RESUMEN
OBJECTIVES: Systemic vasculitis is a heterogenous group of autoimmune diseases characterized by enhanced cardiovascular mortality. Endothelial dysfunction is associated with accelerated vascular damage, representing a core pathophysiologic mechanism contributing to excess CV risk. Recent studies have also shown that complement activation holds significant role in the pathogenesis of Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) -associated vasculitis (AAV). Given the potential crosstalk between the endothelium and complement, we aimed to assess, for the first time simultaneously, easily accessible biomarkers of endothelial dysfunction and complement activation in SV. METHODS: We measured circulating endothelial microvesicles (EMVs) and soluble complement components representative of alternative, classical and terminal activation (C5b-9, C1q, Bb fragments, respectively) in a meticulously selected group of patients with systemic vasculitis, but without cardiovascular disease. Individuals free from systemic diseases, who were matched with patients for cardiovascular risk factors(hypertension, diabetes, smoking, dyslipidemia), comprised the control group. RESULTS: We studied 60 individuals (30 in each group). Patients with systemic vasculitis had elevated EMVs, higher levels of C5b-9 [536.4(463.4) vs 1200.94457.3), p = 0.003] and C1q [136.2(146.5 vs 204.2(232.9), p = 0.0129], compared to controls [232.0 (243.5) vs 139.3(52.1), p < 0.001]. In multivariate analysis both EMVs and C5b-9 were independently associated with disease duration (p = 0.005 and p = 0.004 respectively), yet not with disease activity. CONCLUSION: Patients with systemic vasculitis exhibit impaired endothelial function and complement activation, both assessed by easily accessible biomarkers, even in the absence of cardiovascular disease manifestations. EMVs and soluble complement components such as C5b-9 and C1q could be used as early biomarkers of endothelial dysfunction and complement activation, respectively, in clinical practice during the course of SV, yet their predictive value in terms of future cardiovascular disease warrants further verification in appropriately designed studies.
Asunto(s)
Biomarcadores , Activación de Complemento , Endotelio Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Factores de Tiempo , Endotelio Vascular/fisiopatología , Endotelio Vascular/inmunología , Adulto , Anciano , Estudios de Casos y Controles , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patología , Micropartículas Derivadas de Células/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Complemento C1q/metabolismo , Complemento C1q/inmunología , Células Endoteliales/patología , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/sangre , Vasculitis Sistémica/fisiopatología , Vasculitis Sistémica/diagnósticoRESUMEN
Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.
Asunto(s)
Biomarcadores , Vasculitis Sistémica , Humanos , Vasculitis Sistémica/terapia , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/diagnóstico , Vasculitis Sistémica/epidemiología , Biomarcadores/sangre , Resultado del Tratamiento , Inmunosupresores/uso terapéutico , Factores de RiesgoRESUMEN
Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.
Asunto(s)
Vacuna nCoV-2019 mRNA-1273/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Vacuna BNT162/inmunología , COVID-19/prevención & control , Femenino , Humanos , Italia , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2/inmunología , Esclerodermia Sistémica/inmunología , Vasculitis Sistémica/inmunología , Vacunación , Potencia de la VacunaAsunto(s)
COVID-19/virología , Proteínas del Sistema Complemento/análisis , Endotelio Vascular/virología , SARS-CoV-2/patogenicidad , Enfermedades Cutáneas Virales/virología , Piel/irrigación sanguínea , Piel/virología , Vasculitis Sistémica/virología , Adolescente , COVID-19/complicaciones , COVID-19/diagnóstico , Prueba de Ácido Nucleico para COVID-19 , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Interacciones Huésped-Patógeno , Humanos , Masculino , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , Piel/inmunología , Piel/patología , Enfermedades Cutáneas Virales/diagnóstico , Enfermedades Cutáneas Virales/inmunología , Vasculitis Sistémica/diagnóstico , Vasculitis Sistémica/inmunologíaRESUMEN
Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Arteritis de Células Gigantes/metabolismo , Neutrófilos/inmunología , Vasculitis Sistémica/inmunología , Enfermedades Vasculares/metabolismo , Anciano , Antígenos CD/metabolismo , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Apoptosis/genética , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Linaje de la Célula/genética , Técnicas de Cocultivo , Femenino , Proteínas Ligadas a GPI/metabolismo , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Células Precursoras de Granulocitos/metabolismo , Células Precursoras de Granulocitos/patología , Humanos , Recuento de Leucocitos , Antígeno Lewis X/metabolismo , Masculino , Persona de Mediana Edad , Neprilisina/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Oxidación-Reducción , Pronóstico , Especies Reactivas de Oxígeno/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Análisis de la Célula Individual , Vasculitis Sistémica/sangre , Vasculitis Sistémica/metabolismo , Vasculitis Sistémica/patología , Arterias Temporales/inmunología , Arterias Temporales/metabolismo , Arterias Temporales/patología , Enfermedades Vasculares/sangre , Enfermedades Vasculares/inmunología , Enfermedades Vasculares/patologíaRESUMEN
Aim: Epidemiological studies have reported the association between myelodysplastic syndrome (MDS) and autoimmune diseases (AIDs). Immune dysregulation appears as the common driving force between MDS and AIDs pathogenesis. Low-dose hypomethylating agents might suppress tumor growth and regulate immune balance via its epi-immunomodulatory role. Materials & methods: A high-risk MDS patient presented with systemic vasculitis and was successfully treated with ultra-low-dose decitabine (7 mg/m2/d for 5 days). Results: He achieved complete remission of both MDS and AIDs after two cycles of decitabine treatment, and his overall survival duration was 45 months. Conclusion: Future studies should assess the application of ultra-low-dose decitabine among some high-risk MDS patients, especially among those with comorbid AIDs or in cases warranting the prevention of decitabine-mediated myelosuppression.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Decitabina/uso terapéutico , Síndromes Mielodisplásicos/complicaciones , Vasculitis Sistémica/complicaciones , Vasculitis Sistémica/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Vasculitis Sistémica/inmunología , Resultado del TratamientoRESUMEN
A few weeks after the peak of the global 2019 novel coronavirus disease pandemic, cases of shock, multisystem inflammation and severe myocarditis have occurred in children and adolescents, generating some concerns and above all many questions. An almost immediate association raised with shock syndrome related to Kawasaki disease (KD). However, in light of bo/th experience and literature have taught us about severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, and what already known on the epidemiology of KD, we suggest here the hypothesis of a new 'post-viral' systemic inflammatory disease related to excessive adaptive immune response rather than a form of KD caused by SARS-COV-2. We discuss analogies and differences between the two forms.
Asunto(s)
Infecciones por Coronavirus , Síndrome Mucocutáneo Linfonodular , Pandemias , Neumonía Viral , Vasculitis Sistémica , Betacoronavirus/aislamiento & purificación , COVID-19 , Niño , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/fisiopatología , Diagnóstico Diferencial , Manejo de la Enfermedad , Humanos , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/epidemiología , Síndrome Mucocutáneo Linfonodular/inmunología , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , SARS-CoV-2 , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/fisiopatología , Vasculitis Sistémica/terapia , Terminología como AsuntoAsunto(s)
Neoplasias del Mediastino/complicaciones , Neurilemoma/complicaciones , Síndromes Paraneoplásicos/etiología , Vasculitis Sistémica/etiología , Anciano , Anemia Macrocítica/tratamiento farmacológico , Anemia Macrocítica/etiología , Anemia Macrocítica/inmunología , Anticuerpos Anticardiolipina/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Crioglobulinas/inmunología , Mareo/etiología , Mareo/inmunología , Fiebre/etiología , Fiebre/inmunología , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Inhibidor de Coagulación del Lupus/inmunología , Masculino , Neoplasias del Mediastino/cirugía , Neurilemoma/cirugía , Síndromes Paraneoplásicos/tratamiento farmacológico , Síndromes Paraneoplásicos/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/tratamiento farmacológico , Síndromes Paraneoplásicos del Sistema Nervioso/etiología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Parestesia/etiología , Parestesia/inmunología , Neuropatías Peroneas/etiología , Neuropatías Peroneas/inmunología , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/inmunología , Factor Reumatoide/inmunología , Vasculitis Sistémica/tratamiento farmacológico , Vasculitis Sistémica/inmunologíaRESUMEN
