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

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. 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. Immunoglobulin A (IgA) nephropathy (IgAN) is a major cause of end-stage renal disease and is characterized by pathological deposition of IgA1 complexes in the glomerular mesangium, causing a wide range of pathological lesions going from isolated mesangial matrix expansion to proliferative glomerulonephritis and clinical symptoms of renal injury, such as hematuria and proteinuria, as well as renal failure in about one-third of patients.1.Berger J. Hinglais N. Les dépôts intercapillaires d'IgA-IgG.J Urol Néphol. 1968; 74: 694-695PubMed Google Scholar,2.Galla J.H. IgA nephropathy.Kidney Int. 1995; 47: 377-387Abstract Full Text PDF PubMed Scopus (351) Google Scholar Macromolecular polymeric IgA1-containing complexes have been described in the serum of IgAN patients, but their origin and nature remain poorly understood.3.Novak J. Julian B.A. Tomana M. et al.IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy.Semin Nephrol. 2008; 28: 78-87Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 4.Valentijn R.M. Radl J. Haaijman J.J. et al.Circulating and mesangial secretory component-binding IgA-1 in primary IgA nephropathy.Kidney Int. 1984; 26: 760-766Abstract Full Text PDF PubMed Scopus (108) Google Scholar, 5.Barratt J. Eitner F. Feehally J. et al.Immune complex formation in IgA nephropathy: a case of the 'right' antibodies in the 'wrong' place at the 'wrong' time?.Nephrol Dial Transplant. 2009; 24: 3620-3623Crossref PubMed Scopus (39) Google Scholar Patients’ IgA1 antibodies present hypogalactosylation, which leads to the formation of complexes with IgG anti-IgA1 antibodies.6.Tanaka M. Seki G. Someya T. et al.Aberrantly glycosylated IgA1 as a factor in the pathogenesis of IgA nephropathy.Clin Dev Immunol. 2011; 2011: 470803Crossref PubMed Scopus (22) Google Scholar These IgA1 antibodies can also form complexes with the soluble(s) form of the myeloid IgA receptor FcαRI or CD89.7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar, 8.Launay P. Grossetete B. Arcos-Fajardo M. et al.Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy. Evidence for pathogenic soluble receptor-IgA complexes in patients and CD89 transgenic mice.J Exp Med. 2000; 191: 1999-2009Crossref PubMed Scopus (209) Google Scholar, 9.Vuong M.T. Hahn-Zoric M. Lundberg S. et al.Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy.Kidney Int. 2010; 78: 1281-1287Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Both types of complexes have been recently shown to be associated with disease progression.9.Vuong M.T. Hahn-Zoric M. Lundberg S. et al.Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy.Kidney Int. 2010; 78: 1281-1287Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,10.Berthoux F. Suzuki H. Thibaudin L. et al.Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy.J Am Soc Nephrol. 2012; 23: 1579-1587Crossref PubMed Scopus (178) Google Scholar However, in contrast with the increased circulating levels of IgA1–IgG complexes observed in severe IgAN patients,10.Berthoux F. Suzuki H. Thibaudin L. et al.Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy.J Am Soc Nephrol. 2012; 23: 1579-1587Crossref PubMed Scopus (178) Google Scholar levels of IgA–sCD89 complexes were decreased in these patients,9.Vuong M.T. Hahn-Zoric M. Lundberg S. et al.Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy.Kidney Int. 2010; 78: 1281-1287Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar suggesting that CD89-containing complexes could be selectively trapped by the mesangium aggravating the disease. The pathogenic role of sCD89 was recently demonstrated using a double transgenic mouse model expressing both human CD89 and human IgA1 (α1KI-CD89Tg mice).7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar Circulating IgA1–sCD89 complexes in these mice were shown to induce mesangial deposits, hematuria, and proteinuria along with increased serum creatinine compared with mice expressing human IgA1 alone.7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar