MUCIGAN

IgA nephropathy (IgAN), one of the most common kidney diseases worldwide, is associated with microbial infections at mucosal sites and represents a major cause of renal failure. Its pathogenesis involves IgA1 complexes containing degalactosylated IgA1 (Gd-IgA1), autoantibodies against IgA1, and soluble IgA Fc receptor (sCD89), which are deposited in the renal mesangium. However, the origin of this abnormal IgA and the trigger for IgA immune complex formation is not clear. The IgA system is very different between humans and mice. In humans, two types of IgA are present. They differ in the hinge region: IgA1 has a longer and more heavily glycosylated hinge region compared to IgA2. As there is no homologue for human CD89 and only one type of IgA in the mouse, we previously developed humanized mice expressing both human IgA1 and CD89 (alpha1KI-CD89 transgenic (Tg) mice) as a model of IgAN. These mice spontaneously develop IgA1 mesangial deposits associated with the production of IgA1-sCD89 complexes. Moreover, IgA is differentially distributed between the systemic and mucosal immune system, and plays a key role in mucosal protection, notably secretory IgA (SIgA). In germ-free mice, the production of IgA is very low and the presence of a microbiota induces the production of mucosal SIgA. Reciprocally, IgA secretion limits the expansion of particular bacteria and regulates the microbial composition while, in turn, bacteria are capable of degrading SIgA, including removal of the secretory-component. Moreover, an intestinal microbiota dysbiosis was found in Italian IgAN patients. Recent GWAS data showed that genes involved in intestinal immunity, notably CARD9 and defensins, are linked to IgAN. Our preliminary data show that IgAN patient microbiota is associated with increased proportions of bacterial genera such as Alistipes and Ruminococcus (Firmicutes), Victivallis (Lentisphaerae), Akkermansia (Verrucomicrobia) and Bilophila (Deltaproteobacteria) as compared to control patients with other chronic kidney diseases (CKD). Moreover, faecal levels of Akkermansia muciniphilia correlated significantly with circulating degalactosylated IgA1 levels in IgAN patients. These results suggest a link between microbiota dysbiosis and IgAN. To further understand the role of the microbiota in IgAN we took advantage of our humanized mouse model, the alpha1KICD89Tg mice. Treatment of 12 w-old alpha1KICD89Tg mice with an antibiotic cocktail prevented the disease by abolishing proteinuria and decreasing mesangial IgA1 deposits, but not affecting serum IgA1 levels. In vitro results show that A. muciniphila promotes IgA1 degalactosylation inducing Gd-IgA1 retrotranscytosis by epithelial cells. In addition, alpha-defensin-6 levels are decreased in the stools of patients. In vitro results reveal that A. muciniphila is sensitive to this defensin opening a new therapeutic aproach. In addition, additional experiments have shown that CARD9 is involved in the activation of CD89. These results highlight the important role of the microbiota, defensins and CARD9 in disease development as well as pointing towards a possible origin of nephrotoxic IgA1 from mucosal sites. Our aim is to explore the relationship between the intestinal microbiota, IgA, CD89 and CARD9 using our humanized mouse model and samples from patients. Our tasks are: 1/ To characterize the intestinal microbiota in IgAN patients and in mice 2/ To define the role of mucin-degrading bacteria in IgAN pathogenesis 3/ To characterize the role of CARD9 and CD89 in microbiota dysbiosis during IgAN development 4/ To develop new therapeutic tools in alpha1KICD89Tg mice.