RESUMO
Takayasu arteritis (TAK) is a granulomatous vasculitis that affects large arteries. T cells are important in TAK pathophysiology as these cells orchestrate granulomatous infiltration in arteries. This study aims to evaluate effector CD4+ T cells in the peripheral blood and the aortic wall of TAK patients and to analyze associations with disease activity and therapy. We performed a longitudinal study including 30 TAK patients and 30 controls. CD3+ T cells, CD3+CD4- T cells, CD4+ T cells, and Th1, Th2, and Th17 cells were evaluated in peripheral blood by flow cytometry, and the expression of CD4, CD8, Tbet, GATA-3, and RORγT was analyzed in the aorta of six patients by immunohistochemistry. TAK patients presented lower CD3+ T cells and CD4+ T cells (Pâ =â 0.031 and Pâ =â 0.039, respectively) than controls. Patients with active disease and those in remission had higher proportions of Th17 cells than controls (Pâ =â 0.016 and Pâ =â 0.004, respectively). Therapy for TAK did not result in significant differences concerning CD4+ effector T-cell subpopulations. Disease duration correlated with the number and percentage of Th2 cells (rhoâ =â -0.610 and rhoâ =â -0.463, respectively) and with Th17 cells (rhoâ =â -0.365 and rhoâ =â -0.568). In the aorta, the expression of CD8 was higher than CD4, whereas GATA-3, Tbet, and RORγT were expressed in this order of frequency. In conclusion, TAK patients present an increased Th17 response in the peripheral blood regardless of disease activity, whereas in the aortic tissue CD8 cells and the Th2 response were predominant.
Assuntos
Aorta , Linfócitos T CD4-Positivos , Subpopulações de Linfócitos T , Arterite de Takayasu , Humanos , Arterite de Takayasu/imunologia , Arterite de Takayasu/sangue , Feminino , Adulto , Masculino , Aorta/imunologia , Aorta/patologia , Linfócitos T CD4-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Pessoa de Meia-Idade , Fator de Transcrição GATA3/metabolismo , Proteínas com Domínio T/metabolismo , Células Th17/imunologia , Adulto Jovem , Estudos Longitudinais , Células Th2/imunologia , Células Th1/imunologiaRESUMO
Takayasu arteritis (TAK) is a large-vessel granulomatous vasculitis; the inflammatory infiltration in arteries comprises macrophages, multi-nucleated giant cells, CD4+ and CD8+ T cells, γδ T cells, natural killer (NK) cells and neutrophils. However, it is unknown which subtype of macrophages predominates. This study aims to evaluate macrophages subpopulations in the aorta in TAK. Immunohistochemistry was performed in the aorta from TAK patients (n = 22), patients with atherosclerotic disease (n = 9) and heart transplant donors (n = 8) using the markers CD68, CD86, CD206, CD3, CD20 and CD56. Active disease was observed in 54·5% of patients and active histological lesions were found in 40·9%. TAK patients presented atherosclerotic lesions in 27·3% of cases. The frequency of macrophages, M1 macrophages, T, B and NK cells was higher in the aorta from TAK and atherosclerotic patients compared to heart transplant donors. In TAK, macrophages and T cells were the most abundant cells in the aorta, and the expression of CD206 was higher than CD86 (P = 0·0007). No associations were found between the expression of cell markers and active disease or with atherosclerotic lesions. In TAK patients, histological disease activity led to higher T cell counts than chronic fibrotic lesions (P = 0.030), whereas prednisone use was associated with lower T cell counts (P = 0·035). In conclusion, M1 macrophages were more frequent in TAK and atherosclerotic patients compared to heart transplant donors, while M2 macrophages dominated M1 macrophages in TAK. T cells were associated with histological disease activity and with prednisone use in TAK.
