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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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Qualitative analysis of ANAs inRIIB−⁄−andSLAM129mice. (A) Classification of staining profiles of HEp-2 cells. Representative staining patterns observed for serum samples from RIIB−⁄−SLAM129 mice are shown as fluorescently stained cells. (B) The classification of HEp-2 cell staining pattern and the related antibodies and diseases. (C, Upper) Comparison of the HEp-2 staining patterns of female RIIB−/− mice at different ages. The staining patterns were divided into six categories as shown in (B). (C, Lower) Comparison of the staining patterns between female RIIB−/− and SLAM129 mice at 24 weeks of age. For classification, staining profiles in sera from ≥13 mice were evaluated. Ho, homogeneous; Pe, peripheral; Cen, centromere; Sp, speckled; Nuc, nucleolar; etc, others. Significantly different between RIIB−/− and SLAM129 (P <0.0001 by Chi-square test).
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Fig3: Qualitative analysis of ANAs inRIIB−⁄−andSLAM129mice. (A) Classification of staining profiles of HEp-2 cells. Representative staining patterns observed for serum samples from RIIB−⁄−SLAM129 mice are shown as fluorescently stained cells. (B) The classification of HEp-2 cell staining pattern and the related antibodies and diseases. (C, Upper) Comparison of the HEp-2 staining patterns of female RIIB−/− mice at different ages. The staining patterns were divided into six categories as shown in (B). (C, Lower) Comparison of the staining patterns between female RIIB−/− and SLAM129 mice at 24 weeks of age. For classification, staining profiles in sera from ≥13 mice were evaluated. Ho, homogeneous; Pe, peripheral; Cen, centromere; Sp, speckled; Nuc, nucleolar; etc, others. Significantly different between RIIB−/− and SLAM129 (P <0.0001 by Chi-square test).

Mentions: Examination of the staining profile of HEp-2 cells (Figure 3A, B) indicated that ANAs detected in sera from female RIIB−/− mice at 24 weeks of age comprised a mixture of anti-DNA, histone and nucleolus antibodies, and others, because the staining could be classified into nucleolar, homogeneous, and other types, while for the ANAs at 28 and 36 weeks of age peripheral-type staining was dominant, indicating the anti-dsDNA antibodies were major (Figure 3C). When we compared the staining profiles in female RIIB−/− and SLAM129 mice at 24 weeks of age, we observed that the peripheral-type staining was dominant in SLAM129 mice (Figure 3C, lower), suggesting that the compositions of ANAs produced by RIIB−/− and SLAM129 mice at 24 weeks of age are qualitatively different, as determined based on the HEp-2 cell staining profiles, albeit the assay used is not sufficiently quantitative.Figure 3


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)

Qualitative analysis of ANAs inRIIB−⁄−andSLAM129mice. (A) Classification of staining profiles of HEp-2 cells. Representative staining patterns observed for serum samples from RIIB−⁄−SLAM129 mice are shown as fluorescently stained cells. (B) The classification of HEp-2 cell staining pattern and the related antibodies and diseases. (C, Upper) Comparison of the HEp-2 staining patterns of female RIIB−/− mice at different ages. The staining patterns were divided into six categories as shown in (B). (C, Lower) Comparison of the staining patterns between female RIIB−/− and SLAM129 mice at 24 weeks of age. For classification, staining profiles in sera from ≥13 mice were evaluated. Ho, homogeneous; Pe, peripheral; Cen, centromere; Sp, speckled; Nuc, nucleolar; etc, others. Significantly different between RIIB−/− and SLAM129 (P <0.0001 by Chi-square test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4209029&req=5

Fig3: Qualitative analysis of ANAs inRIIB−⁄−andSLAM129mice. (A) Classification of staining profiles of HEp-2 cells. Representative staining patterns observed for serum samples from RIIB−⁄−SLAM129 mice are shown as fluorescently stained cells. (B) The classification of HEp-2 cell staining pattern and the related antibodies and diseases. (C, Upper) Comparison of the HEp-2 staining patterns of female RIIB−/− mice at different ages. The staining patterns were divided into six categories as shown in (B). (C, Lower) Comparison of the staining patterns between female RIIB−/− and SLAM129 mice at 24 weeks of age. For classification, staining profiles in sera from ≥13 mice were evaluated. Ho, homogeneous; Pe, peripheral; Cen, centromere; Sp, speckled; Nuc, nucleolar; etc, others. Significantly different between RIIB−/− and SLAM129 (P <0.0001 by Chi-square test).
Mentions: Examination of the staining profile of HEp-2 cells (Figure 3A, B) indicated that ANAs detected in sera from female RIIB−/− mice at 24 weeks of age comprised a mixture of anti-DNA, histone and nucleolus antibodies, and others, because the staining could be classified into nucleolar, homogeneous, and other types, while for the ANAs at 28 and 36 weeks of age peripheral-type staining was dominant, indicating the anti-dsDNA antibodies were major (Figure 3C). When we compared the staining profiles in female RIIB−/− and SLAM129 mice at 24 weeks of age, we observed that the peripheral-type staining was dominant in SLAM129 mice (Figure 3C, lower), suggesting that the compositions of ANAs produced by RIIB−/− and SLAM129 mice at 24 weeks of age are qualitatively different, as determined based on the HEp-2 cell staining profiles, albeit the assay used is not sufficiently quantitative.Figure 3

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