'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII

Abstract

Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa-head antibodies' due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

Fig. 1

Medusa-head ataxia. a Detail from Sir Peter Paul Ruben’s (1577–1640) famous painting of a gorgon head (dated 1617/1618; Kunsthistorisches Museum, Vienna, Austria). b A drawing of a Purkinje cell by the Spanish pathologist, histologist, neuroscientist, and Nobel laureate Santiago Felipe Ramón y Cajal (1852–1934). c Purkinje cells somata and dendrites stained by IgG from a patient with autoimmune cerebellar ataxia

Fig. 2

Expression of mGluR1 in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [101])

Fig. 3

Binding of serum anti-mGluR1 from patients with ACA to rat (panels a and d) and mouse (panels b and c) cerebellum tissue sections. Patient antibodies were detected by use of goat anti-human IgG secondary antibodies labelled with Alexa Fluor®488 (panel a and d) or biotin (panel b: avidin/peroxidase; panel c: avidin/Texas red). While anti-mGluR1 strongly stain the molecular layer (a-d), staining of the PC somata varies in intensity depending on detection methods and antibody titres (compare panels a and c to panels b and d). Permission for panels b and c obtained from Massachusetts Medical Society. Copyright © (2000) Massachusetts Medical Society. Sillevis Smitt et al., Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000; 342:21-27

Fig. 4

Expression of Homer-3 in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [101]). Note that the main panel and the inset show different sectional planes

Fig. 5

Binding of anti-Homer-3 antibody from a patient with ACA to a mouse cerebellum tissue section. The patient antibody was detected by use of a goat anti-human IgG secondary antibody labelled with Alexa Fluor®488 (green)

Fig. 6

Expression of ITPR1 in the human cerebellum as demonstrated by IHC using an affinity-isolated rabbit antibody to human ITPR1 (Atlas antibodies, HPA016487). Modified image from the Human Protein Atlas image database [101]

Fig. 7

Binding of IgG from a patient with ITPR1-Ab-positive ACA as determined in a recombinant cell-based assay to formalin-fixed rat cerebellum tissue. Human IgG was detected using a goat anti-human IgG secondary antibody labelled with Alexa Fluor®488 (green fluorescence)

Fig. 8

Expression of CARP VIII in the human cerebellum as demonstrated by IHC (modified image from the Human Protein Atlas image database [101])

Fig. 9

Binding of IgG from a patient with CARP VIII-Ab-positive ACA (as determined using a recombinant cell-based assay) to formalin-fixed rat cerebellum tissue. Human IgG was detected using a goat anti-human IgG secondary antibody labelled with fluorescein isothiocyanate (green fluorescence)