Review: Nephritogenic autoantibodies in lupus: Current concepts and continuing controversies

Lefkowith, James B.; Gilkeson, Gary S.

doi:10.1002/art.1780390605

Cited by 191 publications

(128 citation statements)

References 90 publications

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“…On the basis of the results presented above, serum antibodies and antibodies eluted from kidneys of individual B/W or BALB/c mice were further analyzed for binding to ␣-actinin, dsDNA, and H1. DNase I and heparan sulfate were included as control antigens in all ELISAs, because these ligands bind dsDNA (35) and nucleosomes (16,25).…”

Section: Resultsmentioning

confidence: 99%

“…It is unlikely that nucleosomes, if bound to these antibodies, could mediate binding to both anionic (DNA) and cationic (H1) structures. Nucleosomes are reported to bind anionic heparan sulfate or type IV collagen through protruding tails of cationic histones (16,25,38). In this respect, anti-dsDNA antibody-bound nucleosomes should be repelled by H1 rather than bound to it.…”

Section: Discussionmentioning

confidence: 99%

“…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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Use of this experimental tool has been instrumental in demonstrating the potential pathogenic role of several mediators, including a variety of adhesion molecules, chemokines, and cytokines (23)(24)(25)(26)(27)(28)(29). Proteinuria is typically the first indicator that surfaces in both experimental and spontaneous immune nephritis (1)(2)(3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Xie

Bhaskarabhatla

et al. 2007

Arthritis & Rheumatism

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Objective. Currently, proteinuria is viewed as the earliest indicator of renal disease in immune-mediated nephritis. The objective of this study was to determine whether additional mediators may be excreted in the urine during immune-mediated nephritis, using an experimental model with a well-defined disease course.Methods. Urine samples from mice with antiglomerular basement membrane (anti-GBM) antibodyinduced experimental nephritis were screened using a focused immunoproteome array bearing 62 cytokines/ chemokines/soluble receptors. Molecules identified through this screening assay were validated using an enzyme-linked immunosorbent assay. One of these molecules was further evaluated for its pathogenic role in disease, using antibody-blocking studies.Results. Compared with B6 and BALB/c mice, in which moderately severe immune-mediated nephritis develops, the highly nephritis-susceptible 129/Sv and DBA/1 mice exhibited significantly increased urinary levels of vascular cell adhesion molecule 1 (VCAM-1), P-selectin, tumor necrosis factor receptor I (TNFRI), and CXCL16, particularly at the peak of disease. Whereas some of the mediators appeared to be serum derived early in the disease course, local production in the kidneys appeared to be an important source of these mediators later in the course of disease. Both intrinsic renal cells and infiltrating leukocytes appeared to be capable of producing these mediators. Finally, antibodymediated blocking of CXCL16 ameliorated experimental immune nephritis.Conclusion. These studies identified VCAM-1, P-selectin, TNFRI, and CXCL16 as a quartet of molecules that have potential pathogenic significance; the levels of these molecules are significantly elevated during experimental immune nephritis. The relevance of these molecules in spontaneous immune nephritis warrants investigation.

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“…Nevertheless, the utility of these markers in reflecting disease activity remains controversial [16][17][18], and C3 and C4 not always accurately reflect complement activation [16,19,20]. C3 acts as an acute-phase protein, and thus an increased production can obscure its consumption [21,22].…”

Section: Introductionmentioning

confidence: 99%

Markers of childhood lupus nephritis indicating disease activity

et al. 2010

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Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8±4.7 years), nephrotic syndrome (n =13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p<0.0001) and common pathway (C5a, p<0.0001) and the levels of BAFF (p< 0.0001), RANTES (p=0.0002) and sVCAM-1 (p=0.0004) were significantly higher in active compared to inactive LN. Activation of complement was associated with the occurrence of anti-C1q antibodies and reduced complement

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Review: Nephritogenic autoantibodies in lupus: Current concepts and continuing controversies

Cited by 191 publications

References 90 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

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Markers of childhood lupus nephritis indicating disease activity

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