Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN-alpha by peripheral blood mononuclear cells from patients with type 1 diabetes.
Increased levels of IFN-alpha have been found in patients with type 1 diabetes who have detectable levels of coxsackievirus B4 (CVB4) RNA in their blood. The IFN-alpha-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-alpha 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-alpha obtained after stimulation by PBMCs with CVB4 were higher (P=0.008), an individual IFN-alpha response by PBMCs to CVB4 was more frequent (P=0.0004) and increased levels of IFN-alpha were observed in CVB4-infected whole blood cultures. The IFN-alpha-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-FcgammaRII, anti-FcgammaRIII and anti-CAR (coxsackievirus and adenovirus receptor) antibodies. The strong IFN-alpha responsiveness of PBMCs to CVB4 suggested that IgGs bound to the cell surface might play a role. A short 56 degrees C incubation of PBMCs from patients responsive to CVB4 generated supernatants, which, when added to cells, exhibited IFN-alpha-enhancing activity in combination with CVB4, whereas those of controls did not. Specific antibodies for FcgammaRI, FcgammaRII 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-alpha by PBMCs from patients with type 1 diabetes.
Hober
Didier
D
Laboratory of Virology, UPRES EA 'Viral Pathogenesis of Diabetes Type 1', University Hospital, and University Lille 2, 59037 Lille, France1.
Chehadeh
Wassim
W
SEDAC Therapeutics, IBL-CNRS, 59021 Lille, France2.|Laboratory of Virology, UPRES EA 'Viral Pathogenesis of Diabetes Type 1', University Hospital, and University Lille 2, 59037 Lille, France1.
Weill
Jacques
J
Pediatric Endocrine Unit, University Hospital, Lille, France3.
Hober
Christine
C
Department of Medicine, Endocrinology and Metabolism, Charlon Hospital, Henin-Beaumont, France4.
Vantyghem
Marie-Christine
MC
Department of Endocrinology and Metabolism, University Hospital, Lille, France5.
Gronnier
Pascale
P
Department of Pediatrics, Saint-Antoine Hospital, Catholic University, Lille, France6.
Wattré
Pierre
P
Laboratory of Virology, UPRES EA 'Viral Pathogenesis of Diabetes Type 1', University Hospital, and University Lille 2, 59037 Lille, France1.
D000256:Adenoviridae / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000032:analysis / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D004770:Enterovirus / Q000472:pathogenicity*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D017452:Receptors, IgG / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D016898:Interferon-alpha; D017452:Receptors, IgG; D011991:Receptors, Virus