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Dichotomy in FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis.

Kanari Y, Sugahara-Tobinai A, Takahashi H, Inui M, Nakamura A, Hirose S, Takai T - BMC Immunol. (2014)

Bottom Line: In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys.The present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis.The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Immunology and CREST Program of JST, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan. tostakai@idac.tohoku.ac.jp.

ABSTRACT

Background: The significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. Our objective was to determine the influence of RIIB deletion on the spontaneous development of autoimmune diseases and to compare it with that of potentially pathogenic SLAM.

Results: We established two congenic C57BL/6 (B6) strains, one with the RIIB deletion and the other with SLAM, by backcrossing 129/SvJ-based RIIB-deficient mice into the B6 genetic background extensively. The RIIB deficiency indeed led to the production and/or accumulation of a small amount of anti-nuclear autoantibodies (ANAs) and to weak IgG immune-complex deposition in glomeruli without any obvious manifestation of lupus nephritis. In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys. Naïve SLAM mice but not RIIB-deficient mice exhibited hyperplasia of splenic germinal centers.

Conclusion: The present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis. The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.

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Glomerulonephritis inRIIB−/−,SLAM129, andRIIB−/−SLAM129mice. (A) Kidney sections from each mouse line at week 45 were stained with HE (upper) and PAS (lower) for examination of glomerular disease, which was assessed according to the criteria depicted in Methods. Original magnification, ×200. Scale bar, 100 μm. (B) Comparison of the disease scores among RIIB−/−, SLAM129, RIIB−/−SLAM129 and B6 mice at 45 weeks of age. F, female; M, male. Horizontal bars denote the mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001 (n =3–6). For scoring, ≥25 glomeruli were examined for each line. Student’s t-test. (C, D) For IgG-immune complexes (IgG-ICs) deposition, kidney sections from each mouse line at week 45 were stained with FITC-anti mouse IgG. Original magnification, ×200 (C) or × 100 (D). Scale bar, 10 μm. The figure is representative of most of the glomeruli observed in three mice per group.
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Fig5: Glomerulonephritis inRIIB−/−,SLAM129, andRIIB−/−SLAM129mice. (A) Kidney sections from each mouse line at week 45 were stained with HE (upper) and PAS (lower) for examination of glomerular disease, which was assessed according to the criteria depicted in Methods. Original magnification, ×200. Scale bar, 100 μm. (B) Comparison of the disease scores among RIIB−/−, SLAM129, RIIB−/−SLAM129 and B6 mice at 45 weeks of age. F, female; M, male. Horizontal bars denote the mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001 (n =3–6). For scoring, ≥25 glomeruli were examined for each line. Student’s t-test. (C, D) For IgG-immune complexes (IgG-ICs) deposition, kidney sections from each mouse line at week 45 were stained with FITC-anti mouse IgG. Original magnification, ×200 (C) or × 100 (D). Scale bar, 10 μm. The figure is representative of most of the glomeruli observed in three mice per group.

Mentions: Given the production of anti-DNA antibodies by RIIB−/− mice, we next examined the renal histology, and scored the glomerulonephritis in male and female RIIB−/−, SLAM129, and RIIB−/−SLAM129 mice at 36 weeks of age (Figure 5). While control female RIIB−/−SLAM129 mice exhibited severe glomerulonephritis with occasional crescent formation, mesangial cell proliferation, macrophage and neutrophil infiltration, and lobulation of glomeruli, female RIIB−/− mice exhibited weak but less severe glomerulonephritis than control RIIB−/−SLAM129 animals, with mesangial cell proliferation and neutrophil infiltration (Figure 5A, B). Male RIIB−/−, and male and female SLAM129 mice only showed occasional mesangial cell proliferation. We also examined IgG-IC deposition in renal samples by immunofluorescence microscopy, and found that only female RIIB−/− and RIIB−/−SLAM129 mice exhibited weak deposition (Figure 5C, D), but female SLAM129 mice did not (Figure 5C). These results indicate that the development of glomerulonephritis observed in RIIB−/− mice had occurred in a female-biased manner, while SLAM129 mice did not develop the disease at least until 36 weeks of age. It is noteworthy that the development of glomerulonephritis seemingly correlated with the female-biased ANA increase in RIIB−/− and RIIB−/−SLAM129 animals described above (Figure 4A–C), but SLAM129 mice did not manifest the disease regardless of the fact that they produced ANAs at comparable levels to female RIIB−/− mice, at least at 24 weeks of age (Figure 2B, C). This notion suggests a contribution of FcγRIIB to protection from IgG-IC deposition in glomeruli and glomerulonephritis.Figure 5


Dichotomy in FcγRIIB deficiency and autoimmune-prone SLAM haplotype clarifies the roles of the Fc receptor in development of autoantibodies and glomerulonephritis.

