Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis

被引:147
作者
Kalaaji, M.
Fenton, K. A.
Mortensen, E. S.
Olsen, R.
Sturfelt, G.
Alm, P.
Rekvig, O. P. [1 ]
机构
[1] Univ Tromso, Med Biol Inst, Dept Biochem, N-9037 Tromso, Norway
[2] Univ Tromso, Med Biol Inst, Dept Pathol, Tromso, Norway
[3] Univ Tromso, Dept Electron Microscopy, Tromso, Norway
[4] Univ Lund Hosp, Dept Rheumatol, S-22185 Lund, Sweden
[5] Univ Lund Hosp, Dept Pathol, S-22185 Lund, Sweden
关键词
systemic lupus erythematosus; nephritis; immunology and pathology; immune complexes; glomerulus; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTI-DNA ANTIBODIES; BASEMENT-MEMBRANE; ALPHA-ACTININ; ANTINUCLEAR AUTOANTIBODIES; CELLS; MICE; CLASSIFICATION; REACTIVITY; HISTONES;
D O I
10.1038/sj.ki.5002133
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Antibodies to double-stranded (dsDNA) are associated with systemic lupus erythematosus (SLE) and directly involved in human lupus nephritis. Information about their glomerular target antigens is inconsistent, and whether availability of target antigens, antibody specificity or avidity are nephritogenic parameters, is not determined. In this study, we analyzed renal tissue from anti-dsDNA antibody-positive lupus patients with nephritis by morphological and immunological assays, including immune electron microscopy (IEM) and colocalization IEM, an EM-based confocal microscopy assay. IEM demonstrated that antibody deposits were confined to electron dense structures (EDS) in glomerular membranes. These autoantibodies colocalized with nucleosome-binding anti-dsDNA/-histone/-transcription factor antibodies. To confirm the colocalization IEM-data, we developed a colocalization terminal deoxynucleotidyltransferase (TdT) biotin-dUTP nicked end-labeled (TUNEL) IEM assay where extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and autoantibodies by IEM. Results consistently demonstrated that DNA colocalized with autoantibodies in glomerular membrane-associated EDS. The colocalization IEM and colocalization TUNEL IEM assays thus demonstrate that intra-glomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies in human lupus nephritis. The data provide a new approach to understand basic molecular and immunological processes accounting for antibody-mediated nephritis in human SLE.
引用
收藏
页码:664 / 672
页数:9
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