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)