Novel Conformation of Phenotypespecific Autoantigens

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In spite of the fact that many autoantigens in systemic autoimmune diseases are ubiquitously expressed, there is nevertheless a striking association of specific antibody responses with unique clinical phenotypes. One potential explanation for this observation is that changes in autoantigen structure may be limited to the relevant disease microenvironment and may contribute to initiation of an autoimmune response. As several autoantigens that are targeted in systemic autoimmune diseases can also be targeted in patients with hepatocellular carcinoma (HCC), we have sought to define microenvironment-specific changes in autoantigens in liver tissue of patients with HCC as a model system in which to investigate the link between autoantigen expression and cancer. Interestingly, the nucleolar HCC autoantigen B23 (nucleophosmin) exists in a truncated form in HCC liver, lacking six amino acids at the N-terminus. While full-length B23 (expressed in all other tissues) is very resistant to cleavage by GrB, HCC B23 is strikingly sensitive to such cleavage [97].

B23 has also been found to be a scleroderma autoantigen associated with the development of pulmonary hypertension [98] and, in an analogous fashion to HCC B23, is also uniquely cleaved by GrB in differentiated smooth muscle cells [99]. Whether this selective cleavage in vascular smooth muscle cells reflects expression of cleavable B23 in areas of hyperplasia that is characteristic of pulmonary hypertension is unknown, but the association is tantalizing nonetheless. The striking restriction of a novel B23 conformation to the likely sites of immunization may indicate that distinct autoantigen conformations responsible for specific cellular functions (e.g., cell growth) are present during disease initiation and/or propagation. It is possible that such pathways of autoantigen expression and conformation may become therapeutically tractable in the autoimmune diseases.

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