Auto-antibody production and glomerulonephritis in congenic Slamf1−/− and Slamf2−/− [B6.129] but not in Slamf1−/− and Slamf2−/− [BALB/c.129] mice

International Immunology, Feb 2011

Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1−/− and Slamf2−/−, which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1−/− [BALB/c.129] and Slamf2−/− [BALB/c.129] do not develop disease. Surprisingly, Slamf1−/− [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1−/− [B6.129] mice after 9–14 months. Functional analyses of CD4+ T cells reveals that Slamf2−/− T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2−/− mutation may have a unique influence on T-cell tolerance and lupus.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://intimm.oxfordjournals.org/content/23/2/149.full.pdf

Auto-antibody production and glomerulonephritis in congenic Slamf1−/− and Slamf2−/− [B6.129] but not in Slamf1−/− and Slamf2−/− [BALB/c.129] mice

Marton Keszei 2 3 Yvette E. Latchman 1 2 Vijay K. Vanguri 1 2 Daniel R. Brown 1 2 Cynthia Detre 2 3 Massimo Morra 2 3 Carolina V. Arancibia 1 2 Elahna Paul 0 2 Silvia Calpe 2 3 Wilson Castro 2 3 Ninghai Wang 2 3 Cox Terhorst 2 3 Arlene H. Sharpe 1 2 0 Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02114 , USA 1 Department of Pathology, Harvard Medical School, Brigham and Women's Hospital , Boston, MA 02115 , USA 2 Room CLS 928 , 3 Blackfan Circle, Boston, MA 02115 , USA 3 Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02115 , USA Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf12/2 and Slamf22/2, which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf12/2 [BALB/c.129] and Slamf22/2 [BALB/c.129] do not develop disease. Surprisingly, Slamf12/2 [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf12/2 [B6.129] mice after 9-14 months. Functional analyses of CD41 T cells reveals that Slamf22/2 T cells are resistant to tolerance induction in vivo. We conclude that the Slamf22/2 mutation may have a unique influence on T-cell tolerance and lupus. Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, marked by a range of auto-antibodies with a long prodromal phase of auto-antibody development and epitope spreading. This pre-diagnosis phase [positive antinuclear antibody (ANA) and musculoskeletal discomfort] is often marked by elevated serum BLyS/BAFF and MIF levels, which implicates B-cell activation and myeloid (macrophage and dendritic cells) stimulation. The major hallmark of SLE is the production of auto-antibodies to self-determinants and these auto-antibodies are predominantly directed against intracellular and nuclear antigens. Even if initial events are more focused on the B-cell arm, overt clinical disease involves a network of immunological cells (T, B, dendritic cells and macrophage) and the repertoire of mechanisms for an inflammatory response. A comprehensive genetic dissection of the immunoregulatory pathways that lead to the SLE in humans and mice is therefore necessary. Genome-wide linkage scans in SLE families have identified several lupus susceptibility loci (1). Evidence for one or more lupus susceptibility loci on human 1q23 comes from multiple genome-wide linkage scans in humans, which has been replicated (28). In mice, genome-wide linkage studies have implicated the syntenic region to human 1q23 in three different models of spontaneous lupus: the (NZB 3 NZW)F2 intercross, the NZM/Aeg2410 New Zealand mice and the BXSB mice (911). The phenotype of these mice is very similar to that in SLE patients, with the production of autoantibodies as well as multiorgan involvement, including severe nephritis. In congenic mice derived from crossing the NZM2410 mouse strain with B6 mice, the locus on chromosome 1, i.e. Sle1, by itself was sufficient to generate a strong, spontaneous humoral ANA response, reacting primarily with H2A/H2B/DNA subnucleosomes. Sle1 also led to an expanded pool of histone-reactive T cells. Sle1 is thought to be a major player in orchestrating selective loss of B-cell and T-cell tolerance to chromatin. Fine mapping of the Sle1 locus determined that three loci within this congenic interval, termed Sle1a, Sle1b and Sle1c, could independently cause a loss of tolerance to chromatin, a necessary step for full disease induction (12). More recently, the Sle1b region has been defined as an ;0.9 Mb segment (0.4 cM) that includes seven polymorphic signaling lymphocytic activation molecule family (Slamf) cell surface receptor genes (13). Slamf members regulate T cell, macrophage, dendritic cell, neutrophil and platelet functions, as well as humoral immune responses. Thus, Slamf members are ideal candidates for controlling SLE relevant cellular and signal transduction pathways. Recent studies suggest that the two alternative splice forms of the Slamf receptor Ly108 (CD352 / Slamf6), each of which is found in one of the major haplotypes, could be key contributors to role of Sle1b in tolerance (13, 14). Her (...truncated)


This is a preview of a remote PDF: https://intimm.oxfordjournals.org/content/23/2/149.full.pdf

Marton Keszei, Yvette E. Latchman, Vijay K. Vanguri, Daniel R. Brown, Cynthia Detre, Massimo Morra, Carolina V. Arancibia, Elahna Paul, Silvia Calpe, Wilson Castro, Ninghai Wang, Cox Terhorst, Arlene H. Sharpe. Auto-antibody production and glomerulonephritis in congenic Slamf1−/− and Slamf2−/− [B6.129] but not in Slamf1−/− and Slamf2−/− [BALB/c.129] mice, International Immunology, 2011, pp. 149-158, 23/2, DOI: 10.1093/intimm/dxq465