Brief Alert
Paraneoplastic Cerebellar Degeneration—Role of T cells in Autoimmune Response
Source: Albert ML, et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nature Med 1998;4: 1321-1324.
Paraneoplastic neurologic disease represents a fascinating set of syndromes that arise secondarily from an autoimmune response that is induced first against specific tumor antigens, which are also expressed on neurons in the central nervous system. The main conditions are paraneoplastic cerebellar degeneration (PCD, seen with breast and ovarian cancer, diagnosed by anti-Yo antibodies); paraneoplastic encephalomyelitis/sensory neuropathy (typically seen in smokers with small cell lung cancer, associated with anti-Hu antibodies); paraneoplastic opsoclonus/myoclonus/ataxia (associated with neuroblastoma or small cell lung cancer, diagnosed by anti-Ri antibodies); and cancer-associated retinopathy (CAR, seen with small cell lung cancer, anti-photoreceptor antibodies).
While each disorder can usually be diagnosed by high titers of antigen-specific antibodies, it appears that this humoral immune response is not sufficient to cause disease. Plasmapheresis to reduce antibody titers is an ineffective therapy, and passive transfer of antibodies does not reproduce the disorder, as in Eaton-Lambert syndrome (a paraneoplastic condition with antibodies against the presynaptic terminal calcium channels of the neuromuscular junction) or myasthenia gravis. Furthermore, paraneoplastic antigens, such as Yo, are typically intracellular proteins, and it is unclear how an antibody could disrupt cellular function.
In this report, Albert and associates studied the role of cytotoxic T lymphocytes (CTLs) in tumor immunity and autoimmune neuronal degeneration of PCD. They were able to demonstrate in vitro, expanded populations of MHC class I-restricted T cells in PCD patients, that recognized the Yo protein expressed on antigen-presenting dendritic cells. Thus, B- and T-cell autoimmunity can develop against tissue-restricted antigens, such as neuronal antigens, that occur in organs that are usually immunologically isolated. This CTL activity, in addition to causing neurologic disease, is also probably important in suppressing tumor growth. For this reason, immunosuppressive therapies targeting T cells in PCD could potentially worsen the status of the underlying malignancy.
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