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3.
Indian Pediatr ; 56(5): 407-414, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102381

RESUMO

Common rheumatological disorders encountered in pediatric practice are juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Kawasaki disease, Henoch-Schonlein purpura, systemic lupus erythematosus, chronic uveitis and juvenile dermatomyositis. Diagnosis of these disorders requires a critical appraisal of the clinical history, physical examination and relevant investigations. Laboratory tests are helpful for screening purposes as also for confirmation of diagnosis and monitoring of disease activity. These tests should, however, only be ordered after due deliberation and in the context of clinical findings in a given patient.


Assuntos
Biomarcadores/sangue , Doenças Reumáticas/diagnóstico , Criança , Diagnóstico Diferencial , Marcadores Genéticos , Humanos , Pediatria , Doenças Reumáticas/sangue , Doenças Reumáticas/genética
4.
Mol Immunol ; 106: 12-21, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30576947

RESUMO

Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and ß-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and ß-arrestin 2-deficient mice. These GRK6- and ß-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and ß-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.


Assuntos
Quimiocinas/imunologia , Quinases de Receptores Acoplados a Proteína G/imunologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Macrófagos/imunologia , Receptores Acoplados a Proteínas-G/imunologia , beta-Arrestina 2/imunologia , Animais , Linhagem Celular , Quimiocinas/genética , Quinases de Receptores Acoplados a Proteína G/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Receptores Acoplados a Proteínas-G/genética , Doenças Reumáticas/genética , Doenças Reumáticas/imunologia , Doenças Reumáticas/patologia , beta-Arrestina 2/genética
5.
Arthritis Rheumatol ; 71(4): 486-495, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30507064

RESUMO

One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.


Assuntos
Predisposição Genética para Doença/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Doenças Reumáticas/genética , Alelos , Humanos , Fatores de Risco
7.
Int J Rheum Dis ; 22(3): 386-391, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30548416

RESUMO

Co-occurrence of autoimmune diseases (ADs) within an individual is postulated to be a frequent phenomenon in rheumatic diseases. Similar clinical signs and symptoms, pathophysiological mechanisms, genetic factors within autoimmune diseases and aggregation of diverse ADs within families sustain the theory of shared pathogenesis of several ADs (autoimmune tautology). Polyautoimmunity (PA) is defined as the presence of more than one autoimmune disease in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). This analysis summarizes an estimated prevalence of PA in the most common rheumatic diseases, the presumable risk factors for PA and influence of concomitant diseases on the course of disease.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Doenças Reumáticas/imunologia , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Autoimunidade/genética , Predisposição Genética para Doença , Humanos , Multimorbidade , Fenótipo , Prevalência , Prognóstico , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/genética , Medição de Risco , Fatores de Risco , Síndrome
8.
Ann Rheum Dis ; 78(3): 311-319, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30573655

RESUMO

OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.


Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Miosite/genética , Locos de Características Quantitativas/genética , Doenças Reumáticas/genética , Escleroderma Sistêmico/genética , Adulto , Artrite Reumatoide/imunologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Quinases Lim/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/imunologia , Miosite/imunologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/imunologia , Proteínas Repressoras/imunologia , Doenças Reumáticas/imunologia , Escleroderma Sistêmico/imunologia , alfa Carioferinas/imunologia
9.
Biomed Khim ; 64(3): 221-232, 2018 Jun.
Artigo em Russo | MEDLINE | ID: mdl-29964257

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology, which involves disturbance in immune system signaling pathway functions, damage of other tissues, pain and joint destruction. Modern treatment attempts to improve pathophysiological and biochemical mechanisms damaged by the disease. However, due to the RA patient heterogeneity personalized approach to treatment is required; the choice of personalized treatment is complicated by the variability of patient's response to treatment. Gene expression analysis might serve a tool for the disease control and therapy personification for inhibition of inflammation and pain as well as for prevention of joint destruction.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Medicina de Precisão , Doenças Reumáticas , Animais , Humanos , Doenças Reumáticas/genética , Doenças Reumáticas/metabolismo , Doenças Reumáticas/terapia
10.
Biomed Res Int ; 2018: 6930297, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854780

