Anti-Yo antibodies

Synonyms: Type 1 Purkinje cell cytoplasmic autoantibodies (PCA-1).

Clinical associations: Paraneoplastic cerebellar degeneration. Rarely, patients present with signs of motor neuron disease, involving both upper and lower motor neurons.

Tumor associations: Most patients are women and associated tumors are almost exclusively gynecologic (mainly ovarian) or breast cancers. Some women and men with various adenocarcinomas, transitional cell carcinoma of the bladder or lymphoma have been described.

Frequency of anti-Yo antibodies in patients with suspected paraneoplastic neurological syndromes (PNS) without evidence of cancer after >5 years of follow-up: 2%

Frequency of anti-Yo antibodies in patients with breast or gynecologic cancer without PNS: 2% with titers similar to those of patients with PNS.

Screening test:
Immunohistochemistry on frozen brain sections (human, monkey, rabbit, rat, mouse) (figure 1, 2).

Figure 1. Anti-Yo immunoreactivity in human cerebellum.
Figure 2. Anti-Yo immunoreactivity in rat cerebellum.

Confirmatory test:
Several commercial tests using immunoblots of recombinant CDR62 protein. Immunoblot of cerebellar Purkinje cell extracts (figure 3).

Figure 3. Immunoblot of rat cerebellar extract probed with 3 different anti-Yo sera and a normal control.

Immunologic associations:
Patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies usually do not harbor concurrent antibodies to other onconeuronal antigens.

Yo antigens
Expression of the Yo-antigens is limited to cytoplasm of cerebellar Purkinje cells and brainstem neurons. Two antigens are recognized by anti-Yo antibodies, a major antigen of 62 kDa (CDR62, cerebellar degeneration-related 62 kDa protein) and a minor antigen of 34 kDa (CDR34). Using anti-Yo sera, three genes have been cloned (cdr 1-3). Cdr1 encodes the 34 kDa protein, the predicted amino acid sequence of which reveals an unsual structure composed of nearly identical hexapeptide repeats. Cdr2 encodes the CDR62 protein that contains a helix-leucine zipper dimerization domain that specifically binds to c-Myc thereby downregulating its activity. In addition, cdr2 suppresses the transcriptional activity and DNA binding of nuclear facto-kappa B (NF-?B) by an unknown mechanism. The neuron specific expression of cdr2 is regulated by a post-transcriptional mechanism. A third gene, cdr3, is 45% identical with cdr2 at the predicted amino acid level but has not been further studied. Yo-antigens are expressed in the tumors of all patients with anti-Yo antibodies. Expression in tumors from seronegative patients is more widespread than previously presumed.

References
1. 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; 13:2087-97.
2. Sakai K, Kitagawa Y, Li Y, Shirakawa T, Hirose G. Suppression of the transcriptional activity and DNA binding of nuclear factor-kappa B by a paraneoplastic cerebellar degeneration-associated antigen. J Neuroimmunol 2001; 119:10-5.
3. Corradi JP, Yang C, Darnell JC, Dalmau J, Darnell RB. A post-transcriptional regulatory mechanism restricts expression of the paraneoplastic cerebellar degeneration antigen cdr2 to immune privileged tissues. J Neurosci 1997; 17:1406-15.
4. Darnell JC, Albert ML, Darnell RB. Cdr2, a target antigen of naturally occuring human tumor immunity, is widely expressed in gynecological tumors. Cancer Res 2000; 60:2136-9.
5. Shams'ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, Vecht C, Sillevis Smitt P. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003; 126:1409-18.
6. Rojas I, Graus F, Keime-Guibert F, Rene R, Delattre JY, Ramon JM, Dalmau J, Posner JB. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55:713-5.

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