We have identified a set of natural IgM antibodies in human serum that are reactive with protamines, a class of low molecular weight basic nucleoproteins that are synthesized de novo in the postpubertal testis and are unique to sperm. Those antibodies were detected by ELISA in significant titer in all of 100 sera of normal adult males and females and in 26 of 28 sera of normal pediatrics aged 7 d to 2 yr. Commonality between the protamine-reactive IgM antibodies of pediatric and adult sera was established by the demonstration of similarity in antigen recognition and reaction kinetics. Therefore, the role of protamines as either immunogenic stimulus or antigenic target of that set of natural antibodies is not likely. The antigenic site recognized by the protein-reactive serum IgM antibodies was characterized by comparison with the pattern of antigen recognition by a monoclonal antibody to human sperm protamines (HPmAb). By the use of synthetic peptides simulating the amino acid sequences of various segments of human protamine 2 and of polyarginine, polylysine, and histones as test antigens, the principle characteristic of the antigenic site recognized by both HPmAb and the serum IgM antibodies was inferred to be that of clustered arginyl residues with an apparent minimum requirement of four arginyl residues, including a triplet, within a six residue piece; for both, the reaction was shown to be not dependent upon charge attraction. A series of immunoabsorption procedures indicated that the protamine-reactive serum IgM antibodies are a discrete set with a high order of specificity. A search of protein data bases revealed that the putative minimum epitope is present in four or five human autogenous proteins, all moieties of the immune system, and in a number of viral proteins. The possible implications of those findings are discussed in the light of early hypotheses concerning the origin and function of natural antibodies and the many recent reports of identification of natural antibodies in normal human sera. The set of natural antibodies identified in this study may be unique or may represent a class of antibodies present in the repertoire that, by virtue of the obscurity of their origin or function, have not been previously or extensively recognized.

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