The vasculitides are a heterogeneous group of disorders, characterized by inflammatory cell infiltration and necrosis of blood vessels that cause vascular obstruction or aneurysm formation, affecting various organs such as lungs, kidneys, skin and joints. Cardiac involvement is commonly encountered in primary systemic vasculitis and it is associated with increased morbidity and mortality. Depending on the dominant pathophysiological mechanism, heart complications may manifest in different ways, including myocardial ischemia due to impaired micro- or macrovascular circulation, progressive heart failure following valvular heart disease and myocardial dysfunction, (sub) clinical myocarditis, pericarditis, pulmonary hypertension as well as arteritis of coronary vessels. Beyond cardioprotective regimens, aggressive immunosuppression reduces the inflammatory burden and modulates the progression of cardiovascular complications. Perioperative management of inflammation, when surgical treatment is indicated, improves surgical success rates and postoperative long-term prognosis. We aim to provide an overview of the pathogenetic, diagnostic and therapeutic principles of cardiovascular involvement disease in the various forms of systemic vasculitis.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Sistema Cardiovascular/fisiopatología , Vasculitis Sistémica/complicaciones , Animales , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Sistema Cardiovascular/inmunología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Pronóstico , Medición de Riesgo , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/fisiopatología , Vasculitis Sistémica/terapiaRESUMEN
Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, playing a key role in driving the autoimmune response, the role of neutrophils and NETs in large vessel vasculitis, including giant cell arteritis (GCA), is not well understood. In this review, we summarize the current insight into molecular mechanisms contributing to neutrophil-mediated pathology in small and medium vessel vasculitis, as well as provide potential translational perspectives on how neutrophils, and NETs, may partake in large vessel vasculitis, a rare disease entity of unclear pathogenesis.
Asunto(s)
Neutrófilos/inmunología , Neutrófilos/patología , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/patología , Trampas Extracelulares/inmunología , HumanosRESUMEN
In preclinical toxicity studies, species-foreign proteins administered to animals frequently leads to formation of anti-drug antibodies (ADA). Such antibodies may form circulating immune complexes (CIC) with the administered protein. These CIC can activate the classical complement pathway, thereby forming complement-bound CIC (cCIC); if large of amounts of CIC or cCIC is formed, the clearance mechanism may become saturated which potentially leads to vascular immune complex (IC) deposition and inflammation. Limited information is available on the effect of different treatment related procedures as well as biomarkers of IC-related vascular disease. In order to explore the effect of different dose regimens on IC formation and deposition, and identification of possible biomarkers of IC deposition and IC-related pathological changes, C57BL/6J and BALB/c mice were dosed subcutaneously twice weekly with bovine serum albumin (BSA) for 13 weeks without adjuvant. After 6 and 13 weeks, CIC and cCIC were detected in plasma; after 13 weeks, IC deposition was detected in kidney glomeruli. In particular immunohistochemistry double-staining was shown to be useful for detection of IC deposition. Increasing dosing frequency or changing BSA dose level on top of an already established CIC and cCIC response did not cause changes in IC deposition, but CIC and cCIC concentrations tended to decrease with increased dose level, and increased cCIC formation was observed after more frequent dosing. The presence of CIC in plasma was associated with glomerular IC deposits in the dose regimen study; however, the use of CIC or cCIC as potential biomarkers for IC deposition and IC-related pathological changes, needs to be explored further.
