Antigens in chronic lymphocytic leukemia—Implications for cell origin and leukemogenesis

Several types of B cell tumors, particularly MALT lymphomas, are known to have an antigen-driven component in tumor development. Over the past two decades substantial data have accumulated regarding the restricted immunoglobulin (IG) gene repertoire in chronic lymphocytic leukemia (CLL) and its potential implications for antigenic drive in the disease development and progression. Herein we discuss how evidence first illustrated a link between certain B cell receptor (BCR) specificities and disease outcome and the subsequent large-scale IG analyses which revealed the extent of “stereotyped” BCRs in CLL. More recent studies on CLL antibody reactivity have gradually provided clues as to which antigens may be involved in the tumor development. Significantly, CLL monoclonal antibodies have been shown to resemble natural antibodies recognizing molecular motifs both on apoptotic cells (e.g. modified cytoskeletal proteins and oxidation-specific epitopes), as well as exogenous bacteria, indicating that CLL clones possibly arise from B cells which have dual function as scavengers of apoptotic debris, while also having the ability to bind conserved bacterial cell structures. Such revelations have led us to re-evaluate both the phenotypic and functional characteristics of the tumor B cells and the pathway by which CLL arises and develops.