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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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Chromosomal configurations in the vicinity of theFcgr2bgene andSLAMlocus of congenic mouse lines. (A) Physical mapping was compiled according to the Ensemble Genome Browser (http://www.ensembl.org/). Upper, gross schematic view, and Lower, detailed genomic structure with SSLP markers, and the genes related to the immune system and examined by SNP analysis (Additional file 1: Table S1 and Additional file 1: Figure S1). Scale bar =1 Mbp. Thick horizontal bars below the map indicate 129 strain-derived intervals, and the flanking, thin broken lines denote intervals unidentified for the B6 or 129 strain. Other areas not shown were derived from B6. The RIIB−⁄−TACONIC line had a 129-derived interval from D1Mit34 to D1Mit150 at the minimum, while our N12 RIIB−⁄− had an interval from D1Mit102 to D1Mit221 at the minimum, according to our analysis. The Fcr and SLAM loci are shown as shaded boxes at the top of the Upper panel or as thick lines above the map in the Lower panel. The Fcgr2b gene is boxed. When pertinent, we refer to our N28 RIIB−/− mice used in the present study as RIIB−/−SENDAI and those obtained or purchased from others as RIIB−/−TOKYO or RIIB−/−TACONIC, respectively, in order to distinguish the data in figures. (B) Survival curves for B6 (female, n =17), RIIB−/−SENDAI (female, n =30; male, n =35), SLAM129 (female, n =23; male, n =27), RIIB−/−SLAM129 (female, n =14; male, n =18), RIIB−/−TOKYO (female, n =7; male, n =4), and RIIB−/−TACONIC (female, n =3; male, n =3) mice. Mice of different lines were examined as to their survival until week 45. For comparison, survival curves for B6.lpr (female, n =17) and RIIB−⁄−lpr (female, n =28; male, n =12) from our previous study [16] are superimposed. ****Significantly different between female RIIB−/−TACONIC vs female RIIB−/−SENDAI (P <0.0001, Log-rank test).
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Fig1: Chromosomal configurations in the vicinity of theFcgr2bgene andSLAMlocus of congenic mouse lines. (A) Physical mapping was compiled according to the Ensemble Genome Browser (http://www.ensembl.org/). Upper, gross schematic view, and Lower, detailed genomic structure with SSLP markers, and the genes related to the immune system and examined by SNP analysis (Additional file 1: Table S1 and Additional file 1: Figure S1). Scale bar =1 Mbp. Thick horizontal bars below the map indicate 129 strain-derived intervals, and the flanking, thin broken lines denote intervals unidentified for the B6 or 129 strain. Other areas not shown were derived from B6. The RIIB−⁄−TACONIC line had a 129-derived interval from D1Mit34 to D1Mit150 at the minimum, while our N12 RIIB−⁄− had an interval from D1Mit102 to D1Mit221 at the minimum, according to our analysis. The Fcr and SLAM loci are shown as shaded boxes at the top of the Upper panel or as thick lines above the map in the Lower panel. The Fcgr2b gene is boxed. When pertinent, we refer to our N28 RIIB−/− mice used in the present study as RIIB−/−SENDAI and those obtained or purchased from others as RIIB−/−TOKYO or RIIB−/−TACONIC, respectively, in order to distinguish the data in figures. (B) Survival curves for B6 (female, n =17), RIIB−/−SENDAI (female, n =30; male, n =35), SLAM129 (female, n =23; male, n =27), RIIB−/−SLAM129 (female, n =14; male, n =18), RIIB−/−TOKYO (female, n =7; male, n =4), and RIIB−/−TACONIC (female, n =3; male, n =3) mice. Mice of different lines were examined as to their survival until week 45. For comparison, survival curves for B6.lpr (female, n =17) and RIIB−⁄−lpr (female, n =28; male, n =12) from our previous study [16] are superimposed. ****Significantly different between female RIIB−/−TACONIC vs female RIIB−/−SENDAI (P <0.0001, Log-rank test).

