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Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia.

Jarius S, Scharf M, Begemann N, Stöcker W, Probst C, Serysheva II, Nagel S, Graus F, Psimaras D, Wildemann B, Komorowski L - J Neuroinflammation (2014)

Bottom Line: The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26.By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1.Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.

ABSTRACT
We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.

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Related in: MedlinePlus

Analysis of the IgG subclasses of anti-Sj in the index patient. Subclass analysis revealed mainly IgG1 antibodies (depicted in red) with very few IgG2 and no IgG3 or IgG4 antibodies (not shown); no PC-specific antibodies to IgA or IgM were detectable (not shown). IgG1 was also the main anti-Sj IgG subclass in a second patient (not shown).
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Fig2: Analysis of the IgG subclasses of anti-Sj in the index patient. Subclass analysis revealed mainly IgG1 antibodies (depicted in red) with very few IgG2 and no IgG3 or IgG4 antibodies (not shown); no PC-specific antibodies to IgA or IgM were detectable (not shown). IgG1 was also the main anti-Sj IgG subclass in a second patient (not shown).

Mentions: The immunoglobulin class and IgG subclass repertoire of the PC antibodies was analyzed by IHC in two patients—no material was left for analysis in the remainder—and revealed mainly IgG1 antibodies in both cases (Figure 2). Very weak IgG2 or IgG3 staining was observed in both patients and in one patient, respectively. In both patients, no anti-PC antibodies of the IgM or IgA class were detectable.Figure 2


Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia.

Jarius S, Scharf M, Begemann N, Stöcker W, Probst C, Serysheva II, Nagel S, Graus F, Psimaras D, Wildemann B, Komorowski L - J Neuroinflammation (2014)

Analysis of the IgG subclasses of anti-Sj in the index patient. Subclass analysis revealed mainly IgG1 antibodies (depicted in red) with very few IgG2 and no IgG3 or IgG4 antibodies (not shown); no PC-specific antibodies to IgA or IgM were detectable (not shown). IgG1 was also the main anti-Sj IgG subclass in a second patient (not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4300617&req=5

Fig2: Analysis of the IgG subclasses of anti-Sj in the index patient. Subclass analysis revealed mainly IgG1 antibodies (depicted in red) with very few IgG2 and no IgG3 or IgG4 antibodies (not shown); no PC-specific antibodies to IgA or IgM were detectable (not shown). IgG1 was also the main anti-Sj IgG subclass in a second patient (not shown).
Mentions: The immunoglobulin class and IgG subclass repertoire of the PC antibodies was analyzed by IHC in two patients—no material was left for analysis in the remainder—and revealed mainly IgG1 antibodies in both cases (Figure 2). Very weak IgG2 or IgG3 staining was observed in both patients and in one patient, respectively. In both patients, no anti-PC antibodies of the IgM or IgA class were detectable.Figure 2

Bottom Line: The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26.By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1.Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.

ABSTRACT
We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease.

Show MeSH
Related in: MedlinePlus