Analysis of high complement levels in Mus hortulanus and BUB mice

BUB/BnJ mice were previously identified as having exceptionally potent complement activity, relative to common mouse strains, in the lysis of antibody-coated human tumor cells. We describe herein our investigation into the molecular and genetic basis for this difference between mouse strains, and also our results with wild mice and mouse strains recently derived from the wild, to determine whether low complement levels are characteristic of wild mice. BUB complement was compared with complement from BALB/c and C57BL/6 mice. BUB mice had higher levels of most individual classical pathway components, except for C1, than the other two strains, but the difference was generally only 2-3-fold, so insufficient to fully explain the difference observed with tumor target cells. CH50 titers on antibody-coated sheep erythrocytes also demonstrated only a 2-4-fold difference. However, CH50 titers on antibody-coated human erythrocyte target cells demonstrated a difference similar in magnitude to that seen with human tumor targets. These results suggest that the difference between mouse strains depends partly on the use of human, rather than sheep, target cells. In an assay for alternative complement pathway activity using neuraminidase-treated human erythrocytes as targets, complements of BALB/c and BUB mice were similar in activity, suggesting that the difference between mouse strains is manifested in the early steps of complement activation. Analysis of F1 and backcross mice suggested that the difference in complement level between BUB and BALB/c or C57BL/6 mice is controlled by semi-dominant genes, and cannot be attributed to a single gene. Wild mice and mice recently derived from the wild generally had low complement levels, similar to most laboratory mice. However, three strains of aboriginal mice, including Mus hortulanus (spicilegus) and Mus spretus, had complement levels higher than that of BUB mice, and as high as sera from the rabbit or rat, which are the most potent known complement sources for the lysis of human tumor cells. In comparison with BUB mouse sera, M. hortulanus sera had at least four-fold higher levels of C3, C6, C8 and C9, and some or all of these differences may explain its higher total complement activity. In the lysis of antibody-coated human erythrocytes, M. hortulanus serum was more potent than any other complement source tested, including sera of the guinea pig, rat, rabbit or human. These strains may be useful in investigating the role of complement in various pathological processes, and in investigating the genetic regulation of the complement system.