Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1).
MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-gamma. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1-/- MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1-/- MRL/lpr mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.
Shimizu
Sakiko
S
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan.
Sugiyama
Naonobu
N
Masutani
Kohsuke
K
Sadanaga
Atsushi
A
Miyazaki
Yoshiyuki
Y
Inoue
Yasushi
Y
Akahoshi
Mitsuteru
M
Katafuchi
Ritsuko
R
Hirakata
Hideki
H
Harada
Mine
M
Hamano
Shinjiro
S
Nakashima
Hitoshi
H
Yoshida
Hiroki
H
D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007073:Immunoglobulin E / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000235:genetics / Q000276:immunology*; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics; D018123:Receptors, Interleukin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
C484747:Il27ra protein, mouse; D007074:Immunoglobulin G; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma