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Collagen?induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models, with many features similar to rheumatoid arthritis. This study sought to identify potential genetic regulatory mechanisms of CIA in major histocompatibility complex–matched (H2?q) F2 hybrid mice.We used 126 polymorphic markers to perform simple sequence?length polymorphism analysis on 290 F2 hybrids of arthritis?susceptible (DBA/1J) and arthritis?resistant (FVB/N) inbred mouse strains. The major clinical traits (disease severity and onset) were assessed, and serum antibodies specific to type II collagen (CII) were determined by enzyme?linked immunosorbent assay in 270 F2 mice. Lymph nodes from 94 F2 mice were used to test the ratio of CD4 to CD8 by fluorescence?activated cell sorter analysis, and cell proliferation was determined by XTT test.Two quantitative trait loci (QTLs) identified in previous studies were confirmed; these were severity?controlling Cia2 and onset?controlling Cia4 on chromosome 2. Moreover, we identified 5 new QTLs, 1 for CII?specific IgG2a antibodies on chromosome 5, 2 controlling the CII?specific IgG1 antibody response on chromosomes 10 and 13, 1 for the CD4:CD8 ratio on chromosome 2, and 1 for cell proliferation (measured by XTT test) on chromosome 16. Complement component C5 was identified as the probable main candidate gene for the QTLs Cia2 and Cia4. F2 mice carrying a 2?basepair deletion of C5, the FVB/N allele, had low incidence and less severe disease as compared with those carrying the DBA/1J allele.This genome scan provides additional evidence confirming the role of C5 as a probable candidate gene for Cia2 and Cia4 loci, and identifies new QTLs controlling new traits in autoimmune arthritis. [ABSTRACT FROM AUTHOR]