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1.
BMC Gastroenterol ; 21(1): 325, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425765

RESUMO

BACKGROUND: Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin. METHODS: This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission. RESULTS: Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5-9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54-17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023). CONCLUSIONS: PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC. TRIAL REGISTRATION: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Colite Ulcerativa , Biomarcadores , Colite Ulcerativa/tratamento farmacológico , Humanos , Mieloblastina , Estudos Retrospectivos
2.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360796

RESUMO

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5-234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8-88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31-35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7-30.1 nM). At 7-14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.


Assuntos
Epitopos/sangue , Mieloblastina/antagonistas & inibidores , Deficiência de alfa 1-Antitripsina , alfa 1-Antitripsina/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloblastina/sangue , Índice de Gravidade de Doença , Deficiência de alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/tratamento farmacológico
3.
Semin Arthritis Rheum ; 51(5): 1011-1015, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34416622

RESUMO

OBJECTIVE: To determine the predictive value of disease characteristics at 12-month follow-up after the diagnosis of GPA for subsequent relapses in a cohort of patients followed at a tertiary vasculitis clinic. METHODS: Demographic, clinical, and biological data at diagnosis and during follow-up from patients with GPA followed for at least 24 months at the Mount Sinai Hospital Vasculitis Clinic in Toronto, Canada were extracted from the Canadian Vasculitis Research Network (CanVasc) database and analyzed. The association between ANCA status and type (PR3- or MPO-ANCA), presence of microscopic hematuria, or serum creatinine level at follow-up month 12 ± 3 (M12) and relapses after M12 were assessed using Cox proportional hazard models. RESULTS: A total of 113 GPA patients were included in this study (50 ANCA positive, 63 ANCA negative at M12). Patient demographics and disease characteristics were similar at diagnosis, including the treatments used for induction and at M12. The global 5-year relapse rate was 55.8%, without any difference in the relapse rates after M12 between those ANCA-positive or negative at M12. However, in multivariate analyses, MPO-ANCA positivity at M12 was predictive of increased relapses after M12 (hazard ratio [HR] 3.54, P=0.01), as was the presence of microhematuria at M12 (HR 1.91, P=0.04). In contrast, higher serum creatinine levels at M12 were associated with a decreased risk of subsequent relapse (HR 0.99, P=0.04). CONCLUSION: In this cohort of patients with GPA, MPO-ANCA positivity and persistent microscopic hematuria at M12 were associated with increased risk of subsequent relapse, and could thus have value to predict disease outcome during follow-up.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Canadá , Humanos , Mieloblastina , Recidiva , Estudos Retrospectivos
4.
Front Immunol ; 12: 686462, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276672

RESUMO

Immune homeostasis is disturbed during severe viral infections, which can lead to loss of tolerance to self-peptides and result in short- or long-term autoimmunity. Using publicly available transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression levels of 52 autoantigens, known to be associated with 24 autoimmune diseases, during SAR-CoV-2 infection. Seven autoantigens (MPO, PRTN3, PADI4, IFIH1, TRIM21, PTPRN2, and TSHR) were upregulated in whole blood samples. MPO and TSHR were overexpressed in both lung autopsies and whole blood tissue and were associated with more severe COVID-19. Neutrophil activation derived autoantigens (MPO, PRTN3, and PADI4) were prominently increased in blood of both SARS-CoV-1 and SARS-CoV-2 viral infections, while TSHR and PTPRN2 autoantigens were specifically increased in SARS-CoV-2. Using single-cell dataset from peripheral blood mononuclear cells (PBMCs), we observed an upregulation of MPO, PRTN3, and PADI4 autoantigens within the low-density neutrophil subset. To validate our in-silico analysis, we measured plasma protein levels of two autoantigens, MPO and PRTN3, in severe and asymptomatic COVID-19. The protein levels of these two autoantigens were significantly upregulated in more severe COVID-19 infections. In conclusion, the immunopathology and severity of COVID-19 could result in transient autoimmune activation. Longitudinal follow-up studies of confirmed cases of COVID-19 could determine the enduring effects of viral infection including development of autoimmune disease.


