.6; P = .008) and a longer ARD duration (>84 months; OR, 4.3; P = .018). During the 1-year follow-up, 9 patients with baseline AB remained persistently bacteriuric, whereas 11 were intermittently bacteriuric. Symptomatic UTI developed in 4 of 24 patients (16.7%; 95% CI, 6.1%-36.5%) with baseline AB vs 29 of 236 (12.3%; 95% CI, 8.6%-17.1%) without AB (P = .522). CONCLUSIONS: In our study, the prevalence of AB among women with ARD was not higher than that of controls, and AB was not associated with higher risk for symptomatic UTI. Risk factors for AB were longer duration of ARD and diabetes.
Asunto(s)
Infecciones Asintomáticas/epidemiología , Enfermedades Autoinmunes/complicaciones , Bacteriuria/epidemiología , Huésped Inmunocomprometido , Enfermedades Reumáticas/complicaciones , Infecciones Urinarias/microbiología , Adulto , Anciano , Bacteriuria/complicaciones , Bacteriuria/microbiología , Estudios de Casos y Controles , Escherichia coli/aislamiento & purificación , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Embarazo , Embarazo en Diabéticas , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Infecciones Urinarias/complicacionesRESUMEN
Aberrant removal of necrotic debris is considered a feature with inflammatory consequences in SLE. Herein, primary Sjögren's syndrome (SS) patients were investigated for the first time for the capacity of their sera to degrade secondary necrotic cell remnants (SNEC) and DNA (endonuclease DNase1 activity), as well as for uptake of SNEC by blood-borne phagocytes. For comparison, specimens from unselected SLE and RA patients and from healthy blood donors (HBD) were also studied. Compared to HBD, the sera from SS and SLE patients studied (but not RA) were found to exhibit significantly impaired capacity for degradation of SNEC (both for p = 0.007) and deficient DNase1 activity (both for p < 0.0001). The deficient DNase1 activity in SS and SLE sera did not owe to decreased DNase1 protein levels. It correlated inversely with increased serum levels of circulating nucleosomes and cell-free DNA (p < 0.0001), as well as with the disease activity indices of SS (r = -0.445, p = 0.0001) and SLE (r = -0.500, p = 0.013). In ex-vivo whole blood analyses, SS and SLE patients (but not RA) also manifested significantly increased SNEC-phagocytosis by monocytes and granulocytes (all for p < 0.0001) that also correlated with disease severity indices of SS (p = 0.001) and SLE (p = 0.01). In various cross-admixture experiments, such aberration was found to reside in the hyperfunctional activity of phagocytes, the impaired degrading activity of serum DNase1 and the SNEC-binding capacity of serum IgG of SS and SLE patients. The sera of SS and SLE patients (but not of RA) induced significant SNEC-phagocytosis by healthy monocytes that correlated inversely with the DNase1 activity (r = -0.634, p < 0.0001) of these sera. In line with this, the inhibition of DNase1 in HBD sera by G-actin was found to lead to significantly diminished SNEC degradation and increased SNEC uptake by healthy phagocytes (p = 0.0009), supporting the important physiologic role of serum DNase1 in the prevention of SNEC-phagocytosis. Purified serum IgG preparations from SS and SLE patients manifested increased binding to SNEC and were able to enhance significantly the engulfment of SNEC by healthy phagocytes both directly (under serum-free conditions, p ≤ 0.009) and via the prevention of physiologic degradation of SNEC by serum, most likely due to their "shielding" against endonuclease digestion (p = 0.0005). These data indicate that upon cell necrosis, the immune system of SS and SLE patients may be overly exposed to the necrotic debris, a fact that probably holds a key role in the pathogenesis of inflammatory and autoimmune reactions observed in these disorders.
