Association of α‐actinin–binding anti–double‐stranded DNA antibodies with lupus nephritis

Renaudineau, Yves; Croquefer, Sabine; Jousse, Sandrine; Renaudineau, Éric; Devauchelle, Valérie; Guéguen, Paul; Hanrotel, Catherine; Gilburd, Boris; Saraux, Alain; Shoenfeld, Yehuda; Putterman, Chaim; Youinou, Pierre

doi:10.1002/art.22015

Cited by 70 publications

(52 citation statements)

References 46 publications

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“…Notably, Ig eluted from kidneys of nephritic lupus mice bound to ␣-actinin, further supporting the notion that ␣-actinin is a target for pathogenic lupus autoantibodies (4). Recent human studies have shown that high titers of anti-␣-actinin Abs were detected at an early stage of lupus nephritis and that anti-␣-actinin Abs are significantly associated with glomerulonephritis in lupus patients (5)(6)(7). These latter findings suggest that anti-␣-actinin Abs may be useful as a serological marker in human lupus nephritis.…”

supporting

confidence: 56%

“…Furthermore, all the common peptide sequences from each respective Ag were in B cell epitope regions as determined by Bcepred, a B cell epitope prediction program (22). Importantly, the common peptide sequence from ␣-actinin is found in its actin binding domain, a region recently determined to be targeted by the anti-␣-actinin response in human lupus nephritis (5).…”

Section: Ags Bound By Sera From ␣-Actinin-immunized Mice Share a Commmentioning

confidence: 99%

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α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice

Deocharan¹,

Zhou

Antar

et al. 2007

The Journal of Immunology

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Anti-dsDNA Abs are characteristic of lupus and can be found deposited in the kidneys of lupus mice. Previously, we have shown that pathogenic anti-dsDNA Abs as well as Ig eluted from the kidneys of nephritic lupus mice cross-react with α-actinin. Moreover, cross-reactivity with α-actinin characterizes nephritogenic anti-dsDNA Abs in humans with lupus as well. To determine whether Abs generated against α-actinin in vivo cross-react with nuclear Ags, we s.c. immunized 10-wk-old female BALB/c mice (and several other nonautoimmune mice strains) with α-actinin in adjuvant. Immunized but not control mice displayed high titers of anti-nuclear Abs and IgG anti-chromatin autoantibodies, hypergammaglobulinemia, renal Ig deposition, and proteinuria. The specificity of the anti-chromatin response was determined by Western blotting of purified chromatin with serum from α-actinin immunized mice. By proteomic analysis, a 25-kDa doublet band was conclusively identified as high mobility group box (HMGB) proteins 1 and 3, and a 70-kDa band was identified as heat shock protein 70 (hsp70), both of which are known antigenic targets in murine lupus. Binding to purified HMGB1 and hsp70 by immunized mice sera was confirmed by ELISA and Western blot. Immunized mice sera binding to both 25- and 70-kDa bands were significantly inhibited by α-actinin and chromatin. Importantly, a panel of nephritogenic mAbs had significantly higher affinity for α-actinin, chromatin, HMGB, and hsp70 as compared with nonpathogenic Abs, suggesting a common motif in these Ags that is targeted by pathogenic autoantibodies.

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supporting

confidence: 56%

Section: Ags Bound By Sera From ␣-Actinin-immunized Mice Share a Commmentioning

confidence: 99%

α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice

Deocharan¹,

Zhou

Antar

et al. 2007

The Journal of Immunology

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“…46 The list includes antidsDNA, antihistones, 47-52 and antibodies versus endogenous antigens, such as antiactinin. 10,13,53,54 Actually, definition of specific renal and serum levels of the above antibodies are in progress and will be reported very soon (G.M. Ghiggeri, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11][12] They consider a pre-eminent role of circulating anti-double stranded DNA (dsDNA) antibodies that they can interact, for mimicry, with glomerular antigens expressed at the cell surface of podocytes and mesangial cells 7,[13][14][15] or in the glomerular basement membrane. 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).…”

mentioning

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.…”

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confidence: 99%

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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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Male gender results in more severe lupus nephritis

et al. 2009

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Gender may produce different characteristics in the manifestation of systemic lupus erythematosus (SLE). The present study investigated the influence of gender on clinical, laboratory, autoantibodies and histopathological classes of lupus nephritis (LN). As much as 81 patients diagnosed with SLE (ACR criteria) and active nephritis, who underwent renal biopsy between 1999 and 2004, and who had frozen serum samples and clinical data available from the time of biopsy, were selected for this study. The presence of anti-P and antichromatin antibodies was measured using ELISA, and anti-dsDNA was measured using indirect immunofluorescence. All of the renal biopsies were reviewed in a blinded manner by the same expert renal pathologist. The charts were extensively reviewed for demographic and renal features obtained at the time of the biopsy. Of the 81 patients (13.6%), 11 were male SLE patients. Both male and female lupus patients were of similar age and race, and had similar durations of lupus and renal disease. The female patients had more cutaneous (95.7 vs. 45.5%, P = 0.0001) and haematological (52.9 vs. 18.2%, P = 0.04) involvements than the male SLE patients. In addition, the articular data, central nervous system analyses, serositis findings and SLEDAI scores were similar in both experimental groups. Positivity for anti-dsDNA, anti-ribosomal P and antichromatin did not differ between the two groups, and both groups showed similarly low C3 or C4 serum levels. Our analysis indicated that no histopathological class of LN was predominant in both males and females. Interestingly, the serum creatinine levels were higher in the male SLE patients compared to the female SLE group (3.16 +/- 2.49 vs. 1.99 +/- 1.54 mg/dL, P = 0.03), with an increased frequency of high creatinine (81.8 vs. 47.1%, P = 0.04) as well as renal activity index (7.6 +/- 3.5 vs. 4.8 +/- 3.5, P = 0.02). In addition, whilst the mean levels of proteinuria, cylindruria and serum albumin were markedly altered, they were comparable between both lupus men and women. Moreover, the frequencies of dialysis, renal transplantation and death were similar between the two groups. These data suggest that male patients had a more severe LN compared to women diagnosed with this renal abnormality.

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Association of α‐actinin–binding anti–double‐stranded DNA antibodies with lupus nephritis

Cited by 70 publications

References 46 publications

α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice

α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo

Male gender results in more severe lupus nephritis

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