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Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN- by peripheral blood mononuclear cells from patients with type 1 diabetes

Laboratory of Virology, UPRES EA ‘Viral Pathogenesis of Diabetes Type 1’, University Hospital, and University Lille 2, 59037 Lille, France¹
SEDAC Therapeutics, IBL-CNRS, 59021 Lille, France²
Pediatric Endocrine Unit, University Hospital, Lille, France³
Department of Medicine, Endocrinology and Metabolism, Charlon Hospital, Henin-Beaumont, France⁴
Department of Endocrinology and Metabolism, University Hospital, Lille, France⁵
Department of Pediatrics, Saint-Antoine Hospital, Catholic University, Lille, France⁶

Author for correspondence: Didier Hober. Correspondence address: Laboratoire de Virologie, Bât. Paul Boulanger, Hôpital Albert Calmette, Centre Hospitalier Régional et Universitaire (CHRU), 59037 Lille Cedex, France. Fax +33 3 20 44 52 81. e-mail dhober{at}chru-lille.fr

Increased levels of IFN- have been found in patients with type 1 diabetes who have detectable levels of coxsackievirus B4 (CVB4) RNA in their blood. The IFN--inducing activity of CVB4 in vitro is weak but can be enhanced by human IgGs. Therefore, it was investigated in vitro whether a preferential IFN- response of peripheral blood mononuclear cells (PBMCs) to CVB4 exists in patients with type 1 diabetes (n=56) compared with healthy subjects (n=20) and whether antibodies play a role. In patients, the levels of IFN- obtained after stimulation by PBMCs with CVB4 were higher (P=0·008), an individual IFN- response by PBMCs to CVB4 was more frequent (P=0·0004) and increased levels of IFN- were observed in CVB4-infected whole blood cultures. The IFN--inducing activity of patients plasma and IgGs mixed with CVB4 and then added to PBMCs was high in comparison with healthy subjects (P<0·001) and was inhibited by preincubating the cells with anti-FcRII, anti-FcRIII and anti-CAR (coxsackievirus and adenovirus receptor) antibodies. The strong IFN- responsiveness of PBMCs to CVB4 suggested that IgGs bound to the cell surface might play a role. A short 56 °C incubation of PBMCs from patients responsive to CVB4 generated supernatants, which, when added to cells, exhibited IFN--enhancing activity in combination with CVB4, whereas those of controls did not. Specific antibodies for FcRI, FcRII and CAR inhibited this activity. These studies demonstrate that CVB4, through interactions with circulating and/or cell-bound IgGs, can strongly induce the production of IFN- by PBMCs from patients with type 1 diabetes.

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