Th1 and Th2 cells are differentially induced, and regulate immunity against intracellular and extracellular pathogens, respectively. They are also involved in immune pathologies such as autoimmunity and allergy [2,3]. Th17 cells have been shown to induce host protection against extracellular pathogens and tissue inflammation [4-6], and are thought to play a key role in autoimmune diseases, including the tissue injury associated with these conditions [7,8].

Th17 CD4 T cells are characterized by production of the cytokines interleukin (IL)-17A (IL-17) and IL-17F, and IL-21 and IL-22 [9]. Since their discovery in 2003, there have been numerous studies on Th17 cells, and they have emerged as key players in the pathogenesis of some autoimmune neuroinflammatory diseases and other autoimmune disorders traditionally attributed to Th1 cells. This may be attributable to the induction of neutrophil-recruiting chemokines (chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL8) by IL-17 [10,11].

Autoimmunity may have a role in the pathogenesis of autism in a subgroup of patients. Brain-specific auto-antibodies have been found in some children with autism [12-18], and there is also an increase in the frequency of autoimmune disorders in autistic families [19-26]. Although the origins of autoimmunity in autism are unknown, it is thought that the major histocompatibility complex genes and their products might be involved [23,27,28].

Patients with severe autism had significantly higher serum IL-17A levels than children with mild to moderate autism (P=0.01) (Table1, Figure ​Figure2),2), and the frequency of increased serum IL-17A levels was significantly higher in children with severe autism (19/28; 67.9%) than in patients with mild to moderate autism (3/17; 17.6%) (P=0.001).

In our series, children with autism had significantly higher serum IL-17A levels than healthy controls (P <0.001). Raised serum IL-17A levels were found in 48.9% (22/45) of the patients with autism. A recent study reported significantly higher plasma concentrations of IL-17 in 28 male subjects with high-functioning autism spectrum disorder (ASD) compared with 28 matched controls, and the patients with ASD also had higher plasma concentrations of other cytokines such as IL-1 receptor antagonist, IL-1β, IL-5, IL-8, IL-12 and IL-13 compared with controls. The authors suggested that abnormal immune responses, as assessed by multiplex analysis of cytokines, might be a biological trait marker for ASD [33]. Another study investigated the cellular release of IL-17 and IL-23 after in vitro immunological challenge of peripheral blood mononuclear cells from children with ASD compared with age-matched, typically developing, controls, and found that the concentration of IL-23, but not IL-17, was significantly reduced in ASD compared with controls. Those authors recommended that decreased cellular IL-23 production in ASD warrants further research to determine its role in the generation and survival of Th17 cells, a cell subset important in neuroinflammatory conditions that may include ASD [34].

IL-17A is a pro-inflammatory cytokine that is produced by a number of human immune cells, including Th17 cells, neutrophils, and peripheral blood mononuclear cells. Studies have shown that IL-17A is upregulated and involved in the pathogenesis of various autoimmune inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis [35-38]. In addition, IL-17A has been shown to play an important role in various autoimmune neuroinflammatory diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) [39].

In immune responses against infection and models of autoimmune diseases, Th1 and Th17 cells often develop simultaneously [3].The differentiation of Th1 or Th17 cells occurs after exposure to APC-derived polarizing cytokines such as IL-12 for Th1 cells [40] and transforming growth factor-β, IL-1β, IL-6 and IL-23 for Th17 cells [5,41-43]. These polarizing cytokines further induce the expression of the transcription factors T-bet or retinoic acid receptor-related orphan receptor (ROR)γt and RORα for Th1 and Th17 differentiation respectively [44,45]. Dendritic cells (DCs), which are activated by signals from pathogen-associated recognition receptors, recognize components of intracellular pathogens [46], induce the production of polarizing cytokines, and drive generation of Th17 responses. Consistent with these findings, Th17 cells have a role in immunity against intracellular pathogens. In addition, a clear role for IL-17 in generation of chemokine responses, induction of anti-microbial proteins and recruitment of neutrophils for control of extracellular pathogens has emerged [47]. The pro-inflammatory actions of Th17 cells ,both in the clearance of various pathogens and in autoimmunity, may occur through the induction of neutrophil-recruiting chemokines (CXCL1, CXCL2, CXCL8) by IL-17 [10,11].