Assuntos
Autoantígenos/genética , Autoimunidade/genética , COVID-19/imunologia , SARS-CoV-2/imunologia , Transcriptoma , Doenças Assintomáticas , Autoantígenos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , COVID-19/sangue , COVID-19/patologia , COVID-19/virologia , Simulação por Computador , Bases de Dados Genéticas , Humanos , Pulmão/patologia , Mieloblastina/sangue , Mieloblastina/genética , Ativação de Neutrófilo , Neutrófilos/imunologia , Peroxidase/sangue , Peroxidase/genética , RNA-Seq , Índice de Gravidade de Doença , Regulação para Cima/genética
5.
Diab Vasc Dis Res ; 18(4): 14791641211032547, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34275349

RESUMO

INTRODUCTION: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. METHODS: Plasma NE and PR3 levels were quantified at baseline (n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels (n = 200) were determined at four follow-up visits. RESULTS: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. CONCLUSIONS: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fenofibrato/uso terapêutico , Hipolipemiantes/uso terapêutico , Mediadores da Inflamação/sangue , Elastase de Leucócito/sangue , Mieloblastina/sangue , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Fenofibrato/efeitos adversos , Humanos , Hipolipemiantes/efeitos adversos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
6.
Isr Med Assoc J ; 23(6): 350-352, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34155847

RESUMO

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a rare small vessel vasculitis. It usually involves the respiratory tract and kidney. Rarely, tumor-resembling inflammatory changes ensue. OBJECTIVES: To report three unique cases of GPA presenting with tumor-like lesions in various organs. METHODS: We presented three cases of GPA. Case 1 presented with typical upper respiratory symptoms of GPA and a mediastinal mass. Case 2 presented with low back pain, a large retroperitoneal mass, and nodular skin lesions. Case 3 presented with epigastric pain and a paravertebral inflammatory mass. RESULTS: The patients were treated successfully with rituximab. CONCLUSIONS: Clinicians should be aware of this presentation of granulomatosis with polyangiitis, which is known as Tumefaction Wegener's granulomatosis.


Assuntos
Granulomatose com Poliangiite , Neoplasias Renais/diagnóstico , Neoplasias do Mediastino/diagnóstico , Neoplasias Retroperitoneais/diagnóstico , Rituximab/administração & dosagem , Adulto , Anticorpos Anticitoplasma de Neutrófilos/sangue , Biomarcadores/sangue , Biópsia/métodos , Diagnóstico Diferencial , Feminino , Granuloma/patologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/patologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Imunossupressores/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
7.
Nephrol Dial Transplant ; 36(Suppl 2): 37-43, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34153980

RESUMO

Historically the treatment of lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was 'one size fits all'; however, with the emergence of precision medicine initiatives, the field is moving towards more personalized treatment approaches. The recent development of a more accurate and reproducible histopathological classification system for LN could lead to better disease categorization and therefore more targeted therapies. A better understanding of the pathophysiology of LN has provided evidence that not only T but also B cells play an important role, opening new opportunities for individualized treatment approaches. Recent trials have shown calcineurin inhibitors and the anti-CD20 antibodies rituximab and ofatumumab to be effective in the treatment of LN, adding new treatment options. State-of-the-art targeted therapy in ANCA-associated vasculitis (AAV) takes interindividual heterogeneity in disease severity, type of ANCA antibody [myeloperoxidase versus proteinase 3 (PR3)] and the risk for side effects of therapy into consideration. In addition, within an individual, induction therapy differs from maintenance therapy, the same holding true in incident and relapsing disease. Rituximab is now widely used in AAV and it has become clear that prolonged B cell depletion, as in LN, must be achieved to obtain a long-lasting clinical response, especially in anti-PR3-associated disease. Still, despite these advances, molecular and genetic markers are rarely incorporated into diagnostic and treatment algorithms and true precision medicine remains an aspiration that hopefully can be achieved.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Nefrite Lúpica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/etiologia , Mieloblastina , Medicina de Precisão , Rituximab/uso terapêutico
8.
PLoS One ; 16(6): e0253534, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34153068

