Transglutaminase is essential for IgA nephropathy development acting through IgA receptors

Berthelot, Laureline; Papista, Christina; Maciel, Thiago; Biarnes-Pelicot, Martine; Tissandié, E.; Wang, Pamela H.M.; Tamouza, Houda; Jamin, Agnès; Bex-Coudrat, Julie; Gestin, Aurélie; Boumédiène, A.; Arcos-Fajardo, Michelle; England, Patrick; Pillebout, Évangéline; Walker, Francine; Daugas, Éric; Vrtosvnik, François; Flamant, Martin; Benhamou, Marc; Cogné, Michel; Moura, Ivan C.; Monteiro, Renato C.

doi:10.1084/jem.20112005

Cited by 146 publications

(137 citation statements)

References 42 publications

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“…The latest study suggest that complex interaction of IgA1, soluble CD89 receptor, transferrin receptor 1, and transglutaminase 2 is required for the binding of IgA1 leading to the activation of mesangial cells (38). Whether SYK is involved in the downstream signaling of this complex interaction remains to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Kim

McDaid

McAdoo

et al. 2012

The Journal of Immunology

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IgA immune complexes are capable of inducing human mesangial cell (HMC) activation, resulting in release of proinflammatory and profibrogenic mediators. The subsequent inflammation, cellular proliferation, and synthesis of extracellular matrix lead to the progression of IgA nephropathy (IgAN). Spleen tyrosine kinase (SYK) is an intracellular protein tyrosine kinase involved in cell signaling downstream of immunoreceptors. In this study, we determined whether SYK is involved in the downstream signaling of IgA1 stimulation in HMC, leading to production of proinflammatory cytokines/chemokines and cell proliferation. Incubation of HMC with IgA1 purified from IgAN patients significantly increased the synthesis of MCP-1 in a dose-dependent manner. There was also significantly increased production of IL-6, IL-8, IFN-γ–inducible protein-10, RANTES, and platelet-derived growth factor-BB. Stimulation of HMC with heat-aggregated IgA1 purified from IgAN patients induced significantly increased HMC proliferation. Both pharmacological inhibition of SYK and knockdown of SYK by small interfering RNA significantly reduced the synthesis of these mediators and inhibited HMC proliferation. Moreover, positive immunostaining for total and phospho-SYK in glomeruli of kidney biopsies from IgAN patients strongly suggests the involvement of SYK in the pathogenesis of IgAN. To our knowledge, we demonstrate, for the first time, the involvement of SYK in the downstream signaling of IgA1 stimulation in HMC and in the pathogenesis of IgAN. Hence, SYK represents a potential therapeutic target for IgAN.

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Section: Discussionmentioning

confidence: 99%

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Kim

McDaid

McAdoo

et al. 2012

The Journal of Immunology

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“…Therefore, it remains to be proven whether serum antibodies against GdIgA1 are a specific requirement for the formation of the renal IgA1-containing immune complexes found in IgAN. The deposition of the IgA1-containing immune complexes appears to be mediated by binding to the mesangial transferrin receptor 1 (CD71) and CD89 [37,38]. In transgenic mice expressing human IgA1 and CD89, IgA and CD89 deposition occurs in the mesangium, and IgA nephropathy develops.…”

Section: Etiology and Pathophysiologymentioning

confidence: 99%

“…CD89 deposition has also been found in renal biopsies from patients with IgAN. Thus, the interaction between IgA1, soluble CD89, transglutaminase 2 and transferrin receptor 1 may contribute to the development of IgA nephropathy [37], but it remains to be shown whether this interaction is an important part of the pathophysiology and whether it is also involved in the development of HSPN.…”

Section: Etiology and Pathophysiologymentioning

confidence: 99%

Henoch–Schönlein purpura nephritis

Pöhl

2014

Pediatr Nephrol

121

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Henoch-Schönlein purpura (HSP) is the one of most common types of systemic vasculitis in childhood. Glomerulonephritis (HSPN) occurs in 30-50 % of HSP patients, mostly in a mild form but a small percentage of patients present with nephrotic syndrome or renal failure. HSPN is caused by the glomerular deposition of immunoglobulin A1 (IgA1)-containing immune complexes in the mesangium, the subepithelial and the subendothelial space. Formation of the IgA1 immune complex is thought to be the consequence of aberrantly glycosylated IgA1 molecules secreted into the circulation and their subsequent recognition by IgG specific for galactose-deficient IgA1. Mesangial proliferation and renal damage are triggered by the deposited immune complexes, which likely require activation of the complement system. Whereas other organ manifestations of HSP are mostly benign and self-limiting, HSPN might lead to chronic renal disease and end stage renal failure, thereby justifying immunosuppressive treatment. Long-term renal outcome correlates to the severity of the initial clinical presentation and the extent of renal biopsy changes, both of which are used to decide upon a possible treatment. As there are no evidence-based treatment options for severe HSPN, a large variety of therapeutic regimens are used. Prospective randomized controlled treatment studies are needed, but the low incidence of severe HSPN renders such studies difficult.

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“…Recognition of novel epitopes by IgA and IgG antibodies leads to the formation of immune complexes galactose deficient-IgA1/anti-glycan IgG or IgA [17]. Immune complexes of IgA combined with FcαRI/CD89 have also been implicated in disease exacerbation [18][19][20]. These nephritogenic immune complexes are formed in the circulation and deposited in renal mesangium.…”

Section: Journal Of Clinical and Cellular Immunologymentioning

confidence: 99%

Gluten, Transglutaminase, Celiac Disease and IgA Nephropathy

Lerner¹,

Berthelot²,

Jeremias³

et al. 2017

J Clin Cell Immunol

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Both, celiac disease and IgA nephropathy are autoimmune diseases that are IgA mediated and share multiple clinical, pathophysiological, genetic, nutritional and immunological aspects. In view of recent observations and wider understanding of the central role played by the intestinal ecosystem in celiac disease and IgA nephropathy development, the present review highlights those shared aspects, concentrating on potential nutritional therapeutic strategies in IgA nephropathy.

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Transglutaminase is essential for IgA nephropathy development acting through IgA receptors

Abstract: Transglutaminase 2 is required for the development of IgA nephropathy.

Cited by 146 publications

References 42 publications

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

Henoch–Schönlein purpura nephritis

Gluten, Transglutaminase, Celiac Disease and IgA Nephropathy

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