Brain, Vol. 122, No. 1, 3-4,
January 1999
© 1999 Oxford University Press
Editorial |
Another autoantibody in paraneoplastic neurological disease
Neurosciences Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
Paraneoplastic neurological syndromes (PNS) are an uncommon group of disorders caused by immune responses primarily directed against an underlying neoplasm that cross-react with proteins expressed in the peripheral or central nervous system. Understanding the relationship between expression of specific proteins in the tumour and the autoimmune neurological disease with which they associate is an ongoing challenge.
PNS are frequently associated with the presence of specific serum autoantibodies, which may be used as a diagnostic aid. For example, anti-Hu (also called anti-neuronal nuclear antibody 1, ANNA-1) is an antibody detected in the sera of patients with paraneoplastic encephalomyelitis and/or subacute sensory neuronopathy. More than 80% of anti-Hu+ patients will have an underlying tumour, most commonly a small cell lung carcinoma. Similarly, a distinctive cytoplasmic staining pattern of the Purkinje cells has been noted with sera derived from patients with paraneoplastic cerebellar degeneration and an associated gynaecological (breast or ovarian) tumour. This antibody, anti-Yo or anti-Purkinje cell antibody 1 (APCA-1), has been reported in 40% of patients with paraneoplastic cerebellar degeneration. Several other neurological syndromes have also been associated with an underlying tumour. Opsoclonus/myoclonus syndrome presents with involuntary saccadic eye movements and truncal and limbic myoclonus. Approximately 10% of children with opsoclonus/myoclonus syndrome have an underlying neuroblastoma, whilst 10–15% of the adults have a small cell lung carcinoma or breast cancer. No underlying autoantibody has yet been detected in the childhood form; in adults, anti-Ri (ANNA-2) may be present. Stiff-man syndrome, a central disorder characterized by painful and progressive rigidity, may occur non-paraneoplastically with insulin-dependent diabetes mellitus, but also in conjunction with an underlying neoplasm, often breast cancer. Antibodies against the synaptic vesicle protein amphiphysin have been detected in the sera of patients with the paraneoplastic form of stiff-man syndrome.
Dalmau and his co-authors report in this issue (Dalmau et al., 1999
) the identification of a novel anti-neuronal antibody (Ma1) found in the sera of four out of 1705 patients with suspected PNS. The clinical presentation of these four patients differed; three had brainstem and cerebellar involvement and one had dysphagia and motor weakness. At autopsy, two of the four patients showed selective Purkinje cell loss with local inflammatory infiltrates, mainly CD8+ T cells. The underlying tumour was different in all four cases (breast, parotid, colon and large cell carcinoma of the lung). These different tumour types are surprising, since in general a specific antibody is associated with a specific type of tumour.
Anti-Ma1 antibodies reacted specifically with all central and peripheral neurons, high levels of staining being seen in the nuclei and nucleolus with faint staining of the cytoplasm. Significant staining levels were also observed in testicular germ cells. Anti-Ma1 antibodies reacted immunohistochemically with tumour tissue obtained from three of the four patients, but not with 53 other tumours of various histological types. Using a human cerebellum cDNA expression library, a novel 37 kD protein was isolated, which was recognized by all four anti-Ma1 sera, but not by 337 control sera. Northern blot analysis showed high levels of Ma1 mRNA expression in the brain and testis. However, there are difficulties in attributing a role to the anti-Ma1 antibodies. These antibodies are found, even in the context of other paraneoplastic autoantibodies, at a very low frequency (0.25% of patients with suspected PNS). The frequency in the general population is not known, and only 337 control patients were investigated in this study.
These authors have reported (as an abstract) an extension of this study, describing a group of nine PNS patients presenting with focal encephalitis (limbic, brainstem and basal ganglia) all of whom had an associated testicular cancer (Voltz et al., 1998). In this series of patients an antibody, anti-Ta, which specifically stains the subnuclear structures and cytoplasm of neurons, was detected. Intrathecal synthesis of anti-Ta antibodies in these patients indicated an active immunological response occurring in the patients' nervous system. Screening of an expression library with anti-Ta isolated a protein (Ma2), which showed considerable homology to the Ma1 protein described above (J. Dalmau, personal communication). It appears that Ma1 and Ma2 are members of a novel but expanding gene family of brain/testis-specific proteins. Whilst Ma1 is not found in association with one particular tumour, Ma2 seems to be strongly associated with testicular cancer.
Even when a specific antibody is detected, its role in the pathogenesis of the PNS cannot be assumed (for reviews see Lang and Vincent, 1996; Darnell, 1996). Most of the central PNS antibodies (Hu, Yo, Ri, Ma and Ta) appear to recognize cytoplasmic and nuclear antigens that, under normal circumstances, would be inaccessible to the immune system. Although intrathecal production of anti-Hu antibodies has been reported in patients with paraneoplastic encephalomyelitis and/or subacute sensory neuronopathy, active immunization of mice with either Hu or Yo antigen did not induce the relevant clinical syndrome (Sillevis Smitt et al., 1995; Tanaka et al., 1995a). Similarly, passive immunization of experimental animals with anti-Yo antibodies, either intravenous or intrathecal, or with mononuclear cells derived from a Yo+ patient, failed to reproduce the pathological or neurological changes (Tanaka et al., 1995b). Thus, these antibodies do not appear to be the effector mechanisms in PNS affecting the central nervous system. This contrasts with autoantibodies to neuronal ion channels in PNS affecting the neuromuscular junction (e.g. myasthenia gravis and the Lambert–Eaton myasthenic syndrome), which clearly have a role in reducing the number of functional channels.
In the majority of PNS cases the underlying tumour is not detected until after the presentation of the initial neurological symptoms. The detection of these anti-neuronal antibodies, with their unique staining patterns, is therefore an important aid to clinical diagnosis and should focus the search for the underlying neoplasm.
References
Dalmau J, Gultekin SH, Voltz R, Hoard R, DesChamps T, Balmaceda C, et al. Ma1, a novel neuronal and testis specific protein, is recognised by the serum of patients with paraneoplastic neurological disorders. Brain 1999; 122: 000–000.
Darnell RB. Onconeural antigens and the paraneoplastic neurological disorders: At the intersection of cancer, immunity, and the brain. [Review]. Proc Natl Acad Sci USA 1996; 93: 4529–36.
Lang B, Vincent A. Autoimmunity to ion-channels and other proteins in paraneoplastic disorders. [Review]. Curr Opin Immunol 1996; 8: 865–71.[Web of Science][Medline]
Sillevis Smitt PAE, Manley GT, Posner JB. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 1995; 45: 1873–8.
Tanaka M, Tanaka K, Onodera O, Tsuji S. Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody. 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss. Clin Neurol Neurosurg 1995a; 95: 97–100.
Tanaka K, Tanaka M, Igarashi S, Onodera O, Miyatake T, Tsuji S. Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody. 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to paraneoplastic cerebellar degeneration lymphocytes in severe combined immunodeficiency mice. Clin Neurol Neurosurg 1995b; 97: 101–5.[Web of Science][Medline]
Voltz R, Gultekin HS, Posner JB, Rosenfeld MR, Dalmau J. Sera of patients with testicular cancer and paraneoplastic limbic/brainstem encephalitis harbor an antineuronal antibody (anti-Ta) that recognizes a novel neuronal protein [abstract]. J Neurol 1998; 245: 379.
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