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1.
Nagoya J Med Sci ; 81(1): 151-158, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30962664

RESUMO

Recent epidemiological or immunopathological studies demonstrate the possible association between giant cell arteritis and infectious agents including Chlamydia pneumoniae. A 62-year-old Japanese man with type 1 diabetes mellitus developed biopsy-proven giant cell arteritis after acute upper respiratory infection. Serological examination indicated concurrent re-infection with C. pneumoniae. Clinical manifestations of the vasculitis subsided within a month without any immunosuppressive therapy, and no relapse was observed for the following 12 months. The natural history of this disease is unclear and spontaneous remission is rarely reported. The self-limiting nature of the infection could contribute to this phenomenon.


Assuntos
Anticorpos Antibacterianos/sangue , Chlamydophila pneumoniae/imunologia , Chlamydophila pneumoniae/patogenicidade , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/imunologia , Infecções Respiratórias/sangue , Anticorpos Antibacterianos/imunologia , Arterite de Células Gigantes/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Remissão Espontânea , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia
2.
J Am Coll Cardiol ; 73(14): 1811-1823, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30975299

RESUMO

BACKGROUND: In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets. OBJECTIVES: The authors examined how CD28 signaling affects vasculitis induction and maintenance, and which pathogenic processes rely on CD28-mediated T-cell activation. METHODS: Vasculitis was induced by transferring peripheral blood mononuclear cells from giant cell arteritis patients into immunodeficient NSG mice engrafted with human arteries. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control antibody. Treatment effects and immunosuppressive mechanisms were examined in vivo and in vitro applying tissue transcriptome analysis, immunohistochemistry, flow cytometry, and immunometabolic analysis. RESULTS: Blocking CD28-dependent signaling markedly reduced tissue-infiltrating T cells and effectively suppressed vasculitis. Mechanistic studies implicated CD28 in activating AKT signaling, T-cell proliferation and differentiation of IFN-γ and IL-21-producing effector T cells. Blocking CD28 was immunosuppressive by disrupting T-cell metabolic fitness; specifically, the ability to utilize glucose. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption were all highly sensitive to CD28 blockade. Also, induction and maintenance of CD4+CD103+ tissue-resident memory T cells, needed to replenish the vasculitic infiltrates, depended on CD28 signaling. CD28 blockade effectively suppressed vasculitis-associated remodeling of the vessel wall. CONCLUSIONS: CD28 stimulation provides a metabolic signal required for pathogenic effector functions in medium and large vessel vasculitis. Disease-associated glycolytic activity in wall-residing T-cell populations can be therapeutically targeted by blocking CD28 signaling.


Assuntos
Imunidade Adaptativa , Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/metabolismo , Remodelação Vascular/imunologia , Animais , Anticorpos/metabolismo , Proliferação de Células , Quimiotaxia de Leucócito/imunologia , Modelos Animais de Doenças , Arterite de Células Gigantes/imunologia , Humanos , Camundongos , Neovascularização Patológica/imunologia , Neovascularização Patológica/prevenção & controle
3.
Ann Lab Med ; 39(4): 345-357, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30809980

RESUMO

The platelet-to-lymphocyte ratio (PLR) has emerged as an informative marker revealing shifts in platelet and lymphocyte counts due to acute inflammatory and prothrombotic states. PLR has been extensively examined in neoplastic diseases accompanied by immune suppression and thrombosis, which can be predicted by combined blood cell counts and their ratios. Several large observational studies have demonstrated the value of shifts in PLR in evaluating the severity of systemic inflammation and predicting infections and other comorbidities, in inflammatory rheumatic diseases. The value of PLR as an inflammatory marker increases when its fluctuations are interpreted along with other complementary hematologic indices, particularly the neutrophil-to-lymphocyte ratio (NLR), which provides additional information about the disease activity, presence of neutrophilic inflammation, infectious complications, and severe organ damage in systemic lupus erythematosus. PLR and NLR have high predictive value in rheumatic diseases with predominantly neutrophilic inflammation (e.g., Behçet disease and familial Mediterranean fever). High PLR, along with elevated platelet count, is potentially useful in diagnosing some systemic vasculitides, particularly giant-cell arteritis. A few longitudinal studies on rheumatic diseases have demonstrated a decrease in PLR in response to anti-inflammatory therapies. The main limitations of PLR studies are preanalytical faults, inadequate standardization of laboratory measurements, and inappropriate subject selection. Nonetheless, accumulating evidence suggests that PLR can provide valuable information to clinicians who encounter multisystem manifestations of rheumatic diseases, which are reflected in shifts in platelet, lymphocyte, neutrophil, or monocyte counts. Interpretation of PLR combined with complementary hematologic indices is advisable to more accurately diagnose inflammatory rheumatic diseases and predict related comorbidities.


