Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy

Alexandra Cambier; Patrick J Gleeson; Lilia Abbad; Fanny Canesi; Jennifer da Silva; Julie Bex-Coudrat; Georges Deschênes; Olivia Boyer; Marion Rabant; Tim Ulinski; Julien Hogan; Michel Peuchmaur; Laureline Berthelot; Renato C Monteiro

doi:10.1016/j.kint.2021.09.023

Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy

Kidney Int. 2022 Feb;101(2):274-287. doi: 10.1016/j.kint.2021.09.023. Epub 2021 Oct 28.

Affiliations

¹ Université de Paris, Paris, France; Département de Néphrologie, Immunologie et Hématologie, Centre de Recherche sur l'Inflammation (CRI), Paris, France; INSERM U1149, Paris, France; CNRS ERL8252, Paris, France; Laboratoire d'Excellence INFLAMEX, Paris, France; Service de Néphrologie Pédiatrique, Assistance Publique de Paris, Hôpital Robert Debré, Paris, France.
² Université de Paris, Paris, France; Département de Néphrologie, Immunologie et Hématologie, Centre de Recherche sur l'Inflammation (CRI), Paris, France; INSERM U1149, Paris, France; CNRS ERL8252, Paris, France; Laboratoire d'Excellence INFLAMEX, Paris, France.
³ Université de Paris, Paris, France; Service de Néphrologie Pédiatrique, Assistance Publique de Paris, Hôpital Robert Debré, Paris, France.
⁴ Université de Paris, Paris, France; Service de Néphrologie Pédiatrique, Assistance Publique de Paris, Hôpital Universitaire Necker, Paris, France.
⁵ Université de Paris, Paris, France; Service de Pathologie, Hôpital Universitaire Hôpital Necker Assistance Publique de Paris, Paris, France.
⁶ Service de Néphrologie Pédiatrique, Assistance Publique de Paris, Hôpital Universitaire Armand Trousseau, Paris, France.
⁷ Université de Paris, Paris, France; Service de Pathologie, Hôpital Robert Debré, Assistance Publique de Paris, Paris, France.
⁸ Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, Université de Nantes, INSERM, Nantes, France.
⁹ Université de Paris, Paris, France; Département de Néphrologie, Immunologie et Hématologie, Centre de Recherche sur l'Inflammation (CRI), Paris, France; INSERM U1149, Paris, France; CNRS ERL8252, Paris, France; Laboratoire d'Excellence INFLAMEX, Paris, France; Service d'Immunologie, FHU Apollo, Assistance Publique de Paris, Hôpital Bichat-Claude Bernard, Paris, France. Electronic address: [email protected].

PMID: 34756952
DOI: 10.1016/j.kint.2021.09.023

Abstract

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

Keywords: IgA nephropathy; glomerulonephritis; immune complexes; proteinuria; renal pathology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Child
Glomerular Mesangium / pathology
Glomerulonephritis, IGA* / pathology
Humans
Immunoglobulin A
Kidney Glomerulus / pathology
Mice

Substances

Immunoglobulin A