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2.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
3.
Autoimmun Rev ; 19(9): 102618, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32663621

RESUMO

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos/análise , Consenso , Granulomatose com Poliangiite/imunologia , Hepatite Autoimune/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Humanos , Mieloblastina/imunologia , Peroxidase/imunologia
4.
Am J Pathol ; 190(7): 1438-1448, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251643

RESUMO

The immunologic mechanisms promoting eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. To characterize the mechanisms underlying pulmonary EGPA, we examined and compared EGPA paraffin-embedded lung biopsies with normal lung biopsies, using immunostaining, RNA sequencing, and RT-PCR. The results revealed novel type 2 as well as immuneregulatory features. These features included basophils and increased mast cell contents; increased immunostaining for tumor necrosis factor ligand superfamily member 14; sparse mast cell degranulation; numerous forkhead box protein P3 (FoxP3)+ regulatory T cells and IgG4 plasma cells; and abundant arachidonate 15-lipoxygenase and 25-hydroxyvitamin D-1 α hydroxylase, mitochondrial. Significantly decreased 15-hydroxyprostaglandin dehydrogenase [NAD(+)], which degrades eicosanoids, was observed in EGPA samples. In addition, there was significantly increased mRNA for chemokine (C-C motif) ligands 18 and 13 and major collagen genes, IgG4-rich immune complexes coating alveolar macrophages, and increased immunostaining for phosphorylated mothers against decapentaplegic homolog 2/SMAD2, suggesting transforming growth factor-ß activation. These findings suggest a novel self-promoting mechanism of activation of alveolar macrophages by arachidonate 15-lipoxygenase-derived eicosanoids to express chemokines that recruit a combined type 2/immunoregulatory immune response, which produces these eicosanoids. These results suggest that the pulmonary EGPA immune response resembles the immune response to a tissue-invasive parasite infection.


Assuntos
Síndrome de Churg-Strauss/imunologia , Granulomatose com Poliangiite/imunologia , Imunoglobulina G/imunologia , Plasmócitos/imunologia , Adulto , Síndrome de Churg-Strauss/patologia , Feminino , Granulomatose com Poliangiite/patologia , Humanos , Masculino
5.
Am J Kidney Dis ; 75(1): 124-137, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31358311

RESUMO

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3-ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD's Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Glomerulonefrite/terapia , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Síndrome de Churg-Strauss/genética , Síndrome de Churg-Strauss/imunologia , Síndrome de Churg-Strauss/patologia , Síndrome de Churg-Strauss/terapia , Ciclofosfamida/uso terapêutico , Progressão da Doença , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/patologia , Granulomatose com Poliangiite/terapia , Humanos , Transplante de Rim , Poliangiite Microscópica/genética , Poliangiite Microscópica/imunologia , Poliangiite Microscópica/patologia , Poliangiite Microscópica/terapia , Ácido Micofenólico/uso terapêutico , Mieloblastina/imunologia , Peroxidase/imunologia , Indução de Remissão , Diálise Renal , Rituximab/uso terapêutico
8.
Arthritis Res Ther ; 21(1): 277, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829278

RESUMO

OBJECTIVE: In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab's mechanism of action in GPA. METHODS: B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. RESULTS: NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. CONCLUSION: B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab's mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.


Assuntos
Granulomatose com Poliangiite/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Rituximab/uso terapêutico , Granulomatose com Poliangiite/imunologia , Humanos , Células Matadoras Naturais/imunologia
9.
Front Immunol ; 10: 2617, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798577

RESUMO

Objective: Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA). Methods: Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies. Results: Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils (P < 0.001) and release of higher amounts of NETs (P < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients. Conclusion: Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.


Assuntos
Armadilhas Extracelulares/fisiologia , Granulomatose com Poliangiite/imunologia , Monócitos/fisiologia , Adulto , Calgranulina B/genética , Calgranulina B/fisiologia , Células Cultivadas , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Pessoa de Meia-Idade
11.
Reumatol. clín. (Barc.) ; 15(6): 363-367, nov.-dic. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-189655

