RESUMO
Granulomatosis with polyangiitis (GPA) is an autoimmune disorder characterized by recurrent relapses that can cause severe tissue damage and life-threatening organ dysfunction. Multiple immune cells and cytokines/chemokines are involved in the different stages of the disease. Immune profiling of patients may be useful for tracking disease activity, however, reliable immune signatures for GPA activity are lacking. In this study, we examined circulating immune profiles in GPA patients during active and remission disease states to identify potential immune patterns associated with disease activity. The distribution and phenotypic characteristics of major circulating immune cells, and the profiles of circulating cytokines/chemokines, were studied on cryopreserved peripheral blood mononuclear cells from GPA patients (active, n = 20; remission, n = 20) and healthy controls (n = 20) leveraging a 40-color optimized multicolor immunofluorescence panel (OMIP-69) and in serum using a 46-plex Luminex multiplex assay, respectively. Deep phenotyping uncovered a distinct composition of major circulating immune cells in active GPA and GPA in remission, with the most significant findings emerging within the monocyte compartment. Our detailed analysis revealed circulating monocyte diversity beyond the conventional monocyte subsets. We identified eight classical monocyte populations, two intermediate monocyte populations, and one non-classical monocyte population. Notably, active GPA had a higher frequency of CD45RA+CCR5+CCR6-CCR7+/lowCD127-HLA-DR+CD2- classical monocytes and a lower frequency of CD45RA-CCR5-/lowCCR6-CCR7-CD127-HLA-DR+CD2+/- classical monocytes, which both strongly correlated with disease activity. Furthermore, serum levels of CXCL1, CXCL2, and CCL20, all linked to monocyte biology, were elevated in active GPA and correlated strongly with disease activity. These findings shed light on the circulating immune profile of GPA and may lead to immune signature profiles for assessing disease activity. Monocytes in particular may be studied further as potential markers for monitoring GPA.
Assuntos
Citocinas , Granulomatose com Poliangiite , Humanos , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Citocinas/sangue , Citocinas/metabolismo , Idoso , Adulto , Monócitos/imunologia , Monócitos/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Imunofenotipagem , Biomarcadores/sangueRESUMO
OBJECTIVE: To assess relationship between Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and inflammatory bowel disease (IBD). METHODS: This is a retrospective study design. The patients were identified using a preset criteria of patients who have the diagnosis of ANCA associated vasculitis including a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA) with overlapping inflammatory bowel disease (Crohn's disease or ulcerative colitis) in the time period from 01/01/2020 to 08/03/2023. Subsequently data from each patient was collected that will include baseline demographics, disease characteristics, disease activity, treatment information, multiorgan involvement, and pathology findings which were then analyzed. RESULTS: 39 patients were identified that met criteria. 20 patients carried a diagnosis of GPA, 6 had MPA and 4 patients had EGPA. 20 patients with GPA had inflammatory bowel disease, 13 with ulcerative colitis and 6 with Crohn's disease while 1 GPA patient had unspecified inflammatory bowel disease. 4 patients with EGPA had inflammatory bowel disease, 2 with ulcerative colitis and 2 with Crohn's disease. 6 patients with MPA had inflammatory bowel disease, 4 with ulcerative colitis and 2 with Crohn's disease. IBD diagnosis preceded the diagnosis of ANCA vasculitis in 77.8 % of the cases. CONCLUSION: Objective observation and deductions from this study raise the concern for a possible pathogenic association of ANCA associated vasculitis and inflammatory bowel disease and more research is needed to identify any causal association or influence of the two systemic disease on each other.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Doenças Inflamatórias Intestinais , Humanos , Feminino , Masculino , Estudos Retrospectivos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Pessoa de Meia-Idade , Adulto , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/complicações , Idoso , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/sangue , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/sangueRESUMO
Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early diagnosis of EGPA are needed, especially for differentiating the diagnosis of asthma. Objectives: To identify serum biomarkers that can be used for early diagnosis of EGPA and to distinguish EGPA from severe asthma. Method: Data-independent acquisition (DIA) analysis was performed to identify 45 healthy controls (HC), severe asthma (S-A), and EGPA patients in a cohort to screen biomarkers for early diagnosis of EGPA and to differentiate asthma diagnosis. Subsequently, parallel reaction monitoring (PRM) analysis was applied to a validation cohort of 71 HC, S-A, and EGPA patients. Result: Four candidate biomarkers were identified from DIA and PRM analysis-i.e., serum amyloid A1 (SAA1), fibrinogen-α (FGA), and serum amyloid P component (SAP)-and were upregulated in the EGPA group, while cholesteryl ester transfer protein (CETP) was downregulated in the EGPA group compared with the S-A group. Receiver operating characteristics analysis shows that, as biomarkers for early diagnosis of EGPA, the combination of SAA1, FGA, and SAP has an area under the curve (AUC) of 0.947, a sensitivity of 82.35%, and a specificity of 100%. The combination of SAA1, FGA, SAP, and CETP as biomarkers for differential diagnosis of asthma had an AUC of 0.921, a sensitivity of 78.13%, and a specificity of 100%, which were all larger than single markers. Moreover, SAA1, FGA, and SAP were positively and CETP was negatively correlated with eosinophil count. Conclusion: DIA-PRM combined analysis screened and validated four previously unexplored but potentially useful biomarkers for early diagnosis of EGPA and differential diagnosis of asthma.
