Avaliação das subpopulações de monócitos e quimiocinas em pacientes com Arterite de Takayasu
Data
2022-04-19
Autores
Aguiar, Mariana Freitas de 
Orientadores
Souza, Alexandre Wagner Silva de
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A fisiopatologia da arterite de Takayasu (AT) ainda é pouco conhecida. Apesar da inflamação granulomatosa rica em macrófagos ser a principal característica do infiltrado vascular da doença, nenhum estudo prévio avaliou o papel dos monócitos na patogênese da AT.
Objetivos: Avaliar a distribuição das subpopulações de monócitos no sangue periférico e o perfil das quimiocinas séricas relacionadas à migração dos monócitos em pacientes com AT versus controles, comparando também pacientes com atividade e em remissão. Avaliar associações entre a distribuição das subpopulações de monócitos, as concentrações séricas das quimiocinas e as variáveis clínicas na AT. Analisar as correlações entre as concentrações séricas das quimiocinas e as subpopulações de monócitos no sangue periférico de pacientes com AT.
Métodos: Foi realizado estudo transversal com grupo controle e os pacientes com AT foram avaliados quanto à atividade da doença e tratamento atual. Os monócitos no sangue periférico foram analisados por citometria de fluxo e, com base na expressão de CD14 e CD16, foram divididos em clássicos (CD14++CD16-), intermediários (CD14+CD16dim) e não clássicos (CD14dimCD16high). A dosagem das quimiocinas CCL2, CCL3, CCL4, CCL5, CCL7, CXCL10 e CX3CL1 foi realizada pela técnica de multiplex. Um subgrupo de pacientes com doença ativa foi reavaliado de forma longitudinal, quanto à distribuição das subpopulações de monócitos, após a remissão de doença ter sido alcançada.
Resultados: Trinta e dois pacientes e trinta controles, controlados para sexo e idade, foram incluídos no estudo. Os pacientes com AT apresentaram um maior número de monócitos intermediários quando comparados aos controles [25,0 células x 106/L (16,7-52,0) vs. 17,2 células x 106/L (9,2-25,3); p = 0,014]. Doença em atividade se associou à monocitose (p = 0,005) por aumento das subpopulações de clássicos (p = 0,005) e de intermediários (p = 0,001), na comparação com controles. O uso de prednisona reduziu a porcentagem de monócitos não-clássicos [3,7% (1,3-4,1) vs. 6,9% (3,9-8,5); p = 0,011]. Pacientes com AT apresentaram concentrações mais baixas de CCL3 [6,2 pg/mL (5,0-8,1) vs. 9,3 pg/mL (5,7-14,7); p = 0,009] e CCL4 [37,4 pg/mL (24,5-47,9 vs. 45,4 pg/mL (37,8-63,7); p = 0,008] em comparação a controles, enquanto os valores de CCL22 foram mais altos em pacientes ativos quando comparados aos pacientes que estavam em remissão (1.865,5 ± 967,2 pg/mL vs. 1.229,3 ± 562,4 pg/mL; p = 0,033). A terapia com imunossupressores sintéticos ou biológicos não impactou nas concentrações das quimiocinas séricas, mas o uso de glicocorticoides se associou com valores mais baixos de CXCL10 (p = 0,012). Nos pacientes com AT, a concentração de CCL4 se correlacionou com o número de monócitos totais (Rho = 0,489; p = 0,005), de intermediários (Rho = 0,448; p = 0,010) e de clássicos (Rho = 0,412; p = 0,019). A presença de hipertensão arterial, diabetes tipo 2, eventos isquêmicos prévios e o uso de estatinas não afetou a distribuição das subpopulações dos monócitos na AT. Longitudinalmente, há uma aparente redução das subpopulações de monócitos clássicos e intermediários, quando os pacientes em atividade de doença entram em remissão, mas esse resultado não alcançou significância estatística.
Conclusões: A distribuição das subpopulações de monócitos está alterada no sangue periférico dos pacientes com AT e a quimiocina CCL22 foi a mais associada à atividade de doença.
