Alloantigens are regularly demonstrable by antibodies from alloimmunized individuals, whereas naturally occurring alloantibodies, which could be detected only against a small proportion of alloantigens, occur irregularly and their origin is enigmatic (Perrault 1973, van Loghem 1978). Human A-and B-blood group-specific antibodies are directed towards antigens of a polysaccharide nature which are commonly present in the microbial, animal, and plant worlds. Naturally occurring erythrocyte antibodies to chicken MHC antigens have been found in xenogeneic and allogeneic sera (Longenecker and Mosmann 1980). However, naturally occurring HLA antibodies have been found only in the sera of some patients with myeloma (Smith et al. 1974, Falk et al. 1973), carcinoma (Vos et al. 1975) and chronic immunological disorders (Terasaki et al. 1970, Waters et al. 1971, Collins et al. 1973) and in one case of a nontransfused healthy male (Lepage et al. 1976). We report in this paper on the presence of naturally occurring lymphocytotoxic H-2-specific antibodies in sera from about 25 percent of aged C57BL mice. Some of these antibodies had a high titer and sera from individual mice contained antibodies of different specificities for public H-2 antigens. Thus, age-dependent changes in the regulation of the immunological apparatus and/or modified cell-membrane antigens are implicated in the generation of naturally occurring H-2-specific antibodies.
The search for H-2-specific antibodies in aged mice was initiated by experiments in which it was found that individual mice of one highly inbred strain produced alloantibodies with different H-2 specificities (Ivanyi et al. 1978(Ivanyi et al. , 1979)). During an anti-H-2L d (BALB/c-H-2 am2 anti-BALB/c-H-2 e) immunization, some mice did not produce antibodies reactive with donor cells, although they produced strong cytotoxic antibodies against third-party (H-2 k and H-2 r) cells. We have hypothesized, that these heteroclitic antibodies were not induced by the antigenic