Asunto(s)
Complejo Antígeno-Anticuerpo/análisis , Glomerulonefritis/inmunología , Albúmina Sérica Bovina/toxicidad , Vasculitis Sistémica/inmunología , Animales , Complejo Antígeno-Anticuerpo/inmunología , Biomarcadores/análisis , Vía Clásica del Complemento/efectos de los fármacos , Vía Clásica del Complemento/inmunología , Modelos Animales de Enfermedad , Estudios de Factibilidad , Femenino , Glomerulonefritis/sangre , Glomerulonefritis/inducido químicamente , Glomerulonefritis/diagnóstico , Humanos , Inmunohistoquímica , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Masculino , Ratones , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/inmunología , Vasculitis Sistémica/sangre , Vasculitis Sistémica/inducido químicamente , Vasculitis Sistémica/diagnóstico , Pruebas de Toxicidad/métodosRESUMEN
Vasculitis is a systemic disease characterized by immune-mediated injury of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. Furthermore, the management of both small and large vessel vasculitis is challenging because of a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. In parallel, a diverse range of imaging modalities with the potential to monitor vessel inflammation are emerging. Continued expansion of combined structural and molecular imaging using positron emission tomography with computed tomography or magnetic resonance imaging may soon provide reliable longitudinal tracking of vascular inflammation. In addition, the emergence of radiotracers able to assess macrophage activation and immune checkpoint activity represents an exciting new frontier in imaging vascular inflammation. In the near future, these advances will allow more precise imaging of disease activity enabling clinicians to offer more targeted and individualized patient management.
Asunto(s)
Vasculitis Sistémica/diagnóstico por imagen , Vasculitis Sistémica/tratamiento farmacológico , Eosinófilos/inmunología , Humanos , Depleción Linfocítica , Imagen por Resonancia Magnética , Imagen Molecular , Poliarteritis Nudosa/diagnóstico por imagen , Poliarteritis Nudosa/inmunología , Tomografía de Emisión de Positrones , Vasculitis Sistémica/inmunología , Tomografía Computarizada por Rayos XRESUMEN
The classification of the systemic vasculitides has been controversial for several decades. The Chapel Hill consensus Conference definitions originally developed in 1994, but revised and extended in 2012 are now widely accepted. The American College of Rheumatology (ACR) criteria were first published in 1990, are now generally accepted to be out of date and new criteria are needed. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3-ANCA positive and MPO-ANCA positive groups. The traditional distinction between giant cell arteritis and Takayasu arteritis has been questioned and some recent studies of GCA have included patients with only extra-cranial disease. The Diagnostic and Classification Criteria of Vasculitis study (DCVAS) will provide new validated classification criteria for the systemic vasculitides.
Asunto(s)
Investigación Biomédica/tendencias , Reumatología/tendencias , Vasculitis Sistémica/clasificación , Vasculitis Sistémica/diagnóstico , Terminología como Asunto , Consenso , Conferencias de Consenso como Asunto , Predicción , Humanos , Fenotipo , Vasculitis Sistémica/genética , Vasculitis Sistémica/inmunologíaRESUMEN
Systemic vasculitis are heterogeneous, complex and disabling disorders. Following the previous annual reviews of this series, this paper gives a brief overview on current knowledge about recent literature on small- and large-vessel systemic vasculitis, with a specific focus on pathogenetic and clinical aspects, novel possible disease-related biomarkers and current and future therapies that are in the pipeline.
Asunto(s)
Crioglobulinemia/inmunología , Hepatitis C Crónica/inmunología , Vasculitis Sistémica/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Antirreumáticos/uso terapéutico , Síndrome de Churg-Strauss/tratamiento farmacológico , Síndrome de Churg-Strauss/inmunología , Crioglobulinemia/complicaciones , Crioglobulinemia/tratamiento farmacológico , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/inmunología , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/inmunología , Hepatitis C Crónica/complicaciones , Humanos , Inmunosupresores/uso terapéutico , Poliangitis Microscópica/tratamiento farmacológico , Poliangitis Microscópica/inmunología , Vasculitis Sistémica/tratamiento farmacológico , Vasculitis Sistémica/etiología , Arteritis de Takayasu/tratamiento farmacológico , Arteritis de Takayasu/inmunologíaAsunto(s)
Dolor Abdominal/inmunología , Trastornos de las Proteínas Sanguíneas/complicaciones , Exantema/inmunología , Hemorragia Gastrointestinal/inmunología , Inmunoglobulina A/inmunología , Vasculitis Sistémica/complicaciones , Trastornos de las Proteínas Sanguíneas/inmunología , Femenino , Humanos , Persona de Mediana Edad , Vasculitis Sistémica/inmunologíaRESUMEN
OBJETIVE: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. METHODS: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. RESULTS: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. CONCLUSIONS: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.
