Somewhat surprisingly for a disease of such prevalence, the etiology and pathogenesis of rheumatoid arthritis (RA) remain poorly understood. The diarthrodial joint lesion is marked by hypertrophy of the synovial lining and leukocyte infiltration of the synovium and the joint cavity, leading to erosion and eventual destruction of cartilage and bone. The arthritic process clearly involves an inflammatory cascade, probably pursuant to an initiating immune response. Yet what activates the inflammatory cascade in a joint-specific manner resulting in RA remains obscure: a genetic lesion? some microbial insult? a combination of the two? Also cloudy is whether the initiating event is systemic or joint directed.
A number of groups have attempted to harness the power of genetic analysis to dissect the arthritic process (for a review, see reference 1
). The high prevalence of RA in sibs or twins of affected individuals, its known familial aggregation, and patterns of inheritance suggest inherited influences 23
, prompting the organization of several large multicenter studies of genetic linkage in families of RA patients 45
. Although promising in that a number of “suggestive” linkages were uncovered, these efforts failed to demonstrate reproducible significant linkage, implying that the underlying genetic complexity demands larger numbers of informative families and probably some type of patient stratification.
The identification of loci influencing RA in resemblant animal models could prove a significant aid for the human genetic studies. Recognizing this, multiple groups have reported a number of genetic dissections of collagen-, proteoglycan- or irritant-induced arthritis in rats or mice 67891011121314
. Here again, the picture that has emerged is one of great complexity, with up to eight regions scoring suggestively or significantly 813
although, interestingly, some of the highlighted chromosomal regions are syntenic between mice and rats 10
. This complexity, as in the human studies, probably reflects the multiple steps and molecular pathways involved in a disease-like induced arthritis, for example, for collagen-induced arthritis (CIA), the immune response to injected collagen, translation of that response into joint inflammation, and the magnitude and persistence of the immune and inflammatory components over time. This multiplicity of events reads out as complexity in the inheritance patterns, lowers the signal-to-noise ratios in the analyses, and generally hinders our progression towards identifying heritable influences.
Genetic analyses of animal models of arthritis would no doubt be simplified and clarified by viewing discreet disease phases in isolation. A recently developed model of inflammatory arthritis, K/B×N TCR transgenic mice allows such a “phase separation.” This transgene encodes a TCR which confers reactivity to a self-peptide presented in the context of Ag7
class II molecules of the MHC. All K/B×N animals which carry both the transgene and the stimulatory MHC allele spontaneously develop an autoimmune disorder with most (although not all) of the clinical, histological, and immunological features of human RA patients 15
. Though the murine disease appears to be exquisitely join specific, it is provoked by T cell reactivity to glucose-6-phosphate isomerase (GPI), an enzyme expressed in all cells and also found circulating in the blood 16
. Anti-GPI T cell reactivity results in preferential activation of and help to those B lymphocytes whose Ig receptors recognize GPI and sequester the small amounts in circulation, resulting in massive production of anti-GPI Abs, which somehow provoke arthritis. Transfer of serum from arthritic K/B×N mice into healthy mice routinely provokes arthritis within days, even when the recipients are completely devoid of lymphocytes 17
. This serum-transfer system has obvious attractions for genetic studies: it allows the rapid analysis of any chosen inbred, variant, or mutant mouse strain; it is robust, with essentially 100% incidence in susceptible strains; and it is simple, focussing on end-stage events, leap-frogging the earlier autoimmune initiation phases, potentially greatly reducing the complexity of the genetic analysis.
This report represents a broad genetic analysis of K/B×N serum-tranferred arthritis. We describe genetic heterogeneity in the response to K/B×N serum in inbred mouse strains and genetic intervals responsible for the difference in disease manifestation shown by the C57Bl/6 (B6) and NOD strains.