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Fagocitosis/inmunología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunología , Adulto , Anciano , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Desoxirribonucleasa I/sangre , Activación Enzimática , Femenino , Granulocitos/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Necrosis/inmunología , Fagocitos/inmunología , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/diagnósticoRESUMEN
BACKGROUND & AIMS: Antibodies (Abs) to soluble liver antigen/liver pancreas (anti-SLA/LP) are considered markers of worse prognosis and outcome in patients with autoimmune hepatitis (AIH) although this assumption has recently been attributed to their frequent co-expression with Abs against Ro52 (anti-Ro52). To assess the clinical significance of anti-SLA/LP Abs alone or in combination with anti-Ro52 in AIH patients and determine the immunodominant Ro52 epitopes according to the anti-SLA/LP status. METHODS: Twenty-three anti-SLA/LP-positive and 106 anti-SLA/LP-negative AIH patients were included. Anti-SLA/LP were determined by ELISA using recombinant antigen, and confirmed by immunoblot using cytosolic rat liver fraction or HuH-7 extract. Anti-Ro52 Abs were determined by ELISA using recombinant antigen. Epitope mapping was assessed by ELISA using overlapping peptides covering the whole Ro52 protein in 26 AIH patients and 12 patients with Sjögren's syndrome. RESULTS: Anti-SLA/LP positivity was not associated with the clinical, laboratory or histological characteristics of AIH patients. Treatment response, corticosteroid withdrawal, relapse after stopping treatment and outcome, were not associated with the presence of anti-SLA/LP, anti-Ro52 or double reactivity. Moreover, Ro52 epitope mapping revealed new epitopes unique for AIH and independent from anti-SLA/LP positivity. CONCLUSIONS: Neither anti-SLA/LP nor anti-Ro52 Abs or their combination could specify a distinct group of AIH patients in terms of clinical characteristics, treatment response and outcome. Further studies are needed to clarify whether the newly discovered immunodominant epitopes of Ro52 antigen which were associated specifically with AIH have any clinical or pathogenetic significance in AIH.
Asunto(s)
Autoanticuerpos/sangre , Autoantígenos/inmunología , Biomarcadores/sangre , Hepatitis Autoinmune/inmunología , Ribonucleoproteínas/inmunología , Autoantígenos/sangre , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Grecia , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/clasificación , Humanos , Estimación de Kaplan-Meier , Ácido Micofenólico/análogos & derivados , Oligonucleótidos , Reacción en Cadena de la Polimerasa , Ribonucleoproteínas/sangreRESUMEN
OBJECTIVES: Treatment of rheumatoid arthritis (RA) with disease-modifying anti-rheumatic drugs (DMARDs), either synthetic (sDMARDs) or biologic agents (bDMARDs) has significantly improved disease outcome. However, the impact of therapy-related adverse events (AEs), mild, moderate or serious, on disease outcome is under debate. The purpose of the study was to test the hypothesis that AEs, including infections, are rather common in patients receiving bDMARDs than in those receiving sDMARDs. METHODS: Analysis of the medical records of patients followed in a single outpatient clinic was performed. In total, 1403 adults (295 men, 1108 women) were included in the analysis (969 treated with sDMARDs only, 434 with bDMARDs). All AEs and infections were recorded and their severity was graded according to international criteria. Incident rates were calculated and Kaplan-Meier plots as well as Cox proportional-hazards models were performed to examine the association of treatment groups with the risk of any AE. RESULTS: The risk of any AE, irrespective of severity, was significantly higher in patients with bDMARDs with the adjusted hazard ratio being 1.98 (95% CI: 1.64 to 2.39). Patients in the biologic group treated initially with infliximab or adalimumab had a higher risk of AE compared to patients receiving etanercept or other biologic agents. Among patients treated with methotrexate, those receiving a dose below 10 mg had a higher risk of any AE when compared to those receiving higher doses. CONCLUSIONS: The risk of any AE among RA patients treated with bDMARDs was significantly higher compared to those treated with sDMARDs.
Asunto(s)
Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/efectos adversos , Adulto , Anciano , Instituciones de Atención Ambulatoria , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Enfermedades Transmisibles/inducido químicamente , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/epidemiología , Femenino , Grecia/epidemiología , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.
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Medicina de Precisión , Enfermedades Reumáticas , Humanos , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Consenso , Testimonio de Experto , Inmunosupresores/uso terapéutico , Enfermedades Reumáticas/terapia , Enfermedades Reumáticas/diagnóstico , Enfermedades Reumáticas/tratamiento farmacológicoAsunto(s)
Enfermedades Autoinmunes/genética , Interferón Tipo I/sangre , Enfermedades Pulmonares Intersticiales/genética , Proteínas de la Membrana/genética , Enfermedades Cutáneas Vasculares/genética , Adolescente , Enfermedades Autoinmunes/sangre , Humanos , Enfermedades Pulmonares Intersticiales/sangre , Masculino , Enfermedades Cutáneas Vasculares/sangreRESUMEN
Several previous studies from our laboratory have indicated that the salivary gland epithelia of primary Sjögren's syndrome (SS) patients are not only the target of autoimmune immune responses, but also key instigators of the chronic salivary gland inflammatory infiltrates of patients. In particular, the comparative analysis of salivary gland tissue specimens and of in-vitro cultured non-neoplastic salivary gland epithelial cell lines (SGEC, of ductal type) from SS-patients and non-SS disease-controls, have unequivocally highlighted the presence of intrinsic activation in the ductal epithelia of SS-patients and of aberrant expression of inflammagenic molecules thereof, that correlate with the severity of local histopathologic changes, as well as of systemic manifestations of the disease. In the same context, we have recently shown that the ductal epithelia of SS-patients manifest cell-autonomous activation of the AIM2 inflammasome owing to the presence of aberrant cytoplasmic accumulations of damaged DNA. These findings not only provide a mechanistic explanation for the intrinsic activation and inflammatory status of SS ductal epithelia, but may also point towards the putative instigating role of an exogenous or endogenous agent (i.e., a micro-organism or an endogenous retrovirus, respectively). On this basis and to further explore the nature of epithelial cell-intrinsic activation in SS, the present proposal aims to investigate the expression of endogenous retroviral and/or non-human nucleic acid sequences of microbial origin in the ductal salivary gland epithelia of SS-patients, using metagenomic analysis of high throughput DNA and RNA genome sequencing data, which will be obtained from SGEC lines derived from SS-patients and disease-controls.
