Effect of Human Anti-DNA Antibodies on Proximal Renal Tubular Epithelial Cell Cytokine Expression

Abstract

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-␣, IL-1␤, and IL-6 secretion (P < 0.05). Early induction of TNF-␣ 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-␣, 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.

Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice

“…This is worthy of further investigation in view of the accumulating data on the direct interaction between anti-DNA antibodies and resident kidney cells. 30,31 In conclusion, the results from our studies show that rapamycin is effective in ameliorating aberrant immune hyperactivity and preventing the development of lupus nephritis in the NZB/W F 1 mouse. Further studies are warranted to examine the effect of rapamycin in the treatment of florid disease and its role in the treatment of human lupus.…”

Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system

“…[20][21][22][23][24][25] Some investigators proposed different pathogenic mechanisms inducing tubulointerstitial injury in experimental and human lupus nephritis. These factors include immune complex deposition, 23,26,27 albuminuria macrophage chemokines, 28-33 some autoantibodies, 34,35 and others. 36 Recent studies suggested that activation of tubular Toll-like receptor-9 had a pathogenic role in tubulointerstitial inflammation and damage in lupus nephritis.…”

Bee Venom-Associated Th1/Th2 Immunoglobulin Class Switching Results in Immune Tolerance of NZB/W F1 Murine Lupus Nephritis

“…The important role of anti-DNA antibodies in the pathogenesis of autoimmune glomerulonephritis in lupus mice has been well documented [21]. It was recently demonstrated that anti-DNA antibodies bound to mesangial cells and proximal renal tubular epithelial cells, and were rapidly internalized following cell surface binding [22,23]. This was associated with a proliferative response, decreased cell viability, and increased synthesis of extracellular matrix components and pro-inflammatory cytokines such as IL-6 and TNF-α [23].…”

“…It was recently demonstrated that anti-DNA antibodies bound to mesangial cells and proximal renal tubular epithelial cells, and were rapidly internalized following cell surface binding [22,23]. This was associated with a proliferative response, decreased cell viability, and increased synthesis of extracellular matrix components and pro-inflammatory cytokines such as IL-6 and TNF-α [23]. It has also been reported that mouse anti-dsDNA antibodies penetrate mouse macrophage cells and stimulate nuclear factor-kappa B activation and TNF-α release [24].…”