Assuntos
Asma , Proteínas de Transferência de Ésteres de Colesterol , Síndrome de Churg-Strauss , Fibrinogênio , Granulomatose com Poliangiite , Transtornos Leucocíticos , Proteína Amiloide A Sérica , Componente Amiloide P Sérico , Asma/sangue , Asma/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Diagnóstico Diferencial , Fibrinogênio/metabolismo , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/diagnóstico , Humanos , Proteômica , Proteína Amiloide A Sérica/metabolismo , Componente Amiloide P Sérico/metabolismoRESUMO
We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-γ, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-γ, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Granulomatose com Poliangiite/metabolismo , Poliangiite Microscópica/metabolismo , Estresse Oxidativo , Linfócitos T Reguladores/metabolismo , Antioxidantes/farmacologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Poliangiite Microscópica/sangue , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Objective: The contribution of sustained autologous autoantibody production by B cells to the pathogenesis of systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) is not fully understood. To investigate this, a humanized mouse model was generated by transferring patient-derived peripheral blood mononuclear cells (PBMC) into immunocompromised mice. Methods: PBMC derived from patients with SSc and GPA as well as healthy controls (HD) were isolated, characterized by flow cytometry, and infused into Rag2-/-/IL2rg-/- mice. In addition, PBMC from SSc patients treated with rituximab were transferred into mice. Twelve weeks later, human autoantibodies were determined in blood of the recipient mice and affected tissues were analyzed for pathological changes by histology and immunohistochemistry. Results: Mice engrafted with PBMC derived from SSc patients developed autoantibodies such as antinuclear antibodies (ANA) mimicking the pattern of the respective donors. Moreover, cellular infiltrates dominated by B cells were observed in lung, kidney and muscles of the recipient mice. By contrast, PBMC derived from HD or GPA patients survived in recipient mice after transfer, but neither human autoantibodies nor inflammatory infiltrates in tissues were detected. Furthermore, these pathological changes were absent in mice transferred with PBMC from rituximab-treated SSc patients. Conclusion: This humanized mouse model is indicative for cross-reactivity of human lymphocytes to murine autoantigens and argues for a pivotal role of B cells as well as of sustained autoimmunity in the pathogenesis of SSc. It provides a powerful tool to study interstitial lung disease and so far, under-recognized disease manifestations such as myositis and interstitial nephritis.
Assuntos
Anticorpos Antinucleares/imunologia , Proteínas de Ligação a DNA/metabolismo , Granulomatose com Poliangiite/sangue , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/transplante , Escleroderma Sistêmico/sangue , Adulto , Idoso , Animais , Anticorpos Antinucleares/sangue , Linfócitos B/imunologia , Reações Cruzadas , Proteínas de Ligação a DNA/genética , Feminino , Granulomatose com Poliangiite/imunologia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Fatores Imunológicos/uso terapêutico , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Animais , Rituximab/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.
