Glomerular autoimmune multicomponents of human lupus nephritis in vivo: α-enolase and annexin AI.
Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-α-enolase/low anti-annexin AI IgG2 and patients with low anti-α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum.
Laboratory on Pathophysiology of Uremia.
Maurizio
M
Bruschi
Division of Nephrology and Section of Clinical Immunology, San Carlo Hospital, Milan, Italy;
Renato Alberto
RA
Sinico
Division of Nephrology and Dialysis, Scientific Institute for Research and Health Care (IRCCS) Fondazione Ospedale Maggiore, Mangiagalli, Regina Elena, Milan, Italy;
Gabriella
G
Moroni
Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy;
Federico
F
Pratesi
Clinical Immunology Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy;
Paola
P
Migliorini
Departments of Clinical and Experimental Medicine, Italian Workers' Compensation Authority (INAIL) Research Center, University of Parma, Parma, Italy;
Maricla
M
Galetti
Divisions of Nephrology, Dialysis, and Transplantation, and.
Corrado
C
Murtas
Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy;
Angela
A
Tincani
Department of Medicine, Georgia Health Sciences University, Augusta, Georgia;
Michael
M
Madaio
Division of Nephrology and Section of Clinical Immunology, San Carlo Hospital, Milan, Italy;
Antonella
A
Radice
Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy;
Franco
F
Franceschini
Division of Nephrology and Section of Clinical Immunology, San Carlo Hospital, Milan, Italy;
Barbara
B
Trezzi
Division of Nephrology and Section of Clinical Immunology, San Carlo Hospital, Milan, Italy;
Laura
L
Bianchi
Institute of Biomedicine and Molecular Immunology, CNR, Palermo, Italy;
Agata
A
Giallongo
Biomedical, Biotechnological and Translational Sciences, and.
Rita
R
Gatti
Service of Pathological Anatomy, Division of Nephrology, Spedali Civili di Brescia, Brescia, Italy;
Regina
R
Tardanico
CNR, Institute for Animal Production System in Mediterranean Environment (ISPAAM), Naples, Italy;
Andrea
A
Scaloni
CNR, Institute for Animal Production System in Mediterranean Environment (ISPAAM), Naples, Italy;
Chiara
C
D'Ambrosio
Departments of Clinical and Experimental Medicine.
Maria Luisa
ML
Carnevali
Division of Nephrology and Dialysis, Scientific Institute for Research and Health Care (IRCCS) Fondazione Ospedale Maggiore, Mangiagalli, Regina Elena, Milan, Italy;
Piergiorgio
P
Messa
Division of Nephrology, University of Calgary, Calgary, Alberta, Canada; and.
Pietro
P
Ravani
Divisions of Nephrology, Dialysis, and Transplantation, and.
Giancarlo
G
Barbano
Departments of Clinical and Experimental Medicine.
Beatrice
B
Bianco
Divisions of Nephrology, Dialysis, and Transplantation, and.
Alice
A
Bonanni
Division of Nephrology, University of Brescia, Montichiari Hospital, Brescia, Italy.
Francesco
F
Scolari
Paediatric Rheumatology, Istituto Giannina Gaslini, Genoa, Italy;
Alberto
A
Martini
Laboratory on Pathophysiology of Uremia.
Giovanni
G
Candiano
Departments of Clinical and Experimental Medicine.
Landino
L
Allegri
Divisions of Nephrology, Dialysis, and Transplantation, and GMarcoGhiggeri@ospedale-gaslini.ge.it.
Gian Marco
GM
Ghiggeri
D000293:Adolescent; D000328:Adult; D000818:Animals; D017305:Annexin A1 / Q000276:immunology* / Q000302:isolation & purification; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D001706:Biopsy; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology*; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D016513:Mice, SCID; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D040901:Proteomics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D055815:Young Adult
D017305:Annexin A1; D001323:Autoantibodies; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D025521:Tumor Suppressor Proteins; C573274:annexin A1, mouse; C095157:ENO1 protein, human; C457379:Eno1 protein, mouse; D010751:Phosphopyruvate Hydratase
GN; immunology and pathology; lupus nephritis