Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease

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Abstract

We studied an autoantibody (called anti-Tr), found in the serum and CSF of five patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD). Anti-Tr antibodies labelled the cytoplasm of Purkinje cells of human and rat cerebellum. The molecular layer of rat cerebellum showed a characteristic dotted pattern suggestive of immunoreactivity of dendritic spines of Purkinje cells. Patients with cerebellar disorders without HD (159) or HD without PCD (30) did not harbor anti-Tr antibodies. Immunoblots of human Purkinje cells or rat and mouse cerebellum were negative. Anti-Tr antibodies, as defined in this study, appear specific for HD-associated PCD. The immunohistochemical pattern described in the rat cerebellum coupled with the absence of reactivity in the immunoblot may be used to identify anti-Tr antibodies.

Introduction

Paraneoplastic cerebellar degeneration (PCD) is characterized by the development, over weeks to months, of a severe pancerebellar syndrome. Postmortem study shows extensive loss of Purkinje cells and, sometimes, inflammatory infiltrates in the deep cerebellar nuclei and brainstem. PCD is mostly associated with gynecologic tumors, breast and lung cancer, and Hodgkin's disease (HD) (Henson and Urich, 1982).

Several antineuronal antibodies have been identified in some neurologic paraneoplastic syndromes that are highly specific for particular tumors. In PCD, except for the anti-Yo antibody, that is associated with ovarian or breast cancer (Furneaux et al., 1990; Peterson et al., 1992), no other antineuronal antibodies have been well characterized (Lennon, 1994; Dalmau and Posner, 1994). A few patients with PCD and HD harbor antineuronal antibodies (Trotter et al., 1976; Stefansson et al., 1981; Greenlee et al., 1988; Unger et al., 1991; Hammack et al., 1992). However, there are no clear guidelines to differentiate them from anti-Yo and other less common antineuronal antibodies (Anderson et al., 1988a; Ito et al., 1994; Darnell et al., 1991; Nemni et al., 1993; Valldeoriola et al., 1994).

In the present study, we evaluated the immunohistochemical and immunoblot characteristics of an antineuronal antibody, (that we called anti-Tr) found in the serum and CSF of five patients with HD-associated PCD to allow their correct identification among different laboratories and to demonstrate their specificity for PCD associated with HD.

Section snippets

Patients

The most relevant clinical features of the five patients are summarized in Table 1. Four men developed a progressive subacute pancerebellar syndrome that left them disabled after one to four months. The fifth patient was a 14 years-old girl who developed a cerebellar syndrome and bilateral retrobulbar optic neuropathy two weeks after an episode of fever and tonsillitis. The neurologic deficit resolved over the ensuing two months after treatment with corticosteroids. All five patients had CSF

Results

The serum of the five patients had the same pattern of immunoreactivity on human or rat sections. The staining was obtained with antihuman IgG, kappa, or lambda, but not IgM. The immunoreactivity observed with the biotinylated IgG containing anti-Tr antibodies from one of the patients was abolished when the tissue sections were preincubated with undiluted serum from the five patients with anti-Tr antibodies but not with normal human serum or serum containing high titers of anti-Yo antibodies.

Discussion

Our study shows that patients with HD-associated PCD harbor in their serum and CSF anti-Purkinje cell antibodies that produce a characteristic dotted pattern in the molecular layer of the rat cerebellum. Other anti-Purkinje cell antibodies, including anti-Yo, do not show this characteristic immunoreactivity. The antibodies defined in this study were not observed in a large series of patients with cerebellar disorders or isolated HD suggesting that they probably are highly specific for

Acknowledgements

We wish to thank Ms. Mercé Bonastre and Ms. Eva Sanchez for their technical assistance, Dr. E. Campo for providing the samples of Hodgkin's disease, and Dr. M. Rosenfeld for the critical review of the manuscript. This work was supported by a grant of the Societat Catalana de Neurologia (Fundació Uriach), grant FIS 95/0233 Madrid, Spain, a post-residency grant of the Hospital Clinic (F.V.), and ACS grant 94-18 (J.D.).

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