Immunoglobulin G is an oxytocin-binding protein in plasma – role in oxytocin receptor activation and relevance to aggressive behavior  

H. Vaeroy*^a (Dr), E. Lahaye^b (Dr), C. Dubessy^b (Dr), M. Benard^b (Dr), M. Nicol^b (Dr), S. Takhlidjt^b (Dr), SO. Fetissov^b (Prof)

^a Akershus University Hospital, Loerenskog, NORWAY ; ^b University of Rouen Normandy, Mont-Saint-Aignan, 76130, France., 76130, FRANCE

* henningvaeroy@gmail.com

Background: Oxytocin (OT) is a 9 amino acid hypothalamic neuropeptide activating its receptor (OT-R) triggering intracellular Ca²⁺ release and receptor internalization. OT plays a role in promoting social behavior, while deficient OT signalling can be present in stress-related disorders, including aggression. OT-reactive immunoglobulins (Ig) were found in human plasma, but if their role OT signalling and behavior is unknown.Objectives & Methods: We studied functional effects of plasma extracted IgG in the OT signalling from two mail groups, controls and “aggressive” using HEK 293 cells lines expressing human OT-R. Levels of OT-reactive IgG were analysed using ELISA and their affinity with surface plasmon resonance. Ca²⁺ secretion was assayed using fluorimetry after a 3 min incubation with OT alone (10^-7M) or with OT preincubated with individual IgG (10^-7M). The dynamics of GFP-labelled OT-R cellular internalization was followed during 30 min with confocal microscopy. Aggressive behavior was evaluated by Bryant and Smith revised Aggression Questionnaire.Results: OT in plasma was largely bound to IgG, and its “free” or IgG unbound levels were lower in aggressive subjects. Increased levels but lower affinity of OT-reactive IgG were found in aggressive subjects. OT induced a typical Ca²⁺ release with a fast increase and slow decrease kinetics and OT-R internalisation. IgG/OT also triggered a fast increase of Ca²⁺ secretion with a similar amplitude, but was followed by a faster return to the baseline. Total Ca²⁺ secretion was decreased by about 50% (p<0.0001) as compared to OT alone, and it was also reduced in the aggressive vs. control group (p<0.0001). OT-R internalisation occurs after 5 min incubation with OT or IgG/OT, with a slower dynamic for the aggressive group. The levels of OT-reactive IgG correlated positively with hostility scores in study subjects.Conclusions: These data show that IgG play a role as OT peptide carrier and that IgG/OT immune complexes activate OT-R with different kinetics than neuropeptide alone, suggesting that IgG may play a modulatory role in OT signalling. The data also support the relevance of this mechanism to the aggressive behavior in humans with deficient OT/IgG signaling linked to increased hostility.

The author has declared no conflict of interest.