Mentions: RIIB−/− and SLAM129 mice were generated by backcrossing our 12th-backcross (N12) RIIB−/− mice [13,16] into the B6 genetic background further to the 28th generation (N28). Analysis of a series of microsatellite markers including D1Mit15, 36, and 113 in the vicinities of the Fcgr2b and SLAM loci revealed the successful separation of the RIIB−/− locus and the SLAM129 locus during the backcross (Figure 1A; for details, see Additional file 1: Figure S1 and Additional file 1: Table S1). We also obtained a mouse line with the combined loci, N28 RIIB−/−SLAM129, as a control (Figure 1A and Additional file 1: Figure S1). Both the N28 RIIB−/− (RIIB−/−SENDAI) and N18 SLAM129 mice thrived normally, at least up to 45 weeks after birth, and the RIIB−/−SLAM129 mice did as well despite the fact that female RIIB−/−SLAM129 mice manifested obvious glomerulonephritis, as judged on histology (Figure 1B, see below), which was consistent with our previous observation for N12 RIIB−/− mice [16]. Four (3 females and 1 male) out of six (3 of each gender) RIIB−/− mice obtained from a breeder (RIIB−⁄−TACONIC) died before 45 weeks of age in our facility, due probably to lupus nephritis [21] (Figure 1B). Mice obtained from another facility (RIIB−⁄−TOKYO) [18] thrived like our RIIB−/− mice did. It should be stressed that our RIIB−/−SENDAI line and RIIB−/− animals from other sources were derived from a common origin [13], and backcrossed into the B6 background at different facilities. These results indicate that, even under identical environmental conditions, FcγRIIB-deficient mice with 129-derived genetic intervals of different lengths around the RIIB−/− locus show different mortalities, raising the possibility of some influence(s) of unidentified genetic factor(s) within the intervals in the B6 genetic background. Also, the separation of the RIIB−/− locus from that of autoimmune-prone SLAM129 as well as extensive shortening of the 129-derived interval (Nuf2 to Fcgr4, Figure 1A) allowed the establishment of N28 RIIB−/−SENDAI mice with a normal survival rate, which we mainly used in our analysis described below.Figure 1


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)

Chromosomal configurations in the vicinity of theFcgr2bgene andSLAMlocus of congenic mouse lines. (A) Physical mapping was compiled according to the Ensemble Genome Browser (http://www.ensembl.org/). Upper, gross schematic view, and Lower, detailed genomic structure with SSLP markers, and the genes related to the immune system and examined by SNP analysis (Additional file 1: Table S1 and Additional file 1: Figure S1). Scale bar =1 Mbp. Thick horizontal bars below the map indicate 129 strain-derived intervals, and the flanking, thin broken lines denote intervals unidentified for the B6 or 129 strain. Other areas not shown were derived from B6. The RIIB−⁄−TACONIC line had a 129-derived interval from D1Mit34 to D1Mit150 at the minimum, while our N12 RIIB−⁄− had an interval from D1Mit102 to D1Mit221 at the minimum, according to our analysis. The Fcr and SLAM loci are shown as shaded boxes at the top of the Upper panel or as thick lines above the map in the Lower panel. The Fcgr2b gene is boxed. When pertinent, we refer to our N28 RIIB−/− mice used in the present study as RIIB−/−SENDAI and those obtained or purchased from others as RIIB−/−TOKYO or RIIB−/−TACONIC, respectively, in order to distinguish the data in figures. (B) Survival curves for B6 (female, n =17), RIIB−/−SENDAI (female, n =30; male, n =35), SLAM129 (female, n =23; male, n =27), RIIB−/−SLAM129 (female, n =14; male, n =18), RIIB−/−TOKYO (female, n =7; male, n =4), and RIIB−/−TACONIC (female, n =3; male, n =3) mice. Mice of different lines were examined as to their survival until week 45. For comparison, survival curves for B6.lpr (female, n =17) and RIIB−⁄−lpr (female, n =28; male, n =12) from our previous study [16] are superimposed. ****Significantly different between female RIIB−/−TACONIC vs female RIIB−/−SENDAI (P <0.0001, Log-rank