Identification of rat susceptibility loci for adjuvant-oil-induced arthritis

Abstract

One intradermal injection of incomplete Freund's adjuvant-oil induces a T cell-mediated inflammatory joint disease in DA rats. Susceptibility genes for oil-induced arthritis (OIA) are located both within and outside the major histocompatibility complex (MHC, Oia1). We have searched for disease-linked non-MHC loci in an F2 intercross between DA rats and MHC-identical but arthritis-resistant LEW.1AV1 rats. A genome-wide scan with microsatellite markers revealed two major chromosome regions that control disease incidence and severity: Oia2 on chromosome 4 (P = 4 x 10(-13)) and Oia3 on chromosome 10 (P = 1 x 10(-6)). All animals homozygous for DA alleles at both loci developed severe arthritis, whereas all those homozygous for LEW.1AV1 alleles were resistant. These results have general implications for situations where nonspecific activation of the immune system (e.g., incomplete Freund's adjuvant-oil) causes inflammation and disease, either alone or in conjunction with specific antigens. They may also provide clues to the etiology of inflammatory diseases in humans, including rheumatoid arthritis.

Figure 1

Arthritis scores for the parental rat strains and F₁ and F₂ progeny: DA (no. 12), LEW.1AV1 (no. 16), (DA × LEW.1AV1)F₁ (no. 29), (DA × F₁)Bx (no. 96), and (DA × LEW.1AV1)F₂ (no. 189). Bars indicate the median arthritis score of the affected animals in each group. The incidence is calculated as the percent of animals with arthritis scores between 1 and 92 (the animals affected with arthritis).

Figure 2

Arthritis scores of the (DA × LEW.1AV1)F₂ rats in relation to genoypes at the two Oia loci, as defined by the markers D4Mgh10 (Oia2) and D10Mgh1 (Oia3). Bars indicate the median arthritis severity of affected animals in each group. The Oia2 locus on chromosome 4 exerts additive effects on incidence (DD > DL, P = 1 × 10⁻⁴; DL > LL, P = 7 × 10⁻⁵) and on severity (DD > DL, P = 5 × 10⁻³; DL > LL, P = 1 × 10⁻⁴), whereas the Oia3 locus on chromosome 10 exerts recessive effects on incidence (DD > DL, P = 3 × 10⁻⁴; DL = LL) and on severity (DD > DL, P = 2 × 10⁻²; DL = LL). * Percent animals affected with arthritis (scores, 1–92). ^† Genotypes: DD = DA homozygous; LL = LEW.1AV1 homozygous; DL = heterozygous. ^‡ The markers D4Mgh10 and D10Mgh1 define loci Oia2 and Oia3.

Figure 3

Arthritis scores for (DA × LEW.1AV1)F₂ rats in relation to combinations of genotypes at the two major arthritis loci defined by the markers D4Mgh10 (Oia2) and D10Mgh1 (Oia3). Bars indicate the median arthritis severity of affected animals in each group. * Percent animals with arthritis (scores, 1–92). ^† Markers: D4Mgh10 (Oia2) and D10Mgh1 (Oia3). Genotypes: DD = DA homozygous; LL = LEW.1AV1 homozygous; and DL = heterozygous animals.