ANTI-FGFR3 ANTIBODY EPITOPES ARE FUNCTIONAL SITES AND CORRELATE WITH THE NEUROPATHY PATTERN
- Christian P. Moritz, France
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.