RESUMO

Lung illness encountered in patients with rheumatic diseases bears clinical significance in terms of increased morbidity and mortality as well as potential challenges placed on patient care. Although our understanding of natural history of this important illness is still limited, epidemiologic knowledge has been accumulated during the past decade to provide useful information on the risk factors and prognosis of lung involvements in rheumatic diseases. Moreover, the pathogenesis particularly in the context of genetics has been greatly updated for both the underlying rheumatic disease and associated lung involvement. This review will focus on the current update on the epidemiologic and genetics features and treatment options of the lung involvements associated with four major rheumatic diseases (rheumatoid arthritis, systemic sclerosis, myositis, and systemic lupus erythematosus), with more attention to a specific form of involvement or interstitial lung disease.


Assuntos
Pneumopatias/epidemiologia , Pneumopatias/patologia , Pulmão/patologia , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/patologia , Humanos , Pneumopatias/genética , Prognóstico , Doenças Reumáticas/genética , Fatores de Risco
11.
J Intern Med ; 284(3): 228-239, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908080

RESUMO

The autoimmune rheumatological diseases rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic lupus erythematosus (SLE) are treated with conventional immunosuppressive agents and with modern biological immunomodulators. The latter group of medications have brought about a major change in our ability to control RA and SpA, with more modest results for SLE. The biologicals are very specific in their mechanisms of action, targeting one specific cytokine or one particular cellular marker. Because of this, their efficacy can readily be linked to a single immunomodulatory mechanism. This observation has fuelled hopes that the efficacy of these agents can be predicted at the individual level based on the patient's genetic predisposition, immunological profile or disease phenotype. Whilst the biologic therapies have improved the prospects for patients with these diseases very significantly, the hope that they could be targeted to the patient in an individualized manner has not completely born fruit. In this review, I will argue that we are witnessing important progress in this field, and that justified hope exists for true advances in precision medicine in the autoimmune diseases in the coming years.


Assuntos
Genótipo , Fatores Imunológicos/uso terapêutico , Fenótipo , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/genética , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Biomarcadores/sangue , Predisposição Genética para Doença/genética , Humanos , Fatores Imunológicos/efeitos adversos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Doenças Reumáticas/diagnóstico , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/genética , Resultado do Tratamento
12.
Curr Top Med Chem ; 18(16): 1395-1401, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29766809

RESUMO

Depressive disorders, are not only common but also among the leading causes of disability worldwide. They are associated with increased incidences of various other diseases. It has been shown that in patients with autoimmune diseases, when depression coexists, the quality of life is worse and medical treatment and management is compromised. Depression-like symptoms, such as fatigue and disinterest are also common in inflammatory rheumatic diseases and often associated with poor quality of life. Medical therapy targeting inflammation results in alleviation of these symptoms in many patients. Interestingly, there is cumulating evidence suggesting potential roles of inflammatory cytokines in the pathogenesis of major depression. Effects of some of the biological agents used in rheumatic diseases have been studied on depressive disorders. Results have been controversial and further studies are needed in this area. These findings suggest associations between depression and inflammatory rheumatic diseases and raise the possibility that treatment of one of them might influence the outcome of the other. We have reviewed the current literature on associations between depression and inflammatory rheumatologic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome and ankylosing spondylitis.


Assuntos
Transtorno Depressivo/genética , Inflamação/genética , Doenças Reumáticas/genética , Citocinas/metabolismo , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Doenças Reumáticas/metabolismo , Doenças Reumáticas/patologia
13.
Brief Funct Genomics ; 17(5): 308-318, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-29741584

