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Dysregulated IL-1ß-GM-CSF Axis in Acute Rheumatic Fever That Is Limited by Hydroxychloroquine.
Kim, Man Lyang; Martin, William J; Minigo, Gabriela; Keeble, Joanne L; Garnham, Alexandra L; Pacini, Guido; Smyth, Gordon K; Speed, Terence P; Carapetis, Jonathan; Wicks, Ian P.
Afiliação
  • Kim ML; Divisions of Inflammation (M.L.K., W.J.M., J.L.K., I.P.W.), Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Martin WJ; Medical Biology (M.L.K., W.J.M., J.L.K., A.L.G., I.P.W.), University of Melbourne, Parkville, Victoria, Australia.
  • Minigo G; Divisions of Inflammation (M.L.K., W.J.M., J.L.K., I.P.W.), Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Keeble JL; Medical Biology (M.L.K., W.J.M., J.L.K., A.L.G., I.P.W.), University of Melbourne, Parkville, Victoria, Australia.
  • Garnham AL; Menzies School of Health Research and Charles Darwin University, Casuarina, Northern Territory, Australia (G.M.).
  • Pacini G; Divisions of Inflammation (M.L.K., W.J.M., J.L.K., I.P.W.), Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Smyth GK; Medical Biology (M.L.K., W.J.M., J.L.K., A.L.G., I.P.W.), University of Melbourne, Parkville, Victoria, Australia.
  • Speed TP; Bioinformatics (A.L.G., G.P., G.K.S., T.P.S.), Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Carapetis J; Medical Biology (M.L.K., W.J.M., J.L.K., A.L.G., I.P.W.), University of Melbourne, Parkville, Victoria, Australia.
  • Wicks IP; Bioinformatics (A.L.G., G.P., G.K.S., T.P.S.), Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Circulation ; 138(23): 2648-2661, 2018 12 04.
Article em En | MEDLINE | ID: mdl-30571257
BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease are autoimmune consequences of group A streptococcus infection and remain major causes of cardiovascular morbidity and mortality around the world. Improved treatment has been stymied by gaps in understanding key steps in the immunopathogenesis of ARF and rheumatic heart disease. This study aimed to identify (1) effector T cell cytokine(s) that might be dysregulated in the autoimmune response of patients with ARF by group A streptococcus, and (2) an immunomodulatory agent that suppresses this response and could be clinically translatable to high-risk patients with ARF. METHODS: The immune response to group A streptococcus was analyzed in peripheral blood mononuclear cells from an Australian Aboriginal ARF cohort by a combination of multiplex cytokine array, flow cytometric analysis, and global gene expression analysis by RNA sequencing. The immunomodulatory drug hydroxychloroquine was tested for effects on this response. RESULTS: We found a dysregulated interleukin-1ß-granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine axis in ARF peripheral blood mononuclear cells exposed to group A streptococcus in vitro, whereby persistent interleukin-1ß production is coupled to overproduction of GM-CSF and selective expansion of CXCR3+CCR4-CCR6- CD4 T cells. CXCR3+CCR4-CCR6- CD4 T cells are the major source of GM-CSF in human CD4 T cells and CXCL10, a CXCR3 ligand and potent T helper 1 chemoattractant, was elevated in sera from patients with ARF. GM-CSF has recently emerged as a key T cell-derived effector cytokine in numerous autoimmune diseases, including myocarditis, and the production of CXCL10 may explain selective trafficking of these cells to the heart. We provide evidence that interleukin-1ß amplifies the expansion of GM-CSF-expressing CD4 T cells, which is effectively suppressed by hydroxychloroquine. RNA sequencing showed shifts in gene expression profiles and differentially expressed genes in peripheral blood mononuclear cells derived from patients at different clinical stages of ARF. CONCLUSIONS: Given the safety profile of hydroxychloroquine and its clinical pedigree in treating autoimmune diseases such as rheumatoid arthritis, where GM-CSF plays a pivotal role, we propose that hydroxychloroquine could be repurposed to reduce the risk of rheumatic heart disease after ARF.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Febre Reumática / Regulação da Expressão Gênica / Fator Estimulador de Colônias de Granulócitos e Macrófagos / Interleucina-1beta / Hidroxicloroquina Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Child / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Febre Reumática / Regulação da Expressão Gênica / Fator Estimulador de Colônias de Granulócitos e Macrófagos / Interleucina-1beta / Hidroxicloroquina Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Child / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article