Two Major Interacting Chromosome Loci Control Disease Susceptibility in Murine Model of Spondyloarthropathy

Abstract

Autoimmune spondylitis was induced in BALB/c mice and their MHC-matched (BALB/c × DBA/2)F1 and F2 hybrids by systemic immunization with cartilage/intervertebral disk proteoglycan (PG). As in human ankylosing spondylitis, the MHC was the major permissive genetic locus in murine PG-induced spondylitis (PGIS). Two major non-MHC chromosome loci with highly significant linkage were found on chromosomes 2 (Pgis2) and 18 (Pgis1) accounting for 40% of the entire F2 trait variance. The dominant spondylitis-susceptibility allele for Pgis2 locus is derived from the BALB/c strain, whereas the Pgis1 recessive allele was present in the disease-resistant DBA/2 strain. The Pgis1 locus significantly affected the disease-controlling Pgis2 locus, inducing as high incidence of spondylitis in F2 hybrids as was found in the spondylitis-susceptible parent BALB/c strain. Additional disease-controlling loci with suggestive linkage were mapped to the chromosomes 12, 15, and 19. Severity of spondylitis in F2 mice positively correlated with serum levels of amyloid A, IL-6, and Pg-specific Abs, and showed negative correlation with Ag-induced T cell proliferation, IFN-γ, IL-4, and TNF-α production. A major locus controlling serum IL-6 was found on chromosome 14 near osteoclast differentiation factor Tnfsf11. Locus on chromosome 11 near the Stat3 and Stat5 genes controlled serum level of the Ig IgG2a isotype. The two major genetic loci Pgis1 and Pgis2 of murine spondylitis were homologous to chromosome regions in human genome, which control ankylosing spondylitis in human patients. Thus, this animal model of experimentally induced spondylitis might facilitate the identification of spondylitis-susceptibility genes in humans.

Genetic control of experimental spondylarthropathy

“…Because no other inbred strains have, as yet, been found to be susceptible to SpA (9,13,17), we believe that only a very few genes control SpA susceptibility, and that these genes are most likely the same in the BALB/c and C3H strains. The first genome-wide screening studies of 223 (BALB/c ϫ DBA/ 2)F 2 hybrid mice have been completed recently, and indeed, only 2 definitive loci (on chromosomes 2 and 18) and 4 suggestive loci (on chromosomes 11, 12, 15, and 19) seem to be linked to PGIS in this MHC-matched generation (23).…”

“…This observation may indicate that PGIS is a more uniform disease than PGIA. Indeed, although several genetic loci have been implicated in different forms of autoimmune/experimental arthritis (17,43) and in rheumatoid arthritis (43)(44)(45), only a very few, probably only 2 dominant, non-MHC loci (on chromosomes 2 and 18) have been identified that could control susceptibility to spondylitis in (BALB/c ϫ DBA/2)F 2 hybrid mice (23). Importantly, both of these 2 genetic loci correspond to those identified in human patients with AS (30,31,46,47).…”

Origine génétique de la spondylarthrite ankylosante

“…D'autres formes de SpA se sont déclarées chez des rongeurs transgéniques porteurs de l'HLA-B27 [21], ou chez la souris transgénique exprimant un collagène mutant de type IX ou une forme tronquée de TNF-␣ [28]. Dans cet article, en plus des données chez l'homme, nous discuterons de la spondylarthrite induite par les protéoglycanes (PGIS), un modèle murin autoimmun de SpA [29,30].…”

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

“…Although spondylitis correlated with onset and severity of peripheral arthritis in BALB/c mice, axial disease became independent of peripheral arthritis after the F2 generation. Linkage analysis showed that two spondylitis-related gene loci, pgis1 and pgis2, are linked to the axial disease in F2 mice [187]. Interestingly, combination of DBA/2-derived pgis1 and BALB/C-derived pgis2 result in the highest disease susceptibility.…”

“…Interestingly, combination of DBA/2-derived pgis1 and BALB/C-derived pgis2 result in the highest disease susceptibility. The loci include many genes related to immune responses, such as the IL-1 family gene cluster that had been reported in AS [187].…”