The natural cytotoxicity of human serum on murine L cells, EA and Sa 180 cells is expressed as a rapid cytolysis at 37 degrees C. This cytotoxic system is analyzed as to its active constituents and their functional relationships. Ultrastructural studies indicate that cell injury and death are initiated within 10 min by membrane disruption. A trypan blue assay for cell death was used to study serum toxicity in individual normal healthy adults, pregnant females and newborn infants. Pregnancy sera, particularly in the 2nd and 3rd trimesters, were consistently more toxic than male serum or nonpregnant females. Cord serum was typically nontoxic. Pools of normal fresh pregnancy serum were used for immunochemical analysis of the cytotoxic activity. By a variety of immunologic and immunochemical techniques it was shown that the cytotoxicity was, in part, due to the combined action of alternative and classical pathways of complement, the former being more prominent. The lytic action of complement was shown to be greatly amplified by the prior adsorption of IgM on the target cells' surface. This IgM is a critical determinant of the cytotoxic reaction. It probably contains a natural 'antibody' to cell surface antigen(s), whose combination activates both pathways of C.
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