ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 8.16 | DOI: 10.1530/ey.16.8.16

ESPEYB16 8. Adrenals New Paradigms (1 abstracts)

8.16. Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans

Værøy H , Adori C , Legrand R , Lucas N , Breton J , Cottard C , do Rego JC , Duparc C , Louiset E , Lefebvre H , Déchelotte P , Western E , Andersson S , Hökfelt T & Fetissov SO


Department of Psychiatric Research, Akershus University Hospital, Nordbyhagen, Norway


To read the full abstract: Proc Natl Acad Sci U S A. 2018; 115(28): E6576–E6584.

It is accepted that aggressive behavior can be viewed as a strategy by humans and animals to cope with stress, implying that neurobiological mechanisms involved in stress responses should underlie both physiological and pathological aggression (15, 16). The hypothalamic–pituitary–adrenal (HPA) axis is a key system in the stress response, linking the brain to cortisol secretion via pituitary release of the ACTH. Both deficient and increased activation of the HPA axis have been associated with aggressive behavior. The molecular mechanisms underlying altered activation of the HPA axis that may predispose to aggressive behavior, including proactive violent aggression typical of murder, are currently unknown.

The current study tested the hypothesis that altered activation of the HPA axis in aggressive humans may involve ACTH-reactive immunoglobulins (Igs). Indeed, humans naturally and ubiquitously display IgG and other classes of Igs nonspecifically reactive with ACTH and other peptide hormones, supporting their constitutive contribution to peptidergic signaling (17, 18). Increased plasma levels of ACTH-reactive IgG have been found in male prisoners and adolescents with conduct disorder (18). However, it is unknown whether ACTH-reactive IgG may influence ACTH-induced cortisol secretion and whether such an influence can be different in aggressive subjects.

To address these questions, the authors analyzed plasma levels and affinity kinetics of ACTH-reactive IgG in prisoners who had committed violent acts of aggression, including murder, and compared the results with those from healthy nonaggressive controls [prisoners in whom violence was not a major feature and bodybuilders who were on active treatment with performance-enhancing substances (PES) and who previously had been characterized by increased physical aggressiveness but not hostility and anger]. They then studied the functional relevance of the observed differences in IgG affinity and epitope binding for ACTH with regard to IgG’s ability to modulate ACTH-induced cortisol secretion in vitro. They also studied aggressive behavior in mice after peripheral injections of ACTH and IgG from aggressive and control subjects. Furthermore, to determine the presence of other autoantibodies potentially interfering with the stress axis in aggressive subjects, they performed an immunohistochemical analysis of IgG binding to the rat brain and pituitary as well as guinea pig adrenal cortex sections.

They showed that ACTH-reactive 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.

References: 15. de Boer SF, Olivier B, Veening J, Koolhaas JM. The neurobiology of offensive aggression: Revealing a modular view. Physiol Behav 2015; 146:111–127.

16. Nelson RJ, Trainor BC. Neural mechanisms of aggression. Nat Rev Neurosci 2007; 8: 536–546.

17. Fetissov SO, et al. Autoantibodies against neuropeptides are associated with psychological traits in eating disorders. Proc Natl Acad Sci USA 2005; 102:14865–14870.

18. Fetissov SO, et al. Aggressive behavior linked to corticotropin-reactive autoantibodies. Biol Psychiatry 2006; 60:799–802.

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