RESUMO

BACKGROUND: Neutrophils are important for host innate immune defense and mediate inflammatory responses. Pulmonary tuberculosis (PTB) is associated with increased neutrophil granular protein (NGP) levels in the circulation. However, the systemic levels of neutrophil granular proteins were not examined in tuberculous lymphadenitis (TBL) disease. METHODS: We measured the systemic levels of NGP (myeloperoxidase [MPO], elastase and proteinase 3 [PRTN3]) in TBL and compared them to latent tuberculosis (LTB) and healthy control (HC) individuals. We also measured the pre-treatment (Pre-T) and post-treatment (Post-T) systemic levels of neutrophil granular proteins in TBL individuals upon anti-tuberculosis treatment (ATT) completion. In addition, we studied the correlation and discriminatory ability of NGPs using receiver operating characteristic (ROC) analysis. RESULTS: Our data suggests that systemic levels of NGPs (MPO, PRTN3, elastase) were significantly reduced in TBL individuals compared to LTB and HC individuals. Similarly, after ATT, the plasma levels of MPO and elastase but not PRTN3 were significantly elevated compared to pre-treatment levels. NGPs (except PRTN3) were positively correlated with absolute neutrophil count of TBL, LTB and HC individuals. Further, NGPs were able to significantly discriminate TBL from LTB and HC individuals. CONCLUSION: Hence, we conclude reduced neutrophil granular protein levels might be associated with disease pathogenesis in TBL.


Assuntos
Mieloblastina/sangue , Peroxidase/sangue , Tuberculose dos Linfonodos/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Tuberculose Latente/sangue , Tuberculose Latente/patologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
9.
Clin Exp Rheumatol ; 39 Suppl 129(2): 107-113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014158

RESUMO

OBJECTIVES: It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity. METHODS: Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA). RESULTS: Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p<0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p<0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p<0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009]. CONCLUSIONS: ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Feminino , Granulomatose com Poliangiite/diagnóstico , Humanos , Pessoa de Meia-Idade , Mieloblastina , Peroxidase , Estudos Retrospectivos
10.
Brain Nerve ; 73(5): 503-510, 2021 May.
Artigo em Japonês | MEDLINE | ID: mdl-34006682

RESUMO

Granulomatosis with polyangiitis (GPA) is designated as an intractable disease by the Ministry of Health, Labor and Welfare, Japan, and is classified as an antineutrophil cytoplasmic antibody (ANCA)-related vasculitis syndrome. It is associated with upper respiratory tract symptoms (E; ear and nose), pulmonary symptoms (L; lung), renal symptoms (K; kidney), and systemic vasculitis symptoms, and often involves the central/peripheral nervous system. Patients with GPA can be easily diagnosed as they often show positive serum C (Proteinase 3)-ANCA findings. Remission can be induced using multiple immunosuppressants in combination, but caution is required as relapse and infection is common in patients with GPA.


Assuntos
Granulomatose com Poliangiite , Anticorpos Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Japão , Mieloblastina , Recidiva
11.
Nat Immunol ; 22(6): 711-722, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34017121

RESUMO

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.


Assuntos
Artrite Juvenil/imunologia , Diferenciação Celular/imunologia , Epigênese Genética/imunologia , Histonas/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Adolescente , Artrite Juvenil/sangue , Artrite Juvenil/genética , Sistemas CRISPR-Cas/genética , Catepsina G/genética , Catepsina G/metabolismo , Diferenciação Celular/genética , Núcleo Celular/metabolismo , Criança , Pré-Escolar , Cromatina/metabolismo , Ensaios Enzimáticos , Epigenômica , Feminino , Técnicas de Inativação de Genes , Humanos , Células Jurkat , Elastase de Leucócito/genética , Elastase de Leucócito/metabolismo , Leucócitos Mononucleares/imunologia , Macrófagos/metabolismo , Masculino , Mieloblastina/genética , Mieloblastina/metabolismo , Cultura Primária de Células , Proteólise , RNA-Seq , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Células THP-1 , Adulto Jovem
12.
Curr Rheumatol Rep ; 23(6): 37, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33909191

RESUMO

PURPOSE OF REVIEW: There is ongoing debate concerning the classification of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. That is, whether classification should be based on the serotype (proteinase 3 (PR3)- or myeloperoxidase (MPO)-ANCA) or on the clinical phenotype (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)). To add clarity, this review focused on integration of the most recent literature. RECENT FINDINGS: Large clinical trials have provided evidence that a serology-based risk assessment for relapses is more predictive than distinction based on the phenotype. Research conducted in the past decade indicated that a serology-based approach more closely resembles the genetic associations, the clinical presentation (i.e., lung involvement), biomarker biology, treatment response, and is also predicting comorbidities (such as cardiovascular death). Our review highlights that a serology-based approach could replace a phenotype-based approach to classify ANCA-associated vasculitides. In future, clinical trials and observational studies will presumably focus on this distinction and, as such, translate into a "personalized medicine."


