Genes on the X chromosome affect development of collagen‐induced arthritis in mice

SUMMARY Susceptibility to collagen‐induced arthritis (CIA) in mice is associated with a class II gene in MHC (A q ) but also with unknown genes outside MHC. Investigated here is the influence of genes on the X chromosome as well as the role of the X‐linked immunodeficiency (xid) mutation. Reciprocal male F 1 hybrids, bred to be heterozygous or homozygous for A q , showed a genetic influence in their susceptibility to develop CIA. Crosses were made between B10.G, B10Q, DBA/I, SWR/J, C3H.Q and CBA/Ca, and all F i mice were castrated to avoid sex hormone modulation of the susceptibility. A differential timing of arthritis onset and severity were seen in the reciprocal F 1 males. An exception was the reciprocal F 1 male offspring from SWR/J and DBA/1 crosses which differed only in disease severity late in the course of the disease. The female F 1 crosses did not show the same pattern of differential susceptibility to CIA as the F 1 males. To exclude the possible influence the Y chromosome, F 1 males of reciprocal crosses were back‐crossed to the parental strains creating offspring with equal X chromosomes but divergent Y chromosomes. No difference in development of arthritis was observed in these. The influence of the xid mutation was investigated next. The xid loci from the CBA/N mouse was bred into DBA/1 strain which is highly susceptible to CIA. The resulting congenic DBA/l‐xid strain was resistant to induction of CIA and did not develop an antibody response to type II collagen. We conclude that polymorphic genes on the X chromosome modulate susceptibility to CIA. The results from the experiments with mice carrying xid mutations confirm that such immune modulating genes exist on the sex chromosomes.