The targets of nephritogenic antibodies in systemic autoimmune disorders

Migliorini, Paola; Pratesi, Federico; Bongiorni, F.; Moscato, Stefania; Scavuzzo, Maria Concetta; Bombardieri, Stefano

doi:10.1016/s1568-9972(02)00028-9

Cited by 36 publications

(30 citation statements)

References 21 publications

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“…Circulating anti-aENO IgG has been reported in various autoimmune diseases (22)(23)(24). When characterized, the prevalent isotype was of the IgG 1 and IgG 3 subclasses also in previous reports on MN patients (25), whereas anti-aENO IgG 4 seems to be more specific for MN (8).…”

Section: Discussionsupporting

confidence: 56%

Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

Murtas¹,

Bruschi

Candiano

et al. 2012

Clinical Journal of the American Society of Nephrology

126

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SummaryBackground and objectives The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes.Design, setting, participants, & measurements Serum IgG 1 , IgG 3 , and IgG 4 against aldose reductase (AR), SOD2, and a-enolase (aENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG 4 were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients.Results IgG 4 was the most common isotype for all antibodies; IgG 1 and IgG 3 were nearly negligible. IgG 4 levels were positive in a significant proportion of MN patients (AR, 34%; SOD2, 28%; aENO, 43%). Antibody titers were higher in MN than in healthy and pathologic controls (P,0.005). Anti-NEP IgG 4 did not differ from normal controls (P=0.12). Anti-PLA2r IgG 4 was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-aENO IgG 4 (P,0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P,0.05).Conclusions Our data suggest that IgG 4 is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, aENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.

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Section: Discussionsupporting

confidence: 56%

Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

Murtas¹,

Bruschi

Candiano

et al. 2012

Clinical Journal of the American Society of Nephrology

126

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“…Indeed, anti-a-enolase IgG has been detected in clinical conditions involving the kidney other than LN, and with the methodology limitations that characterized the preproteomics era, it has been generically associated with different autoimmune and inflammatory pathologies. 25,26,[41][42][43] Previous works on anti-a-enolase did not characterize the isotype of antibodies and reported variable results, overall suggesting a limited specificity for various clinical conditions, such as SLE (data on LN not reported), mixed cryoglobulinemia, systemic sclerosis, and ANCA vasculitis. 41 Recently, we eluted anti-a-enolase IgG4 from glomeruli of patients with primary membranous nephropathy 31 and detected specific antibodies of the same isotype in their serum.…”

Section: Discussionmentioning

confidence: 99%

“…12,[16][17][18][19][20] Chromatin and nucleosomes deriving from ineffective fragmentation may interact with negatively charged constituents of the basement membrane 7,16 and become the planted antigen for anti-dsDNA (and autoantibodies of other specificities). 6,7,9,16 Other potentially nephritogenic antibodies different from anti-dsDNA have been proposed 10,11,[21][22][23][24][25][26] ; overall, it has been estimated that anti-DNA deposition in LN accounts for not more than 10%-20% of eluted IgG overall, 27 implying that IgG not recognizing DNA represents the vast majority of antibodies in glomeruli. Renal targets of autoimmunity in human LN are, however, unknown.…”

mentioning

confidence: 99%

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo

Bruschi¹,

Sinico

Moroni

et al. 2014

Journal of the American Society of Nephrology

101

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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.

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“…Glomerular Ags reported to be targets for the pathogenic anti-dsDNA Ab response include laminin, heparan sulfate, fibronectin, and collagen IV (7,8), although the specificity for many of the autoantibodies that are actually deposited in human lupus kidneys in vivo is not known (9). Mostoslavsky et al (10), and subsequently we (11), had identified ␣-actinin as a major target of the murine antidsDNA response in SLE.…”

mentioning

confidence: 99%

Differential Binding of Cross-Reactive Anti-DNA Antibodies to Mesangial Cells: The Role of α-Actinin

Zhao

Deocharan

Scherer

et al. 2006

The Journal of Immunology

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Target Ag display is a necessary requirement for the expression of certain immune-mediated kidney diseases. We previously had shown that anti-DNA Abs that cross-react with α-actinin may be important in the pathogenesis of murine and human lupus nephritis; in murine models, we had found that a significant proportion of pathogenic serum and kidney-deposited Igs are α-actinin reactive. Furthermore, a pathogenic anti-DNA/α-actinin Ab showed enhanced binding to immortalized mesangial cells (MCs) derived from a lupus prone MRL-lpr/lpr mouse as compared with MCs from BALB/c mice which are not susceptible to spontaneous lupus, suggesting that kidney α-actinin expression may be contributing to nephritis. In the current study, we established that two isoforms of α-actinin that are present in the kidney, α-actinin 1 and α-actinin 4, can both be targeted by anti-α-actinin Abs. We found novel sequence polymorphisms between MRL-lpr/lpr and BALB/c in the gene for α-actinin 4. Moreover, α-actinin 4 and a splice variant of α-actinin 1 were both expressed at significantly higher levels (mRNA and protein) in MCs from the lupus prone MRL-lpr/lpr strain. Significantly, we were able to confirm these differences in intact kidney by examining glomerular Ig deposition of anti-α-actinin Abs. We conclude that enhanced α-actinin expression may determine the extent of Ig deposition in the Ab-mediated kidney disease in lupus. Modulation of Ag expression may be a promising approach to down-regulate immune complex formation in the target organ in individuals with circulating pathogenic Abs.

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The targets of nephritogenic antibodies in systemic autoimmune disorders

Cited by 36 publications

References 21 publications

Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

Coexistence of Different Circulating Anti-Podocyte Antibodies in Membranous Nephropathy

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo

Differential Binding of Cross-Reactive Anti-DNA Antibodies to Mesangial Cells: The Role of α-Actinin

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