Assuntos
Alveolite Alérgica Extrínseca/sangue , Granulomatose com Poliangiite/sangue , Fibrose Pulmonar Idiopática/sangue , Imunossupressores/uso terapêutico , Sarcoidose/sangue , Proteína Amiloide A Sérica/metabolismo , Adulto , Idoso , Alveolite Alérgica Extrínseca/diagnóstico , Alveolite Alérgica Extrínseca/tratamento farmacológico , Alveolite Alérgica Extrínseca/patologia , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Expressão Gênica , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/patologia , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Infliximab/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Sarcoidose/patologiaRESUMO
We previously reported that fibrosis-4 (FIB-4) was associated with poor outcomes of microscopic polyangiitis (MPA) and granuloma with polyangiitis (GPA). We also investigated the potential of FIB-5, a novel index, in predicting all-cause mortality and end-stage renal disease (ESRD) during follow-up in patients with MPA and GPA without substantial liver diseases. Clinical and laboratory data at diagnosis were collected by reviewing the medical records of 180 patients with MPA and GPA. FIB-5 was obtained by a following equation: FIB-5 = (serum albumin (g/L) × 0.3 + platelet count (109/L) × 0.05) - (alkaline phosphatase (IU/L) × 0.014 + aspartate aminotransferase/alanine aminotransferase ratio × 6 + 14). The median age of the patients at diagnosis was 61.0 years. FIB-5 at diagnosis could not reflect the cross-sectional vasculitis activity. The cutoffs of FIB-5 for poor outcomes was set as 0.82 (the lowest tertile) and -0.42 (the lowest quartile) at diagnosis. In Kaplan-Meier survival analysis, patients with FIB-5 < 0.82 and those with FIB-5 < -0.42 exhibited lower ESRD-free survival rates than those without. However, it could not predict all-cause mortality. In multivariable Cox hazards analysis, both FFS (Hazard ratio (HR) 1.554) and FIB-5 < 0.82 (HR 2.096) as well as both FFS (HR 1.534) and FIB-5 < -0.42 (HR 2.073) at diagnosis independently predicted ESRD during follow-up. In conclusion, FIB-5 < 0.82 and FIB-5 < -0.42 at diagnosis could predict the occurrence of ESRD, but not all-cause mortality, during follow-up in patients with MPA and GPA without substantial liver diseases.
Assuntos
Granulomatose com Poliangiite/patologia , Falência Renal Crônica/diagnóstico , Poliangiite Microscópica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibrose , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/mortalidade , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Poliangiite Microscópica/sangue , Poliangiite Microscópica/complicações , Poliangiite Microscópica/mortalidade , Pessoa de Meia-Idade , Contagem de Plaquetas , Albumina Sérica Humana/metabolismo , Análise de SobrevidaRESUMO
BACKGROUND: Granulomatosis with polyangiitis (GPA) is a representative of vasculitides associated with anti-neutrophil cytoplasmic autoantibodies. "Classical" antibodies directed against proteinase 3 are involved in the pathogenesis and are part of the GPA diagnosis at the same time. Along with them, however, antibodies against Lysosomal-Associated Membrane Protein-2 (LAMP-2) and antibodies directed against plasminogen have been described in GPA.Objectives and methodology: We performed a cross-sectional study enrolling 34 patients diagnosed with GPA. Our study was aimed at looking for correlations between serum levels of LAMP-2 and plasminogen and the clinical manifestations of the GPA. Furthermore, we examined serum levels of tumor necrosis factor-alpha (TNF-α) and its associated indoleamine-pyrrole 2,3-dioxygenase (IDO), as well as we looked for a correlation between these cytokines and the clinical manifestations of GPA. RESULTS: The results showed that in GPA, serum plasminogen levels were negatively associated with renal involvement (receiver operating characteristic (ROC) area under the curve (AUC) of 0.78) (95% CI 0.53-0.91), p = 0.035, and the extent of proteinuria, Spearman's Rho = -0.4, p = 0.015. Increased levels of TNF-α and IDO correlated with disease activity, Spearman's Rho =0.62, p = 0.001 and Spearman's Rho = 0.4, p = 0.022, respectively, whereas only TNF-α was increased in severe forms of GPA with lung involvement (ROC AUC of 0.8) (95% CI 0.66-0.94), p = 0.005. CONCLUSIONS: In this study, we demonstrate the alteration of soluble factors, which play an important role in the pathogenesis of GPA and their relationship with the clinical manifestations of the disease. Our main results confirm the associations of increased secretory TNF-α and some clinical manifestations, and we describe for the first time decreased serum plasminogen levels and their association with renal involvement.
Assuntos
Granulomatose com Poliangiite/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Plasminogênio/análise , Fator de Necrose Tumoral alfa/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Granulomatose com Poliangiite/diagnóstico , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , PrognósticoRESUMO
Granulomatosis with polyangiitis (GPA) is a necrotising vasculitis of unknown cause that has several systemic manifestations. The disease is characterised by the classical triad involving acute inflammation of the upper and lower respiratory tracts with renal involvement. However, the disease pathology can involve the central nervous system. This case report presents a case of GPA with facial nerve palsy as the first manifestation of the disease, which has been rarely reported in the medical literature.