Moreover, sCD89 was detected in biopsies of patients with IgAN.7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar This model also revealed that pathogenesis involves at least four elements: the interaction of IgA1–sCD89 complexes with another IgA1 receptor, the transferrin receptor 1 (TfR1/CD71), and with the transglutaminase 2 (TGase2), a cross-linking enzyme that may have a role in amplification ofin situ pathogenic complex deposition in the mesangium.7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar,11.Daha M.R. van Kooten C. Deposition of IgA in primary IgA nephropathy: it takes at least four to tango.Nephrol Dial Transplant. 2013; 28: 794-797Crossref PubMed Scopus (15) Google Scholar Antigens that elicit the abnormal IgA immune response that may lead to IgA1 immune complex formation and mesangial deposition are only partially described. Among environmental and infectious antigens, dietary components and especially gliadin, a constituent of the wheat protein gluten, have been proposed to have a role in the onset of IgAN.12.Coppo R. Mazzucco G. Martina G. et al.Gluten-induced experimental IgA glomerulopathy.Lab Invest. 1989; 60: 499-506PubMed Google Scholar, 13.Coppo R. Amore A. Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy.J Am Soc Nephrol. 1992; 2: S173-S180PubMed Google Scholar, 14.Papista C. Berthelot L. Monteiro R.C. Dysfunctions of the IgA system: a common link between intestinal and renal diseases.Cell Mol Immunol. 2011; 8: 126-134Crossref PubMed Scopus (28) Google Scholar, 15.Smerud H.K. Fellstrom B. Hallgren R. et al.Gluten sensitivity in patients with IgA nephropathy.Nephrol Dial Transplant. 2009; 24: 2476-2481Crossref PubMed Scopus (48) Google Scholar, 16.Coppo R. The intestine-renal connection in IgA nephropathy.Nephrol Dial Transplant. 2014; 0: 1-7Google Scholar Coppoet al.12.Coppo R. Mazzucco G. Martina G. et al.Gluten-induced experimental IgA glomerulopathy.Lab Invest. 1989; 60: 499-506PubMed Google Scholar have primarily shown that gliadin induces mesangial IgA deposits in BALB/c mice, and that IgA anti-gliadin antibodies (AGA), associated with elevated IgA levels, are increased in the serum of IgAN patients.13.Coppo R. Amore A. Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy.J Am Soc Nephrol. 1992; 2: S173-S180PubMed Google Scholar Furthermore, the prevalence of celiac disease (CD), a gluten-induced enteropathy linked to AGA and anti-TGase2 antibody generation, increases from 0.5 to 1% in the general population to 4% in IgAN patients.13.Coppo R. Amore A. Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy.J Am Soc Nephrol. 1992; 2: S173-S180PubMed Google Scholar Gliadin was also described to favor polymeric IgA interactions with the mesangial cells through ‘lectinic’ receptors.17.Amore A. Emancipator S.N. Roccatello D. et al.Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.Am J Kidney Dis. 1994; 23: 290-301Abstract Full Text PDF PubMed Scopus (28) Google Scholar Other food-derived antigens (bovine serum albumin, soy, casein, and β-lactoglobulin) have also been identified in serum and/or in the mesangium of a subgroup of IgAN patients.15.Smerud H.K. Fellstrom B. Hallgren R. et al.Gluten sensitivity in patients with IgA nephropathy.Nephrol Dial Transplant. 2009; 24: 2476-2481Crossref PubMed Scopus (48) Google Scholar, 18.Sato M. Kojima H. Takayama K. et al.Glomerular deposition of food antigens in IgA nephropathy.Clin Exp Immunol. 1988; 73: 295-299PubMed Google Scholar, 19.Yap H.K. Sakai R.S. Woo K.T. et al.Detection of bovine serum albumin in the circulating IgA immune complexes of patients with IgA nephropathy.Clin Immunol Immunopathol. 1987; 43: 395-402Crossref PubMed Scopus (18) Google Scholar The role of food antigens in IgAN development remains, however, unknown. Here, we examined the implication of gluten in experimental IgAN by submitting α1KI-CD89Tg mice to a gluten-free diet during three generations and challenging them during 30 days with gluten-containing diet. Moreover, we treated α1KI-CD89Tg mice on a standard gluten-containing diet with a gluten-free diet starting from different stages of disease development. The data revealed that gliadin interaction with CD89 may have a deleterious role in IgAN development. To elucidate the implication of gluten in IgAN development, α1KI-CD89Tg mice, bred in a normal gluten-containing diet, were sensitized to gluten (G- mice), as described previously.20.Papista C. Gerakopoulos V. Kourelis A. et al.Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics.Lab Invest. 2012; 92: 625-635Crossref PubMed Scopus (57) Google Scholar Diet devoid of gluten in α1KI-CD89Tg mice markedly decreased IgA1 deposits in the mesangium (Figure 1, G- mice). This decrease was gluten specific, as shown by its reintroduction in the diet of gluten-sensitized mice being followed by the reappearance of mesangial IgA1 deposits (Figure 1, G+ mice). Diminution of IgA1 deposits was associated with downregulation of mesangial TGase2 and TfR1 expression in kidneys of α1KI-CD89Tg G- mice (Figure 1). Gluten-free diet also resulted in the clearance of C3 glomerular deposits, as well as CD11b+ and CD3+ cell infiltrates, both hallmarks of inflammatory reactions, in glomerular and interstitial areas of G- mice (Figure 2a). α1KI-CD89Tg G+ mice presented the same levels of C3 deposits and cell infiltrates as α1KI-CD89Tg mice, indicating that gluten could be responsible for the local inflammation in kidneys of α1KI-CD89Tg mice (Figure 2a). Gluten removal also resulted in decreased mRNA levels for the IL-6 cytokine (Figure 2b) and in decreased levels of hematuria (Figure 2c), which were significantly enhanced after challenge with gluten in the diet of mice for 30 days (Figures 2b and c). Altogether, these results suggested that the food antigen gluten induces IgA1 immune deposits promoting kidney inflammation and altered function in a mouse model of IgAN. As circulating polymeric IgA1 complexes have been suggested to be the origin of mesangial IgA deposits leading to renal damage,3.Novak J. Julian B.A. Tomana M. et al.IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy.Semin Nephrol. 2008; 28: 78-87Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 4.Valentijn R.M. Radl J. Haaijman J.J. et al.Circulating and mesangial secretory component-binding IgA-1 in primary IgA nephropathy.Kidney Int. 1984; 26: 760-766Abstract Full Text PDF PubMed Scopus (108) Google Scholar, 5.Barratt J. Eitner F. Feehally J. et al.Immune complex formation in IgA nephropathy: a case of the 'right' antibodies in the 'wrong' place at the 'wrong' time?.Nephrol Dial Transplant. 2009; 24: 3620-3623Crossref PubMed Scopus (39) Google Scholar we next explored the implication of gluten in the generation of IgA1–sCD89 complexes in α1KI-CD89Tg mice sensitized to gluten. Gluten depletion from the diet completely abolished IgA1–sCD89 complex formation compared with α1KI-CD89Tg mice on a normal diet, which presented high-molecular-mass forms (>670 kDa) of the complexes, as detected in size-fractionated serum (fractions 6–10;Figures 3a and b). The implication of gluten in complex formation was confirmed by reintroduction of gluten (G+ mice) in the diet of α1KI-CD89Tg G- mice, which resulted in reappearance of IgA1–sCD89 complexes in the serum (Figures 3a and b). The decrease of IgA1–sCD89 complexes was not correlated with decreased IgA1 levels in the circulation (Figure 3c). In addition, surface expression of CD89 on blood monocytes was higher in α1KI-CD89Tg G- than in α1KI-CD89Tg mice (Figure 3d), suggesting that gluten may enhance the shedding of CD89 from the surface of monocytes–macrophages. Similar results were obtained with splenic macrophages (data not shown). Furthermore, the absence of gluten in the diet of α1KI-CD89Tg mice also diminished the deposition of IgA1–sCD89 complexes in the mesangium, as shown by enzyme-linked immunosorbent assay in kidney eluates from α1KI-CD89Tg G- compared with α1KI-CD89Tg G+ mice (Figure 3e). Collectively, these results showed that gluten has an important role in the formation of nephrotoxic IgA1–sCD89 complexes in experimental IgAN. As gliadin favors polymeric IgA interaction with mesangial cells17.Amore A. Emancipator S.N. Roccatello D. et al.Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.Am J Kidney Dis. 1994; 23: 290-301Abstract Full Text PDF PubMed Scopus (28) Google Scholar and sCD89 mediates IgAN development,7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar,11.Daha M.R. van Kooten C. Deposition of IgA in primary IgA nephropathy: it takes at least four to tango.Nephrol Dial Transplant. 2013; 28: 794-797Crossref PubMed Scopus (15) Google Scholar we investigated whether gliadin directly interacts with CD89 and participates in the formation of IgA–sCD89 complexes. Purified gliadin bound to recombinant sCD89 in a dose-dependent manner, but not to irrelevant proteins such as the human serum albumin and β-synuclein-his (Figures 4a and b; data not shown). This was confirmed by surface acoustic wave biosensor using immobilized sCD89 and purified gliadin as ligands (Sam 5 Blue instruments, data not shown). As shown by others,13.Coppo R. Amore A. Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy.J Am Soc Nephrol. 1992; 2: S173-S180PubMed Google Scholar gliadin also bound to IgA1 (anti-ovalbumin IgA1 mAb obtained from a hybridoma derived from α1KI mouse), as well as to normal human serum IgA (Supplementary Figure S1 online). Download .doc (4.54 MB) Help with doc files Supplementary Figures IgAN patients present significantly higher intestinal permeability,21.Kovacs T. Kun L. Schmelczer M. et al.Do intestinal hyperpermeability and the related food antigens play a role in the progression of IgA nephropathy? I. Study of intestinal permeability.Am J Nephrol. 1996; 16: 500-505Crossref PubMed Scopus (39) Google Scholar which can be associated with gastrointestinal inflammation.22.Rostoker G. Delchier J.C. Chaumette M.T. Increased intestinal intra-epithelial T lymphocytes in primary glomerulonephritis: a role of oral tolerance breakdown in the pathophysiology of human primary glomerulonephritides?.Nephrol Dial Transplant. 2001; 16: 513-517Crossref PubMed Scopus (33) Google Scholar It has been proposed that these abnormalities may result in the loss of the capacity for mucosal antigen exclusion and systemic absorption of antigens inducing immune responses. We therefore investigated the possible implication of alimentary antigens in eliciting the mucosal IgA immune response by examining the IgA1 expression in jejunal sections from α1KI-CD89Tg mice fed a gluten-free (G-) or gluten-containing (G+) diet. α1KI-CD89Tg mice presented more human IgA1+ cells in the lamina propria and in the crypts of the small intestine compared with G- mice (Figure 5a). Challenge of the G- mice with gluten induced a higher number of IgA1+ cells localized in Peyer’s patches and isolated lymphoid follicles (Figure 5a), indicating that gliadin may induce an increased IgA1 response in the intestine. Moreover, diet devoid of gluten markedly reduced the infiltration of F4-80+ macrophages and CD3+ T cells, both in the intestinal epithelium and in the lamina propria (four fold decrease,Figure 5b). G+ mice exhibited significantly increased macrophage and T-lymphocyte infiltration in the intestine. Furthermore, we observed that α1KI-CD89Tg mice presented histopathological features of villous atrophy and crypt hyperplasia, which were clearly improved when these mice were maintained on a gluten-free diet (Figure 5c). This was confirmed by morphometric evaluation of villus height/crypt depth ratio, showing that this ratio is higher in G- mice (Figure 5d). These abnormalities reappeared when a gluten-containing diet was provided to G- mice during 30 days (Figures 5c and d), revealing that gluten could affect the intestinal architecture. As elevated levels of salivary and serum secretory IgA have been described in patients with IgAN,23.Rostoker G. Terzidis H. Petitphar M. et al.Secretory IgA are elevated in both saliva and serum of patients with various types of primary glomerulonephritis.Clin Exp Immunol. 1992; 90: 305-311Crossref PubMed Scopus (20) Google Scholar,24.Oortwijn B.D. van der Boog P.J. Roos A. et al.A pathogenic role for secretory IgA in IgA nephropathy.Kidney Int. 2006; 69: 1131-1138Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar we next examined whether this altered mucosal IgA1 immune system observed in α1KI-CD89Tg mice could result in altered IgA1 antibody responses to gliadin. α1KI-CD89Tg mice contained IgA1 AGA in their serum in a CD89-dependent way, as the level of these antibodies was significantly decreased in α1KI mice (Figure 6a). Of note, mouse IgA1 AGA levels also correlated with proteinuria (Figure 6b). We then examined the presence of circulating IgA AGA in a group of 26 IgAN patients with mild proteinuria in comparison with healthy individuals. The demographic and clinical characteristics of the patients and controls are shown inSupplementary Table S1 online. IgAN patients exhibited increased IgA AGA levels (Figure 6c), which correlated with proteinuria (Figure 6d). Download .doc (.03 MB) Help with doc files Supplementary Table 1 Taken together, these results indicated that gluten may be implicated in the induction of gastrointestinal inflammation and systemic immune responses favoring IgAN development in mice. To further examine the role of gluten-free diet in disease severity in an experimental strategy closer to clinical practice, we treated α1KI-CD89Tg mice, fed with standard gluten-containing chow, with a gluten-free diet starting at 3, 6, and 10 weeks of age and killed the mice at 12 weeks (Figure 7a). Gluten-free diet during 6 and 9 weeks of treatment, but not during 2 weeks, induced a significant decrease in hematuria compared with α1KI-CD89Tg mice fed with normal gluten-containing chow (Figure 7b). Diet devoid of gluten in α1KI-CD89Tg mice treated during 6 weeks, but not 2 weeks, reduced IgA1 deposits in the mesangium, and this decrease was even more marked after 9 weeks of treatment (Figure 7c). Of note, IgA1 deposition in the mesangium of α1KI-CD89Tg mice started at 3 weeks and increased progressively at 6 and 12 weeks of age (Supplementary Figure S2 online). Moreover, 6 and 9 weeks of gluten-free diet also decreased IgA1–sCD89 complexes in the serum and increased CD89 expression on the monocyte surface (data not shown). The above results showed that long-term delivery of gluten-free diet introduced in the early stages of IgAN could prevent progression of the disease. Food antigens, including β-lactoglobulin,25.Sato M. Takayama K. Wakasa M. et al.Estimation of circulating immune complexes following oral challenge with cow's milk in patients with IgA nephropathy.Nephron. 1987; 47: 43-48Crossref PubMed Scopus (19) Google Scholar bovine serum albumin,19.Yap H.K. Sakai R.S. Woo K.T. et al.Detection of bovine serum albumin in the circulating IgA immune complexes of patients with IgA nephropathy.Clin Immunol Immunopathol. 1987; 43: 395-402Crossref PubMed Scopus (18) Google Scholar and gliadin,12.Coppo R. Mazzucco G. Martina G. et al.Gluten-induced experimental IgA glomerulopathy.Lab Invest. 1989; 60: 499-506PubMed Google Scholar, 13.Coppo R. Amore A. Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy.J Am Soc Nephrol. 1992; 2: S173-S180PubMed Google Scholar, 16.Coppo R. The intestine-renal connection in IgA nephropathy.Nephrol Dial Transplant. 2014; 0: 1-7Google Scholar have been described to induce a systemic IgA immune response and to form IgA complexes, which in some cases can be deposited in the mesangium of IgAN patients. The role of gliadin in experimental IgAN is now elucidated by evidence showing its implication in nephrotoxic IgA1–sCD89 complex generation, not only by its interaction with IgA1 but also by its binding to sCD89. CD89 was first thought to be a specific IgA receptor, but recent data show that it can also interact with C-reactive protein, having a role in innate immunity,26.Lu J. Marjon K.D. Marnell L.L. et al.Recognition and functional activation of the human IgA receptor (FcalphaRI) by C-reactive protein.Proc Natl Acad Sci USA. 2011; 108: 4974-4979Crossref PubMed Scopus (53) Google Scholar and with the mesangial TfR1, amplifying IgA complex deposition.7.Berthelot L. Papista C. Maciel T.T. et al.Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.J Exp Med. 2012; 209: 793-806Crossref PubMed Scopus (124) Google Scholar Interaction with gliadin may favor circulating IgA–sCD89 complex formation. Indeed, the complete depletion of gluten from the diet during three mouse generations abolished IgA1–sCD89 complexes from kidney eluates and serum of α1KI-CD89Tg mice. Moreover, this was associated with an increased expression of CD89 on the surface of monocytes–macrophages, suggesting that gliadin may be implicated in the CD89-shedding mechanism. It should be noted that the sensitization of mice to gluten by its depletion from the diet during three generations followed by dietary reintroduction is an experimental design serving to mimic the intolerance of some patients with CD and/or IgAN to dietary gluten owing to environmental, genetic, and other factors. Although these experiments allowed us to establish a physio-pathological link between gluten and IgAN onset, this strategy could not be applied to clinical practice. However, using another experimental protocol in mice fed with standard gluten-containing chow, we showed that gluten depletion from the diet in an early stage of the disease (3 weeks after birth) also strongly reduced mesangial IgA1 deposition and hematuria. Our results suggest that gluten may be involved in the generation of multimeric IgA1 complexes containing sCD89 and gliadin that get trapped in the mesangium through TfR1. Indeed, mice fed with a gluten-free diet presented decreased mesangial TfR1 expression. Moreover, gliadin binding on mesangial cellsin vitro was shown by others to modulate the production of immunological mediators and hemodynamic factors contributing to IgAN pathogenesis.17.Amore A. Emancipator S.N. Roccatello D. et al.Functional consequences of the binding of gliadin to cultured rat mesangial cells: bridging immunoglobulin A to cells and modulation of eicosanoid synthesis and altered cytokine production.Am J Kidney Dis. 1994; 23: 290-301Abstract Full Text PDF PubMed Scopus (28) Google Scholar Until now, there has been some evidence for the involvement of the mucosal immune system in the pathogenesis of IgAN. The mesangial IgA deposits of IgAN patients are principally composed of polymeric IgA1, which could originate from mucosal sites.27.Mestecky J. Raska M. Julian B.A. et al.IgA nephropathy: molecular mechanisms of the disease.Annu Rev Pathol. 2013; 8: 217-240Crossref PubMed Scopus (101) Google Scholar Furthermore, IgAN patients exhibit elevated intestinal permeability,21.Kovacs T. Kun L. Schmelczer M. et al.Do intestinal hyperpermeability and the related food antigens play a role in the progression of IgA nephropathy? I. Study of intestinal permeability.Am J Nephrol. 1996; 16: 500-505Crossref PubMed Scopus (39) Google Scholar associated with gastrointestinal inflammation.22.Rostoker G. Delchier J.C. Chaumette M.T. Increased intestinal intra-epithelial T lymphocytes in primary glomerulonephritis: a role of oral tolerance breakdown in the pathophysiology of human primary glomerulonephritides?.Nephrol Dial Transplant. 2001; 16: 513-517Crossref PubMed Scopus (33) Google Scholar Another study demonstrated the presence of a rectal mucosal sensitivity to gluten in one-third of IgAN patients, suggesting that sensitivity to gluten might be involved in the pathogenesis of IgAN.15.Smerud H.K. Fellstrom B. Hallgren R. et al.Gluten sensitivity in patients with IgA nephropathy.Nephrol Dial Transplant. 2009; 24: 2476-2481Crossref PubMed Scopus (48) Google Scholar The efficacy of an enteric formulation of budesonide, a corticosteroid acting locally, in the treatment of IgAN also supports the hypothesis of a mucosal immune response component being an important factor in IgAN.28.Smerud H.K. Barany P. Lindstrom K. et al.New treatment for IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria.Nephrol Dial Transplant. 2011; 26: 3237-3242Crossref PubMed Scopus (69) Google Scholar The number of intestinal IgA-producing plasma cells was shown to be increased in a murine model of IgAN,29.Kamata T. Nogaki F. Fagarasan S. et al.Increased frequency of surface IgA-positive plasma cells in the intestinal lamina propria and decreased IgA excretion in hyper IgA (HIGA) mice, a mur