Assuntos
Plaquetas/citologia , Linfócitos/citologia , Doenças Reumáticas/patologia , Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Humanos , Linfócitos/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/imunologia
4.
J Vis Exp ; (144)2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30799840

RESUMO

Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.


Assuntos
Artérias/metabolismo , Biomarcadores/metabolismo , Receptor 2 de Folato/metabolismo , Arterite de Células Gigantes/diagnóstico , Inflamação/metabolismo , Macrófagos/metabolismo , Músculo Liso Vascular/metabolismo , Idoso , Artérias/imunologia , Artérias/patologia , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/patologia , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/patologia
5.
Int J Rheum Dis ; 22 Suppl 1: 41-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29624864

RESUMO

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are forms of large-vessel vasculitides that affect the aorta and its branches. There is ongoing debate about whether they are within a spectrum of the same disease or different diseases. Shared commonalities include clinical features, evidence of systemic inflammation, granulomatous inflammation on biopsy, role of T-helper (Th)-1 and Th17 in the pathogenesis, and, abnormalities of the aorta and its branches on imaging. However, there are also several differences in the geographic distribution, genetics, inflammatory cells and responses to treatment. This review highlights the similarities and differences in the epidemiology, pathogenesis, clinical manifestations, imaging findings and treatment responses in these conditions. Current data supports that they are two distinct conditions despite the numerous similarities.


Assuntos
Arterite de Células Gigantes/diagnóstico , Arterite de Takayasu/diagnóstico , Adolescente , Adulto , Idade de Início , Diagnóstico Diferencial , Feminino , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/epidemiologia , Arterite de Células Gigantes/imunologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/epidemiologia , Arterite de Takayasu/imunologia , Resultado do Tratamento , Adulto Jovem
6.
Int J Rheum Dis ; 22 Suppl 1: 28-40, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29667308

RESUMO

Giant cell arteritis is the commonest primary vasculitis of the elderly. However, the prevalence does vary widely between populations with highest incidence amongst Northern Europeans and lowest amongst East Asians. Preliminary studies suggest that clinical manifestations may differ between different populations. Newer diagnostic approaches including ultrasound, MR angiography and PET imaging are under review. While there have been recent advances in the diagnosis of GCA particularly with regard to imaging, there is an urgent need for improvements in methods of diagnosis, treatment and requirement for screening. Glucocorticoid treatment remain the backbone of therapy. However, glucocorticoid therapy is associated with significant adverse effects. Conventional and novel immunosuppressive agents have only demonstrated modest effects in a subgroup of steroid refractory GCA due to the different arms of the immune system at play. However, recently a study of IL-6 blockade demonstrated benefit in GCA. Newer approaches such as fast-track pathways can also result in improvements in consequences of GCA including blindness.


Assuntos
Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Idoso , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático , Austrália/epidemiologia , Progressão da Doença , Resistência a Medicamentos , Feminino , Arterite de Células Gigantes/etnologia , Arterite de Células Gigantes/imunologia , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Grupo com Ancestrais Oceânicos , Indução de Remissão , Fatores de Risco , Resultado do Tratamento
7.
JCI Insight ; 3(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30333306

RESUMO

BACKGROUND: In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. METHODS: To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). RESULTS: Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1ß and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1ß and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. CONCLUSIONS: We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment. FUNDING: Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.


Assuntos
Doença da Artéria Coronariana/imunologia , Arterite de Células Gigantes/imunologia , Glucose/metabolismo , Macrófagos/imunologia , Idoso , Idoso de 80 Anos ou mais , Artérias/imunologia , Artérias/patologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Células Cultivadas , Estudos de Coortes , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/patologia , Glucose/imunologia , Glicólise/imunologia , Humanos , Memória Imunológica , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células
8.
Ann Rheum Dis ; 77(12): 1815-1824, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30097452

RESUMO

OBJECTIVES: The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis. METHODS: IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture. RESULTS: Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs. CONCLUSION: IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.


