Selected publications

• Hubball Andrew, Martin Joanne E, Lang Bethan, De Giorgio Roberto, and Knowles Charles H (2009) The role of humoral autoimmunity in gastrointestinal neuromuscular diseases. Prog Neurobiol, 87(1):10-20.

• Irani Sarosh and Lang Bethan (2008) Autoantibody-mediated disorders of the central nervous system. Autoimmunity, 41(1):55-65.

• Maddison Paul and Lang Bethan (2008) Paraneoplastic neurological autoimmunity and survival in small-cell lung cancer. J Neuroimmunol, 201-202:159-62.

• Blaes F, Pike M G, and Lang B (2008) Autoantibodies in childhood opsoclonus-myoclonus syndrome. J Neuroimmunol, 201-202:221-6.

• Vincent Angela, Lang Bethan, and Kleopa Kleopas A (2006) Autoimmune channelopathies and related neurological disorders. Neuron, 52(1):123-38.

Dr Beth Lang

Historically, the group has been involved in the study of autoimmune disorders of the nervous system. The focus of the work has been the prototypic disorder, the Lambert-Eaton myasthenic syndrome (LEMS); a disorder characterised by debilitating muscle weakness and fatiguability, which is commonly associated with small cell lung carcinoma (SCLC). Interestingly, the neurological disorder often precedes the detection of the tumour by several months or years. In paraneoplastic disorders such as LEMS, the body is thought to mount an immune response to antigens expressed on the tumour surface. However, these antibodies are capable of cross-reacting with determinants present in the nervous system, resulting in neurological dysfunction. In LEMS, antibodies have been shown to recognise one subtype of the voltage-gated calcium channel (VGCC), present on both the SCLC surface and on the presynaptic terminal of the neuromuscular junction. These antibodies can be measured by radioimmunoassay, using a toxin (ω-conotoxin MVIIC) derived from the piscivorous snail Conus magus, to label VGCC extracts. The detection of these antibodies can be clinically informative and we run an international diagnostic service for this assay. Patients with SCLC in general have a very poor prognosis, but, those tumour patients with anti-VGCC positive LEMS show a longer survival, supporting the idea that the immune response against the tumour inhibits its growth.  With funding from the Myasthenia Gravis Association (MGA) we are currently developing a novel fluorescence-based assay for the anti-VGCC antibodies and assays for SCLC-specific antigens. The presence of these antibodies may indicate a better clinical prognosis for the patient.

Our experience in studying the effects of antibodies on ion channels in the nervous system has recently led to an interest in the aetiology of epilepsy. In conjunction with Angela Vincent and David Beeson’s groups and with support from the Wellcome Trust and Epilepsy Research UK, we are investigating the possibility that certain forms of epilepsy are autoimmune. Epilepsy is an extremely common disorder, affecting 1-2% of the population at some point in their lives. There is an enormous diversity in the epilepsy syndromes: some have an identifiable cause for their seizures, for example genetic defects or structural brain abnormalities, but many types of epilepsy remain without an explanation. We have recently demonstrated that serum antibodies to voltage-gated potassium channels (VGKC) are present in approximately 10% of patients who present with an acute or subacute onset of seizures, whilst antibodies to glutamic acid decarboxylase (GAD) have been detected in a further 5% of patients. We are currently investigating the pathogenicity of these autoantibodies, using electrophysiological, immunological and biochemical techniques, in various neuronal models including hippocampal explants (see below) and cell lines transfected with the genes encoding the different ion channels.

It is probable that the finding of antibodies to VGKC and GAD in the serum of patients with CNS disorders will not be unique and that antibodies to other parts of the brain may also be present. Therefore we are currently developing a range of novel diagnostic assays for antibodies to a range of proteins normally involved in excitation and inhibition in the CNS, including GABA, NMDA, glycine and neuronal acetylcholine receptors. The detection of these and other pathologically relevant autoantibodies will identify subsets of patients who might benefit from immunotherapy rather than conventional anticonvulsant therapy.

Staining of hippocampal neurones
(18 day in vitro) with antibodies to MAP2 (a neuron-specific marker protein).  Photo courtesy of S. Irani

Causes of epilepsy. In approximately two thirds of all patients with epilepsy the cause is unknown. So in most cases the symptoms are treated rather than the underlying cause.