Assuntos
Antígenos CD/imunologia , Aorta/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Arterite de Takayasu/imunologia , Adulto , Idoso , Aorta/patologia , Estudos Transversais , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Linfócitos/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/patologiaRESUMO
OBJECTIVES: To evaluate serum cytokines as biomarkers of smoldering disease activity in patients with Takayasu's arteritis (TAK) in remission. METHODS: Thirty-four TAK patients with stable disease during the last 6 months and 22 healthy controls (HC) were included in a cross-sectional study. Serum levels of pro-inflammatory, anti-inflammatory, Th1, Th2, Th9, Th17 and Th22 cytokines were measured by the multiplex technique. RESULTS: No significant differences regarding serum cytokine levels were found between TAK patients and HC. Serum TNF-α, IL-17F, IL-21 and IL-23 were higher in patients presenting angiographic type V than in those presenting other angiographic types. Serum IL-17E, IL-17F, IL-22 and IL-23 were higher in TAK patients with previous ischaemic events compared with those without previous ischaemia. No differences in serum cytokines were observed between TAK patients with and without aneurysmal disease in the aorta or among TAK patients without therapy, those under immunosuppressive agents and patients on biological therapy. Independent associations were found regarding angiographic type V and higher serum levels of IL-4, IL-6, IL17A, IL-17E, IL-17F, IL-21, IL-22 and IL-23. Previous ischaemic events were independently associated with higher serum IL-4, IL-17E, IL-22 and IL-23. Daily prednisone dose had an inverse association with lower serum IL-4, IL6, IL-17A, IL-17E, IL-22 and IL-23. The simultaneous use of immunosuppressive and biological agents led to lower serum IL-4, IL-17E and IL-23 levels. CONCLUSIONS: A smoldering inflammatory response with predominantly cytokines involved in Th17 response seems to be ongoing in TAK patients in remission with extensive disease or with previous ischaemic events.
Assuntos
Doenças Assintomáticas , Citocinas/imunologia , Inflamação/imunologia , Arterite de Takayasu/imunologia , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fator de Necrose Tumoral alfa/imunologia , Interleucina 22RESUMO
OBJECTIVES: To evaluate and compare demographic, clinical, laboratory and angiographic data of Brazilian children and adolescents with Takayasu's arteritis. METHODS: In this Brazilian multicentre, retrospective study which included 10 paediatric rheumatology centres, we identified 71 children and adolescents with Takayasu's arteritis which were diagnosed before their 19th birthday. The patients' demographic, clinical, laboratorial and angiographic data were recorded. The participants were divided into two groups: children, defined by the WHO as younger than 10 years old (group 1: 36 patients) and adolescents, defined as individuals aged 10 to 19 years old (group 2: 35 patients). Features of both groups concerning disease manifestations were compared. RESULTS: A total of 21 (58.3%) patients in group 1 and 30 (85.7%) patients in group 2 were girls (p=0.01). The mean age at disease onset, the mean time to diagnosis, and the mean follow-up time were 5.7 and 12.7, 1.8 and 0.7, 7.2 and 3.6 years, respectively, in groups 1 and 2 (p<0.001, 0.001 and <0.001). At initial evaluation, constitutional symptoms (77.5%) were the most predominant symptoms and decreased peripheral pulses (85.9%) was the most predominant clinical sign without differences between groups. The main laboratory findings were increased erythrocyte sedimentation rate followed by leukocytosis. Anaemia, thrombocytosis and higher platelet levels were significantly more frequent in group 1 (p=0.031, 0.001 and 0.018). Angiographic data were similar in both groups. CONCLUSIONS: Children presented more laboratory abnormalities but clinical and angiographic characteristics were similar to those presented by the adolescents. Diagnosis delay is longer in younger patients.
