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

Abstract

SignificanceThe 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.

Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders

“…In contrast to IgG from OB, BN, and BED, IgG from AN patients displayed no binding to the C-terminal, which may facilitate MC4R recognition of α-MSH/IgG IC in AN. The IgG-transporting properties of adrenocorticotropic hormone (ACTH), another melanocortin peptide, have also been recently reported 50 . Of relevance to the present study, the IgG binding to the central part of the ACTH peptide preserved its functional activity to stimulate cortisol secretion.

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Neurobiology of Aggressive Behavior—Role of Autoantibodies Reactive With Stress-Related Peptide Hormones

“…For human beings, the impact of stress already experienced during a child's early rearing environment may influence the development of later psychopathology and possibly identify hormonal substrates related to behavioral changes as the child gets older (37). Recent data have revealed that the HPA axis and associated stress-related behavior can be influenced by immunoglobulins or natural autoAbs reactive with peptide hormones involved in regulation of the HPA axis activity (34). Furthermore, experimental studies have shown enhanced activation of the hypothalamic paraventricular nucleus and amygdala in glucocorticoid-deficient rats after exposure to the resident intruder (RI) stress protocol (33, 38).…”

“…Acute administrations of ACTH fragments increase fighting in mice, independently of corticosterone secretion (44), but ACTH injections in isolated mice may also decrease their aggressiveness (45). It was shown that there is a link between ACTH and aggressive behavior (46), and recently this link has been strengthened through studies on ACTH autoAbs (34).…”

“…Experiments on violent criminals and non–violent individuals describe elevated levels of ACTH autoAbs which may block ACTH secretion and an instant cortisol release during stress. The blocking and non-blocking IgG effects (34) have confirmed a role for ACTH autoAbs in the HPA axis response, but at the same time makes it less likely that aberrant IgG modulation of ACTH induced cortisol response can be causal for violent aggression.…”

“…For instance, in 2002 Fetissov et al described IgG reactive with melanocortin peptides alpha-melanocyte-stimulating hormone (α-MSH) and ACTH in patients with eating disorders (ED) (32), results which later were followed by data showing increased plasma levels of ACTH-reactive autoAbs in subjects with increased aggressive and antisocial behavior (33). Most recently, a modulatory role of ACTH-reactive IgG in ACTH-induced cortisol secretion was demonstrated (34).…”