Gluten exacerbates IgA nephropathy in humanized mice through gliadin–CD89 interaction

Abstract

IgA1 complexes containing deglycosylated IgA1, IgG autoantibodies, and a soluble form of the IgA receptor (sCD89), are hallmarks of IgA nephropathy (IgAN). Food antigens, notably gluten, are associated with increased mucosal response and IgAN onset, but their implication in the pathology remains unknown. Here, an IgAN mouse model expressing human IgA1 and CD89 was used to examine the role of gluten in IgAN. Mice were given a gluten-free diet for three generations to produce gluten sensitivity, and then challenged for 30 days with a gluten diet. A gluten-free diet resulted in a decrease of mesangial IgA1 deposits, transferrin 1 receptor, and transglutaminase 2 expression, as well as hematuria. Mice on a gluten-free diet lacked IgA1-sCD89 complexes in serum and kidney eluates. Disease severity depended on gluten and CD89, as shown by reappearance of IgAN features in mice on a gluten diet and by direct binding of the gluten-subcomponent gliadin to sCD89. A gluten diet exacerbated intestinal IgA1 secretion, inflammation, and villous atrophy, and increased serum IgA1 anti-gliadin antibodies, which correlated with proteinuria in mice and patients. Moreover, early treatment of humanized mice with a gluten-free diet prevented mesangial IgA1 deposits and hematuria. Thus, gliadin-CD89 interaction may aggravate IgAN development through induction of IgA1-sCD89 complex formation and a mucosal immune response. Hence, early-stage treatment with a gluten-free diet could be beneficial to prevent disease.

A comparative study of expression of Fc receptors in relation to the autoantibody-mediated immune response and neutrophil elastase expression in autoimmune blistering dermatoses

“…Thus, the pathogenic association of DH with GSE is probably mediated by CD89. Our results maybeinlinewiththethesisofPapistaet al [22], whorevealedthatglutenexacerbatesIgAnephropathythroughgliadin-CD89interaction.Papistaet al [22] demonstrated that mice on a gluten-free diet lacked IgA1-CD89 complexes, and disease severi-tydependedonglutenandCD89.Itisknownthat aglutendietexacerbatescutaneousIgAdeposition, inflammation,andincreasedserumanti-npGandanti-tTG IgA antibodies. Thus, similarly to DH, the direct binding of the gluten-subcomponent gliadin to CD89 may aggravate DH development through inductionpathologicalimmuneresponse.…”

Gluten, Transglutaminase, Celiac Disease and IgA Nephropathy

“…At the opposite way, a gluten free diet during three generations in α1KI-CD89Tg mice, a humanized model of IgAN, resulted in a massive decrease of IgA1 deposits in kidney associated to the diminution of inflammation and haematuria [32]. These results were strong and reproducible (n=20 animals, 100% of animals).…”

“…Moreover, gliadin binds also directly to mesangial cells in vitro [48] increasing polymeric IgA Moreover, gliadin directly interacts with CD89 and participates in the formation of IgA-sCD89 complexes. Purified gliadin bound to recombinant sCD89 in a dose-dependent way, as shown by ELISA and surface acoustic wave (Figure) [32]. …”

“…Due to recent expanding knowledge on the two entities, on the central role played by nutrients, microbiome, IgA metabolism and functions and the mucosal and systemic immune systems [1][2][3][4]17,[28][29][30], cross-talks between the two diseases, were discovered [16,18,[29][30][31][32][33]. Table 1 summarizes the epidemiological, clinical and pathophysiological aspects of CD and IgAN.…”

“…The role of gluten in IgAN was mainly assessed by in vitro studies with the direct interaction of gliadin and IgA partners and mesangial cells. We studied in vivo the effects of a gluten free diet using a humanized mouse model for IgAN, the α1KI-CD89Tg mice [32], which expressed both human IgA1 and CD89 presenting some features of IgAN.…”