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Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains.

ABSTRACT: OBJECTIVE:To identify the specific domains of the presynaptic protein synapsin targeted by recently described autoantibodies to synapsin. METHODS:Sera of 20 and CSF of two patients with different psychiatric and neurological disorders previously tested positive for immunoglobulin (Ig)G antibodies to full-length synapsin were screened for IgG against synapsin I domains using HEK293 cells transfected with constructs encoding different domains of rat synapsin Ia. Additionally, IgG subclasses were determined using full-length synapsin Ia. Serum and CSF from one patient were also screened for IgA autoantibodies to synapsin I domains. Sera from nine and CSF from two healthy subjects were analyzed as controls. RESULTS:IgG in serum from 12 of 20 IgG synapsin full-length positive patients, but from none of the healthy controls, bound to synapsin domains. Of these 12 sera, six bound to the A domain, five to the D domain, and one to the B- (and possibly A-), D-, and E-domains of synapsin I. IgG antibodies to the D-domain were also detected in one of the CSF samples. Determination of IgG subclasses detected IgG1 in two sera and one CSF, IgG2 in none of the samples, IgG3 in two sera, and IgG4 in eight sera. One patient known to be positive for IgA antibodies to full-length synapsin had IgA antibodies to the D-domain in serum and CSF. CONCLUSIONS:Anti-synapsin autoantibodies preferentially bind to either the A- or the D-domain of synapsin I.

SUBMITTER: Mertens R

PROVIDER: S-EPMC6292584 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains.

Mertens Robert R Melchert Sarah S Gitler Daniel D Schou Morten Brix MB Saether Sverre Georg SG Vaaler Arne A Piepgras Johannes J Kochova Elena E Benfenati Fabio F Ahnert-Hilger Gudrun G Ruprecht Klemens K Höltje Markus M

PloS one 20181213 12

<h4>Objective</h4>To identify the specific domains of the presynaptic protein synapsin targeted by recently described autoantibodies to synapsin.<h4>Methods</h4>Sera of 20 and CSF of two patients with different psychiatric and neurological disorders previously tested positive for immunoglobulin (Ig)G antibodies to full-length synapsin were screened for IgG against synapsin I domains using HEK293 cells transfected with constructs encoding different domains of rat synapsin Ia. Additionally, IgG su ...[more]

PMID: 30543686

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Project description:Systemic sclerosis (SSc) is a severe chronic autoimmune disease with high morbidity and mortality. Sera of patients with SSc contain a large variety of autoantibody (aab) reactivities. Among these are functionally active aab that bind to G protein-coupled receptors (GPCR) such as C-X-C motif chemokine receptor 3 (CXCR3) and 4 (CXCR4). Aab binding to the N-terminal portion of these two GPCRs have been shown to be associated with slower disease progression in SSc, especially deterioration of lung function. Aabs binding to GPCRs exhibit functional activities by stimulating or inhibiting GPCR signaling. The specific functional activity of aabs crucially depends on the epitopes they bind to. To identify the location of important epitopes on CXCR3 recognized by aabs from SSc patients, we applied an array of 36 overlapping 18-20mer peptides covering the entire CXCR3 sequence, comparing epitope specificity of SSc patient sera (N?=?32, with positive reactivity with CXCR3) to healthy controls (N?=?30). Binding of SSc patient and control sera to these peptides was determined by ELISA. Using a Bayesian model approach, we found increased binding of SSc patient sera to peptides corresponding to intracellular epitopes within CXCR3, while the binding signal to extracellular portions of CXCR3 was found to be reduced. Experimentally determined epitopes showed a good correspondence to those predicted by the ABCpred tool. To verify these results and to translate them into a novel diagnostic ELISA, we combined the peptides that represent SSc-associated epitopes into a single ELISA and evaluated its potential to discriminate SSc patients (N?=?31) from normal healthy controls (N?=?47). This ELISA had a sensitivity of 0.61 and a specificity of 0.85. Our data reveals that SSc sera preferentially bind intracellular epitopes of CXCR3, while an extracellular epitope in the N-terminal domain that appears to be target of aabs in healthy individuals is not bound by SSc sera. Based upon our results, we could devise a novel ELISA concept that may be helpful for monitoring of SSc patients.

Dataset Information

Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains.

Publications

Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains.

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