Background and aims We recently identified dopamine-2 receptor (D2R) autoantibodies in children with autoimmune movement and psychiatric disorders. This supported the hypothesis that a subgroup of patients may be autoimmune-mediated. However, the target epitope(s) remain unknown.
Methods Human D2R mutants modified in their extracellular domains were subcloned, and we analysed the region bound by 35 anti-D2R antibody-positive patient sera using quantitative flow cytometry on live transfected cells.
Results No anti-D2R antibody-positive patient sera bound to the three extracellular loops, but all patient sera (35/35) targeted the extracellular N-terminus. Overall, patient antibody binding was dependent on two main regions encompassing amino acids 20 to 29, and 23 to 37. Residues 20 to 29 contributed to the majority of binding (77%, 27/35), among which 26% (7/27) sera bound to amino acids R20, P21, and F22, 37% (10/27) patients were dependent on residues at positions 26 and 29, that are different between humans and mice, and 30% (8/27) sera required R20, P21, F22, N23, D26, and A29. Seven patient sera bound to the region 23 to 37 independently of D26 and A29, but most sera exhibited N-glycosylation-independent epitope recognition at N23. Interestingly, no evident segregation of binding pattern according to patient clinical phenotype was observed.
Conclusions We report a major biological role for D2R extracellular N-terminus as a regulator of receptor surface availability, and as a major epitope targeted and impaired in brain autoimmunity. This knowledge could help the design of novel specific immune therapies tailored to improve patient outcome.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.