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Poliangiite Microscópica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/classificação , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Mieloblastina , Peroxidase , Fenótipo
13.
Front Immunol ; 12: 571933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679731

RESUMO

Granulomatosis with polyangiitis (GPA) is a rare but serious necrotizing auto-immune vasculitis. GPA is mostly associated with the presence of Anti-Neutrophil Cytoplasmic Antibody (ANCA) targeting proteinase 3 (PR3-ANCA), a serine protease contained in neutrophil granules but also exposed at the membrane. PR3-ANCAs have a proven fundamental role in GPA: they bind neutrophils allowing their auto-immune activation responsible for vasculitis lesions. PR3-ANCAs bind neutrophil surface on the one hand by their Fab binding PR3 and on the other by their Fc binding Fc gamma receptors. Despite current therapies, GPA is still a serious disease with an important mortality and a high risk of relapse. Furthermore, although PR3-ANCAs are a consistent biomarker for GPA diagnosis, relapse management currently based on their level is inconsistent. Indeed, PR3-ANCA level is not correlated with disease activity in 25% of patients suggesting that not all PR3-ANCAs are pathogenic. Therefore, the development of new biomarkers to evaluate disease activity and predict relapse and new therapies is necessary. Understanding factors influencing PR3-ANCA pathogenicity, i.e. their potential to induce auto-immune activation of neutrophils, offers interesting perspectives in order to improve GPA management. Most relevant factors influencing PR3-ANCA pathogenicity are involved in their interaction with neutrophils: level of PR3 autoantigen at neutrophil surface, epitope of PR3 recognized by PR3-ANCA, isotype and glycosylation of PR3-ANCA. We detailed in this review the advances in understanding these factors influencing PR3-ANCA pathogenicity in order to use them as biomarkers and develop new therapies in GPA as part of a personalized approach.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Granulomatose com Poliangiite/imunologia , Mieloblastina/imunologia , Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Biomarcadores/metabolismo , Granulomatose com Poliangiite/metabolismo , Granulomatose com Poliangiite/terapia , Humanos , Mieloblastina/metabolismo , Neutrófilos/metabolismo , Peroxidase/imunologia , Peroxidase/metabolismo , Ligação Proteica , Recidiva , Fatores de Risco
14.
J Immunol ; 206(7): 1597-1608, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33579725

RESUMO

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and cytokine storm. Exploring the immune-inflammatory characteristics of COVID-19 patients is essential to reveal pathogenesis and predict progression. In this study, COVID-19 patients showed decreased CD3+, CD4+, and CD8+ T cells but increased neutrophils in circulation, exhibiting upregulated neutrophil-to-lymphocyte and neutrophil-to-CD8+ T cell ratio. IL-6, TNF-α, IL-1ß, IL-18, IL-12/IL-23p40, IL-10, Tim-3, IL-8, neutrophil extracellular trap-related proteinase 3, and S100A8/A9 were elevated, whereas IFN-γ and C-type lectin domain family 9 member A (clec9A) were decreased in COVID-19 patients compared with healthy controls. When compared with influenza patients, the expressions of TNF-α, IL-18, IL-12/IL-23p40, IL-8, S100A8/A9 and Tim-3 were significantly increased in critical COVID-19 patients, and carcinoembryonic Ag, IL-8, and S100A8/A9 could serve as clinically available hematologic indexes for identifying COVID-19 from influenza. Moreover, IL-6, IL-8, IL-1ß, TNF-α, proteinase 3, and S100A8/A9 were increased in bronchoalveolar lavage fluid of severe/critical patients compared with moderate patients, despite decreased CD4+ T cells, CD8+ T cells, B cells, and NK cells. Interestingly, bronchoalveolar IL-6, carcinoembryonic Ag, IL-8, S100A8/A9, and proteinase 3 were found to be predictive of COVID-19 severity and may serve as potential biomarkers for predicting COVID-19 progression and potential targets in therapeutic intervention of COVID-19.


