Antigen specificity of anti‐nuclear antibodies complexed to nucleosomes determines glomerular basement membrane binding <i>in vivo</i>

Bruggen, M.C.J. van; Walgreen, Birgitte; Rijke, T. P. M.; Tamboer, W.P.M.; Kramers, Kees; Smeenk, R. J. T.; Monestier, Marc; Fournié, Gilbert J.; Berden, Jo H. M.

doi:10.1002/eji.1830270636

Cited by 84 publications

(63 citation statements)

References 28 publications

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“…Consistent with this is the observation that nonpurified nucleosome-contaminated DNA6 or 452s46 antidsDNA antibodies bound DNA and nucleosomes, but not H1. None of the mAb or antibodies eluted from kidneys bound type IV collagen, heparan sulfate, or DNase I, which are known to bind nucleosomes (14,16,38) or DNA (35). Such results support the conclusion that these IgG antibodies recognize dsDNA and H1 by their variable regions.…”

Section: Discussionsupporting

confidence: 66%

“…Contemporarily, studies of the nephritogenicity of anti-dsDNA antibodies follow 2 main directions, based on the following theories: either anti-dsDNA antibodies form complexes with nucleosomes that deposit in glomeruli (13)(14)(15)(16), or anti-dsDNA antibodies cross-react with non-nucleosomal glomerular structures (8,9). 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).…”

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confidence: 99%

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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: 66%

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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“…Some antibodies known to be pathogenic in mice were initially thought to bind naked dsDNA, but have subsequently been shown to bind nucleosomes or chromatin instead (11,27,38). Antinucleosome antibodies are thought to cause glomerulonephritis by formation of nucleosome-antinucleosome complexes, which interact with heparan sulfate in the glomerular basement membrane (11,12). Wellmann et al (19) recently showed that 2 somatic mutations in the light chain and 1 in the heavy chain of the human anti-dsDNA monoclonal antibody 33.C9 were essential for binding to either dsDNA or nucleosomes.…”

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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“…Both in vivo transfer experiments with nucleosomes complexed with lupus antibody [23,24] and GBM binding in vitro of sera from lupus-prone mice and SLE patients [25,26] have indicated that nucleosomes, either within circulat-ing immune complexes or present in situ on target tissues, mediate binding of lupus autoantibodies to glomerular antigens. Furthermore, there is also evidence that the nucleosome could exert direct effects on cell function, presumably through binding to specific surface receptors [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Nucleosomes inhibit phagocytosis of apoptotic thymocytes by peritoneal macrophages from MRL+/+ lupus-prone mice

Laderach

Bach

Koutouzov

1998

Journal of Leukocyte Biology

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The nucleosome, the basic structure of chromatin and normal product of cell apoptosis, plays a pivotal role both in the induction and the pathogenesis of systemic lupus erythematosus (SLE). Nucleosomes have been found to circulate at high levels in patients with SLE and apoptosis of lymphoid cells is increased during human and murine lupus. In this study, we examined the presence of possible defects in clearance mechanisms of apoptotic cells in murine lupus, and questioned further whether nucleosomes could compromise this phagocytic process. There did not appear to be any intrinsic functional defect of macrophages from young MRL؉/؉ lupus-prone mice to recognize and phagocytose apoptotic thymocytes. Nucleosomes, as a mimic of increased cell apoptotsis in vivo, induced a strong, dose-dependent, inhibition of phagocytosis of apoptotic thymocytes by young, pre-autoimmune, macrophages of MRL؉/؉ mice, whereas macrophages of non-autoimmune C3H mice only exhibited a trend to inhibition. The nucleosome-elicited inhibitory effect persisted during the development of the autoimmune response and appeared to be specific for the molecular mechanisms involved in macrophage phagocytosis of apoptotic cells. Our data suggest that nucleosome elicited inhibition of phagocytosis of apoptotic cells by MRL؉/؉ macrophages before the onset of the autoimmune response contribute, in a positive loop, to sustain and/or augment the levels of circulating (and potentially immunogenic) nucleosomes in lupus. J. Leukoc. Biol. 64: 774-780; 1998.

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Antigen specificity of anti‐nuclear antibodies complexed to nucleosomes determines glomerular basement membrane binding in vivo

Cited by 84 publications

References 28 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

Nucleosomes inhibit phagocytosis of apoptotic thymocytes by peritoneal macrophages from MRL+/+ lupus-prone mice

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