Genetic influences on the end-stage effector phase of arthritis

K/B X N T cell receptor transgenic mice are a model of inflammatory arthrit is, most similar to rheumatoid arthritis, that is critically dependent on b oth T and B lymphocytes. Transfer of serum, or just immunoglobulins, from a rthritic K/BXN animals into healthy recipients provokes arthritis efficient ly, rapidly, and with high penetrance. We have explored the genetic heterog eneity in the response to serum transfer, thereby focussing on the end-stag e effector phase of arthritis, leapfrogging the initiating events. Inbred m ouse strains showed clear variability in their responses. A few were entire ly refractory to disease induction, and those which did develop disease exh ibited a range of severities. Fl analyses suggested that in most cases susc eptibility was controlled in a polygenic additive fashion. One responder/no nresponder pair (C57B1/6 X NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock -out and congenic strains. Two genomic regions that are major, additive det erminants of the rapidity and severity of K/B X N serum-transferred arthrit is were highlighted. Concerning the first region, on proximal chromosome (c hr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal dir1, coinciding with the Sle I locus implicated in susceptibility t o lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chrl2 and dr;,18 may also contribute t o susceptibility to serum-transferred arthritis, albeit to a more limited d egree. The contributions of these loci are additive, but gene dosage effect s at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis i n the K/B X N model will bear fruit.