Department of Molecular and Experimental Medicine
Molecular and Cell Biology of Autoantibodies and Autoimmunity
Human autoimmune diseases such as lupus and scleroderma are characterized by the presence of autoantibodies against intracellular antigens. We have been involved in the identification of the autoantibodies, characterization of their intracellular antigens, and investigating the relationship of the autoimmune response to disease mechanisms.
The antigens that we have identified include the Sm antigen, a component of small nuclear ribonucleoprotein particles involved in splicing of precursor mRNAs, and proliferating cell nuclear antigen (PCNA), an auxiliary protein of DNA polymerase d (involved in the processivity phase of leading strand DNA replication). Both of these intranuclear proteins are target antigens of patients with lupus erythematosus. In scleroderma, we have identified antigens such as Scl-70, which has been shown to be DNA topoisomerase 1, and centromere proteins, which are components of the primary constrictions in chromosomes and involved in mitosis and cell division.
We have now shown that autoantibodies to intracellular molecules are not restricted to autoimmune diseases like systemic lupus erythematosus and scleroderma, but are also seen in cancer. Some patients who are developing cancer make autoantibodies that appear in their circulation at the same time or before the clinical detection of the tumor. There is much evidence to show that this is an immune response that is "antigen-driven" and in such cases, the antigens that drive the immune response in such patients are intracellular molecules that are likely to have a role in tumorigenesis. Making use of autoantibodies in such patients to immunoscreen cDNA libraries has been a very useful method for identifying such tumor-associated antigens. Recently, we have identified one such tumor-associated antigen as a cytoplasmic protein of 62 kDa (p62) that is a mRNA binding protein and is involved in binding insulin-like growth factor II (IGF-II) mRNA. The gene product IGF-II is a growth factor that has been shown to be an accessory factor or co-factor in tumorigenesis. The mRNA binding protein, p62, is postulated to stabilize the mRNA and increase translatability of the gene, thus supplying growth factors for tumorigenesis. p62 is developmentally regulated in that it has been shown to be expressed in fetal liver but not in normal adult liver. However, in liver cancer, p62 is aberrantly expressed in the cancer cells. Transgenic animals overexpressing p62 are currently being studied to dissect the mechanistic pathways relating aberrant regulation of p62 and tumorigenesis.
Senior Distinguished Scientist Award of the Alexander von Humboldt Foundation, Bonn, Germany; City of Medicine Award, Duke University, Durham, North Carolina; Distinguished Alumnus Award, Duke University Medical Center, Durham, North Carolina; Erwin Neter Award, Association of Medical Laboratory Immunologists; Sydney Watson Smith Award and Lecture, Royal College of Physicians of Edinburgh; Japan Rheumatism Foundation International Prize
Zhang, J.-Y., Chan, E.K.L., Peng, X.-X. and Tan, E.M. "A novel cytoplasmic protein with RNA-binding motifs is an autoantigen in human hepatocellular carcinoma." J. Exp. Med. 189: 1101-1110, 1999.
Lu, M., Nakamura, R.M., Dent, E.D., Zhang, J.-Y., Nielsen, F.C., Christiansen, J., Chan, E.K.L. and E.M. Tan. "Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis." Am. J. Pathol. 159: 945-953, 2001.
Zhu, W., Chan, E.K.L., Li, J., Hemmerich, P. and E.M. Tan. "Transcription activating property of autoantigen SG2NA and modulating effect of WD-40 repeats." Exp. Cell Res. 269: 312-321, 2001.
Tan, E.M. "Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis." J. Clin. Invest., 108: 1411-1415, 2001.