Assuntos
Paralisia Facial/etiologia , Granulomatose com Poliangiite/diagnóstico , Perfuração do Septo Nasal/etiologia , Convulsões/etiologia , Adolescente , Anticorpos Anticitoplasma de Neutrófilos/sangue , Encéfalo/diagnóstico por imagem , Ciclofosfamida/administração & dosagem , Paralisia Facial/sangue , Paralisia Facial/diagnóstico , Paralisia Facial/terapia , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/terapia , Humanos , Imageamento por Ressonância Magnética , Metilprednisolona/administração & dosagem , Perfuração do Septo Nasal/diagnóstico , Septo Nasal/diagnóstico por imagem , Seios Paranasais/diagnóstico por imagem , Plasmaferese , Pulsoterapia , Convulsões/sangue , Convulsões/diagnóstico , Convulsões/terapia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To define the pattern of cardiac involvement in eosinophilic granulomatosis and polyangiitis (EGPA) and propose an algorithm for heart disease screening. METHODS: This was a retrospective study of EGPA patients attending a specialized vasculitis clinic (1989-2016). Clinical characteristics and cardiovascular evaluation (CE) results (serum troponin, ECG, echocardiography and cardiac magnetic resonance) were collected and compared according to symptoms and inflammatory cardiac disease (ICD). RESULTS: A total of 131 EGPA patients were included, of whom 96 (73%) had undergone CE. The median (interquartile range) age was 50 (38-58) years and 36% showed ANCA+. Asthma preceded diagnosis by a median of 97 (36-240) months. Among the 96 patients who underwent CE, 43% were symptomatic, with dyspnea (47%) and chest pain (29%) being the predominant symptoms. In asymptomatic patients, CE reported abnormalities in 45% of cases, with a subsequent earlier diagnosis (4 vs 11 months). Overall, 27 patients had EGPA-related ICD (EGPA-rICD) that was already present at diagnosis in 20 cases, preceded it in 2 cases and developed later in 5 cases. EGPA-rICD patients were younger (46 vs 50 years; P = 0.04), had more frequently abnormal ECG (30.8 vs 2.1%; P < 0.001), negative ANCA (85 vs 69%; NS), higher BVAS score (3 vs 1; P = 0.005), higher eosinophil count (5.60 vs 1.60 × 109/l; P = 0.029) and higher CRP (52 vs 15 mg/l; P = 0.017). Overall, 11% of cases with EGPA-rICD were asymptomatic. CONCLUSION: In our study, 45% of asymptomatic patients had an abnormal baseline cardiac evaluation, which allowed an earlier diagnosis of cardiac disease. We recommend prompt cardiac screening in all EGPA patients, instead of a symptoms-guided algorithm.
Assuntos
Eosinofilia/diagnóstico por imagem , Granulomatose com Poliangiite/diagnóstico por imagem , Cardiopatias/diagnóstico , Programas de Rastreamento/métodos , Adulto , Algoritmos , Diagnóstico Precoce , Ecocardiografia , Eletrocardiografia , Eosinofilia/sangue , Eosinofilia/complicações , Eosinófilos , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/complicações , Fatores de Risco de Doenças Cardíacas , Cardiopatias/etiologia , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Troponina/sangueRESUMO
BACKGROUND: Enzyme-linked immunosorbent assay (ELISA) has traditionally been used to detect myeloperoxidase (MPO) and proteinase 3 (PR3) antibodies, although it is time-consuming and physically demanding. As a novel and highly effective immunoassay, we compared chemiluminescent immunoassay (CIA) with ELISA to verify the application value of CIA in MPO and PR3 antibodies detection. METHODS: By ELISA and CIA, serum levels of anti-MPO and anti-PR3 antibodies were measured in 63 anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients (AAV group), including 47 microscopic polyangiitis (MPA) patients and 16 granulomatosis with polyangiitis (GPA) patients, in addition, 68 patients in interference control group (IC group), 19 healthy subjects in healthy control group (HC group). We compared MPO and PR3 antibodies levels and positive rates measured by these two methods among groups. Relationship and coincidence rate between ELISA and CIA were investigated. Diagnostic values for clinical outcomes for MPO and PR3 antibodies were assessed by receiver operator characteristic (ROC) curve. RESULTS: In AAV patients, when detecting anti-MPO (r = .90) and anti-PR3 (r = .81), CIA was highly correlated with ELISA, companying with highly total (88.89%, 92.06%, respectively) and positive coincidence rates (84.78%, 77.27%, respectively). In HC group, anti-PR3 positive rate detected by both immunoassay were 0, anti-MPO almost were 0, which without statistically significant difference (P = .32). In IC group, the total (76.47%, 58.82, respectively) and positive coincidence rates (48.38%, 30.00%, respectively) of anti-MPO and anti-PR3 were the lowest, but the negative coincidence rates reached 100%. By CIA, similar to ELISA, the levels of anti-MPO were significantly higher both in AAV patients (56.00; [4.40-235.30]) and MPA patients (98.00; [27.90-324.70]) compared with either IC group (3.20; [3.20-18.55) (P < .0001) or HC group (3.20; [3.20-3.20]) (P < .0001), yielded an area under curve (AUC) of 0.76 for AAV and 0.89 for MPA, the concentration of anti-PR3 in GPA group (66.65; [24.43-150.00]) was significantly higher than that in IC group (2.3; [2.3-10.95]) (P < .0001) and HC group (2.3; [2.3-2.3]) (P < .0001), with an AUC of 0.92. CONCLUSION: Similar to ELISA, CIA was competent to detect MPO and PR3 antibodies in AAV patients and healthy population, thus distinguish AAV patients from IC group and HC group and effectively diagnose MPA and GPA.
