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      Pathogenesis of Henoch-Schönlein purpura nephritis

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          Abstract

          The severity of renal involvement is the major factor determining the long-term outcome of children with Henoch-Schönlein purpura (HSP) nephritis (HSPN). Approximately 40% children with HSP develop nephritis, usually within 4 to 6 weeks after the initial onset of the typical purpuric rashes. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition that induce renal injury in HSPN.

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          Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease.

          Anja Roos, Beatrijs D Oortwijn, Maria Rastaldi … (2006)
          IgA nephropathy (IgAN) is characterized by glomerular co-deposition of IgA and complement components. Earlier studies showed that IgA activates the alternative pathway of complement, whereas more recent data also indicate activation of the lectin pathway. The lectin pathway can be activated by binding of mannose-binding lectin (MBL) and ficolins to carbohydrate ligands, followed by activation of MBL-associated serine proteases and C4. This study examined the potential role of the lectin pathway in IgAN. Renal biopsies of patients with IgAN (n=60) showed mesangial deposition of IgA1 but not IgA2. Glomerular deposition of MBL was observed in 15 (25%) of 60 cases with IgAN and showed a mesangial pattern. All MBL-positive case, but none of the MBL-negative cases showed glomerular co-deposition of L-ficolin, MBL-associated serine proteases, and C4d. Glomerular deposition of MBL and L-ficolin was associated with more pronounced histologic damage, as evidenced by increased mesangial proliferation, extracapillary proliferation, glomerular sclerosis, and interstitial infiltration, as well as with significantly more proteinuria. Patients who had IgAN with or without glomerular MBL deposition did not show significant differences in serum levels of MBL, L-ficolin, or IgA or in the size distribution of circulating IgA. Furthermore, in vitro experiments showed clear binding of MBL to polymeric but not monomeric patient IgA, without a significant difference between both groups. Together, these findings strongly point to a role for the lectin pathway of complement in glomerular complement activation in IgAN and suggest a contribution for both MBL and L-ficolin in the progression of the disease.
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            Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies.

            K Matousovic, Anne Novak, J Mestecky … (1999)
            Circulating immune complexes (CICs) isolated from sera of patients with IgA nephropathy (IgAN) consist of undergalactosylated, mostly polymeric, and J chain-containing IgA1 and IgG antibodies specific for N-acetylgalactosamine (GalNAc) residues in O-linked glycans of the hinge region of IgA1 heavy chains. Antibodies with such specificity occur in sera of IgAN patients, and in smaller quantities in patients with non-IgA proliferative glomerulonephritis and in healthy controls; they are present mainly in the IgG (predominantly IgG2 subclass), and less frequently in the IgA1 isotype. Their specificity for GalNAc was determined by reactivity with IgA1 myeloma proteins with enzymatically removed N-acetylneuraminic acid (NeuNAc) and galactose (Gal); removal of the O-linked glycans of IgA1 resulted in significantly decreased reactivity. Furthermore, IgA2 proteins that lack the hinge region with O-linked glycans but are otherwise structurally similar to IgA1 did not react with IgG or IgA1 antibodies. The re-formation of isolated and acid-dissociated CICs was inhibited more effectively by IgA1 lacking NeuNAc and Gal than by intact IgA1. Immobilized GalNAc and asialo-ovine submaxillary mucin (rich in O-linked glycans) were also effective inhibitors. Our results suggest that the deficiency of Gal in the hinge region of IgA1 molecules results in the generation of antigenic determinants containing GalNAc residues that are recognized by naturally occurring IgG and IgA1 antibodies.
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              IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1.

              Jan Novak, Hitoshi Suzuki, Zina Moldoveanu … (2008)
              Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by beta1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine-specific alpha2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in beta1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine-specific alpha2,6-sialyltransferase activity. Also, expression of beta1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine-specific alpha2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target.
              Article 0 comments Cited 86 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : +1-916-7348118 , +1-916-7340629 , keithklou@gmail.com
                Journal
                Journal ID (nlm-ta): Pediatr Nephrol
                Title: Pediatric Nephrology (Berlin, Germany)
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0931-041X
                ISSN (Electronic): 1432-198X
                Publication date (Electronic): 13 June 2009
                Publication date (Print): January 2010
                Volume: 25
                Issue: 1
                Pages: 19-26
                Affiliations
                [1 ]Department of Pediatrics, McMaster University, 1200 Main Street West, HSC 3N27, Hamilton, Ontario Canada L8S 3Z5
                [2 ]Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL USA
                [3 ]Department of Nephrology, Juntendo University School of Medicine, Tokyo, Japan
                [4 ]Children’s Foundation Research Center at the Le Bonheur Children’s Medical Center, Memphis, TN USA
                [5 ]Division of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, TN USA
                Article
                Publisher ID: 1230
                DOI: 10.1007/s00467-009-1230-x
                PMC ID: 2778786
                PubMed ID: 19526254
                SO-VID: 45b51bb6-d374-4398-9042-566f6134fb1c
                Copyright © © The Author(s) 2009
                History
                Date received : 17 March 2009
                Date revision received : 3 May 2009
                Date accepted : 5 May 2009
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © IPNA 2010

                ScienceOpen disciplines: Nephrology
                Keywords: immune complex,pathogenesis,galactose-deficient iga1,henoch-schönlein purpura nephritis,children
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: immune complex, pathogenesis, galactose-deficient iga1, henoch-schönlein purpura nephritis, children

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