RESUMO
Mechanisms that initiate lupus nephritis and cause progression to end-stage renal disease remain poorly understood. In this study, we show that lupus-prone New Zealand Mixed 2410 mice that develop a severe glomerulosclerosis and rapidly progressive renal disease overexpress IL-4 in vivo. In these mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs. STAT4 deficiency, however, decreases type 1 and increases type 2 cytokine responses, and accelerates nephritis, in the absence of high levels of IgG anti-dsDNA Abs. Thus, STAT6 and IL-4 may selectively contribute to the development of glomerulosclerosis, whereas STAT4 may play a role in autoantibody production.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Interleucina-4/fisiologia , Nefrite Lúpica/imunologia , Transdução de Sinais/imunologia , Transativadores/fisiologia , Animais , Anticorpos Antinucleares/biossíntese , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais/administração & dosagem , Cruzamentos Genéticos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/terapia , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Injeções Intraperitoneais , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Interleucina-4/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Nefrite Lúpica/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Camundongos Knockout , Mutagênese Sítio-Dirigida , Fator de Transcrição STAT4 , Fator de Transcrição STAT6 , Transdução de Sinais/genética , Especificidade da Espécie , Transativadores/deficiência , Transativadores/genética , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
We have developed novel genetically lupus-prone (NZB x NZW)F(1)-derived congenic New Zealand mixed (NZM) 2328 lines, which are either Stat4- or Stat6-deficient. Our studies show that the deficiency of Stat4 and Stat6 significantly alters the phenotype of the lupus-like disease in NZM 2328 congenic mice. Specifically, Stat4-deficient NZM mice develop accelerated nephritis and increased mortality in the absence of high levels of autoantibodies including anti-dsDNA Abs, and in the presence of relatively reduced levels of IFN-gamma. In contrast, Stat6-deficient NZM mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs. The lack of correlation between levels of these autoantibodies and kidney disease raises the question of the direct cause-effect relationships between the presence of autoantibodies and kidney disease. Furthermore, these results also question the apparent equation of the effect of Stat deficiency with loss of secretion or response to particular cytokines.