RESUMO

Ankylosing spondylitis (AS) is a highly heritable chronic inflammatory arthritis characterized by osteoproliferation, fusion of affected joints and systemic manifestations. Many disease associations for AS have been reported through genome-wide association studies; however, identifying modulated genes and functional mechanism remains challenging. This review summarizes current genetic associations involving AS and describes strategic approaches for functional follow-up of disease-associated variants. Fine mapping using methods leveraging Bayesian approaches are outlined. Evidence highlighting the importance of context specificity for regulatory variants is reviewed, noting current evidence in AS for the relevant cell and tissue type to conduct such analyses. Technological advances for understanding the regulatory landscape within which functional variants may act are discussed using exemplars. Approaches include defining regulatory elements based on chromatin accessibility, effects of variants on genes at a distance through evidence of physical interactions (chromatin conformation capture), expression quantitative trait loci mapping and single-cell methodologies. Opportunities for mechanistic studies to investigate the function of specific variants, regulatory elements and genes enabled by genome editing using clustered regularly interspaced short palindromic repeats/Cas9 are also described. Further progress in our understanding of the genetics of AS through functional genomic and epigenomic approaches offers new opportunities to understand mechanism and develop innovative treatments.


Assuntos
Estudo de Associação Genômica Ampla , Doenças Reumáticas/complicações , Doenças Reumáticas/genética , Espondilite Anquilosante/complicações , Espondilite Anquilosante/genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Mapeamento Físico do Cromossomo
14.
Autoimmunity ; 51(4): 152-156, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29732925

RESUMO

BACKGROUND: The correct identification of anti-dense fine speckled-70 (DFS70) antibodies represents an important issue in the detection of anti-nuclear antibodies (ANAs) as performed by the indirect immunofluorescence (IIF) test on HEp-2 substrates. In this study, we have evaluated a new method for anti-DFS70 antibody detection employing HEp-2 cells knocked-out for the DFS70 antigen. METHODS: We studied 148 sera with a DFS70-like pattern (91 positive and 57 negative when tested for anti-DFS70 antibodies by a specific chemoluminescence [CLIA] method); 116 sera with infectious disease; 100 healthy donors (HDs), 139 samples from patients with a defined diagnosis of autoimmune rheumatic disease (ARD), and 242 consecutive unselected samples screened for ANA during the routine work-up. RESULTS: The HEp2 DFS70-Ko substrate recognized anti-DFS70 antibodies in 86/91 (94.5%) of the DFS70 CLIA-positive sera and in 9/57 (15.8%) of the DFS70 CLIA-negative samples. None of the 116 infectious diseases were positive for DFS70 using the engineered IIF substrate. Two samples (2%) were positive among HDs and were then confirmed by CLIA. The 139 ANA-positive sera from patients with ARD displaying a defined antibody specificity showed their expected patterns also on DFS70-Ko HEp-2 substrate. Five of the 242 (2.1%) consecutive samples tested in the routine ANA-screening were identified as DFS70-positive using the HEp2 Ko-substrate and were then confirmed by CLIA. CONCLUSIONS: The use of DFS70 HEp-2 Ko cells may offer the unique possibility of simultaneously identifying and confirming the presence of anti-DFS70 antibodies during the standard ANA evaluation, while keeping the expression of other autoantibody markers intact.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Autoanticorpos/imunologia , Técnicas de Silenciamento de Genes , Engenharia Genética , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos/genética , Antígenos/imunologia , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linhagem Celular , Criança , Pré-Escolar , Doenças Transmissíveis/sangue , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/patologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo/métodos , Humanos , Medições Luminescentes/métodos , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/sangue , Doenças Reumáticas/genética , Doenças Reumáticas/imunologia , Doenças Reumáticas/patologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
15.
Rheumatol Int ; 38(8): 1333-1338, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29623390

RESUMO

To date, numerous genetic and epigenetic studies have been performed and provided a crucial step forward in our understanding of the pathogenesis of rheumatic diseases. However, most of the recent advances in the treatment of rheumatic diseases including biological therapies are not based on or even discrepant from these genetic and epigenetic findings. For example, tumor necrosis factor inhibitors are quite successful in the treatment of rheumatoid arthritis (RA), Behçet's disease (BD), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) but not in that of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV), conversely, RA shares genetic backgrounds more with SLE, SSc, SS and AAV than BD, AS and PsA. In this review, we briefly highlight the findings from recent genetic and epigenetic studies and discuss what needs to be studied to provide a novel, more efficacious management of rheumatic diseases.


