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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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Germinal center B cells are increased inSLAM129but notRIIB−/−mice. (A, Left) Slight splenomegaly in female RIIB−/− mice. Spleen weights were measured for each line of both genders (F, female; M, male) and are presented as the ratio of the weight per body weight. Horizontal bars indicate mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001. Student’s t-test. (A, Right) Total splenic lymphocytes in each line. Horizontal bar represents the mean number of total splenocytes, excepting the plot of RIIB−⁄−SLAM129 male for single determination. N.S., not significant. Student’s t-test. (B) Germinal center formation in naïve B6, N22 female RIIB−/−, and female and male SLAM129 mice at 45 weeks of age. Frozen spleen sections were stained with GL7-Alexa488 and Alexa546-labeled anti-mouse IgD antibodies. Scale bar =10 μm. (C) Flow cytometric determination of germinal center (GC) B cells of B6, female SLAM129 and N22 female RIIB−/− mice at 45 week of age. Splenocytes were gated with anti-CD19-APC, and analyzed for anti-Fas-PE and GL7-FITC. (D) Total GC cells and GC B cells are not significantly increased in female RIIB−/− mice. The percentage of GC B cells in splenic CD19+ cells (Left), and the absolute number of splenic GC B cells (Right) of each line of both genders (F, female; M, male) are shown. *P <0.05; ***P <0.001; N.S., not significant. Student’s t-test.
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Fig6: Germinal center B cells are increased inSLAM129but notRIIB−/−mice. (A, Left) Slight splenomegaly in female RIIB−/− mice. Spleen weights were measured for each line of both genders (F, female; M, male) and are presented as the ratio of the weight per body weight. Horizontal bars indicate mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001. Student’s t-test. (A, Right) Total splenic lymphocytes in each line. Horizontal bar represents the mean number of total splenocytes, excepting the plot of RIIB−⁄−SLAM129 male for single determination. N.S., not significant. Student’s t-test. (B) Germinal center formation in naïve B6, N22 female RIIB−/−, and female and male SLAM129 mice at 45 weeks of age. Frozen spleen sections were stained with GL7-Alexa488 and Alexa546-labeled anti-mouse IgD antibodies. Scale bar =10 μm. (C) Flow cytometric determination of germinal center (GC) B cells of B6, female SLAM129 and N22 female RIIB−/− mice at 45 week of age. Splenocytes were gated with anti-CD19-APC, and analyzed for anti-Fas-PE and GL7-FITC. (D) Total GC cells and GC B cells are not significantly increased in female RIIB−/− mice. The percentage of GC B cells in splenic CD19+ cells (Left), and the absolute number of splenic GC B cells (Right) of each line of both genders (F, female; M, male) are shown. *P <0.05; ***P <0.001; N.S., not significant. Student’s t-test.

Mentions: We were interested in determining why ANAs and anti-DNA antibodies in sera were increased in RIIB−/− mice, albeit in very small amounts. To this end, we isolated spleens, and examined their weights, histology, and cellularity. While splenomegaly was observed in RIIB−/−SLAM129 mice, it was much less evident in RIIB−/− mice (Figure 6A, left). This was, however, not pronounced in the total splenic lymphocytes of RIIB−/− animals (Figure 6A, right). Immunohistochemistry of spleen sections prepared from naïve mice indicated that germinal center (GC) formation was grossly normal in RIIB−/− mice of both genders, while it was augmented in SLAM129 mice (Figure 6B). The numbers of total GL7+Fas+ GC cells and CD19+GL7+Fas+ GC B cells were not significantly increased in RIIB−/− mice of both genders, while they tended to be increased in female RIIB−/−SLAM129 and SLAM129 animals (Figure 6C, D), these observations being reminiscent of SLAM’s important role in adequate B–T cell communication in GCs [22]. Thus, we failed to find marked alterations in RIIB−/− mice in terms of the total splenic lymphocyte and GC cell numbers other than slight splenomegaly. Further analysis of other parameters such as plasma cells, antigen-presenting cells and T cells may help to clarify the reason for the production of a small amount of autoantibodies in RIIB−/− mice.Figure 6


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)

