Pathogenesis of Paraneoplastic Nervous System Syndromes

Many SCLC patients mount an antitumor immune response without signs of PNS [9, 167, 174]. Nevertheless, most SCLC patients do not have this immune response. Thus, the rarity of PNS cannot be attributed to infrequency of antigen expression. This discrepancy suggests that additional factors, perhaps related to tumor major histocompatibility complex (MHC) expression, contribute to the initiation of the PNS immune response. A study of Hu antigen and MHC class I expression in SCLC and neuroblastoma supports this theory. Seventeen of 20 tumors from Hu antibody positive patients expressed both proteins, but only 4 of 30 specimens from seronegative individuals expressed both proteins [171]. Altered expression and/or down-regulation of MHC molecules is a common immune-evasive strategy of tumor cells [175], 

The onconeural antigen is not necessarily expressed uniformly throughout the tumor. The cdr2 antigen has been detected in only 10% of the cells in tumors from PCD patients [176]. In one PCD case, the cdr2 antigen was expressed by a primary tumor, but not by its metastasis [177]. 

Cellular infiltrates are found in the tumors from patients with PCD [153, 178] and PEM/SN [90]. These infiltrates may contain CD8+ T cells [114] but are often predominantly composed of plasma cells [153]. Otherwise, the features of tumors from patients with PNS as determined by histological investigation do not differ from those of individuals with a normal nervous system. Moreover, the Hu antigen is not mutated in tumors from PEM patients [179]. 

The tumors found in PNS are generally small and sometimes occult. Several reports indicate that PNS patients have prolonged survival compared 

Antibodies directed to antigens that are components of cell surface receptors are often pathogenic in vivo (such as ion channel antibodies and, possibly, mGluRl antibodies) [95, 182, 183], The pathogenic relevance of antibodies to intracellular targets is much more controversial, but antinuclear antibodies are reported to be pathogenic in some diseases such as systemic lupus erythematosus [184]. 

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