Assuntos
Antirreumáticos/uso terapêutico , Doenças Reumáticas/genética , Doenças Reumáticas/terapia , Artrite Psoriásica/genética , Artrite Psoriásica/terapia , Artrite Reumatoide/genética , Artrite Reumatoide/terapia , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/terapia , Receptores do Fator de Necrose Tumoral/administração & dosagem , Espondilite Anquilosante/genética , Espondilite Anquilosante/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
16.
Clin Exp Immunol ; 193(2): 167-177, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29663334

RESUMO

Triggering of autoimmunity that leads to rheumatic disease has been suggested to depend upon gene-environment interactions occurring in epithelial barriers and associated immune cells. Genetic studies have identified associations of the FAM167A-BLK locus with rheumatoid arthritis, systemic lupus erythematosus (SLE) and Sjögren's syndrome. While BLK (B lymphocyte kinase) has a well-established role in B cells, family with sequence similarity to 167 member A (FAM167A) and its gene family remain uncharacterized. To begin to understand the role of FAM167A in rheumatic disease pathogenesis, we explored this gene family and cloned and investigated the gene products. Expression of quantitative trait locus analysis was performed in immune cells. FAM167A and FAM167B were cloned from human peripheral blood mononuclear cells (PBMC). Gene conservation and protein properties were analysed by online tools, mRNA expression measured in mouse organs by quantitative polymerase chain reaction (qPCR) and protein expression investigated in human tissues by immunohistochemistry. We found that autoimmune risk genotypes within the FAM167A-BLK locus lead to increased expression of FAM167A. The FAM167 gene family includes two members, FAM167A and FAM167B, which are not homologous to any other annotated gene but are evolutionarily conserved. The encoded proteins, which we denote 'disordered autoimmunity' (DIORA)-1 and DIORA-2, respectively, are characterized by a high content of intrinsic disorder. Notably, DIORA-1 has its highest expression in the lung, detectable in both bronchial epithelium and alveolar macrophages with an endosomal localization pattern. In summary, the FAM167A gene is associated with several rheumatic diseases and encodes a novel disordered protein, DIORA-1, which is expressed highly in the lung, consistent with a potential role in disease pathogenesis.


Assuntos
Brônquios/fisiologia , Pulmão/metabolismo , Macrófagos Alveolares/fisiologia , Proteínas/genética , Mucosa Respiratória/fisiologia , Doenças Reumáticas/genética , Animais , Autoimunidade/genética , Clonagem Molecular , Biologia Computacional , Sequência Conservada/genética , Evolução Molecular , Regulação da Expressão Gênica/imunologia , Loci Gênicos/genética , Humanos , Camundongos Endogâmicos C57BL , Conformação Proteica , Locos de Características Quantitativas , Alinhamento de Sequência , Resposta a Proteínas não Dobradas/genética , Quinases da Família src/genética
17.
Nat Rev Rheumatol ; 14(4): 214-228, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29559718

RESUMO

The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including systemic lupus erythematosus, Sjögren syndrome, myositis, systemic sclerosis, and rheumatoid arthritis. In normal immune responses, type I interferons have a critical role in the defence against viruses, yet in many rheumatic diseases, large subgroups of patients demonstrate persistent activation of the type I interferon pathway. Genetic variations in type I interferon-related genes are risk factors for some rheumatic diseases, and can explain some of the heterogeneity in type I interferon responses seen between patients within a given disease. Inappropriate activation of the immune response via Toll-like receptors and other nucleic acid sensors also contributes to the dysregulation of the type I interferon pathway in a number of rheumatic diseases. Theoretically, differences in type I interferon activity between patients might predict response to immune-based therapies, as has been demonstrated for rheumatoid arthritis. A number of type I interferon and type I interferon pathway blocking therapies are currently in clinical trials, the results of which are promising thus far. This Review provides an overview of the many ways in which the type I interferon system affects rheumatic diseases.