Assuntos
COVID-19 , Mediadores da Inflamação , SARS-CoV-2 , Índice de Gravidade de Doença , Idoso , COVID-19/sangue , COVID-19/imunologia , Calgranulina A/sangue , Calgranulina A/imunologia , Calgranulina B/sangue , Calgranulina B/imunologia , Citocinas/sangue , Citocinas/imunologia , Progressão da Doença , Feminino , Receptor Celular 2 do Vírus da Hepatite A/sangue , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mieloblastina/sangue , Mieloblastina/imunologia , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo
15.
An Bras Dermatol ; 96(2): 240-242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33579583

RESUMO

Small vessel vasculitis with anti-proteinase antibodies 3 is an atypical clinical presentation of tuberculosis. The authors present the case of a 47-year-old male patient, with palpable purpura and palmoplantar hemorrhagic blisters, with subsequent dissemination. He presented severe pulmonary symptoms with cavitation, fever, hemoptysis, and high levels of anti-proteinase 3. Histopathological assessment of the skin revealed small vessel vasculitis; pulmonary histopathology showed granulomas with caseation. Bronchoalveolar lavage was positive for alcohol-acid-fast bacilli. In countries with a high prevalence of tuberculosis, the presence of autoantibodies in a patient with vasculitis, fever, and pulmonary cavitation requires investigation of infectious causes.


Assuntos
Dermatopatias Vasculares , Vasculite , Adulto , Anticorpos Anticitoplasma de Neutrófilos , Hemoptise/diagnóstico , Hemoptise/etiologia , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mieloblastina , Vasculite/diagnóstico
16.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562184

RESUMO

The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.


Assuntos
Linhagem da Célula , Monócitos/enzimologia , Células Mieloides/enzimologia , Serina Proteases/metabolismo , Animais , Catepsina G/metabolismo , Humanos , Elastase de Leucócito/metabolismo , Monócitos/citologia , Mieloblastina/metabolismo , Células Mieloides/citologia
17.
Rheumatology (Oxford) ; 60(8): 3845-3850, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33547775

RESUMO

OBJECTIVES: To evaluate the prevalence and meaning of antineutrophil cytoplasmic antibodies (ANCA) positivity in a cohort of IgG4-related disease (IgG4-RD). METHODS: We identified patients with ANCA determination from a retrospective cohort of 69 patients with IgG4-RD. ANCA were measured by indirect immunofluorescence microscopy (IIF) and/or proteinase 3 (PR3)-ANCA and MPO-ANCA by ELISA. IIF patterns were classified as perinuclear (P-ANCA), cytoplasmic (C-ANCA) and atypical (X-ANCA). We compared the ANCA-positive vs the ANCA-negative IgG4-RD group. RESULTS: Out of 69 patients, 31 IgG4-RD patients had an ANCA determination. Four patients with concomitant systemic autoimmune diseases were excluded. We found positive ANCA by IIF in 14 (56%) of 25 patients tested. The most common IIF pattern was C-ANCA in eight (57.1%), followed by dual C-ANCA/X-ANCA in four (28.6%) and P-ANCA and dual C-ANCA/P-ANCA in one each (7.1%). Of the 20 patients with ANCA determination by both IIF and ELISA, four have positive ANCA by ELISA (three for MPO-ANCA and one for PR3-ANCA). Of the two patients with only ELISA determination, one was positive for MPO-ANCA. The prevalence of ANCA positivity by ELISA was 22.7% (5 out of 22 patients). ANCA was more frequent in the Mikulizc/systemic phenotype (42.9%) compared with other phenotypes (P = 0.04). ANCA-positive IgG4-RD patients had more frequently lymph node and kidney involvement, high IgG1 levels and erythrocyte sedimentation rate, and positive antinuclear antibodies. CONCLUSION: ANCA are found in a significant number of patients with IgG4-RD and differed from the ANCA-negative group in terms of clinical and serological features.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Doença Relacionada a Imunoglobulina G4/imunologia , Nefropatias/imunologia , Linfonodos/imunologia , Mieloblastina/imunologia , Peroxidase/imunologia , Adulto , Idoso , Doenças da Aorta/imunologia , Doenças Biliares/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Doenças do Aparelho Lacrimal/imunologia , Hepatopatias/imunologia , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Mieloblastina/metabolismo , Pancreatopatias/imunologia , Peroxidase/metabolismo , Espaço Retroperitoneal , Estudos Retrospectivos , Doenças das Glândulas Salivares/imunologia
18.
Rheumatol Int ; 41(5): 965-972, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33585954