This study is the first to measure serum IL-17 in relation to the disease severity in children with autistic disorder, to our knowledge. A few previous studies measured serum IL-17 in children with ASD, but these studies did not correlate serum IL-17 levels with the degree of severity of autism. In the present study, we found that patients with severe autism had significantly higher serum IL-17A levels than children with mild to moderate autism, P=0.01I, and children with severe autism were also significantly more likely to have increased serum IL-17A (67.9%) than patients with mild to moderate autism (17.6%) (P=0.001). This may indicate that the extent of the increase in serum IL-17A levels is closely linked to the degree of the severity of autism. However, it is not clear whether the increase in serum IL-17A levels is a mere consequence of autism or has a pathogenic role in the disease.

CD4+ CD25^high regulatory T-cells (Tregs) play an important role in the establishment of immunological self tolerance and thereby, in the prevention of autoimmunity [48]. Tregs can suppress Th17 cells and autoimmunity, as activation of Th17 cells can start tissue inflammation [49]. A recent study reported deficiency of Tregs in 73.3% of children with autism [25], an dthus, Deficiency of Tregs may be one of the reasons behind the activation of Th17 cells and the elevation of serum IL-17 A levels in children with autism. Osteopontin is a key pro-inflammatory mediator that may serve to perpetuate and amplify the inflammatory process in many autoimmune neuroinflammatory disorders such as EAE in mice and MS in humans [50]. The Th17-related response in humans is enhanced by osteopontin, which may contribute to the pro-inflammatory actions of Th17 cells in the clearance of pathogens and in autoimmunity [10,11]. A recent study reported increased serum osteopontin levels in 80.95% of children with autism [51]. Thus, increased serum osteopontin levels in autism may be another contributing factor to the elevation of serum IL-17A levels in children with autism.

Autoimmunity to brain tissue may have a pathogenic role in autism [52-55], as indicated by the presence of brain-specific auto-antibodies in some children with autism [12-18]. Levels of IL-12 and interferon (IFN)-γ have been reported to be significantly increased in patients with autism [56]. It was suggested that increased IL-12 and IFNγ may indicate stimulation of Th1 cells pathogenetically linked to autoimmunity in autism [56]. Recently, increased pro-inflammatory Th1 cytokines were reported to be associated with greater impairments in core features of autism [57]. Macrophages and DCs express IL-17A receptors, and can respond to IL-17, producing cytokines and chemokines [58,59]. These data suggest that IL-17 responses can regulate the induction and generation of Th1 responses. The mechanism by which IL-17 regulates the Th1 pathway seems to be via induction of IL-12 and IFN-γ in APCs. After IL-17 stimulation, DCs and macrophages produce IL-12 and IFN-γ, respectively. IL-17-dependent-DC-derived IL-12 was able to drive the differentiation of naive T cells into Th1 cells, and IL-17-dependent macrophage-derived IFN-γ was able to activate macrophages for control of intracellular pathogens [59]. Because IL-17A is a stimulator of pro-inflammatory cytokines, IFN-γ and IL-12 [59], it could be the inducer of the Th1 response that has been reported previously to be linked to autoimmunity in autism [56]. In addition, the possible role of IL-17A in induction of the production of brain auto-antibodies may be associated with induction of the production of neutrophil-recruiting chemokines [10,11]. Moreover, osteopontin, which was recently reported to be increased in many children with autism [51], induces myelin antigen-specific IL-17 production from Th17 cells via specific osteopontin receptors (β3 integrin receptors) on T cells [50].