Assuntos
Antirreumáticos/uso terapêutico , Interferon Tipo I/metabolismo , Doenças Reumáticas/tratamento farmacológico , Antirreumáticos/farmacologia , Ensaios Clínicos como Assunto , Redes Reguladoras de Genes , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Doenças Reumáticas/genética , Doenças Reumáticas/imunologia , Transdução de Sinais/efeitos dos fármacos
18.
Amyloid ; 25(1): 37-45, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29364741

RESUMO

BACKGROUND: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis. METHODS: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease. FINDINGS: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease. CONCLUSIONS: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.


Assuntos
Amiloidose , Predisposição Genética para Doença , Leptina/sangue , Obesidade , Polimorfismo Genético , Proteína Amiloide A Sérica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/sangue , Amiloidose/epidemiologia , Amiloidose/etiologia , Amiloidose/genética , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Leptina/genética , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Doenças Reumáticas/sangue , Doenças Reumáticas/complicações , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/genética , Proteína Amiloide A Sérica/metabolismo
19.
Rev Med Suisse ; 14(588-589): 93-96, 2018 Jan 10.
Artigo em Francês | MEDLINE | ID: mdl-29337460

RESUMO

Tumor cells express checkpoint proteins in order to prevent an immune reaction by T-cells. Checkpoint inhibitors are successfully used in oncology to unleash a cytotoxic immune response. Unfortunately this treatment increasingly leads to immune-related adverse events which resemble various primary autoimmune disorders known in rheumatology. Potentially, checkpoint dysfunction also underlies rheumatic diseases which would open the way for new treatment options to restore immune tolerance.


Assuntos
Doenças Autoimunes , Doenças Reumáticas , Doenças Autoimunes/genética , Autoimunidade , Humanos , Doenças Reumáticas/genética , Reumatologia/tendências
20.
Curr Opin Rheumatol ; 30(1): 65-71, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28984647

RESUMO

PURPOSE OF REVIEW: Stroma is a broad term referring to the connective tissue matrix in which other cells reside. It is composed of diverse cell types with functions such as extracellular matrix maintenance, blood and lymph vessel development, and effector cell recruitment. The tissue microenvironment is determined by the molecular characteristics and relative abundances of different stromal cells such as fibroblasts, endothelial cells, pericytes, and mesenchymal precursor cells. Stromal cell heterogeneity is explained by embryonic developmental lineage, stages of differentiation to other cell types, and activation states. Interaction between immune and stromal cell types is critical to wound healing, cancer, and a wide range of inflammatory diseases. Here, we review recent studies of inflammatory diseases that use functional genomics and single-cell technologies to identify and characterize stromal cell types associated with pathogenesis. RECENT FINDINGS: High dimensional strategies using mRNA sequencing, mass cytometry, and fluorescence activated cell-sorting with fresh primary tissue samples are producing detailed views of what is happening in diseased tissue in rheumatoid arthritis, inflammatory bowel disease, and cancer. Fibroblasts positive for CD90 (Thy-1) are enriched in the synovium of rheumatoid arthritis patients. Single-cell RNA-seq studies will lead to more discoveries about the stroma in the near future. SUMMARY: Stromal cells form the microenvironment of inflamed and diseased tissues. Functional genomics is producing an increasingly detailed view of subsets of stromal cells with pathogenic functions in rheumatic diseases and cancer. Future genomics studies will discover disease mechanisms by perturbing molecular pathways with chemokines and therapies known to affect patient outcomes. Functional genomics studies with large sample sizes of patient tissues will identify patient subsets with different disease phenotypes or treatment responses.


Assuntos
Artrite Reumatoide/genética , Doenças Inflamatórias Intestinais/genética , RNA Mensageiro/metabolismo , Células Estromais/citologia , Artrite Reumatoide/imunologia , Diferenciação Celular , Quimiocinas , Células Endoteliais/citologia , Células Endoteliais/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Citometria de Fluxo , Genômica , Humanos , Doenças Inflamatórias Intestinais/imunologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Pericitos/citologia , Pericitos/imunologia , Doenças Reumáticas/genética , Doenças Reumáticas/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/imunologia , Membrana Sinovial/citologia , Antígenos Thy-1/imunologia
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