Two major interacting chromosome loci control disease susceptibility in murine model of spondyloarthropathy.
Autoimmune spondylitis was induced in BALB/c mice and their MHC-matched (BALB/c x 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-gamma, IL-4, and TNF-alpha 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.
Végvári
Anikó
A
Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA.
Szabó
Zoltán
Z
Szántó
Sándor
S
Nesterovitch
Andrew B
AB
Mikecz
Katalin
K
Glant
Tibor T
TT
Adarichev
Vyacheslav A
VA
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015994:Incidence; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D012689:Sequence Homology, Nucleic Acid; D025242:Spondylarthropathies / Q000235:genetics* / Q000276:immunology*
D005819:Genetic Markers; D011509:Proteoglycans