Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Narrowing the Protein Tyrosine Phospahatse-22 Locus in Mice with Cartilage Proteoglycan-Induced Arthritis Explores Disease-Promoting and Disease-Suppressive Sub-Loci Neutralizing Their In Vivo Arthritis Susceptibility and Severity.
Besenyei1, Timea, Kadar1, Andras, Tryniszewska1, Beata, Adarichev2, Vyacheslav A., Mikecz1, Katalin, Glant1, Tibor T.
Genome-wide screening of cartilage proteoglycan (PG)-induced arthritis (PGIA) in six different genetic combinations explored 29 QTLs (Pgia1-Pgia29), of which 8 showed high correlations with other arthritis models and GWAS of RA. We have selected Pgia 26 locus on chromosome 3 (Chr3), because this is one of the most complex traits (after the MHC) regulating arthritis susceptibility and severity both in RA (PTPN22 locus on human Chr1) and in PGIA (Pgia26 ). (Another study targets the Traf1/C5 locus on mouse Chr2 syntenic with human Chr9.) The goal was to narrow mouse Chr3 to as small as possible for candidate gene selection. Our hypothesis was that certain genes associated with these loci in murine autoimmune arthritis (PGIA) will correspond to genes involved in RA.
To achieve these goals, we intentionally excluded MHC (intercrossing arthritissusceptible BALB/c and arthritis-resistant DBA/2 strains, both having the same H2d MHC), and replaced the entire genome with arthritis-prone BALB/c (congenic/sub-congenic stains) except the DBA/2 region of Chr3 (Pgia26).
Eight subcongenic strains (n=355 animals) from Chr3 congenic (DBA/2 92.7130 Mbp) and WT (n =102) mice were immunized for PGIA, scored, and serum markers such as autoantibodies (RF, ACPA, anti mouse PG), cytokines, in vitro T cell responses (PG-specific proliferation and cytokine production) were tested to select regions for further narrowing using interval-specific subcongenic strains.
Figure 1. Linkage analysis for clinical and immune parameters in chr3 sub-congenic strains. Associations between traits and genotypes are presented as negative logarithms of p-values after Mann-Whitney U test [-Lg (p-value) on y-axis] (Panels B and C). Only traits (markers) that showed an association greater than p< 0.01 [-Lg (p-value) >2] are shown. Vertical shadowed areas indicate intervals of chr3 that were found to be associated with either arthritis promoting (Pgia26b ) or arthritis suppressive (Pgia26a ) effects using three independent analyses. Although we have localized the two major Pgia26 loci, The intermediate region between the loci, however, does not seem to be "silent" either (white area throughout Fig. 1AC).
We were able to distinguish between (i) a disease promoting region (both susceptibility and severity)(Pgia26b, Chr3: 92.799.5Mbp, approximately 40 genes in both human and mouse genomes), (ii) a disease suppressive locus (Pgia25a: Chr3: 109.2115.8, ~20 genes) and (iii) regions appearing to control antigen (PG)-specific cytokine production and T cell proliferation (Fig. 1). The reduction of the sizes of these three "subloci" are in progress, and interval-specific subcongenic breeding pairs are established.
To cite this abstract, please use the following information:
Besenyei, Timea, Kadar, Andras, Tryniszewska, Beata, Adarichev, Vyacheslav A., Mikecz, Katalin, Glant, Tibor T.; Narrowing the Protein Tyrosine Phospahatse-22 Locus in Mice with Cartilage Proteoglycan-Induced Arthritis Explores Disease-Promoting and Disease-Suppressive Sub-Loci Neutralizing Their In Vivo Arthritis Susceptibility and Severity. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1921