Autism Spectrum Disorders and Allergy: Observation from a Pediatric Allergy/immunology Clinic

Harumi Jyonouchi


Expert Rev Clin Immunol. 2010;6(3):397-411. 

In This Article

Mechanisms of IgE-mediated allergy & Non-IgE-mediated immune reactions

The word 'allergy' is generally used to describe immediate immune reactions mediated by IgE Ab. The interactions between allergens and IgE Ab cause the rapid release of mediators from effector cells (i.e., mast cells and basophils), resulting in acute skin, airway and GI symptoms.[5] As opposed to IgE-mediated immune responses, non-IgE-mediated allergic reactions are mediated by non-IgE antibodies and/or cellular immune responses.[19] Delayed-type FA, for example, is thought to be mediated by allergen-specific cellular immune responses, with TNF-α being one of the main inflammatory mediators.[19]

Table 1 summarizes IgE-mediated 'allergic' conditions as well as non-IgE-mediated conditions frequently seen in ASD children referred to the pediatric allergy/immunology clinic at our institution. The author will briefly summarize these conditions, including their pathogenesis, in this section.

IgE-mediated Allergic Reaction

Allergen Sensitization & IgE Synthesis Most allergens are proteins that are taken up by antigen (Ag)-presenting cells (APCs), and then presented to T-helper (Th) cells as immunogenic peptides (epitopes) within the Ag-binding groove of MHC class II molecules.[5] Allergen presentation to Th cells leads to the differentiation of naive Th cells into Th2 effector cells in genetically predisposed (atopic) individuals.[5,20] Currently, it is not well understood how allergens preferentially induce Th2-cell differentiation in atopic individuals.

Th2 cells are characterized by the presence of a lineage-specific transcription factor (GATA3) and the production of Th2 cytokines (IL-4, IL-5, IL-13 and IL-25).[21] Of these cytokines, IL-4 and IL-13 are critical for the synthesis of IgE, the key immunoglobulin (Ig) in immediate allergic reactions. Binding of IL-4 and IL-13 to their respective receptors leads to the activation of the transcription factor termed signal transduction and activation of transcription (STAT)6.[5,22,23] This results in the transcription of Ce IgE genes. Additional signals for IgE synthesis are provided by ligation between CD40 ligand (CD40L) and CD40 expressed on Th cells and B cells, respectively.[24] That is, CD40L/CD40 interactions lead to the activation and translocation of NF-κB to the nucleus, initiating the transcription of two key enzymes (activation-induced cytidine deaminase and uracil nucleotide glycosylase), both of which are essential for Ig class switch recombination.[24,25] Following these events, B cells start producing IgE Ab.

Differentiation of Th2 cells and the actions of Th2 cytokines are counter-regulated by other Th-cell subsets, namely Th1 cells and Tregs.[5] For example, IFN-γ, a characteristic Th1 cytokine, and IL-10, a counter-regulatory cytokine produced by multiple lineage cells, including Tregs, both suppress differentiation of Th2 cells.[5,21,26] They also suppress the actions of Th2 cytokines.[5,21,26] Environmental exposure to Th1-inducing stimulants (e.g., endotoxin or livestock) during the first few years of life has decreased in developed countries with improvement of general hygiene. This change has been implicated in a general trend of increased prevalence of Th2-skewed allergic diseases in developed countries; this is commonly referred to as the 'hygiene hypothesis'.[8,27] Improvements in hygiene have also resulted in a lack of immunoregulatory stimuli from exposure to helminths.[23] This has also been shown to contribute to the increased prevalence of atopy in developed countries.[23]

Previously, subtle changes of immunological parameters have been reported in ASD children, including Th1- or Th2-deviated cytokine levels, as reviewed elsewhere.[10,28,29] Specifically, higher plasma levels of Th1-associated cytokines were reported,[30,31] along with increased Th1 cytokine levels in the limited numbers of brain tissues from autistic individuals,[32] while others reported Th2-skewed cytokine levels/expression.[33,34] Moreover, Th17-deviated responses and evidence of mast cell activation have also been reported in ASD children.[35,36] The heterogeneity of ASD children may be the reason behind these conflicting data and the group that initially reported Th1-skewed responses attribute this to the presence of a subset of 'autoimmune ASD'.[37] In our previous studies, significant Th1- or Th2-skewed responses in ASD children were not observed.[38,39] However, the prevalence of atopic disease is as common in ASD children as in the general population.[10,11,38,40]