RESUMEN
MicroRNAs (miRNAs) are small non-coding RNA molecules that suppress gene expression at post-transcriptional level. miRNAs are considered as fine-tuning regulators of diverse biological processes, including the development and function of the immune system. Emerging data have implicated the deregulated expression of certain miRNAs or miRNA networks in the pathogenesis of autoimmune diseases. Sjögren's syndrome (SS) is a common chronic autoimmune disease, characterized by destruction and dysfunction of the exocrine glands (predominantly of the salivary and lachrymal glands). Humoral autoimmune responses observed in the disease, primarily target Ro/SSA and La/SSB ribonucleoproteins, whilst aberrantly increased expression of these autoantigens has been described in the salivary glands (SG) and the salivary gland epithelial cells (SGEC) of SS patients. Comparative array analysis of miRNA expression in the SGs of SS and control subjects had revealed distinctive miRNA signatures in SS patients, associated with glandular inflammation and dysfunction. Furthermore, the expression analysis of miRNAs that are predicted to target Ro/SSA and La/SSB autoantigens revealed differential expression of certain miRNAs in the SG tissues, SGECs and peripheral blood mononuclear cells (PBMC) of SS patients and controls. Although these association data implicate miRNAs in SS pathogenesis, thorough functional studies are needed to delineate their role in disease.
Asunto(s)
Autoantígenos/metabolismo , Células Epiteliales/metabolismo , MicroARNs/inmunología , ARN Citoplasmático Pequeño/metabolismo , Ribonucleoproteínas/metabolismo , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Animales , Autoantígenos/genética , Autoantígenos/inmunología , Autoinmunidad/genética , Células Epiteliales/inmunología , Células Epiteliales/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Análisis por Micromatrices , Procesamiento Proteico-Postraduccional , ARN Citoplasmático Pequeño/genética , ARN Citoplasmático Pequeño/inmunología , Ribonucleoproteínas/genética , Ribonucleoproteínas/inmunología , Glándulas Salivales/patologíaRESUMEN
Perinuclear anti-neutrophilic cytoplasmic antibodies (P-ANCA) recognize heterogeneous antigens, including myeloperoxidase (MPO), lactoferrin, elastase, cathepsin-G and bactericidal/permeability-increasing protein. Although P-ANCA have diagnostic utility in vasculitides, they may also be found in patients with various other systemic autoimmune rheumatic diseases (SARDs). Nevertheless, the clinical significance and the targets recognized by P-ANCA in such patients remain unclear. For this purpose, herein we investigated the occurrence of ANCA-related antigenic specificities in 82 P-ANCA-positive sera by multiplex ELISA, as well as their association with other autoantibodies. The P-ANCA-positive sera corresponded to patients with vasculitides (n = 24), systemic lupus erythematosus (n = 28), antiphospholipid syndrome (n = 5), Sjögren's syndrome (n = 7), rheumatoid arthritis (n = 3), systemic scleroderma (n = 1), sarcoidosis (n = 1) and Hashimoto's thyroiditis (n = 13). In most P-ANCA-positive patients studied (51/82, 62.3%), these autoantibodies occurred in high titers (>1:160). The analysis of P-ANCA-positive sera revealed reactivity to MPO in only 50% of patients with vasculitides, whereas it was infrequent in the other disease groups studied. Reactivity to other P-ANCA-related autoantigens was also rarely detected. Our findings support that high P-ANCA titers occur in SARD. The P-ANCA-positive staining pattern is associated with MPO specificity in vasculitides, while in other autoimmune diseases, it mostly involves unknown autoantigens.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Enfermedades Autoinmunes/metabolismo , Vasculitis/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Elastasa Pancreática/metabolismo , Adulto JovenRESUMEN
Sjögren's syndrome (SS) is a chronic autoimmune disorder that is characterized by dysfunction and destruction of the exocrine glands. Exocrinopathy is associated with periductal mononuclear cell infiltrates in the affected exocrine glands and B-cell hyperreactivity. Epithelial cells are thought to play an important pathogenetic role, as suggested by the occurrence of infiltrating lesions in various epithelial tissues (described as autoimmune epithelitis) as well as the increased epithelial expression of several inflammatory proteins in the histopathologic lesions of patients. The application of long-term cultured non-neoplastic salivary gland epithelial cell (SGEC) lines has permitted the more explicit investigation of the role of these cells in the pathophysiology of SS. These studies have revealed the inherent capacity of SGEC to induce and promote chronic inflammatory reactions, as corroborated by the constitutive or inducible expression of various molecules implicated in innate and acquired immune responses. Furthermore, significantly increased constitutive expression of several molecules has been observed in SGEC lines derived from SS patients, as compared to those obtained from disease control patients. This fact strongly indicates the operation of intrinsic activation mechanisms in the epithelia of SS patients and further supports the active participation of these cells in the pathogenesis of the disorder.
