Is α‐actinin a target for pathogenic anti‐DNA antibodies in lupus nephritis?

Mason, Lesley; Ravirajan, C. T.; Rahman, Anisur; Putterman, Chaim; Isenberg, David

doi:10.1002/art.20103

Cited by 94 publications

(80 citation statements)

References 13 publications

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“…This finding is in contrast with a recent report of the weak expression of anti-␣-actinin antibodies in kidney eluates from (NZB ϫ NZW)F 1 mice (11). Thus, our data confirm the presence of serum antibodies to ␣-actinin in SLE (19,20) but not their nephritogenic potential. In contrast, the present IEM analyses revealed antibodies deposited in electrondense structures associated with the GBM in both the early stages of nephritis (Kalaaji M, et al: unpublished observations) and the advanced stages of nephritis.…”

Section: Discussionsupporting

confidence: 62%

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Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Kalaaji¹,

Sturfelt²,

Mjelle³

et al. 2006

Arthritis & Rheumatism

102

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Objective. Although anti-double-stranded DNA (anti-dsDNA) antibodies are important in lupus nephritis, the question regarding which glomerular structures (␣-actinin, nucleosomes, or others) are recognized by nephritogenic anti-dsDNA antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivobound nephritogenic antibodies.Methods.Western blotting was used to analyze the ability of nephritogenic anti-dsDNA antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody-positive patients, and paired antibodies from sera and kidney eluates from nephritic (NZB ؋ NZW)F 1 mice were analyzed for activity against proteins identified by monoclonal nephritogenic antibodies, and against ␣-actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of ␣-actinin and in vivo-bound autoantibodies in nephritic (NZB ؋ NZW)F 1 mouse kidneys.Results. Anti-␣-actinin antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic anti-dsDNA antibodies recognized a 32-kd band, identified as histone H1. Competitive enzyme-linked immunosorbent assay demonstrated that nephritogenic monoclonal antibodies, and dominant antibodies eluted from nephritic kidneys, cross-reacted with dsDNA and H1. This cross-reactive anti-H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB ؋ NZW)F 1 mouse kidneys revealed that antibodies eluted from kidneys, but not anti-␣-actinin antibodies, bound to distinct nephritis-associated electrondense structures linked to glomerular basement membranes. Conclusion.Cross-reactive anti-dsDNA/antihistone H1 antibodies, but not anti-␣-actinin antibodies, are central among those deposited in nephritic glomeruli.

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Section: Discussionsupporting

confidence: 62%

“…Recently, antibodies to ␣-actinin, a major structural component of glomerular podocytes and mesangial cells (17,18), have attracted particular attention, because ␣-actinin may represent a target molecule for nephritogenic anti-dsDNA antibodies (10,11,19,20).…”

mentioning

confidence: 99%

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Kalaaji¹,

Sturfelt²,

Mjelle³

et al. 2006

Arthritis & Rheumatism

102

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“…Two groups have shown that binding to ␣-actinin is an important factor in the pathogenicity of anti-dsDNA antibodies in mouse models (9,10,35). These results were supported in a clinical study (32). No group has previously published an analysis of effects of somatic mutations in human anti-dsDNA antibodies on ability to bind ␣-actinin.…”

Section: Lambrianides Et Almentioning

confidence: 94%

“…The direct ELISAs used to detect binding of IgG molecules to ␣-actinin, cardiolipin, and ␤ 2 GPI have been described previously (25,32). The assay for IgG binding to cardiolipin was performed using fetal calf serum (FCS) containing ␤ 2 GPI.…”

Section: Lambrianides Et Almentioning

confidence: 99%

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

Lambrianides¹,

Giles²,

Ioannou³

et al. 2007

Arthritis & Rheumatism

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Objective. Previous studies have shown the importance of somatic mutations and arginine residues in the complementarity-determining regions (CDRs) of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies in human and murine lupus, and in studies of murine antibodies, a role of mutations at position 53 in V H CDR2 has been demonstrated. We previously demonstrated in vitro expression and mutagenesis of the human IgG1 monoclonal antibody B3. The present study was undertaken to investigate, using this expression system, the importance of the arginine residue at position 53 (R53) in B3 V H .Methods. R53 was altered, by site-directed mutagenesis, to serine, asparagine, or lysine, to create 3 expressed variants of V H . In addition, the germline sequence of the V H 3-23 gene (from which B3 V H is derived) was expressed either with or without arginine at position 53. These 5 new heavy chains, as well as wild-type B3 V H , were expressed with 4 different light chains, and the resulting antibodies were assessed for their ability to bind to nucleosomes, ␣-actinin, cardiolipin, ovalbumin, ␤ 2 -glycoprotein I (␤ 2 GPI), and the N-terminal domain of ␤ 2 GPI (domain I), using direct binding assays.Results. The presence of R53 was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of R53 reduced binding to ␣-actinin, ovalbumin, ␤ 2 GPI, and domain I of ␤ 2 GPI. The combination B3 (R53S) V H /B3 V L bound human, but not bovine, ␤ 2 GPI.Conclusion. The fact that the R53S substitution significantly alters binding of B3 to different clinically relevant antigens, but that the alteration is in opposite directions depending on the antigen, implies that this arginine residue plays a critical role in the affinity maturation of antibody B3.

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“…Purified anti-dsDNA antibodies from patients with SLE showed cross-reactivity with α-actinin and this was most commonly observed in patients with lupus nephritis (285). This argument was strengthened by demonstrating an association between antibody affinity for α-actinin and binding to glomeruli in vitro (286) .…”

Section: Discussionmentioning

confidence: 98%

Golgi Specificity and Development of Autoreactive B Cells

Nawazi¹

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Is α‐actinin a target for pathogenic anti‐DNA antibodies in lupus nephritis?

Cited by 94 publications

References 13 publications

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

Golgi Specificity and Development of Autoreactive B Cells

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