Abstract
: BackgroundIgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1–sCD89, and mIgG–hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1–sCD89 and mIgG–hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.
Highlights
Gd-IgA1-CD89 interaction induces the release of the extracellular portion of CD89 leading to the formation of circulating CD89-IgA immune complexes, which bind to CD71 leading to IgA1 deposits and mesangial cells proliferation in IgAN patients [6]
Mice treated with rifaximin for two weeks had a reduction in proteinuria compared to the mice treated with just the vehicle which showed an increase in proteinuria
It has been shown that epithelial-derived BAFF is the major modulator of B cell development and it has a key role in IgA class switching and plasma cell survival in the mucose-associated lymphoid tissue (MALT) [14,15]
Summary
Glycosylated IgA1 (Gd-IgA1) has a central role in the multi-hit process in IgAN patients [4]. It has been demonstrated that there are two IgA receptors involved in IgAN pathogenicity: the FcαRI (CD89), expressed by blood myeloid cells and the transferrin receptor (CD71), expressed by mesangial cells [5]. Gd-IgA1-CD89 interaction induces the release of the extracellular portion of CD89 (soluble form of CD89) leading to the formation of circulating CD89-IgA immune complexes, which bind to CD71 leading to IgA1 deposits and mesangial cells proliferation in IgAN patients [6]. In patients with progressive disease, the IgA-CD89 complex has a role in the pathogenesis of IgAN and it seems to be positively correlated with proteinuria, microalbuminuria, and with some features of the Oxford score (endocapillary and extracapillary proliferation) [7]
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