RESUMO

The objective of this study is to evaluate the association between antineutrophil cytoplasmic autoantibody (ANCA) subtype and ANCA titers on clinical outcomes and disease activity among a cohort of patients from Central Appalachia diagnosed with ANCA-associated vasculitis (AAV) over a 3-decade period. This is a retrospective chart review of all patients diagnosed with AAV. ANCA subtypes (myeloperoxidase (MPO) and proteinase 3 (PR3)) and titers at the time of diagnosis and at the time of relapse or last follow-up were evaluated along with patient outcomes. Outcomes of interest included relapse, development of end-stage renal disease (ESRD) and mortality. Sensitivity analysis and multivariable analysis were performed. Of the 202 patients, 111 patients were MPO-ANCA positive and 91 patients were PR3-ANCA positive. Relapse was more frequent among patients with PR3-ANCA compared to MPO-ANCA (35% vs 12%, p < 0.001). In both ANCA subgroups, the strongest predictor of relapse was an increase in titers prior to relapse, HR 8.1 (95% CI 1.6-40), p 0.009. Patients who achieved serological remission had a lower risk of ESRD [sub-HR 0.31 (95% CI 0.11-0.89)] and mortality [HR (95% CI) 0.24 (0.07-0.7)]. PR3-ANCA was associated with higher risk of ESRD [sub-HR 3.1 (95% CI 1.1-8.5)]. There was no difference in mortality between patients with MPO-ANCA and PR3-ANCA. Our study supports the use of both ANCA subtypes and titer levels for predicting clinical outcomes in patients receiving treatment for AAV. Monitoring of ANCA antibody titers may be useful since both serological remission and increase in titers provide prognostic information.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Mieloblastina/sangue , Peroxidase/sangue , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/classificação , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Mieloblastina/imunologia , Peroxidase/imunologia , Recidiva , Estudos Retrospectivos
19.
Clin Rheumatol ; 40(7): 2843-2853, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33452661

RESUMO

The incidence of venous thromboembolism (VTE) in ANCA-associated vasculitis patients varies in different populations. Moreover, the risk factors for VTE in these patients are poorly described due to the small number of events. Ovid MEDLINE, EMBASE, and the Cochrane Library were searched for eligible articles. The inclusion criteria included observational studies that enrolled patients age ≥ 18 years diagnosed with ANCA-associated vasculitis. The incidence of VTE is the outcome of interest. Of 1362 citations, a total of 21 studies (n = 4422) dated from 2006 to 2019 were included in the systematic review. The mean age was 54.2 ± 4.0 years. Most were male (52.0%) and Caucasian (80.9%). With a mean follow-up duration of 5.2 ± 2.8 years, the pooled incidence of VTE in ANCA-associated vasculitis patients was 12.4% (95% CI, 8.8-17.2). Of these, 63.4% (95% CI, 57.3-69.1) had deep vein thrombosis and 26.3% (95% CI, 17.6-37.4) had pulmonary embolism. Recurrent VTE occurred in 10.0% (95% CI, 5.2-18.6). From the metaregression adjusted for age, sex, and ethnicity; positive MPO-ANCA, increasing Birmingham Vasculitis Activity Score at time of vasculitis diagnosis, and presence of renal involvement were positively associated with increased VTE events. Positive PR3-ANCA profile was inversely associated with increased VTE events. Increasing follow-up duration was not associated with increased VTE events. VTE in ANCA-associated vasculitis is common. Positive MPO-ANCA, increasing vasculitis activity, and presence of renal involvement were significant risk factors for VTE while positive PR3-ANCA was inversely associated with increased VTE. Key Points • Venous thromboembolism (VTE) is common in ANCA-associated vasculitis with a pooled incidence of 12.4% • Deep vein thrombosis accounts for two-third of total VTE cases • Positive MPO-ANCA profile, higher disease activity at ANCA-associated vasculitis diagnosis, and renal involvement are risk factors for VTE • Positive PR3-ANCA profile is protective factor for VTE.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Tromboembolia Venosa , Adolescente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Anticorpos Anticitoplasma de Neutrófilos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mieloblastina , Peroxidase , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
20.
Autoimmun Rev ; 20(3): 102759, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33476813

RESUMO

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Biologia , Humanos , Mieloblastina , Peroxidase
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