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Contributed by Tomas Hökfelt, April 4, 2018 (sent for review November 22, 2017; reviewed by Stefan R. Bornstein, Jordan D. Dimitrov, and Brian C. Trainor)
Significance
The number of inmates imprisoned for violent aggression is increasing, as are the penitentiaries, but still our understanding of mechanisms underlying criminality is limited. Our analysis of violent aggressor inmates reveals unique properties of IgG reactive with adrenocorticotropic hormone (ACTH). We show that these IgGs can regulate ACTH-induced cortisol secretion in the adrenal gland, and they exhibit a clear-cut difference in ACTH epitope binding in violent aggressors vs. controls. Additionally, IgG from a subset of aggressive subjects selectively bind to hypothalamic vasopressin neurons. Thus, using several in vitro and in vivo approaches, the study reveals a molecular mechanism involved in the variability of stress response relevant to the neurobiology of aggression and possibly other stress-related conditions.
Abstract
Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11–24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1–13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident–intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors’ sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.
Footnotes
- ↵1To whom correspondence may be addressed. Email: Henning.Vaeroy{at}ahus.no, tomas.hokfelt{at}ki.se, or Serguei.Fetissov{at}univ-rouen.fr.
Author contributions: H.V., E.L., H.L., P.D., T.H., and S.O.F. designed research; H.V., C.A., R.L., N.L., J.B., C.C., J.-C.d.R., C.D., E.W., and S.A. performed research; H.V., C.A., T.H., and S.O.F. analyzed data; and H.V., C.A., T.H., and S.O.F. wrote the paper.
Reviewers: S.R.B., University Hospital Carl Gustav Carus Dresden; J.D.D., Centre de Recherche des Cordeliers; and B.C.T., University of California, Davis.
Conflict of interest statement: P.D. has received research grants from Nestlé and Fresenius Kabi and honoraria for speeches and consulting from Nestlé, Fresenius-Kabi, and Aguettant, is a cofounder of TargEDys SA, and is a member of its advisory board. S.O.F. is a cofounder of and serves as a consultant to TargEDys SA. N.L. and R.L. are currently employees of TargEDys SA. T.H. owns shares in AstraZeneca.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1720008115/-/DCSupplemental.
- Copyright © 2018 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
References
Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans
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