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Glomerular Activation of the Lectin Pathway of Complement in IgA Nephropathy Is Associated with More Severe Renal Disease

Anja Roos^*, Maria Pia Rastaldi, Novella Calvaresi, Beatrijs D. Oortwijn^*, Nicole Schlagwein^*, Danielle J. van Gijlswijk-Janssen^*, Gregory L. Stahl, Misao Matsushita, Teizo Fujita^||, Cees van Kooten^* and Mohamed R. Daha^*

^* Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands; Renal Immunopathology Laboratory, Fondazione D’Amico per la Ricerca sulle Malattie Renali, Associazione Nuova Nefrologia, San Carlo Borromeo Hospital, Milano, Italy; Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Institute of Glycotechnology and Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan; and ^|| Department of Immunology, Fukushima Medical University, Fukushima, Japan

Address correspondence to: Dr. Anja Roos, Department of Clinical Chemistry, Leiden University Medical Center, L2-27, Postbox 9600, 2300 RC Leiden, The Netherlands. Phone: +31-71-526-4971/2278; Fax: +31-71-526-6753; E-mail: a.roos{at}lumc.nl

Received for publication September 8, 2005. Accepted for publication April 11, 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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