IgE & Effector Cells IgE Ab is distinct from other subsets of Ig: first, IgE is present in a minute amount, far less than most other isotypes of Ig (e.g., IgA, IgG and IgM), and turns over rapidly in the serum (serum half-life: 2–3 days); second, IgE stabilizes when bound to high-affinity IgE receptors (FcɛRI) expressed on mast cells and basophils; and third, the affinity of IgE Ab for Ag (allergens) is much greater than any other class of Ig. Thus, exposure to even minute amounts of allergen results in a cross-linking of IgE Abs on the cell surface of effector cells.[23] This results in activation of the FcɛRI-expressing effector cells (mast cells and basophils), causing the release of various mediators, including histamine, leukotrienes and interleukins within minutes of allergen exposure.[41]

It is believed that Th2-mediated immune defense developed against large extracellular organisms, such as helminths, and that IgE is a key factor in such a mechanism. However, unlike allergic diseases, helminth infection also induces systemic immune suppression exerted by Tregs and other suppressive cells.[23] That is, typical defense to helminth infection is thought to evolve into downregulated systemic proinflammatory responses, activated tissue repair and tightly controlled antiparasite Th2 responses in the mucosal locus.[23] By contrast, allergen-induced Th2 responses lack such suppressive components, leading to uncontrolled inflammatory responses. In other words, allergic diseases may be regarded as the result of ill-adapted Th2 responses.

Atopic diseases are associated with allergen sensitization in genetically predisposed individuals. Although seldom fatal, allergic disorders impose significant morbidity in the general population secondary to the chronic nature of the disease. This is evidenced by the mounting medical cost and loss of productivity (missed work/school days) associated with allergic diseases.[7] Discomfort and pain associated with allergic diseases are also known to cause psychiatric and neurological conditions in 'normal' individuals and will be discussed later in this review. This is probably also true for ASD children and has been observed in our clinic. It has been our experience that in ASD children, behavioral changes caused by both IgE- and non-IgE-mediated diseases are often attributed to just being 'autistic' and no proper diagnosis and treatment for the child's condition was implemented prior to their arrival at our facility. Our observation indicates the need for physicians involved in the care of ASD children to be aware of the importance of diagnosing common allergic as well as nonallergic diseases in these children. It is also important for the physician to not attribute certain symptoms displayed by ASD children to just being 'autistic', even if the symptoms are frequently associated with ASD.

Non-IgE-mediated Immune Diseases (Conditions) Associated with Respiratory & GI Symptoms

Nonallergic Rhinitis Rhinitis is a common condition affecting up to 25% of the general population.[42] Rhinitis is subdivided into two categories, depending on the presence or absence of allergen-specific IgE Abs; AR and nonallergic rhinitis. The etiology of nonallergic rhinitis is not well understood and is thought to be heterogeneous. Various terms have been used to refer to nonallergic rhinitis, including: noninfectious, nonallergic rhinitis; nonallergic, noninfectious, perennial eosinophilic rhinitis; and nonallergic rhinitis with eosinophilic syndrome. The latter two are characterized by the presence of eosinophils in nasal mucosa.[42] Since the terminology is confusing, we will briefly discuss known or suspected causes of nonallergic rhinitis.

Young children, including ASD children we have treated, often demonstrate nasal congestion with exposure to cold air. This is called 'cold air-induced rhinitis' – in adults, unilateral challenge of cold air was seen to induce the release of mast-cell mediators bilaterally, indicating involvement of neural reflex.[6,43] The mechanisms of this condition are not well understood; however, evidence indicates the presence of neural hyperresponsiveness that is mediated by capsaicin-sensitive sensory nerves.[44]

Rhinitis is also associated with the ingestion of certain drugs. Aspirin-induced rhinitis is well known in association with nonatopic asthma and nasal polyp[42,45] but this condition is seldom seen in children. Likewise, the prolonged use of topical decongestants can cause rebound nasal congestion (rhinitis medicamentosa), which is much less frequent in the pediatric population.[42,45] Rhinitis also occurs with changes in hormonal balance, such as during pregnancy and the menstrual cycle, at the onset of puberty or with hypothyroidism.[42]

The remaining types of rhinitis are of unknown etiology and are generally categorized as idiopathic rhinitis. Although its etiology is probably heterogeneous, idiopathic rhinitis is generally characterized by hyperreactivity of the nasal mucosa. The proposed etiology of idiopathic rhinitis includes autonomic neural dysfunction and upregulated tachykinin responses.[42,45] Such conditions are thought to lead to 'neuroinflammation', resulting in inflammation of the local mucosa with subsequent activation of the mucosal immune system.[42] IgE-mediated immune responses localized to the nasal mucosa have been reported in a subset of patients with idiopathic rhinitis.[42,45]

In children, anatomical causes of chronic rhinitis, such as adenoid hypertrophy, also need to be taken into consideration. This is a predisposing factor for recurrent ear/sinus infection and obstructive sleep apnea in infants and young children.[46–48] Since disturbed sleep is a well-known comorbidity in ASD children,[4] hypertrophy of adenoids and tonsils should be ruled out as a possible contributing factor to sleep disturbance in young ASD children.

