The Immune System’s Moderating Response to Inflammation Relieves Autistic Behavior: Response to Peter Good

Abstract

Authors Helt, Kelley, Boorstein, Pandey, and Fein, askedauthors Kinsbourne and Herbert to respond to the Goodletter because of their expertise in this area. Following isDr. Kinsbourne’s response.Curran et al. (2007) confirmed that children with autismbehaveless aberrantly when they are febrile due to infections,a phenomenon that might offer insight into the cause andtreatment of autistic symptoms. Good (2011) attributes theimprovement to an increase in cerebral blood flow. Somebrain regions related to autistic symptoms are indeed under-perfused (Ohnishi et al. 2000). However, because regionalcerebral blood flow is proportionate to metabolic need,diminished perfusion reflects diminished metabolism ratherthan cause it. Evidence is lacking that fever increases theperfusion of these regions, or that they would function betterif it did. Indeed, Curran et al. (2007) found no relationshipbetween degree of fever and degree of improvement.Fever is the presenting symptom of inflammatoryreactions to a pathogen. Absent inflammation, heat stressdoes not improve behavior in autism (Miles 2010, cited byGood). Therefore, the benefits do not accrue from the risingtemperature as such. I suggest that they derive from theimmune system’s efforts to limit the inflammatory reaction.The febrile inflammatory response to pathogens ismediated by proinflammatory cytokines, notably IL-1 betaand TNF-alpha (Mackowiak 1998) and promoted by thesympathetic nervous system. In excess, these cytokineswould be toxic. The proinflammatory cytokine response israpidly curtailed by IL-1ra, a specific IL-1 antagonist, andby anti-inflammatory cytokines, such as IL-10, TNF-binding protein and transforming growth factor-b (TGF-b)(Czura and Tracey 2005). Moreover, the inflammatoryreaction with its sympathetic activation is buffered by thevagal cholinergic anti-inflammatory system (CAIS) (Tracey2007; Thayer 2009).The inflammatory reflex of the vagus nerve preventsexcessive release of cytokines from macrophages. Whenthe CAIS of mice was inactivated, the cytokine response toendotoxin was excessive (Borovikova et al. 2000). Electri-cal vagal stimulation is used to treat inflammatory diseases,including depression, which features neuroinflammation(Pucak et al. 2007). Vagal stimulation also increases heartrate variability, as autonomic tone veers from sympathetictoward parasympathetic dominance.In controlling inflammation and sympathetic predomi-nance, the CAIS may lower arousal level. Much autisticbehavior appears to be a compensatory reaction to chronicpathologically heightened arousal (Kinsbourne 2011).Vargas et al. (2005)discoveredneuroinflammation in peoplewith autism, both in vivo and at autopsy. An outpouring ofcytokines from activated microglia, the CNS counterparts ofmacrophages, involves the excessive release of glutamate,the preponderant excitatory neurotransmitter, increasing thebrain activation toward hyperarousal. By subduing neuro-inflammation (Nizri et al. 2009), the CAIS would down-regulate arousal and enable adaptive behavior to emerge.Sympathetic hyperarousal in autism is also well docu-mented. By fostering parasympathetic (vagal) predominance,the CAIS might ameliorate the fearful sensory rejection andurge toward isolation and inward shift of attention thatcharacterizes the autistic state (Kinsbourne 2011).That autistic behavior can improve during fever demon-strates that it is not necessarily fixed but can constitute areaction to potentially remediable factors. If the suggested