In the mouse, most anti-PC antibody is found in one of the three murine anti-PC idiotype families: T15, M603, or M511. The antibodies within each of these idiotypic families have characteristic fine specificities for phosphorylcholine (PC)-analogues. In this paper we compare the ability of hybridoma IgM anti-PC antibodies of the three idiotype families to protect mice from fatal infection with S. pneumoniae. Antibody bearing the T15 idiotype was approximately 8 times as effective as antibody with the M603 idiotype and approximately 30 times as protective as antibody with the M511 idiotype. Reports by others have shown that the heavy chains of virtually all mouse anti-PC antibodies are produced by translocation of a single variable region gene and that the direct translation of this gene (in the absence of somatic mutations) results in heavy chains characteristic of the T15 idiotype. Thus, our findings suggest that the T15 germ line heavy chain variable region gene may have been selected through evolution to code for antibody binding PC-containing pathogens such as S. pneumoniae. Our observations may also explain the existence of regulatory mechanisms that result in maintenance of T15 idiotype expression in murine anti-PC immune responses.

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Williams et al.(1) in a study of monoclonal IgM cold agglutinins noted that antisera to different cold agglutinins possessed specificity not only for antigenic determinants unique to the individual proteins but also for determinants that were shared by cold agglutinins from a number of individuals . This phenomenon of shared or cross-idiotypy among immunoglobulins with similar specificity also has been demonstrated for human proteins with anti-7-globulin activity (2) and among rabbit (3, 4) and mouse (5) antibodies to streptococcal group carbohydrates . In most instances the proteins exhibiting cross-idiotypic reactions had similar, but not necessarily identical, combining sites, and the idiotypic determinant shared by them was associated with the combining site (2, 5-8) . Support for the structural similarity of antibodies with similar specificity and shared idiotypy has been provided by recent findings showing that IgM cold agglutinins, anti-y-globulins (9, 11), or rabbit antibodies to streptococcal group C carbohydrate (7) have strikingly similar heavy and/or light chains .Previous studies from our laboratory have demonstrated a remarkable similarity in the combining sites of mouse antibodies to phosphorylcholine (PC)' regardless of the genetic background of the mice. The antibodies from the mouse strains tested possessed indistinguishable binding specificities for a number of choline analogues (12) and had identical binding-site antigenic determinants (13) . This suggests a striking conservation of the binding site region of mouse anti-PC antibodies, even though differences have been shown to exist in other portions of the variable region (14-16) . In contrast, it was shown (17) that three PC-binding myeloma proteins that differed in combining specificity (18), as well as in idiotypes (19) and in light chains (17), have heavy chain sequences which are virtually identical through the first hypervariable region . These findings *

The interaction of antigen with immunoglobulin-like receptors on immunocompetent lymphocytes is considered fundamental to the activation of these committed lymphocytes (1). Using a variety of techniques, independent laboratories have demonstrated the existence of such receptor-bearing cells and their predominantly bone marrow (B)-lymphocyte nature. Selective depletion or enrichment of lymphoid cell function by passage through antigen-coated immunoadsorbents (2-4), by treatment with heavily labeled radioactive antigen (5), or after specific fluorescent labeling and separation in a photoactivated cell sorter (6) has demonstrated indirectly the immunocompetence of these cells. More direct evidence for the presence of lymphocyte receptors has been obtained from autoradiographic studies of specific binding of radioactive antigen to the surface of lymphocytes (4, 7-9). In these studies, the receptors were found to possess heavy-and light-chain determinants (10), and the high degree of hapten specificity (4, 9, 11) classically attributed to circulating antibody. However, neither the immunocompetence of these antigen-binding cells nor their relationship to precursor cells has been proven.A corollary theme and one central to clonal selection theories of antibody formation is that the receptors on a given clone of immunocompetent cells possess essentially the same structural features, at least in the region of the antibody-combining site, as the antibody molecules to be secreted by the descendents of this clone of precursor cells (1). Indirect evidence in support of this hypothesis has been provided by recent studies which have utilized antisera directed to variable region, if not binding site, antigenic determinants. Passive transfer of such specific anti-idiotypic antiserum into unimmunized mice renders them incompetent to produce antibody bearing that idiotype upon immunization (12,13). This suggests the existence, before immunization, of a population of committed lymphocytes with receptors bearing the same idiotypic determinants as circulating antibody.We have pursued directly the relationship between cell surface receptor and secreted antibody molecules in the immune response to phosphorylcholine

A comparison of the clonal nature of the immune response to phosphorylcholine (PC) was made in nine different inbred mouse strains. Quantitative idiotypic analysis showed that anti-PC antibodies from each strain were composed of antibodies bearing binding-site idiotypic determinants indistinguishable from two different BALB/c myeloma proteins, T15 and M511. Idiotypic determinants of two other PC-binding proteins, M167 and M603, were not detected. Isoelectric focusing of the light (L) chains verified the presence of antibodies similar to T15 and M511 in each strain and indicated the presence of two additional antibodies, one of which has an L chain which cofocuses with M603. Fractionation of anti-PC antibody with anti-idiotypic antibody showed that immunoglobulins bearing T15 and M511 idiotypic determinants are separate and contain L chains that are unifore and resemble those of T15 and M511, respectively. Thus, these mice which differ genetically at multiple loci including the heavy chain allotype complex locus each possess, at least in part, an equivalent set of clonotypes specific for PC. This indicates that the genes encoding these antibodies must be contained in the germ line.