RESUMO

OBJECTIVE: To determine to neutrophil-to-lymphocyte ratio (NLR) in granulomatosis with polyangiitis (GPA) patients and to study its relation to disease manifestations and activity. METHODS: The study included 44 GPA patients and 44 matched age and sex controls. Full history taking, thorough clinical examination with more attention to ocular examination, laboratory and radiological investigations were considered. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: The patients (21 males and 23 females) had a mean age of 45.66+/-7.24 years, disease duration 6.8+/-3.6 years and BVAS 50.1+/-14.3. All patients had a positive cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) while only 5 had a positive p-ANCA. The NLR was significantly increased in the GPA patients (5.1+/-2.4) compared to the control (1.5+/-0.8) (P<.0001). Ten patients with uveitis had a significantly higher NLR (6.5+/-1.9) compared to those without (4.7+/-2.4) (0.03) while those with proptosis (n=10), cutaneous manifestations (n=17) or ischemic heart disease (n=9) had a significantly lower NLR than those without (P=.0001, P=.017 and P=.046 respectively). The NLR did not significantly correlate with any of the patients' characteristics. The NLR inversely yet insignificantly correlated with the disease activity (r=-0.02, P=.93). CONCLUSION: The NLR may have a significant role in the pathogenesis of GPA, the development of uveitis or proptosis, cutaneous manifestations and ischemic heart disease. NLR may serve as a future potential companion to c-ANCA positivity in diagnosing and evaluating GPA and may play a role in the tissue-specific and clinical characteristics


OBJETIVO: Determinar el ratio neutrófilos/linfocitos (RNL) en pacientes con granulomatosis con poliangeítis (GP), y estudiar su relación con las manifestaciones y actividad de la enfermedad. MÉTODOS: El estudio incluyó a 44 pacientes con GP, y 44 controles pareados por edad y sexo. Se consideraron la historia clínica completa, la exploración minuciosa con especial atención al examen ocular, así como las pruebas de laboratorio y radiológicas. La actividad de la enfermedad se evaluó utilizando la clasificación Birmingham Vasculitis Activity Score (BVAS). RESULTADOS: Los pacientes (21 varones y 23 mujeres) tenían una edad media de 45,66+/-7,24 años, duración de la enfermedad de 6,8+/-3,6 años, y BVAS 50,1+/-14,3. Todos los pacientes tenían anticuerpos anticitoplasma de anti-neutrófilos positivos (c-ANCA), y únicamente 5 de ellos tenían p-ANCA positivo. El RNL se vio significativamente incrementado en los pacientes de GP (5,1+/-2,4) en comparación con el grupo control (1,5+/-0,8) (p < 0,0001). En 10 pacientes con uveítis se observó un RNL significativamente superior (6,5+/-1,9) en comparación con aquellos sin uveítis (4,7+/-2,4) (0,03), mientras que en aquellos con proptosis (n=10), manifestaciones cutáneas (n=17) o cardiopatía isquémica (n=9) se observó un RNL significativamente inferior al de aquellos sin dichas manifestaciones (p = 0,0001; p = 0,017 y p = 0,046, respectivamente). El RNL no guardó una correlación significativa con ninguna de las características de los pacientes. Sin embargo, el RNL guardó una correlación no significativa con la actividad de la enfermedad (r=-0,02; p = 0,93). CONCLUSIÓN: El RNL puede desempeñar un papel significativo en la patogenia de la GP, el desarrollo de uveítis o proptosis, manifestaciones cutáneas y cardiopatía isquémica. El RNL puede servir como futuro complemento potencial de la positividad de c-ANCA a la hora de diagnosticar y evaluar la GP, y jugar un papel con relación a sus características tisulares específicas y clínicas


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Granulomatose com Poliangiite/sangue , Linfócitos , Neutrófilos , Granulomatose com Poliangiite/imunologia , Contagem de Leucócitos
12.
Front Immunol ; 10: 2467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708920

RESUMO

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)-iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103-offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3·ANCA interactions as new GPA treatments.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autoantígenos/imunologia , Epitopos/imunologia , Granulomatose com Poliangiite/imunologia , Mieloblastina/imunologia , Simulação por Computador , Granulomatose com Poliangiite/terapia , Células HEK293 , Humanos , Mutação , Mieloblastina/química , Mieloblastina/genética , Conformação Proteica
13.
Nat Commun ; 10(1): 5120, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719529

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/imunologia , Eosinófilos/patologia , Estudos de Associação Genética , Humanos , Análise da Randomização Mendeliana
14.
Expert Rev Clin Immunol ; 15(12): 1273-1286, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31762340

RESUMO

Introduction: The majority of the patients with anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV) achieve remission with effective induction therapy. Therefore, prevention of relapses and avoiding long-term damage and treatment-related toxicity are major challenges.Areas covered: This review provides an update on maintenance therapy in AAV, emphasizing the available treatment options for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Among the spectrum of all patients with AAV, those at higher risk of relapse have recently been identified. Clinical trials have yielded robust results about various options for maintenance of remission including common disease-modifying anti-rheumatic drugs (DMARDs, i.e. azathioprine, methotrexate, and mycophenolate mofetil) and rituximab (RTX). However, outcomes of these studies are not easy to compare.Expert opinion: Regardless of the treatment used, patients presenting with an anti-proteinase-3 ANCA, relapsing GPA have a substantially higher risk of relapse compared to patients with newly diagnosed MPA or positive anti-myeloperoxidase ANCA. While the efficacy of common DMARDs for remission maintenance is heterogeneous, the role of RTX seems particularly promising for the high-risk patients, although the most appropriate dose and timing of retreatment with RTX remain under controversial. Low-dose glucocorticoid use for remission maintenance versus complete discontinuation also remains under investigation.


