Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease
Penelope Fouka1, Harry Alexopoulos1, Ioanna Chatzi1
1Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine (P.F., H.A., I.C., A.T., M.C.D.), and Department of Biology (S.G.D.), National and Kapodistrian University of Athens; Department of Molecular Oncology (M.S., G.P.), B.S.R.C. "Alexander Fleming," Athens; and Center of Basic Research (P.P.), Biomedical Research Foundation of the Academy of Athens, Greece.
Objective:
To describe newly identified autoantibodies associated with cerebellar disorders.
Design/Methods:
We first screened the sera of 15 patients with cerebellar ataxia, without any known associated autoantibodies, with immunocytochemistry on mouse brain. After characterization and validation of a newly identified antibody, 85 additional patients with suspected autoimmune cerebellar disease were screened using a cell-based assay.
Results:
Immunoglobulin G from one of the first 15 patients demonstrated a distinct staining pattern on Purkinje neurons. This autoantibody, as characterized further by immunoprecipitation and mass spectrometry, was binding inositol 1,4,5-triphosphate receptor 1 (IP3R1), an intracellular channel that mediates the release of Ca2+ from intracellular stores. Anti-IP3R1 specificity was then validated with a cell-based assay. On this basis, screening of 85 other patients with cerebellar disease revealed 2 additional IP3R1-positive patients. All 3 patients presented with cerebellar ataxia; the first was eventually diagnosed with primary progressive multiple sclerosis, the second had a homozygous CAG insertion at the gene TBP, and the third was thought to have a neurodegenerative disease.
Conclusions:
We independently identified an autoantibody against IP3R1, a protein highly expressed in Purkinje neurons, confirming an earlier report. Because a mouse knockout model for IP3R1 exhibits ataxia and epilepsy, this autoantibody may have a functional role. The heterogeneity of the antibody-positive patients suggests that this antibody may either have a direct involvement in disease pathogenesis or it is a surrogate marker secondary to cerebellar injury. Anti-IP3R1 antibodies should be further explored in various ataxic and epileptic syndromes as they may denote a marker of response to immunotherapies.