test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Chromosomal configurations in the vicinity of theFcgr2bgene andSLAMlocus of congenic mouse lines. (A) Physical mapping was compiled according to the Ensemble Genome Browser (http://www.ensembl.org/). Upper, gross schematic view, and Lower, detailed genomic structure with SSLP markers, and the genes related to the immune system and examined by SNP analysis (Additional file 1: Table S1 and Additional file 1: Figure S1). Scale bar =1 Mbp. Thick horizontal bars below the map indicate 129 strain-derived intervals, and the flanking, thin broken lines denote intervals unidentified for the B6 or 129 strain. Other areas not shown were derived from B6. The RIIB−⁄−TACONIC line had a 129-derived interval from D1Mit34 to D1Mit150 at the minimum, while our N12 RIIB−⁄− had an interval from D1Mit102 to D1Mit221 at the minimum, according to our analysis. The Fcr and SLAM loci are shown as shaded boxes at the top of the Upper panel or as thick lines above the map in the Lower panel. The Fcgr2b gene is boxed. When pertinent, we refer to our N28 RIIB−/− mice used in the present study as RIIB−/−SENDAI and those obtained or purchased from others as RIIB−/−TOKYO or RIIB−/−TACONIC, respectively, in order to distinguish the data in figures. (B) Survival curves for B6 (female, n =17), RIIB−/−SENDAI (female, n =30; male, n =35), SLAM129 (female, n =23; male, n =27), RIIB−/−SLAM129 (female, n =14; male, n =18), RIIB−/−TOKYO (female, n =7; male, n =4), and RIIB−/−TACONIC (female, n =3; male, n =3) mice. Mice of different lines were examined as to their survival until week 45. For comparison, survival curves for B6.lpr (female, n =17) and RIIB−⁄−lpr (female, n =28; male, n =12) from our previous study [16] are superimposed. ****Significantly different between female RIIB−/−TACONIC vs female RIIB−/−SENDAI (P <0.0001, Log-rank test).
Mentions: RIIB−/− and SLAM129 mice were generated by backcrossing our 12th-backcross (N12) RIIB−/− mice [13,16] into the B6 genetic background further to the 28th generation (N28). Analysis of a series of microsatellite markers including D1Mit15, 36, and 113 in the vicinities of the Fcgr2b and SLAM loci revealed the successful separation of the RIIB−/− locus and the SLAM129 locus during the backcross (Figure 1A; for details, see Additional file 1: Figure S1 and Additional file 1: Table S1). We also obtained a mouse line with the combined loci, N28 RIIB−/−SLAM129, as a control (Figure 1A and Additional file 1: Figure S1). Both the N28 RIIB−/− (RIIB−/−SENDAI) and N18 SLAM129 mice thrived normally, at least up to 45 weeks after birth, and the RIIB−/−SLAM129 mice did as well despite the fact that female RIIB−/−SLAM129 mice manifested obvious glomerulonephritis, as judged on histology (Figure 1B, see below), which was consistent with our previous observation for N12 RIIB−/− mice [16]. Four (3 females and 1 male) out of six (3 of each gender) RIIB−/− mice obtained from a breeder (RIIB−⁄−TACONIC) died before 45 weeks of age in our facility, due probably to lupus nephritis [21] (Figure 1B). Mice obtained from another facility (RIIB−⁄−TOKYO) [18] thrived like our RIIB−/− mice did. It should be stressed that our RIIB−/−SENDAI line and RIIB−/− animals from other sources were derived from a common origin [13], and backcrossed into the B6 background at different facilities. These results indicate that, even under identical environmental conditions, FcγRIIB-deficient mice with 129-derived genetic intervals of different lengths around the RIIB−/− locus show different mortalities, raising the possibility of some influence(s) of unidentified genetic factor(s) within the intervals in the B6 genetic background. Also, the separation of the RIIB−/− locus from that of autoimmune-prone SLAM129 as well as extensive shortening of the 129-derived interval (Nuf2 to Fcgr4, Figure 1A) allowed the establishment of N28 RIIB−/−SENDAI mice with a normal survival rate, which we mainly used in our analysis described below.Figure 1

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