ABROGATION OF THE ALTERNATIVE COMPLEMENT PATHWAY BY TARGETED DELETIONOF MURINE FACTOR-B

To investigate the role of complement protein factor B (Bf) and altern ative pathway activity in vivo, and to test the hypothesized potential genetic lethal effect of Bf deficiency, the murine Bf gene was interr upted by exchange of exon 3 through exon 7 (including the Factor D cle aving site) with the neo(r) gene, Mice heterozygous for the targeted E f allele were interbred, yielding Bf-deficient: offspring after the F- 1 generation at a frequency suggesting that BE deficiency alone has no major effect on fertility or fetal development. However, in the conte xt of one or more genes derived from the 129 mouse strain, offspring h omozygous for Bf deficiency were generated at less than expected numbe rs (P = 0.012), Bf-deficient mice showed no gross phenotypic differenc e from wild-type litter-mates, Sera from Bf-deficient mice lacked dete ctable alternative complement pathway activity; purified mouse Ef over came the deficit, Classical pathway-dependent total hemolytic activity was lower in Bf-deficient than wild-type mice, possibly reflecting lo ss of the alternative pathway amplification loop, Lymphoid organ struc ture and IgG1 antibody response to a T-dependent antigen appeared norm al in Bf-deficient mice. Sensitivity to lethal endotoxic shock was not significantly altered in Bf-deficient mice, Thus, deficiency of Ef an d alternative complement activation pathway led to a less dramatic phe notype than expected, Nevertheless, these mice provide an excellent mo del for the assessment of the role of Bf and the alternative pathway i n host defense and other functions in vivo.