Autoimmunity and cancer

In patients with systemic lupus erythematosus, there is a well-docu­mented increased risk of non-Hodgkin’s lymphoma. Analogously, the B/W mouse develops lupus disease and reca­pitulates the human disease in most clinical aspects, and also suffers from hyper­proliferation of lymphocytes and, eventually, lymphoma. In mice, lymphomas are generally caused by insertional mutagenesis. Similarly, in autoimmune disease we hypothesize that immature B cells are not tolerized to self-antigen because of a retroelement insertion blocking the relevant pathway. Because a single mu­tation in a stem cell may jeopardize the tolerization of a larger lymphocyte population, but cancer generally requires accu­mulation of se­veral mutations within the same cell, autoim­mu­ne disease will precede cancer.

Be­cause B lymphocytes of B/W mice produce large amounts of endo­genous MLV, B lymphoid hyperplasia in these mice may occur by de novo proviral insertions into the genome. To identify retroviral integration sites, we isolate genomic DNA from B/W lymphomas and from clones of hyper­proliferating (autoimmu­ne) spleen cells. Using an anchored PCR technique, we determine the genes affected by retroviral insertion. We then study the effects of the mutations on B lymphocyte apoptosis and proliferation.