Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice - PubMed (original) (raw)

Comparative Study

. 2005 Dec 19;202(12):1643-8.

doi: 10.1084/jem.20051984. Epub 2005 Dec 13.

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Comparative Study

Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice

Taku Okazaki et al. J Exp Med. 2005.

Abstract

Because most autoimmune diseases are polygenic, analysis of the synergistic involvement of various immune regulators is essential for a complete understanding of the molecular pathology of these diseases. We report the regulation of autoimmune diseases by epistatic effects of two immunoinhibitory receptors, low affinity type IIb Fc receptor for IgG (FcgammaRIIB) and programmed cell death 1 (PD-1). Approximately one third of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice developed autoimmune hydronephrosis, which is not observed in either BALB/c-Fcgr2b(-/-) or BALB/c-Pdcd1(-/-) mice. Hydronephrotic mice produced autoantibodies (autoAbs) against urothelial antigens, including uroplakin IIIa, and these antibodies were deposited on the urothelial cells of the urinary bladder. In addition, approximately 15% of the BALB/c-Fcgr2b(-/-)Pdcd1(-/-) mice produced antinuclear autoAbs. In contrast, the frequency of the autoimmune cardiomyopathy and the production of anti-parietal cell autoAb, which were observed in BALB/c-Pdcd1(-/-) mice, were not affected by the additional FcgammaRIIB deficiency. These observations suggest cross talk between two immunoinhibitory receptors, FcgammaRIIB and PD-1, on the regulation of autoimmune diseases.

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Figures

Figure 1.

Figure 1.

Spontaneous hydronephrosis in BALB/c-Fcgr2b −/− Pdcd1 −/− mice. (A) Macroscopic images of a hydronephrotic kidney (right) and a normal kidney control (left) are shown. (B–F) Representative hematoxylin and eosin (H&E) staining histologies of kidney (B), ureteropelvic junction (C), ureter (D), and urinary bladder (E) are shown for hydronephrotic (right) and healthy control (left) mice. (F) High-power fields of ureter. Urothelial cells of hydronephrotic mice (right) are apparently unchanged from those of healthy control mice (left), except for the two- to threefold increase in the number of cells (brackets). Asterisks and arrowheads in C indicate orifice of pelvis and ureteral lumen, respectively. Magnifications: (B and C) 100; (D) 200; (E) 50; (F) 400.

Figure 2.

Figure 2.

AutoAbs against urothelial cells. (A–D) Sera from hydronephrotic mice recognized urothelial cells of renal pelvis (A), ureter (B), and urinary bladder (C and D). Green signals (left) represent staining by serum IgG. H&E staining of corresponding organs is also shown (right). (E) IgG deposition was strongly observed on the apical surface of the urothelium. (F) All of the sera from hydronephrotic (lanes 1–7) but not from healthy control (lanes 8–14) mice recognized a 45-kD urothelial cell–specific antigen. (G) Sera from two hydronephrotic mice (lanes 1 and 2) and anti-UPKIIIa Ab (lanes 3–5; ×2, ×5, and ×10 dilutions, respectively) recognized similar bands on urothelial extract. (H) Sera from hydronephrotic (lanes 1–6) but not from healthy control (lanes 7–12) mice recognized the recombinant UPKIIIa protein. PC, positive control of anti-UPKIIIa Ab.

Figure 3.

Figure 3.

Production of antinuclear Ab and anti–parietal cell Ab by BALB/c-Fcgr2b −/− Pdcd1 −/− mice. (A and B) Anti–parietal cell Ab (A) and antinuclear Ab (B) were detected by immunohistochemistry. The inset shows a higher magnification. (C and D) Representative histology of healthy (C) and inflamed stomach (D) by H&E staining. Magnifications, 200. (E) Frequencies of anti–parietal cell Ab–positive mice are shown for indicated genotype. n = 20, 10, 40, 23, and 15 mice from left to right. (F) Antinuclear Ab titer was examined for mice with indicated genotypes. PC, positive control of 10-wk-old MRL-lpr-MpJ mice.

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