Nonatopic Asthma Nonatopic (intrinsic) asthma is defined as asthma in the absence of allergen-specific IgE antibodies and accounts for approximately 20% of the asthma population.[49] In adults, occupational asthma and drug-induced asthma account for a large number of cases of nonatopic asthma.[49] In infants and young children, wheezing commonly occurs following infection.[50] Respiratory tract infection in early infancy/childhood and persistent allergen sensitization during preschool years are independently associated with the risk of developing asthma.[9] Decreased lung function in infancy is also a risk factor for airway hyperresponsiveness.[51] A genetic risk factor for low lung functions and the immunogenotype skewed to Th2 responses are thought to be associated with the development of asthma.[9] It was proposed that nonatopic asthma patients may lack persistent aeroallergen sensitization.[9]

The most common cause of acute exacerbations of asthma is a viral respiratory infection, with rhinovirus being the most common causative organism.[50] Evidence indicates that asthma patients with recurrent asthma exacerbations have suboptimal production of IFN-γ and type 1 interferons, which are crucial for eradicating viral pathogens.[52] The risk factors for recurrent exacerbation of asthma also include chronic rhinosinusitis (CRS), gastroesophageal reflux disease, history of pneumonia, and impaired immune functions (immunodeficiency).[53,54] Hypersensitivity to non-steroidal anti-inflammatory drugs (mainly for adults), psychiatric conditions such as depression, morbid obesity and social factors (e.g., lack of medical insurance) also impose a risk of recurrent asthma exacerbation.[53,54] However, previous reports also indicate a negative association between ADHD and asthma.[55]

In summary, patients with nonatopic asthma may share a similar genetic predisposition for developing asthma as individuals diagnosed with atopic asthma. The resultant airway inflammatory condition needs to be treated effectively in order to prevent recurrent exacerbations of asthma. However, it has been our experience that treating asthma in autistic children may be much more challenging than in typically developing children. For example, ASD children may not be physically or developmentally capable of using standard asthma medications such as metered-dosed inhalers. It has been our experience that some ASD children do not tolerate nebulizer treatments owing to sensory integration disorders (they are intolerant to the noise caused by a nebulizer or unable to tolerate the placement of a mask on their faces). In either case, early diagnosis and proper education of parents regarding asthma is extremely important in order to provide optimal asthma treatment for both 'normal' and ASD children. Early signs of asthma such as frequent coughing may be overlooked secondary to the lack of complaints of shortness of breath or chest tightness in ASD children owing to their limited expressive language. Parents and primary care physicians need to be aware that asthma-induced respiratory distress can potentially worsen behavioral symptoms in ASD children, as will be discussed in the next section.

Rhinosinusitis/Otitis Media Sinusitis and otitis media (OM) often cause significant respiratory symptoms. Although OM may be easily diagnosed by otoscopic examination, diagnosis of OM in ASD children may be more challenging since, based on our experience, these children are generally more resistant to physical examination, including ear examination.[56] Acute sinusitis is often diagnosed on the basis of clinical findings, since CT scan causes exposure to high doses of irradiation.[57] However, we have experienced difficulty in diagnosing sinusitis in children due to their impaired expressive language and the presence of aberrant behaviors. In some cases, we also find it challenging to obtain a clinical history and/or positive physical findings indicating sinusitis in ASD children.

Chronic rhinosinusitis is often suspected with persistent purulent rhinorrhea and sinus symptoms despite appropriate antibiosis.[57] Since not all CRS patients present with typical clinical features, CRS may also be more difficult to diagnose in the general population without a CT scan.[57] Chronic rhinitis, both atopic and nonatopic, is a leading predisposing factor for CRS.[58] However, other underlying conditions also predispose individuals to CRS. These include immunodeficiency (mainly Ab-deficiency syndromes), cystic fibrosis, anatomical (mechanical) problems such as adenoid/tonsillar hypertrophy and nasal polyposis (mainly in adults), and the presence of systemic diseases such as vasculitis.[57] Both sinusitis and asthma are implicated in mucosal susceptibility to environmental stimuli. In addition, sinusitis is one of the major triggers for asthma.[59] This is probably also the case for ASD children. In our pediatric allergy/immunology clinic, we observed a high frequency of nonatopic asthma in ASD children diagnosed with CRS.[10]

