by Guest Blogger John Varga MD, Northwestern University, Chicago, IL
Scleroderma, or systemic sclerosis, remains a mystery. The cause of this rare autoimmune disease is unknown, and genetics appears to play only a modest role. It has long been known that like dermatomyositis and other autoimmune disease, scleroderma coexists with cancer more often than would be expected. Could scleroderma in some cases arise as fallout from an anti-cancer immune response mounted against a nascent tumor?
This is the provocative hypothesis examined by Rosen and colleagues from Johns Hopkins in the January 10 issue of Science. Rosen et al observed that while cancer can coexist with scleroderma, the temporal relationship between the two seems random, with cancer antedating scleroderma in some cases, or following it in others. The interval between the cancer diagnosis and scleroderma can range from years to decades. There is one exception, however. In scleroderma patients with cancer whose antibodies are directed against RNA polymerase III, scleroderma almost always arises within 4 years of the detection of cancer. This is in striking contrast to the majority of patients with scleroderma and cancer, who have autoantibodies to centromere (CENPB) or topoisomerase-1. What is it about anti-RNA polymerase III autoimmunity that links scleroderma with cancer?
To address this conundrum, Rosen et al. revisited an old hypothesis – that the antigen triggering autoimmune diseases in some patients is actually the tumor itself! Rosen et al analyzed genetic alterations in tumor tissue from eight patients with scleroderma and cancer who were RNA polymerase III-positive, and eight patients with scleroderma and cancer who were RNA polymerase III-negative. These latter had autoantibodies to CENPB or to Topo-1. Tumors from RNA polymerase III-positive patients were found to have clear-cut genetic alterations (missense mutation or loss of heterozygosity) involving the POLR3A gene encoding RNA polymerase III PRC1 subunit. In contrast, none of the scleroderma patients with cancer who had other autoantibodies had genetic alterations in ROLR3A.
Moreover, the authors go on to demonstrate a unique T cell subset, found only in RNA polymerase III-positive patients with scleroderma, that reacts specifically with the RNA Polymerase III epitope. This cell-mediated self-reactivity might represent an anti-cancer immune response targeting the tumors with the somatic alterations in POLR3A. These results lead to the speculation that a nascent tumor harboring a genetic alteration might generate an antibody response that, on the one hand, leads to immune attack against the tumor itself (a phenomenon called tumor immune editing), but on the other, leads to an autoimmune disease like scleroderma.
In this scenario, some cases of scleroderma might be viewed as a paraneoplastic condition, and anti-RNA Polymerase III autoimmunity might actually represent an ineffective anti-cancer response whose goal is to eradicate the tumor harboring the genetic alteration. Perhaps RNA polymerase III-positive scleroderma patients who have no detectable cancer have succeeded in deploying the break in immune tolerance to rid themselves of the tumor.
A major unanswered question remains: how does an antigen-specific immune response specifically directed against RNA polymerase III result in the microvascular injury and tissue fibrosis that are the hallmarks of scleroderma?
Image credit: Anne Weston, LRI, CRUK. This image is made available from Wellcomeimages.org and used under the Creative Commons license CC-BY-NC-ND 2.0