Effect of human anti-DNA antibodies on proximal renal tubular epithelial cell cytokine expression : Implications on tubulointerstitial inflammation in lupus nephritis

• Published in: Journal of the American Society of Nephrology Vol. 16; no. 11; pp. 3281 - 3294
• Main Authors: SUSAN YUNG, TSANG, Ryan C. W, YULING SUN, LEUNG, Jack K. H, TAK MAO CHAN
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.11.2005
• Subjects: Antibodies - pharmacology; Biological and medical sciences; Cells, Cultured; Cycloheximide - pharmacology; Cytokines - genetics; Dactinomycin - pharmacology; DNA - immunology; Flow Cytometry; Humans; Immunoglobulin G - analysis; Immunoglobulin G - pharmacology; Inflammation; Interleukin-6 - analysis; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - immunology; Kidneys; Lupus Nephritis - immunology; Medical sciences; Nephrology. Urinary tract diseases; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Urinary system involvement in other diseases. Miscellaneous; Urothelium - drug effects; Urothelium - immunology; Kidney disease; Human; Proximal; Immunopathology; Connective tissue disease; Skin disease; Nephrology; Urinary system disease; Antibody; Pathogenesis; Cytokine; Autoimmune disease; Inflammation; Lupus nephritis; Urology; Renal tubule; Systemic lupus erythematosus; DNA; Tubulointerstitial nephritis; Systemic disease; Epithelial cell; Complication
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2004110917

This study aimed to investigate the effects of human anti-DNA antibodies (Ab) from patients with lupus on renal proximal tubular epithelial cells (PTEC), focusing on alterations in cell morphology and proinflammatory cytokine synthesis. Immunohistochemistry showed increased tubulointerstitial IL-6 expression and IgG deposition in renal biopsies from patients with diffuse proliferative lupus nephritis, not observed in controls or membranous lupus nephritis, which correlated with the severity of inflammatory cell infiltration. Sera from patients with lupus nephritis contained IgG that bound to cultured PTEC. Such binding increased with disease activity and correlated with the level of anti-DNA Ab. Incubation of PTEC with anti-DNA Ab that were isolated during active (active Ab) or inactive (inactive Ab) disease induced IL-6 synthesis, both apically and from the basolateral aspect. This was accompanied by altered cell morphology, increased cell proliferation (P < 0.05), and lactate dehydrogenase release (P < 0.05). The binding of inactive Ab and active Ab to PTEC resulted in differential and sequential upregulation of TNF-alpha, IL-1beta, and IL-6 secretion (P < 0.05). Early induction of TNF-alpha was observed with active Ab; the two then acted synergistically to induce IL-6 secretion. Exposure of PTEC to inactive Ab was associated with modest induction of TNF-alpha, which was not involved in downstream induction of other proinflammatory peptides. These data suggest distinct immunopathogenetic mechanisms during disease flare or remission. Conditioned media from human mesangial cells acted synergistically with anti-DNA Ab to induce cytokine secretion in PTEC. Results from these studies underscore the pivotal role of PTEC in the pathogenesis of tubulointerstitial inflammation and fibrosis in lupus nephritis.