Abstract
We report on a newly discovered serum and cerebrospinal fluid (CSF) reactivity to Purkinje cells (PCs) associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000) IgG antibody to the cerebellar molecular layer, Purkinje cell (PC) layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein) as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease.
Highlights
Autoimmune cerebellar ataxia (ACA) is an etiologically and pathologically heterogeneous syndrome
Double labeling with anti-GFAP and anti-AQP4 revealed no binding of the patient antibody to astrocytes in the white matter (WM) and the granular layer (GL), or to Bergman glial cells in the Purkinje cell layer (PCL) and molecular layer (ML) (Figure 4)
Co-localization with the inositol-3-phosphate receptor type I On cerebellum sections, we found an almost perfect overlay of the staining pattern found with the patient antibody in the molecular layer and that found with a commercial antibody to the inositol-3-phosphate receptor type I (IPR3I) (Figure 13A-C and 13D), which was used as a well established marker of Purkinje cells (PCs)
Summary
Autoimmune cerebellar ataxia (ACA) is an etiologically and pathologically heterogeneous syndrome. Many cases of paraneoplastic ACA are associated with serum or CSF antibodies to neuronal and/or glial antigens such as anti-Hu[3], anti-Yo[4], anti-CV2/CRMP5 [5,6], anti-Tr[7], anti-Zic4[8], anti-protein kinase C gamma (PKCg)[9], anti-mGluR1[10,11], anti-PCA2[12], anti-ANNA3[13], or antibodies to voltage gated calcium channels (VGCC)[14]. We report a newly discovered autoantibody to Purkinje cells in a patient with subacute cerebellar ataxia but no tumor. This antibody binds to the inner membrane and cytoplasm of PC somata, dendrites and axons. It is produced intrathecally, belongs to the IgG1 subclass and activates complement in vitro. Probing of a protein microarray with the patient’s serum and additional confirmatory experiments identified the Rho GTPase activating protein 26 (ARHGAP26) as the target antigen
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