Assuntos
Aorta/patologia , Diagnóstico Tardio , Imunossupressores/uso terapêutico , Arterite de Takayasu , Adolescente , Idade de Início , Angiografia/métodos , Brasil/epidemiologia , Criança , Pré-Escolar , Diagnóstico Tardio/prevenção & controle , Diagnóstico Tardio/estatística & dados numéricos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Gravidade do Paciente , Projetos de Pesquisa , Estudos Retrospectivos , Fatores Socioeconômicos , Inquéritos e Questionários , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/epidemiologia , Arterite de Takayasu/imunologia , Arterite de Takayasu/fisiopatologiaRESUMO
We report an adult female patient with Takayasu arteritis (TA) receiving conventional medical treatment and anti-TNF therapy, which developed progressive thoracic and abdominal aortic aneurysms. She developed imminent rupture of the thoracic aneurysm and an endovascular stent-graft (EVSG) was emergency implanted and a year after this procedure the abdominal aneurysm increased in size requiring reoperation and placement of another EVSG. Both procedures had a very good outcome. This case shows the effectivity and security of multiple EVSG implantations in multiple aortic aneurisms in patients with TA.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Procedimentos Endovasculares/instrumentação , Stents , Arterite de Takayasu/complicações , Arterite de Takayasu/tratamento farmacológico , Adulto , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/etiologia , Aortografia/métodos , Produtos Biológicos/uso terapêutico , Feminino , Humanos , Reoperação , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/imunologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Takayasu's arteritis (TA) is a chronic inflammatory arteritis of unknown etiology involving mainly the aorta and its major branches. The interleukin (IL) 1ß and IL-1 receptor antagonist have been playing an important role as regulators of inflammation. We investigated whether the polymorphisms at the IL-1B and IL-1RN gene cluster were associated with the genetic susceptibility to develop TA. We analyzed the IL-1B, IL-1F10.3, and IL-1RN polymorphisms in a sample of 58 TA patients, and 248 clinically healthy unrelated Mexican individuals by 5' exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. We found increased frequencies of different polymorphisms (C allele and TC genotype of IL-1F10.3; TT genotype of IL-1RN.4; C allele and TC genotype of IL-1RN6.1; G allele of IL-1RN6.2 and haplotypes "1T" and "1C" of IL-RN VNTR and IL-1RN6.1) in the group of TA when compared to healthy controls. On the other hand, decreased frequency of IL-1-511 TC genotype was found in the TA group compared to controls. IL-1B and IL-1RN gene polymorphisms could be involved in the risk of developing TA in the Mexican population. These associations were independent of the affected vessels.
Assuntos
Predisposição Genética para Doença , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/genética , Interleucina-1beta/genética , Arterite de Takayasu/genética , Arterite de Takayasu/imunologia , Adolescente , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , México , Pessoa de Meia-Idade , Família Multigênica , Polimorfismo Genético , Risco , Adulto JovemRESUMO
A 28-year-old patient with Takayasu's arteritis (TA) failed to respond to high doses of prednisone in combination with methotrexate, pulses of cyclophosphamide and methylprednisolone, azathioprine, mycophenolate mofetil, adalimumab and monthly infusions of infliximab 5 mg/kg. After the beginning of tocilizumab therapy (4-8 mg/kg at monthly infusions), an impressive improvement in clinical and laboratory parameters of disease activity occurred, allowing the reduction of prednisone dose from 30 to 5 mg/day. However, after the 8th dose the patient developed symptoms of vertebrobasilar insufficiency, despite maintaining a good clinical condition and normal values of inflammatory markers. Angio-computed tomography repeated at one year of therapy showed reduction in aortic wall thickness, but also narrowing of the luminal diameters of the right subclavian, renal arteries, and left vertebral artery. Therefore, despite a significant clinical and laboratory improvement, vascular disease may progress in aortic branches in TA patients under tocilizumab therapy.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Resistência a Medicamentos , Imunossupressores/administração & dosagem , Arterite de Takayasu/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Imunossupressores/efeitos adversos , Mediadores da Inflamação/sangue , Infusões Intravenosas , Arterite de Takayasu/sangue , Arterite de Takayasu/diagnóstico por imagem , Arterite de Takayasu/imunologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Takayasu's arteritis (TA) is a chronic, occlusive, inflammatory disease of the aorta, its major branches and the pulmonary arteries. Its etiology remains unclear, although it has been suggested that a variety of antigens from Mycobacterium tuberculosis and probably other mycobacteria may trigger inflammatory pathology either directly in the arterial wall or remote from the actual location of mycobacterial infection, possibly through molecular mimicry mechanisms. However, recent evidence showing absence of both mycobacteria directly into arterial tissue as well as latent M. tuberculosis infection is challenging this notion. The hypothesis offered in this manuscript postulates that the lost of tolerance against self stress proteins is a primal pathogenic event in TA with the innate immune system as key culprit in the initiation and amplification of inflammatory response, while the extensive sequence homology between mycobacterial and human stress proteins leads to epiphenomenal cross-reactions mediated by adaptive immune system. If it is so, this postulate reconciles epidemiological, immunological and genetic linkage between TA and mycobacteria, while supporting the widespread Bacille Calmette-Guérin (BCG) vaccination worldwide and giving rationale to a safety use of anti-tumor necrosis factor (TNF) therapy in patients with TA.
