Immunoglobulin genes in chronic lymphocytic leukemia

Common B cell chronic lymphocytic leukemia (CLL) cells frequently produce polyreactive autoantibodies. Molecular studies have revealed that the leukemia cells in this disease use a restricted repertoire of conserved immunoglobulin variable region genes (Ig V genes) that generally have not undergone somatic mutation. Studies indicate that this polyreactive autoantibody activity expressed in CLL is dependent upon the third complementarity determining region (CDR) of the heavy chain variable region and on proper pairing of the Ig light and heavy chains. In this light, the high frequency at which CLL patients have leukemia cells that make IgM autoantibodies does not appear secondary to the genetic constraints on the potential diversity of the antibodies that may be expressed in this disease. Rather, even though they express nonmutated Ig V genes, CLL B cells appear to have been selected for their ability to bind self-antigens. Conceivably, normal B cells that express such autoantibodies may be perpetually stimulated, thereby increasing their risk for malignant transformation into CLL. Alternatively, anti-self-reactivity may enhance the survival of a B cell clone subsequent to its malignant transformation. In either case, the autoantibody activity of the immunoglobulins expressed by leukemia B cells may be an important factor in the etiopathogenesis of this disease.