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Pathogenic Role of Defective IgA Galactosylation in a Murine Model of IgA Nephropathy

English title Pathogenic Role of Defective IgA Galactosylation in a Murine Model of IgA Nephropathy
Applicant Izui Shozo
Number 135229
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.04.2011 - 31.03.2013
Approved amount 238'615.00
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Keywords (4)

IgA nephropathy; Galactosylation; Glomerulonephritis; Immune complex

Lay Summary (English)

Lead
Lay summary

IgA nephropathy (IgAN) is the most common form ofglomerulonephritis worldwide. -linked oligosaccharide chains in itshinge region.O-linked oligosaccharidechains uniquely attached to the IgA1 hinge region with the development of IgAN,it has been suggested that the production of poorly galactosylated IgA1 iscritically involved in the pathogenesis of IgAN. However, the causal role ofundergalactosylation of IgA1 remains largely unknown. Progress towardsunderstanding the pathogenesis of IgAN has been hindered by the absence ofappropriate mouse models of IgAN because mouse IgA, unlike human IgA1, lacks O-linkedoligosaccharide chains are only present in the hinge region of IgA1, but not inIgA2 and other classes of immunoglobulines). Because of an association ofgalactose deficiency of Oside chains in the hinge region of IgA1 (oligosaccharide-linked OKidney lesions in patients with IgAN arecharacterized by immune deposits of IgA in glomeruli. Significantly, glomerularimmune deposits are restricted to the IgA1 subclass, not the IgA2 subclass. Themost prominent structural difference between IgA1 and IgA2 is the presence of

We have recently developed a new mouse model of IgAN,which is induced by 6-19 IgA anti-IgG2a rheumatoid factor monoclonalautoantibody. However, this model is not totally relevant tohuman IgAN, because of the absence of O-linked oligosaccharide chains. The assessment of in vivo pathogenicity of thesevariants should be able to determine whether undergalactosylation of 6-19 IgAin its hinge region is indeed critically involved in the development of IgAN.O-linkedglycosylation sites by recombinanttechnology. Then, we will produce different 6-19 IgA variants, the hinge regionof which are highly or poorly galactosyled by over- or under-expressing anenzyme critically involved in the galactosylation of O-linked oligosaccharide chains in its hinge regionthrough the introduction of O-linked oligosaccharides chains in the hinge regionof 6-19 antibody. Therefore, we will produce an engineered 6-19 antibody carrying

Theresults obtained from the proposed research project should improve our understanding of the immunopathological mechanismscritically involved in the development of IgAN and thus help to identifymolecules central to the development of human IgAN. This should provide us with promising new targets for the design of noveltherapeutic strategies.

 

Keywords: IgA nephropathy, Galactosylation,Glomerulonephritis, Immune complex

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Development of a model of early-onset IgA nephropathy.
Okazaki Keiko, Suzuki Yusuke, Otsuji Mareki, Suzuki Hitoshi, Kihara Masao, Kajiyama Tadahiro, Hashimoto Azusa, Nishimura Hiroyuki, Brown Rhubell, Hall Stacy, Novak Jan, Izui Shozo, Hirose Sachiko, Tomino Yasuhiko (2012), Development of a model of early-onset IgA nephropathy., in Journal of the American Society of Nephrology : JASN, 23(8), 1364-74.
O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.
Otani Masako, Nakata Junichiro, Kihara Masao, Leroy Valérie, Moll Solange, Wada Yoshinao, Izui Shozo (2012), O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis., in Journal of the American Society of Nephrology : JASN, 23(3), 438-46.

Associated projects

Number Title Start Funding scheme
127644 Immunopathogenesis of spontaneous murine models of SLE: genetic, cellular and molecular analysis 01.10.2009 Project funding

Abstract

The aim of our research is to gain a better understanding of the pathogenic role of galactose deficiency in N-linked and O-linked glycans of 6-19 IgA rheumatoid factor (RF) monoclonal antibody (mAb) in the induction of IgA nephropathy (IgAN).IgAN is the most common form of glomerulonephritis worldwide. Glomerular lesions in patients with IgAN are characterized by immune deposits of the IgA1 subclass in the mesangium, and by mesangial proliferation and expansion of extracellular matrix. IgA1 deposits are accompanied by deposition of the C3 component of complement and by variable co-deposition of IgG, IgM or both. Because of an association between galactose deficiency of O-linked glycans uniquely present in the IgA1 hinge region and the development of IgAN, and because of the presence of increased titers of high molecular-weight IgA1 complexes in sera from IgAN patients, it has been suggested that the production of aberrantly galactosylated IgA1 and the subsequent development of IgA1 complexes are critically involved in the pathogenesis of IgAN. However, the causal role of undergalactosylation of IgA1 remains largely unsubstantiated and the molecular features of IgA1 complexes implicated in IgAN are still poorly defined. Notably, progress towards understanding the pathogenesis of IgAN has been hindered by the absence of appropriate mouse models of IgAN because murine IgA, unlike human IgA1, lacks O-linked glycans in its hinge region.Our ongoing studies revealed that 6-19 IgA anti-IgG2a RF mAb induced IgAN-like glomerular lesions, the development of which was dependent on the formation of IgA-IgG2a immune complexes (IC), while 46-42 and 102C6 anti-IgG2a RF failed to do so. Therefore, we first propose to conduct the oligosaccharide structural analysis of these three RF mAb to clarify whether this difference in nephritogenicity could be related to variations in the extent of galactosylation of N-glycans present in the CH1 and CH3 domains of murine IgA. Then, the implication of IgA galactosylation will be studied by analysing the pathogenic potential of 6-19 IgA variants carrying more or less galactosylated N-glycans. To determine more specifically the pathogenic role of aberrant galactosylation of O-linked glycans in IgAN, we propose to generate a 6-19 IgA variant bearing O-linked glycans by introducing the human IgA1 hinge sequence. Then, by selectively modulating the galactosylation of O-linked glycans, we will investigate whether defective galactosylation of O-glycans in the hinge region is critically involved in the development of IgAN. Finally, we will evaluate the pathogenic role of IgG antibodies against neoantigenic N-acetylgalactosamine (GalNAc) exposed on galactose-deficient O-linked glycans. This will be done by assessing the nephritogenicity of the 6-19 IgA hinge variant in C57BL/6 mice, which can generate 6-19 IgA-IgG IC implicating neoantigenic GalNAc but not 6-19 IgA RF-IgG2a IC (because of a lack of expression of IgG2a), thus defining the respective contributions of these two different IgA-IgG IC to the development of IgAN.The results obtained from the proposed research project should improve our understanding of the immunopathological mechanisms critically involved in the development of IgAN and thus help to identify target molecules central to the development of human IgAN.
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