Anti-Ri antibodies

Synonyms: Anti-neuronal nuclear antibody type 2 (ANNA-2)

Clinical associations: Opsoclonus-myoclonus syndrome. Not all patients present opsoclonus but the majority develop other symptoms of brainstem involvement characterized by supranuclear gaze palsies, parkinsonism, rigidity, dizziness, dysarthria, and dysphagia.

Tumor associations: Breast cancer or small-cell lung cancer (SCLC).

Frequency of anti-Ri antibodies in patients with suspected paraneoplastic neurological syndromes (PNS) without evidence of cancer: 3%

Frequency of anti-Ri antibodies in patients with cancer without PNS:
4% in a series of 161 patients with ovarian cancer. Frequency in breast cancer or SCLC is unknown.

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

Figure 1. Anti-Ri immunoreactivity is identical to that of anti-Hu on neurons of the central nervous system but, unlike anti-Hu, anti-Ri antibodies do not immunoreact with neurons of the peripheral nervous sytem. Immunostaining of a rat section showing the spinal cord (SC) and spinal ganglia (SG).

Confirmatory test:
Several commercial tests using immunoblots of recombinant NOVA protein. Immunoblot of neurons identifies a set of antigens of 53 to 61 Kd and 79-84 Kd (figure 2)

Figure 2. Immunoblot of neuronal nuclei homogenate probed with serum (1) and CSF (2) of a patient with anti-Ri antibodies. Lane 3, anti-Hu positive serum.

Immunologic associations:
Patients with paraneoplastic syndromes, anti-Ri antibodies and SCLC may also harbor anti-Hu antibodies.

Nova antigens

The target of anti-Ri antibodies is a family RNA-binding proteins that are mainly expressed in the nervous system. The two Ri antigens are Nova-1 and Nova-2. The Nova proteins contain three RNA-binding domains called KH (for K homology). The Nova proteins are critical for the development and maintenance of the neuronal phenotype in mammals. Postnatal Nova-1-null mice present an increase in apoptosis in hindbrain and ventral spinal cord neurons.

References

1. Drlicek M, Bianchi G, Bogliun G, et al. Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J neurol 1997;244:85-9.

2. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-51.

3. Musunuru K, Darnell RB. Paraneoplastic neurological disease antigens:RNA-binding proteins and signaling proteins in neuronal degeneration. Annu Rev Neurosci 2001;24:239-62.
4. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type-2: Paraneoplastic accompaniments. Ann Neurol 2003;53:580-7.
5. Sutton IJ, Barnett MH, Watson JDG, et al. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol 2002;249:1597-8.

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