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1.
J Immunol ; 208(5): 1115-1127, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35165166

RESUMO

Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-γ and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-γ by effector/memory CD4+ T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y11 receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/imunologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/metabolismo , Células Th17/imunologia , Animais , Artrite Reumatoide/patologia , Benzodiazepinonas/farmacologia , Diferenciação Celular/imunologia , Células Cultivadas , Humanos , Memória Imunológica/imunologia , Interferon gama/biossíntese , Interleucina-17/biossíntese , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Receptores Nucleares Órfãos , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Purinérgicos P2X4/genética , Proteínas com Domínio T/biossíntese , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia
2.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884486

RESUMO

Lysophosphatidylserine (lysoPS) is known to regulate immune cell functions. Phospholipase A1 member A (PLA1A) can generate this bioactive lipid through hydrolysis of sn-1 fatty acids on phosphatidylserine (PS). PLA1A has been associated with cancer metastasis, asthma, as well as acute coronary syndrome. However, the functions of PLA1A in the development of systemic autoimmune rheumatic diseases remain elusive. To investigate the possible implication of PLA1A during rheumatic diseases, we monitored PLA1A in synovial fluids from patients with rheumatoid arthritis and plasma of early-diagnosed arthritis (EA) patients and clinically stable systemic lupus erythematosus (SLE) patients. We used human primary fibroblast-like synoviocytes (FLSs) to evaluate the PLA1A-induced biological responses. Our results highlighted that the plasma concentrations of PLA1A in EA and SLE patients were elevated compared to healthy donors. High concentrations of PLA1A were also detected in synovial fluids from rheumatoid arthritis patients compared to those from osteoarthritis (OA) and gout patients. The origin of PLA1A in FLSs and the arthritic joints remained unknown, as healthy human primary FLSs does not express the PLA1A transcript. Besides, the addition of recombinant PLA1A stimulated cultured human primary FLSs to secrete IL-8. Preincubation with heparin, autotaxin (ATX) inhibitor HA130 or lysophosphatidic acid (LPA) receptor antagonist Ki16425 reduced PLA1A-induced-secretion of IL-8. Our data suggested that FLS-associated PLA1A cleaves membrane-exposed PS into lysoPS, which is subsequently converted to LPA by ATX. Since primary FLSs do not express any lysoPS receptors, the data suggested PLA1A-mediated pro-inflammatory responses through the ATX-LPA receptor signaling axis.


Assuntos
Artrite/patologia , Fibroblastos/patologia , Gota/patologia , Lúpus Eritematoso Sistêmico/patologia , Fosfolipases A1/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Sinoviócitos/patologia , Artrite/genética , Artrite/imunologia , Artrite/metabolismo , Estudos de Casos e Controles , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Gota/genética , Gota/imunologia , Gota/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Fosfolipases A1/genética , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Sinoviócitos/imunologia , Sinoviócitos/metabolismo
3.
PLoS One ; 14(8): e0221528, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437241

RESUMO

Expressed strongly by myeloid cells, damage-associated molecular pattern (DAMP) proteins S100A8 and S100A9 are found in the serum of patients with infectious and autoimmune diseases. Compared to S100A9, the role of S100A8 is controversial. We investigated its biological activity in collagen-induced arthritis using the first known viable and fertile S100a8-deficient (S100a8-/-) mouse. Although comparable to the wild type (WT) in terms of lymphocyte distribution in blood and in the primary and secondary lymphoid organs, S100a8-/- mice had increased numbers of neutrophils, monocytes and dendritic cells in the blood and bone marrow, and these all expressed myeloid markers such as CD11b, Ly6G and CD86 more strongly. Granulocyte-macrophage common precursors were increased in S100a8-/- bone marrow and yielded greater numbers of macrophages and dendritic cells in culture. The animals also developed more severe arthritic disease leading to aggravated osteoclast activity and bone destruction. These findings were correlated with increased inflammatory cell infiltration and cytokine secretion in the paws. This study suggests that S100A8 is an anti-inflammatory DAMP that regulates myeloid cell differentiation, thereby mitigating the development of experimental arthritis.


Assuntos
Artrite Experimental/patologia , Calgranulina A/deficiência , Mielopoese , Animais , Artrite Experimental/diagnóstico por imagem , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Calgranulina A/metabolismo , Cartilagem/patologia , Diferenciação Celular , Células Dendríticas/metabolismo , Feminino , Deleção de Genes , Camundongos , Células Mieloides/patologia
5.
J Rheumatol ; 37(1): 87-90, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19955051

RESUMO

OBJECTIVE: Associations between the use of micronutrient supplements (MS) and disease activity, quality of life (QOL), and healthcare resource utilization were studied in a Canadian population of patients with systemic lupus erythematosus (SLE). METHODS: QOL was assessed by the Medical Outcomes Study 36-item Short Form. Healthcare resource utilization and disease activity/damage were determined. RESULTS: Of the 259 subjects studied, 53% were MS users and 34% used only calcium/vitamin D. MS users had a higher Systemic Lupus International Collaborating Clinics score and utilized more healthcare resources. Disease activity and QOL were similar between MS users and nonusers. CONCLUSION: MS are frequently used by patients with SLE and are not associated with concomitant benefit on QOL. MS users utilized more healthcare resources.


Assuntos
Suplementos Nutricionais , Nível de Saúde , Lúpus Eritematoso Sistêmico , Micronutrientes/uso terapêutico , Qualidade de Vida , Adolescente , Adulto , Idoso , Cálcio da Dieta/uso terapêutico , Canadá , Feminino , Recursos em Saúde/estatística & dados numéricos , Humanos , Lúpus Eritematoso Sistêmico/dietoterapia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Vitamina D/uso terapêutico , Adulto Jovem
6.
Med Decis Making ; 27(2): 138-50, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17409364

RESUMO

BACKGROUND: Individuals' valuation of changes in health states in monetary terms have been measured by examining changes in the direct and indirect costs of disease and by the willingness-to-pay (WTP) methodology. METHODS: In 2002, a 2-part study was conducted in Quebec. In one part of the study, 121 rheumatoid arthritis (RA) patients from the McGill University Health Centre were mailed the Stanford Cost Assessment Questionnaire, which enabled the elicitation of direct costs and indirect costs, according to the friction cost and the human capital methods. The other part was a phone survey conducted in a representative sample of the general population and in the same sample of patients, aiming to elicit the societal WTP for a complete cure of RA in the context of 2 different scenarios: a public coverage or private insurance. These estimates were then compared. RESULTS: Estimates of the cost of illness of RA ranged from 11,717 to 28,498 Canadian Dollars (CAD) depending on the method. These estimates are higher than those previously published in Canada from the 1990s, which is partly due to the recent and costly biological therapies and to a change in the measurement of productivity losses. These estimates are somewhat lower than the societal WTP elicited from the WTP survey, that is, 26,717 and 36,817 CAD per RA case, depending on the public or private health insurance context in which the cure would be available. CONCLUSION: Given that neither method is ideal, data from both methods would provide an important sensitivity analysis when monetary estimates of health state changes are required.


Assuntos
Artrite Reumatoide/economia , Efeitos Psicossociais da Doença , Adulto , Idoso , Antirreumáticos/economia , Artrite Reumatoide/tratamento farmacológico , Canadá , Eficiência Organizacional , Feminino , Financiamento Pessoal , Humanos , Seguro Saúde/economia , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/economia , Inquéritos e Questionários
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