Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo

Abstract

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 a-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of a-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-a-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-a-enolase/low anti-annexin AI IgG2 and patients with low anti-a-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-a-enolase IgG2 recognized specific epitopes of a-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human a-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against a-enolase and annexin AI predominate in the glomerulus and can be detected in serum.

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo (2)

“…The third category includes several podocyte antigens, mainly a-enolase and annexin AI, that have been only recently identified. 11 Other glomerular antigens can be included as well. 11,12 Evidence from the literature suggests that it is the combination of all antibodies that produces stable renal lesions in LN and that different subsets have specific implications.…”

“…11 Other glomerular antigens can be included as well. 11,12 Evidence from the literature suggests that it is the combination of all antibodies that produces stable renal lesions in LN and that different subsets have specific implications. [12][13][14][15][16] Experimental studies support the role of anti-DNA antibodies in starting the process 2,17 and antipodocyte antibodies in its maintainance.…”

“…[12][13][14][15][16] Experimental studies support the role of anti-DNA antibodies in starting the process 2,17 and antipodocyte antibodies in its maintainance. 11 In the case of antibodies versus DNA and/or DNA components (i.e., histones and nucleosomes), 17 the binding is directed to basement membrane and mesangial matrix and seems propedeutic to further immune complex deposition. 8,9 Antibodies versus podocyte antigens induce lupus-like renal lesions in mice, and the same antigens (i.e., a-enolase) are targets of nephrogenic antibodies purified from MLR/MLR lupusprone mice.…”

“…8,9 Antibodies versus podocyte antigens induce lupus-like renal lesions in mice, and the same antigens (i.e., a-enolase) are targets of nephrogenic antibodies purified from MLR/MLR lupusprone mice. 11 Human studies are still weak, because renal tissue findings are mainly on the basis of histopathology and electron microscopy. Relevant information is lacking on the composition and characteristics of autoantibodies on the basis of an in vivo characterization of Igs microeluted directly from renal biopsies; until recently, 11 studies addressing composition and quality of renal autoantibodies in human LN were limited to postmortem kidney tissues.…”

“…11 Human studies are still weak, because renal tissue findings are mainly on the basis of histopathology and electron microscopy. Relevant information is lacking on the composition and characteristics of autoantibodies on the basis of an in vivo characterization of Igs microeluted directly from renal biopsies; until recently, 11 studies addressing composition and quality of renal autoantibodies in human LN were limited to postmortem kidney tissues. 18,19 Technologies are now available that allow minute isolation of glomeruli from fresh renal biopsies and characterization of autoantibodies/ antigens.…”