Germinal center B cells are increased inSLAM129but notRIIB−/−mice. (A, Left) Slight splenomegaly in female RIIB−/− mice. Spleen weights were measured for each line of both genders (F, female; M, male) and are presented as the ratio of the weight per body weight. Horizontal bars indicate mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001. Student’s t-test. (A, Right) Total splenic lymphocytes in each line. Horizontal bar represents the mean number of total splenocytes, excepting the plot of RIIB−⁄−SLAM129 male for single determination. N.S., not significant. Student’s t-test. (B) Germinal center formation in naïve B6, N22 female RIIB−/−, and female and male SLAM129 mice at 45 weeks of age. Frozen spleen sections were stained with GL7-Alexa488 and Alexa546-labeled anti-mouse IgD antibodies. Scale bar =10 μm. (C) Flow cytometric determination of germinal center (GC) B cells of B6, female SLAM129 and N22 female RIIB−/− mice at 45 week of age. Splenocytes were gated with anti-CD19-APC, and analyzed for anti-Fas-PE and GL7-FITC. (D) Total GC cells and GC B cells are not significantly increased in female RIIB−/− mice. The percentage of GC B cells in splenic CD19+ cells (Left), and the absolute number of splenic GC B cells (Right) of each line of both genders (F, female; M, male) are shown. *P <0.05; ***P <0.001; N.S., not significant. Student’s t-test.
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Related In: Results  -  Collection

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Fig6: Germinal center B cells are increased inSLAM129but notRIIB−/−mice. (A, Left) Slight splenomegaly in female RIIB−/− mice. Spleen weights were measured for each line of both genders (F, female; M, male) and are presented as the ratio of the weight per body weight. Horizontal bars indicate mean values, excepting the plot of RIIB−⁄−SLAM129 male for single determination. ***P <0.001. Student’s t-test. (A, Right) Total splenic lymphocytes in each line. Horizontal bar represents the mean number of total splenocytes, excepting the plot of RIIB−⁄−SLAM129 male for single determination. N.S., not significant. Student’s t-test. (B) Germinal center formation in naïve B6, N22 female RIIB−/−, and female and male SLAM129 mice at 45 weeks of age. Frozen spleen sections were stained with GL7-Alexa488 and Alexa546-labeled anti-mouse IgD antibodies. Scale bar =10 μm. (C) Flow cytometric determination of germinal center (GC) B cells of B6, female SLAM129 and N22 female RIIB−/− mice at 45 week of age. Splenocytes were gated with anti-CD19-APC, and analyzed for anti-Fas-PE and GL7-FITC. (D) Total GC cells and GC B cells are not significantly increased in female RIIB−/− mice. The percentage of GC B cells in splenic CD19+ cells (Left), and the absolute number of splenic GC B cells (Right) of each line of both genders (F, female; M, male) are shown. *P <0.05; ***P <0.001; N.S., not significant. Student’s t-test.
Mentions: We were interested in determining why ANAs and anti-DNA antibodies in sera were increased in RIIB−/− mice, albeit in very small amounts. To this end, we isolated spleens, and examined their weights, histology, and cellularity. While splenomegaly was observed in RIIB−/−SLAM129 mice, it was much less evident in RIIB−/− mice (Figure 6A, left). This was, however, not pronounced in the total splenic lymphocytes of RIIB−/− animals (Figure 6A, right). Immunohistochemistry of spleen sections prepared from naïve mice indicated that germinal center (GC) formation was grossly normal in RIIB−/− mice of both genders, while it was augmented in SLAM129 mice (Figure 6B). The numbers of total GL7+Fas+ GC cells and CD19+GL7+Fas+ GC B cells were not significantly increased in RIIB−/− mice of both genders, while they tended to be increased in female RIIB−/−SLAM129 and SLAM129 animals (Figure 6C, D), these observations being reminiscent of SLAM’s important role in adequate B–T cell communication in GCs [22]. Thus, we failed to find marked alterations in RIIB−/− mice in terms of the total splenic lymphocyte and GC cell numbers other than slight splenomegaly. Further analysis of other parameters such as plasma cells, antigen-presenting cells and T cells may help to clarify the reason for the production of a small amount of autoantibodies in RIIB−/− mice.Figure 6

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