The immunoproteasome in cancer-associated myositis - a possible link between autoimmunity and cancer

Dermatomyositis (DM) is a systemic autoimmune disease with close association of subgroups to malignancy. As an immune response, diverse autoantibodies as well as characteristic cellular infiltration, overexpression of MHC class-I and an interferon signature are detectable in affected skin, muscle and organ tissues such as lungs. The associated pathogenesis is unclear, whereby only specific autoantibodies such as against TIF1g are available to date for the risk assessment of a malignancy. Preliminary results show an increased expression of immunoproteasome subunits in DM, whereby this was detectable in muscle cells as well as in infiltrating dendritic cells, CD68+ macrophages and CD8+ T cells. Of note, an overexpression of certain, inducible subunits of the immunoproteasome was shown particularly in cancer-associated DM. Since the proteasome system is variously involved in the regulation of cellular homeostasis as well as in immune regulation via the production of antigenic peptides for the MHC class I presentation pathway, and became activated under the influence of inflammatory cytokines such as interferon-g into the immunoproteasome, these results are to be expected. However, the proteasome also plays a relevant role in malignant diseases and proteasome inhibitors represent an effective therapy option, e.g. in multiple myeloma. This raises the question for us whether and how the proteasome is involved in the pathogenesis of cancer-associated DM? The investigations planned for this purpose can clarify whether there are differences in the expression and function of the proteasome in DM patients with malignancy. To investigate the involvement of the proteasome in the pathogenesis of cancer-associated DM in more depth, our aim is to clarify if i) identification of DM patients at risk of cancer is possible by cytometric and/or mRNA profiles, ii) the relevant myositis antigens TIF1-γ and Mi-2 show different expression and modification in skeletal muscle samples as well as in cell lines, iii) the tumor suppressor proteins p53/pRb and the anti-oxidative stress transcription factor Nrf2, which are regulated by proteasome, show an association to cancer development, iv) selected peptides of TIF1-γ and Mi-2 exhibit an effect on the TCR and BCR repertoire, and v) if isolated anti-TIF1-γ and anti-Mi-2 antibodies express effects upon proliferation, apoptosis and cytokine production of primary muscle cell culture and cancer cell lines.