Experimental Glomerulonephritis following Successive Inoculation of Five Different Serotypes of Group B Coxsackieviruses in Mice

Abstract

The purpose of the present investigation is to study renal injury by monthly viral inoculation into mice, using several different types of strains of enterovirus. A group of mice were inoculated intravenously with five different serotypes of group B coxsackieviruses (CB1 to CB5), once a month from 1 to 5 months of age and sacrificed monthly from 6 to 12 months of age. Mesangial proliferation and PAS-positive mesangial deposits in light microscopy and electron-dense deposits in electron microscopy were observed at maximum from 6 to 7 months of age. The CB viral RNA detected by in situ hybridization were observed in the mesangial lesion. By immunofluorescence findings, positive findings for IgG and IgA were observed. These results demonstrated that intermittent intravenous inoculation with different serotypes CB in mice provoked pathological changes closely resembling those in human proliferative glomerulonephritis. Moreover, the detection of CB viral RNA in glomerular lesions suggested that renal injury was induced by immune complexes correlated with CB viral replication in renal tissues.

Detection of enteroviruses in renal biopsies from patients with immunoglobulin A nephropathy

“…They have also been reported to be etiological agents in some renal diseases [7,8,9,10]. For example, experimental nephritis induced by CB4 was first described by Sun et al [11], and subsequent reports indicated relationships of CB4 with renal disease in humans [7,8] and experimental animals [12,13,14]. We recently demonstrated glomerular lesions with IgA deposits induced by intraperitoneal inoculations of CB4 in mice [13].…”

“…By using pure cultures of human glomerular and tubular cells, Conaldi et al demonstrated that the infection of six CBs led to cytolysis in proximal tubular epithelial cells and glomerular podocytes [20]. Previously, we reported that CB4 caused pathological changes in experimentally infected mouse kidney [12,13,14]. We recently observed lesions similar to those of human IgA nephropathy in mice intravenously inoculated with CB4 once a month from 1 to 5 months of age, and we detected CB4 viral RNA in the mesangial lesions, using in situ hybridization [13].…”

“…There have been many reports on the relationship between viral infection and renal injury [1,2,3,4,5,7,8,9,10,11,12,13,14]. Clinically, it has been noted that viral infection often provokes transient proteinuria, hematuria, and renal dysfunction in patients who develop IgAN.…”

Prospects and Perspectives on IgA Nephropathy from Animal Models

“…In many of these systems, genetic proclivity for altered systemic immunity is recognized and likely explains the predominance of IgAN [49][50][51]. However, in some instances, the known parameters of the immune response would not necessarily predict predilection for a strong IgA response or alterations in immunoregulation; nonetheless, strong serum IgA responses and IgA predominance or co-dominance in a subsequent glomerulonephritis is observed [68][69][70][71][72]. The antigens in these systems are bacterial or viral pathogens that might invoke innate immunity, which modulates the adaptive antibody response through mechanisms that are currently being elucidated (see 'T Cell Regulation and Cytokine Polarity' , below).…”

“…Indeed, co-stimulation with 'superantigen' , vaccination of selected strains of rodents predisposed towards an immune response favoring IgA production and/or Th2 cytokine profiles, or immunomodulation by innate responses can also lead to IgAN [33,36,[49][50][51][68][69][70][71][72]. In addition, very intense cognate responses can drive immune responses with specificity for elements that are not a component of the intense stimulus, which is especially true for simpler antigens, those that resemble commensals or pathogens, or those that are prevalent in the environment in which the host survives.…”