CD22 x Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

J. Jellusova, U. Wellmann, K. Amann, T. H. Winkler, L. Nitschke
2010 Journal of Immunology  
Material Supplementary 1.DC1 http://www.jimmunol.org/content/suppl/2010/03/03/jimmunol.090271 Subscription http://jimmunol.org/subscription is online at: The Journal of Immunology Information about subscribing to Permissions CD22 and Siglec-G are inhibitory coreceptors for BCR-mediated signaling. Although CD22-deficient mice show increased calcium signaling in their conventional B2 cells and a quite normal B cell maturation, Siglec-G-deficient mice have increased calcium mobilization just in B1
more » ... lization just in B1 cells and show a large expansion of the B1 cell population. Neither CD22-deficient, nor Siglec-G-deficient mice on a pure C57BL/6 or BALB/c background, respectively, develop autoimmunity. Using Siglec-G 3 CD22 double-deficient mice, we addressed whether Siglec-G and CD22 have redundant functions. Siglec-G 3 CD22 double-deficient mice show elevated calcium responses in both B1 cells and B2 cells, increased serum IgM levels and an enlarged population of B1 cells. The enlargement of B1 cell numbers is even higher than in Siglecg 2/2 mice. This expansion seems to happen at the expense of B2 cells, which are reduced in absolute cell numbers, but show an activated phenotype. Furthermore, Siglec-G 3 CD22 doubledeficient mice show a diminished immune response to both thymus-dependent and thymus-independent type II Ags. In contrast, B cells from Siglec-G 3 CD22 double-deficient mice exhibit a hyperproliferative response to stimulation with several TLR ligands. Aged Siglec-G 3 CD22 double-deficient mice spontaneously develop anti-DNA and antinuclear autoantibodies. These resulted in a moderate form of immune complex glomerulonephritis. These results show that Siglec-G and CD22 have partly compensatory functions and together are crucial in maintaining the B cell tolerance. The online version of this article contains supplemental material. Abbreviations used in this paper: BM, bone marrow; KO, knockout; LN, lymph node; MZ, marginal zone; PC, peritoneal cavity; SLE, systemic lupus erythematosus; spl, spleen. FIGURE 3. Increased calcium mobilization in Siglecg 2/2 Cd22 2/2 mice. Calcium mobilization in splenic follicular B cells (CD21 lo CD23 hi ) and in peritoneal B1a cells (CD5 + B220 + ), which were stimulated with anti-IgM (clone B7.6) at indicated time (arrow). Concentrations of anti-IgM are depicted in histograms. Results are plotted as medians of bound/unbound Indo-1 over time, smoothed by the Gaussian algorithm. One of five experiments with similar results is shown. FIGURE 7. Glomerular damage and IgG immune-complexes in kidneys of CD22 3 Siglec-G double-deficient mice. A, Example of kidney sections of control mice and CD22 3 Siglec-G double-deficient mice, shown in two different magnifications (320 and 340) with periodic acid Schiff or anti-IgG staining. B, Quantification of kidney pathology analysis. Mice, which showed moderate glomerular damage, are summarized here. The group of control mice, included Siglecg +/+ Cd22 +/+ and Siglecg +/+ Cd22 +/2 mice. 3 Mut: mice with three mutant alleles (Siglecg 2/2 Cd22 +/2 or Siglecg +/2 Cd22 2/2 ).
doi:10.4049/jimmunol.0902711 pmid:20200274 fatcat:zzmmqqk5ebcztev6vedkpg6qla