Assuntos
Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Proliferação de Células/fisiologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Artérias Temporais/patologia
9.
Rheumatology (Oxford) ; 57(suppl_2): ii51-ii62, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982777

RESUMO

GCA is a chronic granulomatous vasculitis that affects large- and medium-sized vessels. Both the innate and the adaptive immune system are thought to play an important role in the initial events of the pathogenesis of GCA. Amplification cascades are involved in the subsequent development and progression of the disease, resulting in vascular inflammation, remodelling and occlusion. The development of large-vessel vasculitis in genetically modified mice has provided some evidence regarding potential mechanisms that lead to vascular inflammation. However, the participation of specific mechanistic pathways in GCA has not been fully established because of the paucity and limitations of functional models. Treatment of GCA is evolving, and novel therapies are being incorporated into the GCA treatment landscape. In addition, to improve the management of GCA, targeted therapies are providing functional proof of concept of the relevance of particular pathogenic mechanisms in the development of GCA and in sustaining vascular inflammation.


Assuntos
Arterite de Células Gigantes/imunologia , Imunidade Adaptativa/fisiologia , Animais , Artérias/imunologia , Arterite de Células Gigantes/tratamento farmacológico , Humanos , Imunidade Inata/fisiologia , Inflamação , Camundongos , Transdução de Sinais/imunologia
10.
BMC Med Genomics ; 11(1): 61, 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30037347

RESUMO

BACKGROUND: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. METHODS: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. RESULTS: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. CONCLUSIONS: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Fatores de Tempo
11.
Circ Res ; 123(6): 700-715, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29970365

RESUMO

RATIONALE: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. OBJECTIVE: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. METHODS AND RESULTS: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects. CONCLUSIONS: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.


Assuntos
Artéria Axilar/enzimologia , Linfócitos T CD4-Positivos/enzimologia , Movimento Celular , Arterite de Células Gigantes/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Monócitos/enzimologia , Artérias Temporais/enzimologia , Remodelação Vascular , Idoso , Idoso de 80 Anos ou mais , Animais , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/farmacologia , Artéria Axilar/efeitos dos fármacos , Artéria Axilar/imunologia , Artéria Axilar/patologia , Membrana Basal/enzimologia , Membrana Basal/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Arterite de Células Gigantes/prevenção & controle , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Neointima , Neovascularização Patológica , Transdução de Sinais , Artérias Temporais/efeitos dos fármacos , Artérias Temporais/imunologia , Artérias Temporais/patologia , Remodelação Vascular/efeitos dos fármacos
12.
Hum Pathol ; 81: 65-70, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29953896

RESUMO

Giant cell arteritis (GCA) primarily involves medium-to-large arteries. Small-vessel inflammation is a recognized phenomenon occurring in association with GCA. However, its significance is poorly elucidated. Histologic sections and medical records of105 temporal artery specimens were retrospectively reviewed between 2008 and 2017 to examine associated clinical manifestations and laboratory data including antinuclear antibody and p-antineutrophilic cytoplasmic antibody titers. Immunohistochemical staining for CD4 and CD8 was performed in select cases to assess the nature of the inflammatory response. Seventy-eight patients meeting the diagnostic criteria of temporal arteritis were included in the analysis. Twenty-eight specimens demonstrated temporal arteritis with small arterial inflammation (SAI), and 50 specimens showed temporal arteritis without SAI. Eight (28.6%) of 28 patients with SAI presented with jaw claudication, whereas 5 (17.9%) were febrile at presentation. In contrast, in 50 patients without SAI, jaw claudication and fever were seen in 11 and 2 cases, respectively (P = .01 and P = .0047, respectively). No statistically significant difference was noted between other symptoms and laboratory indices between the 2 groups. Elevated p-antineutrophilic cytoplasmic antibody titers in GCA may be associated with concomitant polymyalgia rheumatica or treatment-resistant disease. We also identified a higher count of CD4 and CD8 T cells in SAI cases, although the ratio of CD4/CD8 T lymphocytes was within normal limits. In conclusion, simultaneous involvement of arterioles and medium- to large-sized arteries is common in GCA and may be associated with treatment-refractory disease. Documentation of small arterial involvement in GCA will help the clinicians to manage the disease more effectively.


