Lymphomas and autoimmunity

N.R. Rose, M.D., Ph.D.

Johns Hopkins University, Baltimore, MD

Aim: This presentation summarizes a workshop on the topic, Autoimmunity and Lymphoma, held in Baltimore in July 2001. Methods: Approximately 25 senior investigators interested in various phases of lymphocyte activation, proliferation and regulation were invited to summarize their recent research and speculate on the connections between autoimmune diseases and lymphoproliferative disease. Results: There have been indications of an association between autoimmune disease and lymphoid malignancy since the early 1950s, but information about possible mechanisms has been limited. Recent investigations have elucidated the accelerators and brakes that govern the normal immune cell proliferation or death. For example, IL-2 is pivotally involved in activation-induced cell death (AICD) of lymphocytes, whereas IL-15 extends their survival by inhibiting IL-2-mediated AICD. A dramatic example of defective apoptosis is seen in patients with autoimmune lymphoproliferative syndrome (ALPS) of childhood. ALPS results from mutation in the gene for TNFR SF6, which encodes the transmembrane protein Fas, a major mediator of lymphocyte apoptosis. The disease features extensive lymphocyte proliferation accompanied by autoimmune responses to red blood cells and platelets. Frank lymphomas tend to occur after many years. Histologically, the lymphoproliferation includes CD4-CD8 double negative "$ T cells and CD5+ (B-1) lymphocytes. Analogous findings have been described in the MRL-lpr mouse, in which defective apoptosis leads to autoimmunity and B-cell lymphoma. Several autoimmune diseases, especially Sjögrens syndrome, are associated with a high incidence of B-cell lymphoma. B-cell development entails V(D)J recombination of immunoglobulin (Ig) genes for production of B-cell receptor diversity. Pathological translocations seem to be relatively frequent during the recombination process and Ig class switching, which occur primarily in germinal centers. Finally, antigen-driven B-cell proliferation favors lymphomagenesis. Autoantigens as well as persistent extrinsic antigens may drive clonal expansion and thus favor the development of lymphoid malignancy. Conclusions: A number of mechanisms involved in mounting autoimmune responses seem to contribute, separately or in combination, to the reported association of autoimmune disease and lymphoma.

KEY WORDS: autoimmune disease, apoptosis, lymphoproliferation.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.