MANNOSE-BINDING PROTEIN IS INVOLVED IN FIRST-LINE HOST-DEFENSE - EVIDENCE FROM TRANSGENIC MICE

Mannose binding protein (MBP) is a calcium-dependent C-type lectin sec reted by the liver which seems to be an important component of innate or natural immunity. We have investigated the effects of Candida albic ans and thioglycolate injection into transgenic mice bearing the human MBP gene, The transgenes contained a 15 kb fragment of the MBP gene w hich included the complete coding sequence, Northern blot hybridizatio n showed human MBP mRNA transcripts in the liver of two transgenic lin es with low and high copy number respectively. Western blot analysis s howed the presence in serum of human MBP which associated into the hig her multimeric forms which are capable of activating complement. Enzym e-linked immunosorbent assays (ELISA) showed that serum human MBP conc entrations in the transgenes (1.90 +/- 0.16 mg/l, mean +/- SEM) were a bout twice as high as the levels in man, The serum concentration of MB P A, which is the mouse homologue of MBP, (13.9 +/- 0.45 mg/l) was abo ut seven times that of human MBP, Intravenous injection of Candida alb icans caused the serum human MBP level to fall by more than 50% in the first hour and then slowly recover, but it did not return the initial value by 72 hr. Candida injection caused a 25% fall in serum mouse MB P A in the first hour which then rose to supranormal levels by 72 hr. Following Candida injection mouse MBP A mRNA concentrations increased over 72 hr in contrast to human MBP mRNA which remained constant in bo th transgenic lines. These data indicate that the human MBP gene fragm ent in the transgene did not include the regulatory elements of the ge ne. Total haemolytic complement activity and C3 concentrations also fe ll. immediately after Candida and thioglycolate injection while the co ncentrations of mannose specific immunoglobulin G (IgG) and immunoglob ulin M (IgM) did not fall. The data indicate that mannose binding prot ein plays an important role in the initial stages of defence against i nfection which, in this model, is quantitatively greater than that of mannose-specific IgG and IgM antibodies. Mannose binding protein is pr obably most important in defense of previously unexposed and non-immun e hosts.