Assuntos
Proteínas de Choque Térmico/metabolismo , Imunidade Inata/imunologia , Mycobacterium tuberculosis/metabolismo , Arterite de Takayasu/imunologia , Tuberculose/imunologia , Reações Cruzadas/imunologia , Proteínas de Choque Térmico/genética , Humanos , Mycobacterium tuberculosis/genética , Homologia de Sequência , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/etiologiaRESUMO
La vasculitis es un proceso anatomo-clínico caracterizado por la inflamación y lesión de los vasos sanguíneos. La arteritis de células gigantes y la arteritis de Takayasu se clasifican dentro de las vasculitis de grandes vasos. Ambas se caracterizan por la formación de granulomas. Los linfocitos T CD4 dirigen el daño a los tejidos como un sine qua non en el proceso vasculítico; la activación de los linfocitos T en el ambiente no linfoide de las paredes arteriales requiere la activación de las células dendríticas. Como consecuencia, la activación de monocitos y macrófagos es responsable de un síndrome sistémico inflamatorio. El resultado final es una vasculopatía oclusiva causada por una rápida proliferación de la íntima (arteritis de células gigantes) o la formación de un aneurisma causado por la destrucción de la pared arterial (arteritis de Takayasu).
Vasculitis is a clinical anatomic process characterized by inflammation, and blood vessel damage. Giant cell arteritis and Takayasu arteritis are classified into large-vessel vasculitis. Both are characterized by the formation of granulomas. CD4 T cells direct the tissue damage as a sine qua non in the vasculitic process; activation of T cells in the nonlymphoid environment of the arterial walls requires activation of dendritic cells. As a result, the activation of monocytes and macrophages is responsible for a systemic inflammatory syndrome. The end result is an occlusive vasculopathy caused by a rapid proliferation of the intima (giant cell arteritis), or the formation of an aneurysm caused by the destruction of the arterial wall (Takayasu arteritis).
Assuntos
Humanos , Arterite de Células Gigantes/imunologia , Arterite de Takayasu/imunologia , /imunologia , Formação de Anticorpos , Apoptose , Arterite de Células Gigantes/terapia , Arterite de Takayasu/terapia , Granuloma/imunologia , Imunidade Celular , Receptores Toll-Like , Vasculite/classificação , Vasculite/imunologiaRESUMO
BACKGROUND: Antilipoprotein lipase (anti-LPL) antibodies were described in rheumatic diseases. In systemic lupus erythematosus they were highly associated with inflammatory markers and dyslipidemia, and may ultimately contribute to vascular damage. The relevance of this association in Takayasu's arteritis, which is characterized by major inflammatory process affecting vessels, has not been determined. OBJECTIVES: To analyze the presence of anti-LPL antibodies in patients with Takayasu's arteritis and its association with inflammatory markers and lipoprotein risk levels. Methods. Thirty sera from patients with Takayasu's arteritis, according to ACR criteria, were consecutively included. IgG anti-LPL was detected by a standard ELISA. Lipoprotein risk levels were evaluated according to NCEP/ATPIII. Inflammatory markers included ESR and CRP values. RESULTS: Takayasu's arteritis patients had a mean age of 34 years old and all were females. Half of the patients presented high ESR and 60% elevated CRP. Lipoprotein NCEP risk levels were observed in approximately half of the patients: 53% for total cholesterol, 43% for triglycerides, 16% for HDL-c and 47% for LDL-c. In spite of the high frequency of dyslipidemia and inflammatory markers in these patients no anti-LPL were detected. CONCLUSIONS: The lack of anti-LPL antibodies in Takayasu's disease implies distinct mechanisms underlying dyslipidemia compared to systemic lupus erythematosus.