Celiac Disease Celiac disease (CD) is now considered to be an immune-mediated enteropathy caused by wheat protein ingestion in susceptible individuals, most of whom carry HLA-DQ2 or DQ8 molecules.[60,61] Tissue transglutaminase (tTG) was identified as the dominant autoantigen in CD. Serological screening of CD depends on the presence of anti-tTG Ab[60] as well as Ab against synthetic deamidated gliadin peptides.[62] However, histology remains the 'gold standard' for CD diagnosis. tTG, a calcium-dependent enzyme, is thought to form new Ags with gliadin-derived peptides by deamidation of gliadin glutamines to glutamates.[60] Deamidated gliadin peptides bind tightly to HLA-DQ2/DQ8 heterodimers.[63] Anti-tTG antibodies are detected in most CD patients and react to multiple conformational epitopes of tTG, as well as the gliadin fraction of wheat protein.[64] In addition to GI inflammation, CD patients manifest a variety of non-GI symptoms (atypical CD) and may even be totally asymptomatic (silent CD).[60,65,66] The prevalence of CD is now considered to be much higher than initially thought.[60]

Given its relatively high prevalence and varied clinical manifestations, CD is often included in the differential diagnoses for ASD children with GI symptoms.[67] One case study reported autistic symptoms in a child with untreated CD and deficiency of multiple micronutrients.[68] Resolution of behavioral symptoms occurred following the implementation of a gluten-free diet and proper supplementation of nutrients.[68] However, others report a low prevalence of neurologic and psychiatric symptoms in CD children compared with adult CD patients.[69] It should be noted that a recent epidemiological study indicated a possible association between maternal CD and the development of autism.[70]

Non-IgE-mediated Food Allergy During the first few years of life, aberrant immune reactions to food proteins are likely to occur more frequently. This is due to the immature gut mucosal immune system.[19] Therefore, during the first few years of life, non-IgE-mediated FA (NFA) is probably more common than potentially life-threatening IgE-mediated FA. In contrast to IgE-mediated FA, NFA symptoms typically occur hours after exposure, rendering it difficult to appreciate a causal relationship between exposure to the offending food and resulting clinical symptoms. In addition, no diagnostic measures for NFA are readily available for primary care physicians to utilize. As a result, NFA is frequently underdiagnosed even in the general population, despite the fact that presence of NFA has been described in the literature for more than 60 years.[19] This leaves the parents of NFA patients very frustrated, since these NFA children remain undiagnosed despite persistent GI symptoms.

Non-IgE-mediated food allergy to cow's milk protein (CMP) was initially reported in the 1940s, describing infants with bloody diarrhea and resolution of symptoms following the implementation of a dairy-free diet.[71] Since then, infants with non-IgE-mediated immune reactivity to CMP and soy have been described as having a wide range of clinical features. This condition is currently often referred to as food protein-induced enterocolitis syndrome (FPIES).[72] Determination of reactivity to the offending food (mainly milk and soy) is generally based on in vivo responses – that is, the resolution of GI symptoms with avoidance of the offending food and recurrence of symptoms following oral challenge. Most patients with NFA lack skin-prick test reactivity or food-allergen-specific IgE.[72,73]

Food protein-induced enterocolitis syndrome often manifests as infantile colic and recurrent vomiting during early infancy. On the other hand, diarrhea and loose stool are more common clinical findings in older infants and young children.[19] In cases with severe FPIES, clinical features may resemble sepsis with lethargy, hypotension, dehydration, abdominal distention and acidemia.[74] These patients may also reveal hypoalbuminemia and failure to thrive (FTT).[72] In patients with severe FPIES, reintroduction of the offending food can cause shock, despite the absence of IgE antibodies.[74,75] The immune mechanisms of FPIES are not well understood. However, evidence indicates a crucial role of aberrant cellular immune reactivity to food proteins with the production of proinflammatory cytokines such as TNF-α, along with impaired oral tolerance, in the development of NFA.[19,74]

Although it can be potentially life-threatening in very severe cases, such instances are rare and the prognosis of FPIES is generally excellent. Resolution of symptoms is typically expected to occur within a few weeks following the implementation of an elimination diet (ED).[73] It is also known that many infants with NFA to CMP and soy eventually outgrow this condition, establishing oral tolerance in the gut mucosal immune system.[76] This may also be the case in ASD children. In our clinic, we diagnose FPIES more frequently in younger ASD children (<6 years of age) than older children. In our previous studies assessing IgE- and non-IgE-mediated FA in ASD children, we found a fairly high frequency of FPIES against milk protein in young ASD children (2–6 years of age).[10,40] In typically growing children without ASD, FPIES resolves by 3–4 years of age. However, it is our observation that ASD children may take longer to outgrow FPIES. This may be partly attributed to difficulty of diagnosing FPIES in this population and subsequent under-diagnosis and delayed introduction of treatment measures.[10]


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