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BXSB-Type Genome Causes Murine Autoimmune Glomerulonephritis: Pathological Correlation Between Telomeric Region of Chromosome 1 and Yaa

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BXSB-Type Genome Causes Murine Autoimmune Glomerulonephritis: Pathological Correlation Between Telomeric Region of Chromosome 1 and Yaa Genes and Immunity (2014) 15, 182–189 & 2014 Macmillan Publishers Limited All rights reserved 1466-4879/14 www.nature.com/gene ORIGINAL ARTICLE BXSB-type genome causes murine autoimmune glomerulonephritis: pathological correlation between telomeric region of chromosome 1 and Yaa J Kimura1, O Ichii1, T Nakamura1,2, T Horino3, S Otsuka1 and Y Kon1 The autoimmune-prone BXSB/MpJ-Yaa mouse is a model of membranous proliferative glomerulonephritis (MPGN). Severe MPGN has been reported only in male BXSB/MpJ-Yaa mice because of the Y-linked autoimmune accelerator (Yaa) locus. However, we show that female BXSB/MpJ mice develop age-related MPGN without Yaa. Female BXSB/MpJ mice clearly developed MPGN characterized by increased mesangial cells, thickening of the glomerular basement membrane (GBM), double contouring and spike formation of GBM with T-cell infiltrations and podocyte injuries corresponding with increased autoantibody production and albuminuria. Analysis of the renal levels of the Fc gamma receptor (Fcgr) and interferon-activated gene 200 (Ifi200) family genes, which are MPGN candidate genes localized to the telomeric region of chromosome 1 (Chr.1), showed that Fcgr2b levels decreased, whereas Fcgr3 and Ifi202b levels increased in female BXSB/MpJ mice compared with healthy C57BL/6 mice. Furthermore, in isolated glomeruli, microarray analysis revealed that Fcgr3, Fcgr4 and Ifi202b expression was higher in male BXSB/MpJ-Yaa mice than in male BXSB/MpJ mice. These findings indicate that the BXSB/MpJ-type genome causes age-related MPGN with significant contribution from the telomeric region of Chr.1, and Yaa enhances the expression of genes localizing to this locus, thereby leading to severe MPGN in male mice. Genes and Immunity (2014) 15, 182–189; doi:10.1038/gene.2014.4; published online 30 January 2014 Keywords: autoimmune; BXSB/MpJ; Fc gamma receptor; interferon-activated gene 200; membranous proliferative glomerulonephritis; telomeric region of chromosome 1 INTRODUCTION receptor proteins (FcgRs) recognize the Fc portion of Systemic lupus erythematosus (SLE) is an autoimmune disease immunoglobulin G (IgG) and have crucial roles in determining characterized by autoantibody production and complement-fixing the response to deposited ICs.5 Immune response activation immune complex (IC) deposition that result in tissue inflammation through FcgR is caused by binding of ICs containing IgG to active and damage.1 SLE-related glomerulonephritis (GN) (lupus FcgRs, such as FcgRIII and FcgRIV in mouse.5,6 FcgRs also nephritis; LN) is one of the most common and severe compli- negatively regulate immune responses; mouse FcgRIIB, which is cations of SLE with high mortality because of the risk of not only the only inhibitory FcgR, takes balance of immune responses to end-stage renal disease but also cardiovascular diseases.1 Thus, deposited ICs.5–7 We previously demonstrated that altered ratios understanding the pathophysiology of SLE and subsequent LN is of mouse FcgRIIB and FcgRIII in the kidney are strongly related to important to improve the morbidity and mortality of patients. the development of autoimmune-mediated MPGN in congenic Lupus-prone mice, such as NZB, (NZB Â NZW) F1 hybrid, mice carrying the telomeric region of MRL/MpJ-type Chr.1 and BXSB/MpJ-Yaa and MRL/MpJ-lpr, are commonly used as sponta- C57BL/6-type background (B6.MRLc1 strain).8 The Ifi200 family, neous SLE models.2 These strains develop systemic autoimmune including Ifi202b, Ifi203, Ifi204 and Ifi205, consists of genes induced diseases characterized by increased serum autoantibody levels by IFNs.9 These genes encode highly homologous proteins and and vasculitis, as well as membranous proliferative GN (MPGN) are suggested to have important roles in the regulation of cellular similar to human LN.2 Recent studies have revealed susceptibility growth, differentiation, survival and death.9–11 Recent studies loci linked with the development of SLE in mouse models, such as using B6.MRLc1 and BXSB/MpJ-Yaa mice clarified that renal Ifi202b Sle1–6, Lbw1–7, Sbw1–2, Nba1–3, Lprm1–5 and Mag.3,4 Sle1, Nba2 expression increased with the development of autoimmune- and Mag are linked to the development of GN, and Lbw7 is linked mediated MPGN.12,13 to autoantibody production and splenomegaly. Interestingly, BXSB/MpJ-Yaa mice carry a mutant gene located on the Y these loci were mapped to the same telomeric region of chromosome, namely, Y-linked autoimmune acceleration (Yaa), chromosome 1 (Chr.1) in different inbred mouse SLE models.3 and it was thought that only males show severe MPGN.14 We have The telomeric region of Chr.1 includes major immune-related previously demonstrated that BXSB/MpJ-Yaa mice develop genes such as those of the Fc gamma receptor (Fcgr) family and glomerular lesions with decreased functional podocyte proteins, interferon (IFN)-activated gene 200 (Ifi200) family.4 Fc gamma thereby leading to proteinuria subsequent to the formation of 1Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan; 2Section of Biological Safety Research, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Japan and 3Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Nankoku, Japan. Correspondence: Dr Y Kon, Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita18-Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan. E-mail: [email protected] Received 16 October 2013; revised 5 December 2013; accepted 19 December 2013; published online 30 January 2014 BXSB/MpJ-type genome causes glomerulonephritis J Kimura et al 183 tubulointerstitial lesions.15,16 Interestingly, the C57BL/6-type The glomerulus damage score (Figure 1i) and cell number in background congenic strain carrying Yaa does not develop an one glomerulus (Figure 1j) significantly increased from 7 months, autoimmune phenotype.17 These findings indicate that Yaa in a and the thickness of the GBM (Figure 1k) increased from BXSB/MpJ genomic background is associated with the disruption 10 months of age. of autoimmunity. Furthermore, Haywood et al.12 used male backcrosses between BXSB/MpJ-Yaa and C57BL/10 to identify six Immune cell infiltration of the glomerulus of female BXSB/MpJ autosomal loci (Bxs1–6) that have important roles in suscept- mice ibilities of mortality, autoantibody production, splenomegaly and The glomerular infiltration of immune cells in female BXSB/MpJ MPGN. In particular, similar to Sle1, Lbw7, Nba2 and Mag, Bxs3 mice was assessed by immunohistochemistry for CD3 (T-cell localizes to the telomeric region of BXSB/MpJ-type Chr.1, which marker) and B220 (B-cell marker). CD3-positive cells were includes the coding regions of Fcgr2b, Fcgr3, Fcgr4 and Ifi202b, and observed in the glomerulus as well as the tubulointerstitium at also closely links to the development of autoantibody production, 12 13 months (Figure 2b) but not at 2 months of age (Figure 2a). splenomegaly and GN. Comparatively, B220-positive cells were scarcely observed in In this study, we found age-related MPGN development with female BXSB/MpJ mice at 2 and 13 months of age (Figures 2c increased autoantibody production and albuminuria in female and d). In histoplanimetry, the number of CD3-positive cells in BXSB/MpJ mice, thereby indicating that the BXSB/MpJ-type the glomerulus was significantly higher at 13 months than at genome alone can lead to an autoimmune state. Furthermore, 2 months of age (Figure 2e). Consistent with the histological the expression of GN candidate genes on the telomeric region of observation, the number of B220-positive cells in the glomerulus Chr.1, such as Fcgr3 and Ifi202b, was significantly altered in the was quite low at both 2 and 13 months of age. kidney of female BXSB/MpJ mice and drastically increased in the glomerulus of male BXSB/MpJ-Yaa mice. We concluded that the BXSB/MpJ-type genome causes MPGN with significant Glomerular ultrastructure in female BXSB/MpJ mice contribution of the telomeric region of Chr.1, and Yaa enhances The glomerular ultrastructure of female BXSB/MpJ mice was the expression of GN candidate genes localizing to this locus, analyzed at 2 and 10 months by using transmission electron thereby leading to severe MPGN in males. microscopy. Female BXSB/MpJ mice at 2 months of age showed clear cytopodium (foot process), which is also known as secondary process (Figures 3a and c). At 10 months of age, foot processes RESULTS showed irregular arrangements with hypertrophy and partial Clinical parameters of female BXSB/MpJ mice fusions (Figures 3b and d). Furthermore, at 10 months of age, the We analyzed the spleen/body weight ratio, serum levels of anti- GBM was thickened and wrinkled (Figures 3b and d), and high double-strand DNA (dsDNA) antibody, serum blood urea nitrogen electron-dense deposits resembling ICs were observed at the (sBUN) levels, serum creatinine (sCre) levels and urine albumin subendothelial regions (Figure 3b, asterisk) and in the double- creatinine ratio (uACR) in female BXSB/MpJ mice at 2, 7, 10 and 13 countered GBM (Figure 3d). months of age to assess the systemic autoimmune conditions and renal functions (Table 1). The spleen/body weight was significantly Podocyte injuries in female BXSB/MpJ mice higher at 13 months than that at 2 months. Although no The localization of podocyte functional molecules (nephrin, significant increase was detected in the sBUN and sCre levels podocin and synaptopodin) was examined by immunostaining between 2 months of age and other ages, the uACR and anti- (Figure 4). Linear-positive immunofluorescence reactions for dsDNA antibody levels significantly increased from 7 months nephrin, podocin and synaptopodin were observed along the onward. All examined parameters were the highest at 13 months glomerular capillary rete in female BXSB/MpJ mice at 2 months of ages. (Figures 4a, c and e). In contrast, those at 13 months of age tended to be faint, showed partial granular patterns and localized to the Glomerular histopathology in female BXSB/MpJ mice glomerular edge rather than the center (Figures 4b, d and f).
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