Elsevier

Molecular Immunology

Volume 121, May 2020, Pages 1-6
Molecular Immunology

Review
Food antigens and Transglutaminase 2 in IgA nephropathy: Molecular links between gut and kidney

https://doi.org/10.1016/j.molimm.2020.02.019Get rights and content

Highlights

Abstract

The transglutaminase 2 (TG2) is one of the enigmatic enzymes with important functional diversity. It plays an important role in several pathologies such as celiac disease (CD). In patients with active CD, the abnormal retrotranscytosis of IgA/gliadin complexes is mediated by Transferrin Receptor 1 (TfR1). This triad association takes also place in IgA nephropathy (IgA-N). IgA-N is characterized by the formation of nephrotoxic complexes of IgA1 and soluble CD89 (sCD89). These complexes are abnormally deposited in the kidney. Using a humanized mouse model of IgA-N (α1KI-CD89Tg), we showed that IgA1-sCD89 complexes engender mesangial cell activation and proliferation with TfR1 and TG2 up-regulation, associated with IgA-N features. This TG2-TfR1 interaction enhances mesangial IgA1 deposition promoting inflammation. Humanized α1KI-CD89Tg mice deficient for TG2 show a decrease in TfR1 expression in kidney leading to reduced IgA1-sCD89 deposits and an improvement in IgA-N features. Moreover, TG2 is active and overexpressed in the intestine of IgA-N mice and gliadin participates to this renal pathology. In kidney as in intestine, the TG2 has a crucial role in the cooperation between TfR1-IgA and a central role in the pathogenic amplification.

Introduction

The transglutaminase 2 (TG2) is one of the enigmatic enzymes with important functional diversity. This protein plays an important role in several pathologies such as cancer, neurologic disorders and celiac disease (CD). During CD, TG2 regulates the disease at different levels: deamidation of the gliadin, the retrotranscytosis of IgA through the epithelial layer and is also recognized by IgG and IgA as an auto-antigen. Interestingly, in IgA nephropathy (IgA-N), a disease characterized by IgA deposition in kidney, similar mechanisms are involved. In this review, the molecular mechanisms involving TG2, IgA and TfR1 will be explored in intestine and kidney to decipher pathological mechanism in IgA nephropathy.

Section snippets

IgA and its receptors

IgA is the most abundant antibody isotype produced in our body (Macpherson et al., 2008). Human IgA exists in two subclasses, termed IgA1 and IgA2. In the secretions, IgA is formed as dimers linked by the J chain and associated to the secretory component, which is a part of the extracellular domain of the polymeric Ig receptor (pIgR) generating secretory IgA (Brandtzaeg et al., 1999; Kaetzel, 2005). Quantitative studies of the origin of S-IgA in human external secretions have convincingly

TG2 as an auto-antigen

Celiac disease (CD) is an autoimmune inflammatory disease of the small intestine triggered by a dysregulated response to gluten. Patients suffering with CD exhibit increased circulating IgA and IgG antibodies against gliadin (one component of gluten), endomysium (a substrate of TG2) and TG2. Celiac autoantibodies are produced in the small intestinal mucosa, and it has been recognized that the small intestinal epithelial membrane of CD patients contains deposited IgA (Picarelli et al., 1996).

TG2 on mesangial cells

IgA nephropathy (IgA-N), a leading cause of renal failure, is characterized by the deposition of hypogalactosylated IgA1 complexes in the renal mesangium. IgG anti-hypogalactosylated IgA1 autoantibodies have been identified within circulating IgA immune complexes (IC) associated with disease progression (Suzuki et al., 2011). We and others have shown that that other types of IgA-IC, namely IgA-soluble CD89 complexes (IgA-sCD89), are essential for disease initiation, present in the mesangium and

Conclusions

Molecular mechanisms involving IgA, TG2 and TfR1 are shared between CD and IgA-N (Fig. 1). CD patients exhibit overexpression of TfR1 and TG2 on enterocytes leading to the retrotranscytosis of IgA bearing gliadin (Lebreton et al., 2012; Matysiak-Budnik et al., 2008). In kidney, TfR1 and TG2 overexpression results in increase of IgA deposits in IgA-N (Berthelot et al., 2012; Moura et al., 2005, 2004). The binding of IgA1 complexes on TfR1 at the cell surface of mesangial cells induces the

Author contribution statement

Conceptualization: LA, LB; Formal analysis: LA; Funding acquisition LB; Project administration LB; Supervision: RCM, LB; Writing – original draft: LA, LB; Writing – review & editing: LA, RCM, LB.

Funding statement

Lilia Abbad PhD was supported by Laboratory of Excellence Inflamex, funded by the «Investissements d'Avenir» French Government program, managed by the French National Research Agency (ANR). Renato Monteiro is employed by Assitante Publique et Hopitaux de Paris (AP-HP) and Laureline Berthelot by </GS4>French National Institute of Health and Medical Research (INSERM)</GS4>. This work was support by ANR (grant number ANR-14-CE15-0011).

Declaration of Competing Interest

The authors have declared that no conflict of interest exists.

Acknowledgments

We thank Prof. Kiyotaka Hitomi (Laboratory of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Nagoya, Japan) for providing peptide T26.

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