Asunto(s)
Citocinas/metabolismo , Células Epiteliales/metabolismo , Receptores Inmunológicos/metabolismo , Glándulas Salivales/patología , Síndrome de Sjögren/inmunología , Linfocitos B/inmunología , Línea Celular , Movimiento Celular , Células Epiteliales/inmunología , Células Epiteliales/patología , Humanos , Activación de Linfocitos , Sialadenitis , Síndrome de Sjögren/patología , Síndrome de Sjögren/fisiopatología , Linfocitos T/inmunologíaRESUMEN
Costimulatory molecules are cell-surface glycoproteins that can direct, modulate and fine tune immune responses. B7-2(CD86) costimulatory molecules are considered as major regulators of T cell responses, acting by appropriate interactions with the stimulatory CD28 or inhibitory CTLA-4 receptors found on T cells. Although their expression is thought to be restricted in lymphoid cells, evidence raised during the last decade show their expression in other types of cells, including human non-neoplastic salivary gland epithelial cells (SGEC). The expression of B7-2 molecules by SGECs requires special attention, due to their unique expression pattern and distinctive binding properties. Thus, SGECs express three B7-2 alternate transcripts that encode the full-length protein, the soluble form and a truncated membrane-bound molecule, that lacks the IgV-like counter-receptor binding domain and has a negative regulatory role. A similar pattern of expression is observed in monocytes, but not in several other types of cells, including dendritic cells. Furthermore, the full-length B7-2 molecules in SGEC display unique binding properties, denoted by the functional interaction with CD28 receptor, but reduced binding of the negative regulator CTLA-4. These distinctive features suggest the tight regulation of B7-2 molecules expression and indicate the key immunoregulatory role of SGECs.
Asunto(s)
Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Células Epiteliales/metabolismo , Isoformas de Proteínas/metabolismo , Síndrome de Sjögren/inmunología , Empalme Alternativo , Antígenos CD/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígeno CTLA-4 , Células Epiteliales/inmunología , Células Epiteliales/patología , Retroalimentación Fisiológica , Perfilación de la Expresión Génica , Humanos , Modelos Inmunológicos , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Unión Proteica/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Glándulas Salivales/patologíaRESUMEN
In certain types of cells, Toll-like receptor-3 (TLR-3) ligation by viral dsRNA induces apoptotic death, likely engaged into the elimination of virus-infected cells. We have previously shown that TLR-3 ligation on cultured non-neoplastic salivary gland epithelial cells (SGEC) with polyI:C (a synthetic analogue of viral dsRNA) results in the induction of surface immunoactive molecules, however, the pro-apoptotic effect of such signaling has not been addressed. In this study, polyI:C-treated SGEC were found to suffer severe detachment from substratum and subsequent apoptosis, a phenomenon suggestive of anoikis or anoikia (detachment-induced apoptosis). PolyI:C-induced anoikis in SGEC was associated with the upregulation of the pro-apoptotic Bmf, BimEL and Bax and the down-regulation of the pro-survival Bcl-2 (real-time PCR analyses). Finally, the comparative analysis of SGEC lines derived from primary Sjogren's syndrome (SS) patients (SS-SGEC) and non-SS controls had revealed that SS-SGEC are particularly susceptible to TLR-3-induced anoikis, as it was triggered by suboptimally low concentrations of polyI:C. This finding correlated with significantly higher constitutive surface TLR-3 expression by SS-SGEC, a feature indicative of their intrinsic activation status. In conclusion, TLR-3 signaling pathway in the salivary epithelium appears to extend beyond the induction of innate immune responses and to involve the activation of programmed-cell death via anoikis. In the same context, the increased vulnerability of SS-SGEC to the injurious effect of TLR-3 ligation is likely associated with the intrinsic activation processes that apparently operate in the epithelia of SS patients, and a feature of key pathogenetic importance for the disorder.
