Genetic potential for an acute inflammatory response in IgA glomerulonephritis in mice

Abstract

Mice selected on the basis of an acute inflammatory response (AIR) can provide information about the immunopathological mechanisms of glomerulonephritis. We studied the differences between mice selected for a maximal AIR (AIRmax that attract more polymorphonuclear cells to the site of injury) or a minimal AIR (AIRmin that attract more mononuclear cells) in an experimental model of IgA nephropathy in order to investigate the effect of genetic background on glomerular disease progression and the participation of the monocyte chemoattractant protein-1 (MCP-1) chemokine. IgA nephropathy was induced by intraperitoneal ovalbumin injection and bile duct ligation in AIRmax and AIRmin mice. Histological changes, urinary protein/creatinine ratio, serum IgA levels, immunofluorescence for IgA, IgG and complement C3 fraction, immunohistochemistry for macrophages and MCP-1, and MCP-1 levels in macerated kidney were determined. Mesangial IgA deposition was seen only in AIRmin mice, which presented more renal lesions. Increased serum IgA levels (1.5 ± 0.4 vs 0.3 ± 0.1 mg/mL, P < 0.001), high glomerular MCP-1 expression and decreased monocyte/macrophage infiltration in the interstitial area (0.3 ± 0.3 vs 1.1 ± 0.9 macrophages/field, P < 0.05) were detected in AIRmin mice compared to AIRmax mice. No glomerular monocyte/macrophage infiltration was detected in either strain. In spite of the absence of IgA deposition, AIRmax mice presented discrete or absent mesangial proliferation. The study showed that there are differences between mice selected for AIRmax and AIRmin with respect to serum IgA levels, histological damage and MCP-1 chemokine production after ovalbumin injection in combination with bile duct ligation.

Prospects and Perspectives on IgA Nephropathy from Animal Models

“…This diversity lends credibility to the principle that mucosal immunization by a wide range of antigens favors an IgA response in mammals generally. In other rodent systems, parenteral vaccination was supplemented by use of mucosal boosting, polarizing immunization or stimulation by superantigens [36,38,48], and a few models leveraged genetic predisposition to favor Th2 responses and/or IgA production [33,[49][50][51].…”

“…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].…”

“…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.…”

“…Given the importance of the liver in clearance of IgA immune complexes from the circulation and in cognizance of the occurrence of secondary IgAN in patients with cirrhosis and other hepatobiliary disease, several models of IgAN secondary to liver injury and/or cholestasis were developed in rats [6,7,9,61,117,[119][120][121][122][123] and mice [8,50]. Severe hepatocellular injury induced by carbon tetrachloride progressed to cirrhosis; affected rats developed IgAN characterized by proteinuria and hematuria, and associated with increased levels of circulating immune complexes and serum IgA [6,7].…”

“…Modulators include mucosal boosting with antigen [33, 38, 48], superantigens [36, 47, 49, 85] or stimuli of innate immunity [31,32,34,49,68]. Genetic or transgenic proclivity to dysregulation of B cells by T cells [50][51][52]75] and induced alterations in T cell cytokine profiles [33,38,77] are also recognized. Often, immune dysregulation arises from unknown mechanisms ascribed to T cells largely by intuitive guesswork [10, 30, 35-37, 44-46, 53-56, 59-61, 69-72, 81].…”