Assuntos
Arterite de Células Gigantes/patologia , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Imuno-Histoquímica , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Artérias Temporais/química , Artérias Temporais/imunologia
13.
Front Immunol ; 9: 809, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29731755

RESUMO

Background: Giant-cell arteritis (GCA) is considered a T helper (Th)1- and Th17-mediated disease. Interleukin (IL)-12 is a heterodimeric cytokine (p35/p40) involved in Th1 differentiation. When combining with p19 subunit, p40 compose IL-23, a powerful pro-inflammatory cytokine that maintains Th17 response. Objectives: The aims of this study were to investigate p40, p35, and p19 subunit expression in GCA lesions and their combinations to conform different cytokines, to assess the effect of glucocorticoid treatment on subunit expression, and to explore functional roles of p40 by culturing temporal artery sections with a neutralizing anti-human IL-12/IL-23p40 antibody. Methods and results: p40 and p19 mRNA concentrations measured by real-time RT-PCR were significantly higher in temporal arteries from 50 patients compared to 20 controls (4.35 ± 4.06 vs 0.51 ± 0.75; p < 0.0001 and 20.32 ± 21.78 vs 4.17 ± 4.43 relative units; p < 0.0001, respectively). No differences were found in constitutively expressed p35 mRNA. Contrarily, p40 and p19 mRNAs were decreased in temporal arteries from 16 treated GCA patients vs those from 34 treatment-naïve GCA patients. Accordingly, dexamethasone reduced p40 and p19 expression in cultured arteries. Subunit associations to conform IL-12 and IL-23 were confirmed by proximity-ligation assay in GCA lesions. Immunofluorescence revealed widespread p19 and p35 expression by inflammatory cells, independent from p40. Blocking IL-12/IL-23p40 tended to reduce IFNγ and IL-17 mRNA production by cultured GCA arteries and tended to increase Th17 inducers IL-1ß and IL-6. Conclusion: IL-12 and IL-23 heterodimers are increased in GCA lesions and decrease with glucocorticoid treatment. p19 and p35 subunits are much more abundant than p40, indicating an independent role for these subunits or their potential association with alternative subunits. The modest effect of IL-12/IL-23p40 neutralization may indicate compensation by redundant cytokines or cytokines resulting from alternative combinations.


Assuntos
Arterite de Células Gigantes/imunologia , Subunidade p35 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/genética , Subunidade p19 da Interleucina-23/genética , Células Th1/imunologia , Células Th17/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Citocinas , Feminino , Arterite de Células Gigantes/patologia , Glucocorticoides/uso terapêutico , Humanos , Subunidade p35 da Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/imunologia , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Artérias Temporais/efeitos dos fármacos , Artérias Temporais/imunologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
14.
Cell Mol Biol (Noisy-le-grand) ; 64(5): 46-51, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29729713

RESUMO

This study explored whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) G788A (R263Q) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted using 23 comparative studies with a total of 16,719 patients and 17,783 controls. The meta-analysis showed an association between the A allele of the PTPN22 G788A polymorphism and decreased risk of autoimmune diseases in all subjects (p < 0.001). Analysis after stratification by ethnicity indicated that the PTPN22 788A allele was significantly associated with autoimmune diseases in Europeans (p < 0.001) but not in Latin Americans. Meta-analysis by autoimmune disease type showed a significant negative association between the PTPN22 788A allele and systemic lupus erythematous (SLE) (p = 001), rheumatoid arthritis (RA) (p = 0.008), ulcerative colitis (UC) (p = 0.016), but not Crohn's disease (CD). A single study for each showed no association between the PTPN22 788A allele and systemic sclerosis, giant cell arteritis, Henoch-schonlein purpura, uveitis, and Grave's disease. This meta-analysis demonstrates that the PTPN22 G788A polymorphism confers protection against SLE, RA, and UC, supporting evidence of association of the PTPN22 gene with a subgroup of autoimmune diseases.