Asunto(s)
Sitios Genéticos/genética , Histona Demetilasas con Dominio de Jumonji/genética , Fenotipo , Vasculitis Sistémica/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Estudios de Casos y Controles , Epigénesis Genética , Femenino , Sitios Genéticos/inmunología , Predisposición Genética a la Enfermedad , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DQ/inmunología , Humanos , Histona Demetilasas con Dominio de Jumonji/inmunología , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Análisis por Matrices de Proteínas , Vasculitis Sistémica/inmunología , Arteritis de Takayasu/genética , Arteritis de Takayasu/inmunologíaRESUMEN
The exact classification of Kawasaki disease (KD) has been debated. Infectious disease specialists have claimed it as an infection with a classic immune responses to an as yet unidentified pathogen that localizes to the coronary arteries. Others have favored an autoreactive hypothesis that KD is triggered by an antigen that shares homology with structures in the vascular wall, and molecular mimicry resulting in an immune response directed to that tissue. Rheumatologists have classified it as a systemic vasculitis, while some immunologists have stressed the robust nature of the innate immune response that causes both systemic inflammation as well as damage to the coronary arterial wall and questioned whether KD falls within the spectrum of autoinflammatory diseases. This review will describe the evidences available up to now regarding these hypotheses.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Síndrome Mucocutáneo Linfonodular/diagnóstico , Vasculitis Sistémica/diagnóstico , Enfermedades Autoinmunes/inmunología , Vasos Coronarios/inmunología , Vasos Coronarios/patología , Diagnóstico Diferencial , Enfermedades Autoinflamatorias Hereditarias/inmunología , Humanos , Inflamación/inmunología , Síndrome Mucocutáneo Linfonodular/clasificación , Síndrome Mucocutáneo Linfonodular/inmunología , Vasculitis Sistémica/inmunologíaRESUMEN
Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in L-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as L-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of L-arginine bioavailability and NO2- were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas L-arginine levels were significantly reduced, and these changes were followed by reductions in NO2- levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with L-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma L-arginine and NO2- levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity.
Asunto(s)
Arginasa/metabolismo , Arginina/sangre , Endotelio Vascular/metabolismo , Hígado/metabolismo , Óxido Nítrico/sangre , Obesidad/metabolismo , Vasculitis Sistémica/metabolismo , Animales , Aorta/enzimología , Aorta/metabolismo , Arginasa/sangre , Arginasa/genética , Aterosclerosis/etiología , Biomarcadores/sangre , Biomarcadores/metabolismo , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Inducción Enzimática , Hígado/inmunología , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Obesidad/etiología , Obesidad/inmunología , Obesidad/patología , Especificidad de Órganos , Índice de Severidad de la Enfermedad , Vasculitis Sistémica/etiología , Vasculitis Sistémica/inmunología , Vasculitis Sistémica/fisiopatología , Aumento de PesoRESUMEN
Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for over 40 years. The aim is to rapidly remove autoantibodies or circulating immune complexes from the plasma. The two main indications at present are vasculitis associated with Antineutrophil Cytoplasmic Antibodies (ANCAs) manifesting as severe renal involvement and/or intraalveolar hemorrhage and antiglomerular basement membrane disease (Goodpasture syndrome). The ongoing PEXIVAS randomized controlled trial is assessing plasmapheresis to treat ANCA-associated vasculitis with or without severe renal involvement or intraalveolar hemorrhage. The two main apheresis techniques used to treat systemic vasculitis are plasmapheresis (by filtration, centrifugation, or double filtration) and immunoadsorption. The advantages and drawbacks of each technique are discussed here. Whether one technique is superior over the other in the current indications has not been proven.