Anti-CV2 antibodies

 

Synonyms: Anti-CRMP5 antibodies

 

Clinical associations: see table

 

Clinical characteristics of 47 patients with anti-CV2 antibodies

 

Neurological syndromes (click here)	%
Peripheral neuropathy	59.6
Cerebellar ataxia	51.1
Ocular involvement (optic neuritis/uveitis)	17
Limbic encephalitis	14.9
Myasthenic syndrome	10.6
Gastroparesia	10.6
Chorea	8.5
Dysautonomia	4.3
Opsoclonus	2.1

 

 

Tumor associations :

Small cell lung cancer (SCLC) is the most frequent associated tumor (59.6%) with thymoma (12.8%). Extrathoracic tumors included in order of frequency: undifferenciated carcinoma, uterus sarcoma, prostate small cell carcinoma.

Frequency of anti-CV2 antibodies in patients with suspected paraneoplastic neurological syndromes (PNS) without evidence of cancer during follow-up: 4%

Frequency of anti-CV2 antibodies in patients with small-cell lung cancer without PNS:
9%

 

Screening test:

Immunohistochemistry on paraformaldehyde fixed rat brainstem and cerebellum sections. The typical staining is that of oligodendrocytes. Additionnaly, the neuropile may be stained. (figure).

 

Figure Immunoreactivity of anti-Cv2 antibodies on rat cerebellum is mainly restricted to a subpopulation of oligodendrocytes. Immunoblots of rat brain homogenate probed with anti-CV2 antibodies show a 66Kd band.

Confirmatory test:

Immunoblots of recombinant CRMP5 protein. Immunoblot of brain homogenates (figure)

Immunologic associations:

Patients with paraneoplastic syndromes and anti-CV2 antibodies may develop concurrent antibodies to other onconeuronal antigens. They include, anti-Hu, anti-amphiphysin, anti-Ri, and anti-Zic4 antibodies.

CV2 antigens

The target of anti-CV2 antibodies is a family of ~66 kDa proteins that are mainly expressed in the nervous system called CRMP for Collapsin Response Mediator Proteins. The CRMP family is composed of five cytosolic phosphoproteins highly expressed throughout the brain during development. CRMP5 is the main antigen recognized by anti-CV2 antibodies and other members such as CRMP2, CRMP3 or CRMP4 are inconsistently recognized. The first identified member, CRMP2, was identified as an intracellular messenger required for the growth cone-collapse induced by semaphorin 3A (Sema 3A). A rapidly accumulating evidence indicates that the functions of CRMPs are not solely limited to the signalling transduction of Sema 3A guidance cue. There are likely responsive to multiple cellular and molecular events involved in apoptosis/proliferation, cell migration and differentiation of neural cells. In the adult brain, the expression of CRMPs is dramatically down-regulated. However, they remain expressed in structures that have been shown to retain capacity of differentiation and also in a subpopulation of oligodendrocytes (CRMP2 and CRMP5). In the peripheral nervous system CRMP5 is expressed in a subset of sensory neurons and Schwann cells.The human CRMP proteins are expressed by small-cell lung cancers.

References

1-Honnorat J., Antoine J. C., Derrington E. et al. Antibodies to a subpopulation of glial cells and a 66 kD developmental protein in patients with paraneoplastic neurological syndromes. J. Neurol. Neurosurg. Psychiatry. 1996;61: 270-78.

2- Honnorat J., Byk T., Kusters I., et al. Ulip/CRMP proteins are recognized by autoantibodies in paraneoplasic neurological syndromes. Eur. J. Neurosci. 1999;11:4226-32.

3- Rogemond V., and Honnorat J. Anti-CV2 autoantibodies and paraneoplastic neurological syndromes. Clin. Rev. Allergy. Immunol. 2000;19: 51-9.

4- Antoine J. C., Honnorat J., Camdessanche J. P., et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann. Neurol. 2001;49: 214-21.

5- Ricard D., Rogemond V., Charrier E., et al. Isolation and expression pattern of human Unc-33-Like Phosphoprotein 6/Collapsin Response Mediator Protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3A-sensitive oligodendrocytes. J. Neurosci. 2001;21: 7203-14.

6- Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001;49:146-54.