Expression of the onconeural CV2/CRMP5 antigen in thymus and thymoma

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Abstract

Anti-CV2 antibodies (AB) react with the developmentally regulated neural proteins CRMPs and particularly with CRMP5. They occur with small cell lung cancer (SCLC) and thymoma. SCLCs universally express CRMP5. We investigated the expression of CRMPs in thymoma and thymus. In thymoma, none of the CRMPs were detected by immunohistochemistry in tumorous epithelial cells with specific antibodies including CRMP5 but an antibody reacting with a peptide common to the CRMPs labeled a 66-kDa protein in Western blot of rat brain, thymus, and thymoma extracts. Thus, the normal CRMP5 is probably not expressed by tumorous epithelial cells. These results indicate that the mechanisms leading to CRMP5 autoimmunization are different in SCLC and thymoma.

Introduction

Paraneoplastic neurological syndromes (PNS) are thought to result from an immunological reaction directed against onconeural antigens shared by the tumor and the nervous system. In this hypothesis, tumorous expression of an onconeural antigen is a necessary but not sufficient step to initiate the mechanism leading to the breakdown of self-tolerance. The onconeural anti-CV2 antibodies are associated with a neurological syndrome affecting the central and peripheral nervous system (Antoine et al., 1993, Honnorat et al., 1999, Ricard et al., 2001, Yu et al., 2001). They react with CRMPs, a family of five developmentally regulated neural proteins (CRMP1–5) (Byk et al., 1998, Charrier et al., 2003) that share a high degree of homology, except CRMP5 which is only 50% homologous with the others (Fukada et al., 2000). Anti-CV2 antibodies constantly recognize CRMP5 and occasionally CRMP1 or 3 (Honnorat et al., 2001). Small cell lung cancer (SCLC) is the most frequent malignancy in patients with anti-CV2/CRMP5 antibodies and universally expresses CRMP5 (Honnorat et al., 2001, Yu et al., 2001). However, almost 15% of patients develop thymoma (Cartalat-Carel et al., 2004, Yu et al., 2001) some of them having simultaneously myasthenia gravis (MG) (Antoine et al., 1995). Here we found that thymoma probably do not express the normal CRMP5 indicating that the mechanisms leading to CRMP5 immunization are different in SCLC and thymoma.

Section snippets

Thymic tissues

Thymus samples of adult and 3- to 17-day-old Sprague–Dawley rat (Harland, Indianapolis, IN, USA) were obtained with or without prior fixation by intracardiac perfusion of 4% paraformaldehyde and 0.2% picric acid in 0.1 M phosphate buffer pH 7.4 under pentobarbital anaesthesia. All the animal procedures were performed according to the French guidelines for experimental animal care. Tissues were cryoprotected in isopentane and snap-frozen at − 80 °C until utilization.

Human thymus and thymoma samples

Immunohistochemistry

In thymoma samples (nine frozen and eight paraffin-embedded samples) including the sample from a patient with anti-CV2 antibody, the tumorous contingent of epithelial cells did not specifically react with the CRMP5 antibody (Fig. 1E). In one sample from a patient with an AB type thymoma, occasional cells having the morphology of dendritic cells were immunolabeled in the neoplastic epithelial contingent. These were not observed in the other samples. Nerve fibers grouped in small fascicles around

Discussion

In patients with PNS, expression by the tumor of an onconeural antigen is thought to be the first step toward a break down of self tolerance (Dalmau et al., 1995, Darnell, 1996). Using a panel of specific anti-CRMP antibodies, we did not detect CRMP1–5 in different types of thymoma both by immunohistochemistry and by Western blot, although a level of expression below the threshold of detection could not be excluded. Only one thymoma sample from a patient with anti-CV2/CRMP5 antibody could be

Acknowledgement

This work was supported by la Délégation à la Recherche Clinique (CHU de Saint-Etienne), l'Association Française contre la Myopathie et l'Association pour la Recherche sur la Sclérose en Plaques.

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