Assuntos
Artrite Reumatoide/genética , Colite Ulcerativa/genética , Resistência à Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Colite Ulcerativa/etnologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/etnologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/patologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Estudos de Associação Genética , Genótipo , Arterite de Células Gigantes/etnologia , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Doença de Graves/etnologia , Doença de Graves/genética , Doença de Graves/imunologia , Doença de Graves/patologia , Hispano-Americanos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Púrpura de Schoenlein-Henoch/etnologia , Púrpura de Schoenlein-Henoch/genética , Púrpura de Schoenlein-Henoch/imunologia , Púrpura de Schoenlein-Henoch/patologia , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Uveíte/etnologia , Uveíte/genética , Uveíte/imunologia , Uveíte/patologia
15.
Clin Exp Rheumatol ; 36 Suppl 111(2): 12-32, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29799395
16.
Rheumatology (Oxford) ; 57(8): 1377-1380, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29697809

RESUMO

Objective: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. Methods: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. Results: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . Conclusion: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity.


Assuntos
Complexo CD3/metabolismo , Arterite de Células Gigantes/diagnóstico , Imuno-Histoquímica/métodos , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Complexo CD3/imunologia , Feminino , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fotomicrografia , Curva ROC , Estudos Retrospectivos , Artérias Temporais/metabolismo
17.
J Biol Regul Homeost Agents ; 32(2): 313-319, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29685012

RESUMO

In patients with giant cell arteritis (GCA), autoantibodies against cytoskeletal elements, cardiolipin, neutrophil cytoplasmic antigens, ferritin, endothelial and smooth muscle cells have been reported, however no updated reviews are available evaluating their clinical utility. Methodology of detection is important, especially for quantitative assays, e.g. enzyme-linked immunoassays and multiplex beadbased immunoassays, while semiquantitative assays contribute valuable data on isoforms, epitope mapping and cellular localization. Most studies to date reporting on antiphospholipid antibodies in GCA have focused on anti-cardiolipin antibodies (aCL), while the highest prevalence of autoantibodies in GCA patients was reported for the anti-N-terminal peptides of the ferritin heavy chain (92%). Antineutrophil cytoplasmic antibodies were shown to be present in only a small percentage of GCA patients, decreasing after therapy, however in combination with aCL and antibodies against peptides of N-terminal ferritin heavy chain, they could represent an added value in detecting relapse in GCA patients.


Assuntos
Autoanticorpos/sangue , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/sangue , Humanos , Recidiva
18.
Arthritis Rheumatol ; 70(9): 1366-1376, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29648680

RESUMO

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.


Assuntos
Arterite de Células Gigantes/imunologia , Isquemia Encefálica/imunologia , Arterite de Células Gigantes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Prognóstico , Recidiva , Fatores de Risco
19.
Curr Rheumatol Rep ; 20(5): 25, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29611005

RESUMO

PURPOSE OF REVIEW: Giant cell arteritis (GCA) is the most common systemic vasculitis. GCA is categorized as a granulomatous vasculitis of large and medium size vessels. Majority of the symptoms and signs of GCA result from involvement of the aorta and its branches intra- and extracranial. Temporal artery biopsy continues to be the cardinal diagnostic procedure despite new imaging modalities for diagnosing GCA with cranial involvement. Great advances in awareness have led to improvement in preventing irreversible vision loss due to early diagnosis. RECENT FINDINGS: The cause of GCA has not been elucidated but major progress has been made in the knowledge of its pathogenesis leading to new therapeutic targets, particularly inhibition of interleukin 6. IL 6 plays a key role in the regulation of TH17/Tregs imbalance in GCA and appears to correlate with clinical disease activity in GCA. All of this has led to the first FDA (food and drug administration) approved treatment for GCA, Tocilizumab. Abatacept and Ustekinumab are promising targets for therapy in LVV but still need further research. This paper is a review of the recent progress in the understanding of GCA pathogenesis, diagnosis, treatment, and prognosis.


Assuntos
Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/imunologia , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Prognóstico , Ustekinumab/uso terapêutico
20.
Reumatismo ; 70(1): 10-17, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29589398

RESUMO

Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.


Assuntos
Polimialgia Reumática/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Imunidade Adaptativa/imunologia , Idoso , Linfócitos B/imunologia , Biomarcadores/sangue , Diferenciação Celular/imunologia , Medicina Baseada em Evidências , Arterite de Células Gigantes/imunologia , Humanos , Imunidade Inata/imunologia , Polimialgia Reumática/complicações
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