title: Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis.
abstract: Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (∼3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.
authors.affiliation: Department of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL 60612, USA. tglant@rush.edu
authors.forename: T T
authors.initials: TT
authors.lastname: Glant
authors.forename: V A
authors.initials: VA
authors.lastname: Adarichev
authors.forename: F
authors.initials: F
authors.lastname: Boldizsar
authors.forename: T
authors.initials: T
authors.lastname: Besenyei
authors.forename: A
authors.initials: A
authors.lastname: Laszlo
authors.forename: K
authors.initials: K
authors.lastname: Mikecz
authors.forename: T A
authors.initials: TA
authors.lastname: Rauch
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002356:Cartilage / Q000276:immunology; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D056426:Genetic Loci; D005819:Genetic Markers; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011509:Proteoglycans / Q000009:adverse effects / Q000276:immunology; D040641:Quantitative Trait Loci
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D005819:Genetic Markers; D011509:Proteoglycans