Abstract
To understand the role of genetic factors involved in the development of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA), we have identified a genomic region containing a major quantitative trait locus (QTL) for this disease. The QTL is on chromosome 1 and appears to be the strongest genetic region regulating arthritis. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c−/− which are susceptible. Genetic markers along every chromosome were used to assist in the selection of progeny in each generation to backcross to BALB/c−/−. By the 6th generation we determined that all of the chromosomes in the progeny were of BALB/c origin with the exception of portions of chromosome 1. At this stage we intercrossed selected mice to produce homozygous strains containing the genomic background of BALB/c−/− except for the QTL region on chromosome 1, which was from DBA/1. We were able to establish two congenic strains with overlapping DBA/1 DNA segments. These strains were observed for the development of spontaneous arthritis. Both congenic strains were relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. The gene/s that regulates this major QTL would appear to be located in the region of the QTL that is shared by both strains. The common transferred region is between D1Mit110 and D1Mit209 on chromosome 1. We evaluated this region for candidate genes and have identified a limited number of candidates. Confirmation of the identity and precise role of the candidates will require additional study.
Highlights
Interleukin 1 (IL-1) is a major contributor to the development of immune mediated arthritis
Most of the transferred genomic region in BALB.D12 is not located within the quantitative trait locus (QTL) region identified in our initial mapping
Our congenic breeding was successful in identifying a QTL associated with the development of spontaneous arthritis
Summary
Interleukin 1 (IL-1) is a major contributor to the development of immune mediated arthritis. This cytokine is expressed by macrophages, monocytes and synovial fibroblasts. The importance of IL-1RA in regulation of IL-1 activity has been established by generating mice deficient in IL-1RA. These IL-1RA deficient mice develop spontaneous arthritis as first described by Horai and colleagues [1]. The development of disease is in part dependent upon genetic background since DBA/1 mice with a similar deficiency in IL-1RA do not develop spontaneous arthritis [2]
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