Assuntos
Antirreumáticos/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Quimioterapia de Manutenção , Poliangiite Microscópica/tratamento farmacológico , Ensaios Clínicos como Assunto , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/patologia , Humanos , Poliangiite Microscópica/imunologia , Poliangiite Microscópica/patologia , Indução de Remissão
15.
Front Immunol ; 10: 2170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572380

RESUMO

Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression. Methods: RNA isolated from FACS-sorted memory (M) Tregs (CD4+CD45RO+CD25+CD127-) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in MTregs from patients and HCs. cAMP levels were measured using flow cytometry. Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in MTregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of MTregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, MTregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed MTregs by forskolin restored their suppressive function in vitro. Conclusion: Overexpression of miR-142-3p in MTregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.


Assuntos
Granulomatose com Poliangiite/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Adenilil Ciclases/genética , AMP Cíclico/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Front Immunol ; 10: 2221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31608054

RESUMO

Background: Granulomatosis with polyangiitis (GPA) patients are prone to disease relapses. We aimed to determine whether GPA patients at risk for relapse can be identified by differences in B cell subset frequencies. Methods: Eighty-five GPA patients were monitored for a median period of 3.1 years (range: 0.1-6.3). Circulating B cell subset frequencies were analyzed by flow cytometry determining the expression of CD19, CD38, and CD27. B cell subset frequencies at the time of inclusion of future-relapsing (F-R) and non-relapsing (N-R) patients were compared and related to relapse-free survival. Additionally, CD27+CD38hi B cells were assessed in urine and kidney biopsies from active anti-neutrophil cytoplasmic autoantibody-associated vasculitides (AAV) patients with renal involvement. Results: Within 1.6 years, 30% of patients experienced a relapse. The CD27+CD38hi B cell frequency at the time of inclusion was increased in F-R (median: 2.39%) compared to N-R patients (median: 1.03%; p = 0.0025) and a trend was found compared with the HCs (median: 1.33%; p = 0.08). This increased CD27+CD38hi B cell frequency at inclusion was correlated to decreased relapse-free survival in GPA patients. In addition, 74.7% of patients with an increased CD27+CD38hi B cell frequency (≥2.39%) relapsed during follow-up compared to 19.7% of patients with a CD27+CD38hi B cell frequency of <2.39%. No correlations were found between CD27+CD38hi B cells and ANCA levels. CD27+CD38hi B cell frequencies were increased in urine compared to the circulation, and were also detected in kidney biopsies, which may indicate CD27+CD38hi B cell migration during active disease. Conclusions: Our data suggests that having an increased frequency of circulating CD27+CD38hi B cells during remission is related to a higher relapse risk in GPA patients, and therefore might be a potential marker to identify those GPA patients at risk for relapse.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Linfócitos B/metabolismo , Granulomatose com Poliangiite/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Subpopulações de Linfócitos B/metabolismo , Biomarcadores/metabolismo , Feminino , Citometria de Fluxo/métodos , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Remissão Espontânea
17.
Expert Rev Clin Immunol ; 15(9): 959-967, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31424304

RESUMO

Introduction: The basis of the development of the anti-interleukin-5 monoclonal antibody mepolizumab was the acknowledgment of the crucial importance of this cytokine in promoting eosinophils production, activation, and survival, which is associated with the eosinophilic asthma phenotype, as well as with other disorders characterized by high levels of eosinophils. Areas covered: All the available literature on the outcomes treatment with mepolizumab in eosinophilic disorders are reviewed, including asthma, chronic rhinosinusitis, esophagitis, granulomatosis with polyangiitis, eosinophilic chronic obstructive pulmonary disease, hypereosinophilic syndrome, and allergic bronchopulmonary aspergillosis. Expert opinion: The efficacy of mepolizumab in eosinophilic asthma is clearly demonstrated by a number of controlled trials and by meta-analyses. Among other eosinophilic disorders, controlled trials are available for chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic obstructive pulmonary disease. Allergic bronchopulmonary aspergillosis, as well as other minor eosinophilic disorders, are backed only by case reports and are waiting controlled trials to verify the therapeutic role of mepolizumab.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Interleucina-5/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/imunologia , Asma/imunologia , Ensaios Clínicos como Assunto , Esofagite/tratamento farmacológico , Esofagite/imunologia , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-5/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/imunologia , Resultado do Tratamento
18.
Clin Rheumatol ; 38(11): 3297-3305, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31338700

RESUMO

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCAs) are considered a risk factor for granulomatosis with polyangiitis (GPA) exacerbation, especially when staphylococcal superantigens (SAgs) are present in nasal swabs. Their role in monitoring disease activity remains controversial. This study determined the relationship of ANCAs with disease activity and presence of SAgs in GPA patients. METHODS: Among a total of 115 GPA patients hospitalized in the period 2009-2016, we investigated the presence of SAgs and ANCA concentration. Blood samples and nasal swabs were taken at each visit (referred further to as episodes). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). RESULTS: We analyzed 362 episodes. ANCAs were detected in 215 (59.4%), while SAgs were detected in 126 (34.8%) episodes. We found a significant correlation between the presence of ANCAs and disease activity (p = 0.0032), as well as between their level and GPA severity (r = 0.25363, p = 0.000001). We also determined that an ANCA values ≥ 138 Ru/ml were an indicator of active disease with high specificity and low sensitivity (84.4% and 37.3%, respectively). The relationship between ANCA presence and the presence of SAgs was not confirmed; however, when SAgs were analyzed based on the different types, ANCA levels were found to be significantly higher in the group with SAg type B (p = 0.031). CONCLUSIONS: There was no detectable evidence for the association between ANCA level and the presence of SAgs. Although monitoring ANCA levels as a marker of disease activity may be clinically relevant, GPA management cannot proceed on the basis of ANCA levels alone. Key Points • ANCA concentration usually correlates with GPA activity, although in half of patients, ANCAs persist despite effective treatment and clinical remission. • ANCA values of 138 Ru/ml seem to be an indicator of active disease with high specificity, but low sensitivity. • Although there is a relevance for ANCA monitoring as a marker of disease activity, GPA management cannot be based on ANCA levels alone. • The suspected clinical correlation between ANCA formation and SAg presence in nasal swabs is not obvious and requires further investigations.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Granulomatose com Poliangiite/imunologia , Staphylococcus/imunologia , Superantígenos/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
PLoS One ; 14(7): e0218705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291263

RESUMO

AIMS: Cytomegalovirus (CMV) infection under immunosuppression sometimes causes death. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Patients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months. RESULTS: Of the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92-60.23, and OR = 7.46, 95% CI = 1.46-47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid-related diabetes mellitus (p = 0.025). CONCLUSION: Our study highlights disease severity and subgroups of AAV as risk factors for CMV infection.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Granulomatose com Poliangiite/imunologia , Infecções Oportunistas/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Citomegalovirus/isolamento & purificação , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/virologia , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/patologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Japão , Modelos Logísticos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/etiologia , Infecções Oportunistas/virologia , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
20.
Int Arch Allergy Immunol ; 180(1): 64-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189169

RESUMO

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis associated with asthma, anti-neutrophil cytoplasmic antibodies (ANCA) positivity, and tissue eosinophilia. OBJECTIVE: To describe the presenting clinical features, significant biochemical alterations, and also potential pathogenic factors in adult patients diagnosed in our Center over a period of >20 years. METHOD: A retrospective study of EGPA patients diagnosed from 1994 to 2019 at ASST Grande Ospedale Metropolitano Niguarda Ca' Granda, Milan (Italy), which was performed according to the 1990 American College of Rheumatology criteria and Chapel Hill Consensus Conference definition. A dataset was compiled, registering demographic and clinical features, biochemical analysis at onset, and also the therapies received 3 months prior to EGPA diagnose. Statistical analyses were subsequently conducted dividing patients in 2 groups based on ANCA positivity and comparing them. RESULTS: Two groups were clearly identified by ANCA serology and specific organ involvement in accordance with literature reports; however, our data underline for the first time the association between anti-leukotriene receptor antagonists (LTRAs) and ANCA positivity. The group of previously treated patients presents an OR of 6.42 to be ANCA positive. This finding could be attributed to an imbalanced stimulation of leukotriene receptors, inducing both mast cells activation and an increased neutrophil extracellular traps release from neutrophils. CONCLUSION: Despite the limitations of this retrospective study, the association between LTRAs and ANCA antibodies elucidates the mechanism by which innate immunity is directly involved in tolerance breakdown and autoantibodies production. Validation of our results with targeted studies could clarify the differences between ANCA-positive and ANCA-negative patients with important consequences on the use of some drug classes in the treatment of EGPA and asthmatic subjects.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autoanticorpos/imunologia , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/imunologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Leucotrienos/imunologia , Adulto , Anticorpos Anticitoplasma de Neutrófilos/sangue , Autoanticorpos/sangue , Biomarcadores , Síndrome de Churg-Strauss/sangue , Feminino , Granulomatose com Poliangiite/sangue , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Avaliação de Sintomas
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