Onconeural antigens

The cdr2 antigen, the target antigen of the Yo antibodies in paraneoplastic cerebellar degeneration, is located in the cytoplasma. The cdr2 protein is a neuronal signaling protein, and is, like the Ma proteins, normally expressed 

The expression of onconeural antigens is highly restricted in some instances. Recoverin is found in the retinal cells only, and cdr2 expression is restricted to the Purkinje cells and brain stem. Other antigens such as Nova are widely distributed in the CNS, whereas the HuD and CRMP-5 antigens are expressed by neurons of both the CNS and the peripheral nervous system. The extensive immunoreactivity is reflected by the heterogenous clinical manifestations in patients with Ri, CRMP-5, Hu, and amphiphysin antibodies [15,29, 30]. 

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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]. 

Autoantigen-specific CD8+ T cells may mediate autoimmune injury in the CNS [215], and cytotoxic T lymphocytes can attack and injure neurons [208, 210, 216, 217]. In a study of the effects of T cells specific for the onconeural antigen PNMA1 of the Ma family, transfer of CD4+ T cells to rats resulted in a perivascular inflammatory response that involved CNS regions affected... 

Darnell RB. Onconeural antigens and the paraneoplastic neurologic disorders At the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci USA 1996 93(10) ... 

Okano HJ, Park WY, Corradi JP, Darnell RB. The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function Implications for neuronal and tumor cell survival. Genes Dev 1999 13(16) 2087-2097. 

Major Onconeural Antibodies and Antigens and Associated Neurological Findings and Tumors"... 

The second most common tumor in LE is testicular germ cell cancer [43], and these patients usually harbor antibodies to the Ma2 protein. Antibodies to Ma2 antigen alone are usually associated with testicular cancer. Similar to many other onconeural antibodies, Ma2 is associated with clinical multi-focality. Many patients have symptoms of brain stem and hypothalamic dysfunction, and only one-fourth of Ma2 positive patients exhibit classical LE [45]. Patients with antibodies to the major antigen Ma2 and antibodies to Mai or Ma3 have different tumors [43, 46], and are more likely to have additional neurological signs [45],... 

Numerous studies have tried to elucidate the role of onconeural antibodies in other PNS. Immunoglobulin G (IgG) containing Hu antibodies penetrated viable neurons expressing the Hu antigen in in vitro experiments [185], When the IgG fraction of Yo antibody positive sera is administered intraperitoneally in laboratory animals and the blood-brain barrier is disrupted, intracellular IgG can be demonstrated in Purkinje cells [186]. Intrathecal antibody production takes place in many of the PNS [159, 187], and autopsy studies of affected individuals show deposits of IgG in neurons [80, 188, 189] and in the tumor [189]. These results all favor a pathogenic role for the onconeural antibodies. 

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