Oncogenes, growth factors, and autoimmune diseases (review)

Autoimmune diseases are benign proliferative diseases characterized by the expansion and activation of the autoreactive immune cells and the proliferation of connective tissue elements. Because both cytokines and oncogenes products are necessary for expansion of immune cells, it is possible that inappropriate activation of oncogenes might influence cytokine and lymphokine secretion as well as the expression of immune response genes necessary for the development of autoimmunity in a susceptible individual. At least four gene families of the immune system are involved in the induction and perpetuation of autoimmunity: 1) genes associated with the major histocompatibility complex, 2) germline immunoglobulin genes, 3) T cell receptor genes, and 4) complement genes. The hypothetical genetic locus responsible for the induction of autoimmunity is the "rheumogene". Oncogenes are obvious candidates for rheumogenes and activation of such genes may be necessary for the development of autoimmunity. Certain protooncogenes are activated in systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, progressive systemic sclerosis, and dermatomyositis, supporting this hypothesis. However, the activation of oncogenes in autoimmunity is not associated with gene translocation, deletions, point mutations, loss of regulatory sequences, or amplification, indicating that autoimmunity involves different mechanisms of oncogene activation than do many malignancies. Oncogene expression in autoimmune diseases tends to mimic the expression of oncogenes in normal activated lymphocytes, macrophages, and fibroblasts. Rheumogenes, if they exist, may be disordered regulatory genes which suppress or enhance the expression of cellular oncogenes in a non-malignant fashion. The existence of regulator gene demethylation and the presence of DNA-binding proteins specific for oncogene regulator sequences provide support for the concept of that regulator gene dysfunction, rather than oncogene activation per se is the more primary event in autoimmune diseases.