Assuntos
Anticorpos/sangue , Imunoensaio/métodos , Mieloblastina/imunologia , Peroxidase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Humanos , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto JovemRESUMO
BACKGROUND: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. METHODS: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). RESULTS: Results revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.
Assuntos
Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/terapia , Fator A de Crescimento do Endotélio Vascular/sangue , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Biomarcadores/sangue , Síndrome de Churg-Strauss/sangue , Estudos de Coortes , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Japão , Masculino , Poliangiite Microscópica/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de RemissãoRESUMO
OBJECTIVES: To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). RESULTS: GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21- B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). CONCLUSION: Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.
Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite/sangue , Poliangiite Microscópica/sangue , Linfócitos T/imunologia , Linfócitos B/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/metabolismo , Humanos , Poliangiite Microscópica/imunologia , Poliangiite Microscópica/metabolismo , Linfócitos T/metabolismoAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Eosinofilia/tratamento farmacológico , Granulomatose com Poliangiite/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Circulação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Eosinofilia/sangue , Eosinofilia/imunologia , Eosinofilia/fisiopatologia , Eosinófilos/imunologia , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Imunoglobulina E/sangue , Interleucina-5/antagonistas & inibidores , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/imunologia , Estudos Retrospectivos , Nervo Sural/efeitos dos fármacos , Nervo Sural/fisiologiaAssuntos
Medula Óssea/irrigação sanguínea , Medula Óssea/patologia , Granulomatose com Poliangiite/patologia , Anemia/sangue , Anemia/etiologia , Angiodisplasia/complicações , Angiodisplasia/patologia , Angiodisplasia/terapia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Epistaxe/etiologia , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/patologia , Hemorragia Gastrointestinal/terapia , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico por imagem , Hemostase Endoscópica , Humanos , Masculino , Mastoidite/diagnóstico por imagem , Mastoidite/etiologia , Pessoa de Meia-Idade , Mieloblastina/imunologia , Necrose , Trombocitopenia/sangue , Trombocitopenia/etiologiaRESUMO
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Anticorpos Anticitoplasma de Neutrófilos/genética , Mieloblastina/genética , Peroxidase/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/classificação , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Biomarcadores/sangue , Síndrome de Churg-Strauss/sangue , Síndrome de Churg-Strauss/genética , Síndrome de Churg-Strauss/patologia , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/patologia , Humanos , Poliangiite Microscópica/sangue , Poliangiite Microscópica/genética , Poliangiite Microscópica/patologia , Prognóstico , SorogrupoRESUMO
Granulomatosis with polyangiitis (GPA) is an autoimmune disease which is a type of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that frequently affects the lungs and kidneys. However, GPA limited to a single organ has also been reported. A 71-year-old man was admitted for back pain and fever. We detected elevated levels of inflammatory markers and myeloperoxidase-ANCA. Magnetic resonance imaging indicated diffuse inflammation of the back and psoas muscles. Histology showed degenerated muscle fibers and granulomatosis vasculitis with mixed lymphoplasma cell infiltration. High-dose methylprednisolone therapy improved his symptoms. A final diagnosis of GPA limited to the muscles was made.
Assuntos
Músculos do Dorso/patologia , Granulomatose com Poliangiite/patologia , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Músculos do Dorso/diagnóstico por imagem , Biomarcadores/sangue , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/diagnóstico por imagem , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Masculino , Metilprednisolona/uso terapêutico , Peroxidase/sangue , Músculos Psoas/diagnóstico por imagem , Músculos Psoas/patologiaAssuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Granulomatose com Poliangiite/diagnóstico , Imunoensaio/normas , Mieloblastina/imunologia , Peroxidase/imunologia , Autoantígenos/imunologia , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Humanos , Padrões de ReferênciaRESUMO
Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.