Genetic influences on the end-stage effector phase of arthritis.
K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/BxN animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/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 determinants of the rapidity and severity of K/BxN serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects 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 in the K/BxN model will bear fruit.
Ji
H
H
Section on Immunology and Immunogenetics, Joslin Diabetes Center, One Joslin Place, Boston, MA 02115, USA.
Gauguier
D
D
Ohmura
K
K
Gonzalez
A
A
Duchatelle
V
V
Danoy
P
P
Garchon
H J
HJ
Degott
C
C
Lathrop
M
M
Benoist
C
C
Mathis
D
D
D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002874:Chromosome Mapping; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006824:Hybridization, Genetic; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell