The identification of immune responses against neuronal proteins in patients with cancer and neurologic disorders, known as paraneoplastic neurologic disorders (PNDs), has uncovered the existence of antigens (onconeuronal proteins) shared by some cancers and the nervous system. As part of the immune response associated to PND, patients develop serum and cerebrospinal onconeuronal antibodies. Detection of these antibodies in a patient with neurologic disease of unknown etiology establishes the diagnosis of PND and focuses the search of the tumor to a few organs. This is important for two reasons: 1) Prompt diagnosis of PND is critical for early cancer detection and treatment, and 2) allows for immunologic intervention within a limited time frame that improves neurologic outcome. Of all patients suspected of having a PND, only 50% harbor onconeuronal antibodies. Clinical, pathological and CSF findings of these patients are similar to those with onconeuronal antibodies. We hypothesized that many """"""""antibody negative"""""""" patients did in fact, have immune mediated disorders that current techniques failed to identify. We postulated that standard serologic probing of cDNA libraries is insufficient to comprehensively characterize the target onconeuronal antigens. To support our hypothesis we developed a highly sensitive strategy for the rapid identification of onconeuronal antibodies in patients previously considered antibody negative. The method was validated by the characterization of a number of antibodies and the cloning of 14 genes coding for autoantigens of several PND. In addition to new diagnostic tests, several novel concepts emerge from these studies: 1) different immunities can result in similar syndromes, 2) several onconeuronal immunities may occur in one patient, and 3) some immune responses define novel syndromes. This proposal is an extension of this work and focuses on the comprehensive identification of autoantigens specific for the three most common PNDs of the CNS: cortical and limbic encephalitis, cerebellar degeneration, and brainstem encephalitis. A long-term goal is to develop an autoantigen array that will facilitate the diagnosis of PND through the use of a single test. The two specific aims are: 1) to isolate autoantigens of PND using a modified highly sensitive method of serologic screening of cDNA expression libraries, and 2) to isolate autoantigens of PND not identified in Aim 1, such as cell surface antigens and antigens with epitopes formed through post-translational processing, using immunoprecipitation. ? ?
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