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Marginal zone B cells produce 'natural' atheroprotective IgM antibodies in a T cell-dependent manner.
Harrison, James; Newland, Stephen A; Jiang, Wei; Giakomidi, Despoina; Zhao, Xiaohui; Clement, Marc; Masters, Leanne; Corovic, Andrej; Zhang, Xian; Drago, Fabrizio; Ma, Marcella; Ozsvar Kozma, Maria; Yasin, Froher; Saady, Yuta; Kothari, Hema; Zhao, Tian X; Shi, Guo-Ping; McNamara, Coleen A; Binder, Christoph J; Sage, Andrew P; Tarkin, Jason M; Mallat, Ziad; Nus, Meritxell.
Afiliación
  • Harrison J; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Newland SA; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Jiang W; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Giakomidi D; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Zhao X; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Clement M; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Masters L; Laboratory for Vascular Translational Sciences (LVTS), Université de Paris, INSERM U1148, Paris, France.
  • Corovic A; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Zhang X; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Drago F; Department of Medicine, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ma M; Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
  • Ozsvar Kozma M; Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, UK.
  • Yasin F; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • Saady Y; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Kothari H; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Zhao TX; Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
  • Shi GP; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • McNamara CA; Department of Medicine, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA.
  • Binder CJ; Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
  • Sage AP; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • Tarkin JM; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Mallat Z; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • Nus M; Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Cardiovasc Res ; 120(3): 318-328, 2024 03 14.
Article en En | MEDLINE | ID: mdl-38381113
ABSTRACT

AIMS:

The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis. METHODS AND

RESULTS:

We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh.

CONCLUSION:

Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-18 / Aterosclerosis Límite: Animals / Humans Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-18 / Aterosclerosis Límite: Animals / Humans Idioma: En Revista: Cardiovasc Res Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Reino Unido