Christian P. Moritz, France
Institut NeuroMyoGène Medicine FacultyPresenter of 2 Presentations
HOLISTIC CHARACTERIZATION OF THE AUTOANTIGEN REPERTOIRE IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY VIA AUTOANTIGENOMICS
Abstract
Background and Aims
To characterize the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP) for systemic peculiarities, we detected the autoantigens of patients and controls and analyzed them in a holistic way.
Methods
We screened 43 human sera, comprising 22 CIDP patients, 12 patients with other neuropathies (ONP), and 9 apparently healthy controls (HC) via HuProt protein microarrays testing about 16,000 distinct human bait proteins in parallel. Autoantigen repertoires were analyzed via bioinformatical approaches of autoantigenomics: principle component and hierarchical cluster analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, overrepresentation analyses using databases like those of Gene Ontology, Reactome Pathway, and pathway representation.
Results
1) The cohort of CIDP patients was heterogeneous regarding their autoantigen repertoires; 2) the number of the targeted antigens per CIDP patient depended on the clinical situation: intravenous immunoglobulin therapy responders targeted three times more autoantigens than non-responders; 3) a significant part of the autoantibody set specifically targeted proteins involved in anchoring junction components, motile cilium proteins, glycoprotein metabolic processes, and certain signaling pathway proteins; 4) ≥9 out of 23 central signaling proteins of the growth factor receptor pathway are targeted by CIDP-specific antibodies.
Conclusions
The repertoire of targeted autoantigens of CIDP patients differs systematically from those of controls. Considering systemic autoantigenomic approaches in addition to single antibody approaches may help to understand the disease and to discover novel options for improved diagnosis and prognosis.
ANTI-FGFR3 ANTIBODY EPITOPES ARE FUNCTIONAL SITES AND CORRELATE WITH THE NEUROPATHY PATTERN
Abstract
Background and Aims
Sera autoantibodies against Fibroblast Growth Factor Receptor 3 (FGFR3) were recently identified in a subgroup of 15% of patients with sensory neuropathy (SN). In order to better understand the anti-FGFR3 autoantibodies’ role, we aimed for confirming their intracellular target and to detecting their epitope(s) more precisely.
Methods
In the mapping approach, 25 amino acids (aa) long peptides covering the FGFR3 full-length or intracellular sequence, were spotted onto a cellulose membrane. A second version was phosphorylated at their natural sites. In the screening approach, 7 cytosolic candidate epitopes were screened with 68 anti-FGFR3-positive SN patients and 35 HC. Clinical and paraclinical data were compared between the different subgroups of patients.
Results
Mapping with 4 anti-FGFR3-positive sera resulted in major epitope candidates in the intracellular domain. Furthermore, the reactivity of several epitope regions strongly depended on their phosphorylation state. In the systematic screening approach, 15 of 66 anti-FGFR3-positive SN patients significantly bound 5 epitopes: 4 cases bound to 3 epitopes in the juxtamembrane domain; 11 cases bound to 2 epitopes in the tyrosine kinase domain (TKD). The identified epitopes cover 6/15 functionally relevant sites. The epitope with most frequent reactivity was located in the activation loop. Moreover, patients with anti-FGFR3 antibodies recognizing TKD exhibited a higher anti-FGFR3 antibody level and a more severe clinical and electrophysiological impairment than others.
Conclusions
Anti-FGFR3 autoantibodies target ≥ 5 different functionally relevant epitopes on the FGFR3 protein, suggesting pathogenetic roles of the autoantibodies. To our knowledge, our results represent the first description of phosphorylation state-dependent autoantibodies in a neurological disease.