In contrast, several stimulatory signals delivered from the microenvirontment may represent important promoting factors in the development and evolution of the disease. One of these – antigen stimulation – appears to play a major role in the pathogenesis of B-CLL; this conclusion is based on the existence of remarkable similarities in the structures of BCRs of unrelated patients. This similarity in BCR structure is especially striking for about  25% of patients, with some patients clones using identical IgVH, D and JH genes. Extraordinarily, in some of these cases, these rearranged Ig heavy-chain genes are paired with identical IgVL genes, yielding antigen-binding sites that are virtually identical at the amino acid level. Given the enormous number of possible combinations of IgV gene segments encoding antibody-binding domains, one would not expect to find B-CLL patients having such structurally similar “stereotypic” BCRs by chance  until well over 1 million cases have been screened. Hence, their occurence is not likely random, making a plausible argument for the importance of antigen stimulation and drive in this disease.