The immune system and subsets of lymphocytes recognize pathogenic determinants and are expressed even in immunologically naive animals... implying an evolutionary memory which also bridges patterns in microbial components. hybridomas and a comprehensive series of antibody specificity tests, these authors show that a major portion of the response can be attributed to the expansion and activation of independently arising T15+ clones, and they confirm this finding with molecular analyses (6). Although the anti-PC response has been studied for more than 30 years, this study appears to provide the first clues to the nature of the ligand that selects for T15+ clones during development. As shown in Figure 1, other B-cell clones also respond to modified lipoprotein determinants, but the T15 response predominates in most mice. Interestingly, the anti-PC responses employ different Vκ regions but the same Jκ5 region. Jκ5 is located at the 3′-most end of the Jκ locus, and its use has been interpreted as an indication that the progenitors of these B cells have revised their receptors during early development to escape from self-reactivity (14). This model suggests a possible mechanism by which multispecific T15+ B-cell clones may have been positively selected. These clones, which react not only with OxLDL and bacterial PC but also with apoptotic cells, may have been selected by interaction with apoptotic debris at sites of B-cell development in fetal liver and bone marrow (15), in a process that could involve receptor editing before or during the proliferation of specific B cells. Although the present authors have previously shown (16, 17) that deliberate immunization of hypercholesterolemic rabbits or mice expressing high levels of OxLDL lessens atherosclerosis, the role of these autoantibodies against OxLDL needs more evaluation.

The exuberant response of the T15+ clones in ApoE–/–mice is clearly antigen-driven, and the antigens appear to be oxidized phospholipids and/or their protein counterparts. It will be important to determine the fine specificity and the affinity of their binding to each of these species of modified LDL. Additionally, mechanisms involved in the activation of these B cells needs evaluation. Normally, T15+ B cells can be triggered into proliferation and IgM antibody production in a T-independent fashion. The role of T cells in the response is not yet clear, nor is it known whether switching to