Kanari Y, Sugahara-Tobinai A, Takahashi H, Inui M, Nakamura A, Hirose S, Takai T - BMC Immunol. (2014)

Glomerulonephritis inRIIB−/−,SLAM129, andRIIB−/−SLAM129mice. (A) Kidney sections from each mouse line at week 45 were stained with HE (upper) and PAS (lower) for examination of glomerular disease, which was assessed according to the criteria depicted in Methods. Original magnification, ×200. Scale bar, 100 μm. (B) Comparison of the disease scores among RIIB−/−, SLAM129, RIIB−/−SLAM129 and B6 mice at 45 weeks of age. F, female; M, male. Horizontal bars denote the mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001 (n =3–6). For scoring, ≥25 glomeruli were examined for each line. Student’s t-test. (C, D) For IgG-immune complexes (IgG-ICs) deposition, kidney sections from each mouse line at week 45 were stained with FITC-anti mouse IgG. Original magnification, ×200 (C) or × 100 (D). Scale bar, 10 μm. The figure is representative of most of the glomeruli observed in three mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig5: Glomerulonephritis inRIIB−/−,SLAM129, andRIIB−/−SLAM129mice. (A) Kidney sections from each mouse line at week 45 were stained with HE (upper) and PAS (lower) for examination of glomerular disease, which was assessed according to the criteria depicted in Methods. Original magnification, ×200. Scale bar, 100 μm. (B) Comparison of the disease scores among RIIB−/−, SLAM129, RIIB−/−SLAM129 and B6 mice at 45 weeks of age. F, female; M, male. Horizontal bars denote the mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001 (n =3–6). For scoring, ≥25 glomeruli were examined for each line. Student’s t-test. (C, D) For IgG-immune complexes (IgG-ICs) deposition, kidney sections from each mouse line at week 45 were stained with FITC-anti mouse IgG. Original magnification, ×200 (C) or × 100 (D). Scale bar, 10 μm. The figure is representative of most of the glomeruli observed in three mice per group.
Mentions: Given the production of anti-DNA antibodies by RIIB−/− mice, we next examined the renal histology, and scored the glomerulonephritis in male and female RIIB−/−, SLAM129, and RIIB−/−SLAM129 mice at 36 weeks of age (Figure 5). While control female RIIB−/−SLAM129 mice exhibited severe glomerulonephritis with occasional crescent formation, mesangial cell proliferation, macrophage and neutrophil infiltration, and lobulation of glomeruli, female RIIB−/− mice exhibited weak but less severe glomerulonephritis than control RIIB−/−SLAM129 animals, with mesangial cell proliferation and neutrophil infiltration (Figure 5A, B). Male RIIB−/−, and male and female SLAM129 mice only showed occasional mesangial cell proliferation. We also examined IgG-IC deposition in renal samples by immunofluorescence microscopy, and found that only female RIIB−/− and RIIB−/−SLAM129 mice exhibited weak deposition (Figure 5C, D), but female SLAM129 mice did not (Figure 5C). These results indicate that the development of glomerulonephritis observed in RIIB−/− mice had occurred in a female-biased manner, while SLAM129 mice did not develop the disease at least until 36 weeks of age. It is noteworthy that the development of glomerulonephritis seemingly correlated with the female-biased ANA increase in RIIB−/− and RIIB−/−SLAM129 animals described above (Figure 4A–C), but SLAM129 mice did not manifest the disease regardless of the fact that they produced ANAs at comparable levels to female RIIB−/− mice, at least at 24 weeks of age (Figure 2B, C). This notion suggests a contribution of FcγRIIB to protection from IgG-IC deposition in glomeruli and glomerulonephritis.Figure 5

Bottom Line: In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys.The present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis.The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Immunology and CREST Program of JST, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan. tostakai@idac.tohoku.ac.jp.

ABSTRACT

Background: The significance of a unique inhibitory Fc receptor for IgG, FcγRIIB (RIIB), in the prevention of spontaneous production of autoantibodies remains controversial, due mainly to the fact that the RIIB locus is adjacent to the autoimmune-related SLAM locus harboring the genes coding for signaling lymphocyte activation molecules, making it difficult to isolate the effect of RIIB deletion from that of SLAM in gene-targeted mice. Our objective was to determine the influence of RIIB deletion on the spontaneous development of autoimmune diseases and to compare it with that of potentially pathogenic SLAM.

Results: We established two congenic C57BL/6 (B6) strains, one with the RIIB deletion and the other with SLAM, by backcrossing 129/SvJ-based RIIB-deficient mice into the B6 genetic background extensively. The RIIB deficiency indeed led to the production and/or accumulation of a small amount of anti-nuclear autoantibodies (ANAs) and to weak IgG immune-complex deposition in glomeruli without any obvious manifestation of lupus nephritis. In contrast, pathogenic SLAM in the B6 genetic background induced ANAs but no IgG immune-complex deposition in the kidneys. Naïve SLAM mice but not RIIB-deficient mice exhibited hyperplasia of splenic germinal centers.

Conclusion: The present results clarify the roles of RIIB in preventing production and/or accumulation of a small amount of ANAs, and development of glomerulonephritis. The combined effects of RIIB deletion and pathogenic SLAM can lead to severe lupus nephritis in the B6 genetic background.

Show MeSH
Related in: MedlinePlus