Asunto(s)
Anoicis , Células Epiteliales/efectos de los fármacos , Glándulas Salivales/patología , Síndrome de Sjögren/inmunología , Receptor Toll-Like 3/metabolismo , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Anoicis/efectos de los fármacos , Anoicis/inmunología , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Adhesión Celular/efectos de los fármacos , Adhesión Celular/inmunología , Línea Celular , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inmunidad Innata , Interferón beta/biosíntesis , Interferón beta/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Poli I-C/farmacología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Síndrome de Sjögren/patología , Síndrome de Sjögren/fisiopatología , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 3/genética , Proteína X Asociada a bcl-2/biosíntesis , Proteína X Asociada a bcl-2/genéticaRESUMEN
CD91 molecule is a multifunctional receptor of alpha 2-macroglobulin, heat-shock proteins and calreticulin. CD91 has been implicated in cross-presentation of peptides chaperoned by these proteins to MHC molecules, thus eliciting antigen-specific immune responses. Hence, CD91 is considered as a major regulator of innate and acquired immune responses. Herein, we show that CD91 molecules are expressed by human salivary gland epithelial cells (SGEC), as indicated by immunohistochemical studies in minor salivary gland biopsy tissues (n = 21) as well as by the analyses of human long-term cultured non-neoplastic SGEC lines (n = 11) and the neoplastic HSG cell line. In these cell lines CD91 expression was evaluated by RT-PCR, flow cytometry and confocal microscopy. Standard internalization assays revealed that HSG and SGECs are capable to bind and internalize the CD91 ligand alpha 2-macroglobulin. This internalization is specific, as attested by inhibition studies using unlabeled alpha 2-macroglobulin and a blocking antibody against human CD91 receptor. Conclusively, our findings indicate that SGEC functionally express CD91 receptor, suggesting that this pathway might be involved in the presentation of exogenous antigens in SGEC.
Asunto(s)
Antígenos CD/metabolismo , Células Epiteliales/metabolismo , Glándulas Salivales/metabolismo , alfa-Macroglobulinas/metabolismo , Presentación de Antígeno , Antígenos CD/inmunología , Línea Celular , Línea Celular Tumoral , Células Epiteliales/citología , Células Epiteliales/inmunología , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Glándulas Salivales/citología , Glándulas Salivales/inmunología , alfa-Macroglobulinas/inmunologíaRESUMEN
Salivary gland epithelial cells (SGECs) have been shown to participate in immunological responses and have been implicated in the pathogenesis of Sjögren's syndrome (SS). Experimental evidence from animal models indicates that estrogen deficiency may also participate in SS pathogenesis. However, the expression and functionality of the estrogen receptors alpha (ERalpha) and beta (ERbeta) in normal human salivary epithelium is unknown. To investigate these points, formalin-fixed, paraffin-embedded specimens and cultured non-neoplastic SGEC lines derived from nine minor salivary gland (MSG) biopsies with normal histology were studied. Immunohistochemical analyses detected the epithelial expression of ERalpha, ERbeta1, and ERbeta2 protein isoforms both in MSG tissues and in cultured SGECs. Such epithelial expression was verified by immunoblotting of various ER proteins in cellular extracts of cultured SGECs (full-length-ERalpha, ERalpha-Delta3, ERbeta1-long, ERbeta1-short, and ERbeta2-long isoforms). Estrogens did not induce growth or apoptosis in cultured SGECs. However, similarly to other cellular systems, treatment of cultured SGECs with estrogens (17beta-estradiol and the ERalpha- and ERbeta-selective agonists propylpyrazole-triol and diarylpropiolnitrile, respectively) inhibited the interferon-gamma-inducible expression of intercellular adhesion molecule-1. This finding corroborated the functionality of ER expressed by SGEC. Our results suggest that salivary epithelium expresses constitutively functional ERalpha and ERbeta proteins that apparently mediate immunomodulatory effects.