Introduction: The pathogenesis of Takayasu arteritis (TAK) is poorly understood. Although a macrophage-rich vessel wall granulomatous inflammation is a hallmark of TAK pathology, no previous studies have analyzed the monocytes’ role in the pathogenesis of the disease. Aims: To evaluate the distribution of monocytes subsets and the monocyte-related chemokines´ profile in the peripheral blood of TAK patients and healthy controls (HC). In addition, associations between monocyte subsets and serum chemokines were analyzed regarding disease status, disease activity, and therapy. Methods: We performed a cross-sectional study with a control group to assess monocytes and relevant chemokines in TAK. Patients were evaluated for current disease activity and therapy. Monocyte subsets were identified by flow cytometry according to the surface expression of CD14 and CD16 as classical (CD14+CD16-), intermediate (CD14+CD16dim), and non-classical (CD14dimCD16high) subtypes in the peripheral blood. Multiplex was used to measure serum monocytes-related chemokines including CCL2, CCL3, CCL4, CCL5, CCL7, CXCL10 and CX3CL1. A subgroup of TAK patients with active disease was reassessed for monocyte subsets in the peripheral blood when achieving remission. Results: Thirty-two consecutive TAK patients and 30 HC were evaluated. TAK patients presented a higher number of circulating intermediate monocytes compared to HC [25.0 cells x 106/L (16.7-52.0) vs. 17.2 cells x 106/L (9.2-25.3); p = 0.014]. Active disease was associated with monocytosis (p = 0.005) along with the increase of the classical (p = 0.005) and intermediate (p = 0.001) subtypes compared to HC. Prednisone use reduced the percentage of non-classical monocytes [3.7% (1.3-4.1) vs. 6.9% (3.9-8.5); p = 0.011]. TAK patients had lower CCL3 [6.2 pg/mL (5.0-8.1) vs. 9.3 pg/mL (5.7-14.7); p = 0.009] and CCL4 [37.4 pg/mL (24.5-47.9 vs. 45.4 pg/mL (37.8-63.7); p = 0.008] levels than HC, whereas CCL22 levels were higher in active TAK compared to the remission state (1,865.5 ± 967.2 pg/mL vs. 1,229.3 ± 562.4 pg/mL; p = 0.033). Therapy with immunosuppressive agents or biologics did not impact serum chemokines, but glucocorticoids were associated with lower CXCL10 levels (p = 0.012). In TAK patients, CCL4 concentration correlated with the number of total monocytes (Rho = 0.489; p = 0.005), intermediate (Rho = 0.448; p = 0.010) and classical monocytes (Rho = 0.412; p = 0.019) in the peripheral blood. Hypertension, type 2 diabetes, ischemic events, and the use of statins did not affect the numbers or the distribution of monocytes´ subpopulations in TAK. Despite the low number of patients assessed longitudinally, an apparent decrease in the median number of cells in the peripheral blood was observed between active disease and remission in TAK in paired analyses of total monocytes. Conclusions: TAK is associated with altered distribution of monocytes subtypes in the peripheral blood compared to HC and CCL22 is the chemokine with the strongest association with active disease in TAK.
Introduction: The pathogenesis of Takayasu arteritis (TAK) is poorly understood. Although a macrophage-rich vessel wall granulomatous inflammation is a hallmark of TAK pathology, no previous studies have analyzed the monocytes’ role in the pathogenesis of the disease. Aims: To evaluate the distribution of monocytes subsets and the monocyte-related chemokines´ profile in the peripheral blood of TAK patients and healthy controls (HC). In addition, associations between monocyte subsets and serum chemokines were analyzed regarding disease status, disease activity, and therapy. Methods: We performed a cross-sectional study with a control group to assess monocytes and relevant chemokines in TAK. Patients were evaluated for current disease activity and therapy. Monocyte subsets were identified by flow cytometry according to the surface expression of CD14 and CD16 as classical (CD14+CD16-), intermediate (CD14+CD16dim), and non-classical (CD14dimCD16high) subtypes in the peripheral blood. Multiplex was used to measure serum monocytes-related chemokines including CCL2, CCL3, CCL4, CCL5, CCL7, CXCL10 and CX3CL1. A subgroup of TAK patients with active disease was reassessed for monocyte subsets in the peripheral blood when achieving remission. Results: Thirty-two consecutive TAK patients and 30 HC were evaluated. TAK patients presented a higher number of circulating intermediate monocytes compared to HC [25.0 cells x 106/L (16.7-52.0) vs. 17.2 cells x 106/L (9.2-25.3); p = 0.014]. Active disease was associated with monocytosis (p = 0.005) along with the increase of the classical (p = 0.005) and intermediate (p = 0.001) subtypes compared to HC. Prednisone use reduced the percentage of non-classical monocytes [3.7% (1.3-4.1) vs. 6.9% (3.9-8.5); p = 0.011]. TAK patients had lower CCL3 [6.2 pg/mL (5.0-8.1) vs. 9.3 pg/mL (5.7-14.7); p = 0.009] and CCL4 [37.4 pg/mL (24.5-47.9 vs. 45.4 pg/mL (37.8-63.7); p = 0.008] levels than HC, whereas CCL22 levels were higher in active TAK compared to the remission state (1,865.5 ± 967.2 pg/mL vs. 1,229.3 ± 562.4 pg/mL; p = 0.033). Therapy with immunosuppressive agents or biologics did not impact serum chemokines, but glucocorticoids were associated with lower CXCL10 levels (p = 0.012). In TAK patients, CCL4 concentration correlated with the number of total monocytes (Rho = 0.489; p = 0.005), intermediate (Rho = 0.448; p = 0.010) and classical monocytes (Rho = 0.412; p = 0.019) in the peripheral blood. Hypertension, type 2 diabetes, ischemic events, and the use of statins did not affect the numbers or the distribution of monocytes´ subpopulations in TAK. Despite the low number of patients assessed longitudinally, an apparent decrease in the median number of cells in the peripheral blood was observed between active disease and remission in TAK in paired analyses of total monocytes. Conclusions: TAK is associated with altered distribution of monocytes subtypes in the peripheral blood compared to HC and CCL22 is the chemokine with the strongest association with active disease in TAK.
Descrição
Citação
AGUIAR, M.F. Avaliação das subpopulações de monócitos e quimiocinas em pacientes com arterite de Takayasu. São Paulo, 2022. 114 f. Tese (Doutorado em Ciências da Saúde Aplicadas à Reumatologia) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo 9UNIFESP). São Paulo, 2022.