Development with Th2-Type Immune Membranous Glomerulonephritis

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-␥. 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-␥ 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. S ystemic lupus erythematosus (SLE) 4 is characterized by multiorgan inflammation and the production of autoanti-bodies by activated B lymphocytes. These autoantibodies lead to immune complex (IC) formation that can cause a renal disorder called lupus nephritis, one of the most serious complications of SLE (1, 2). Lupus nephritis is manifested with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative glomerulonephritis (DPGN; World Health Organization (WHO) class IV) and membranous glomerulonephri-tis (MGN; WHO class V) represent two morphologic forms that are polar opposites (3, 4). The pathogenesis of DPGN is associated with a predominance of Th1 cytokines, indicating that DPGN occurs in a Th1-dominant immune milieu. The renal tissue of DPGN patients shows increased levels of Th1 cytokines, including IFN-␥ (5, 6). Furthermore, the ratio of IFN-␥ vs IL-4 production correlates positively with the histological activity index of the nephritis (5, 6). In contrast, PBLs from MGN patients show a decreased IFN-␥ vs IL-4 production ratio (5), suggesting that a Th2-dominant cytokine response is associated with the pathogenesis of MGN. This hypothesis is supported by the phenotype of serum cryo-globulins isolated from DPGN and MGN patients, with mostly Th1-related IgG3 autoantibodies (murine equivalent IgG3) being present in DPGN cases, and mostly Th2-related IgG4 (murine IgG1) autoantibodies dominating in MGN cases (7). …