Autismo y Autoinmunidad

Immune Dysfunction and Autoimmunity as Pathological
Mechanisms in Autism Spectrum Disorders

Heather Hughes1, Emily Mills Ko1, Destanie Rose1, Paul Ashwood1*
1
University of California, Davis, United States
Submitted to Journal:
Frontiers in Cellular Neuroscience
ISSN:
1662-5102
Article type:
Review Article
Received on:
14 May 2018
Accepted on:
19 Oct 2018
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Provisional PDF published on:
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19 Oct 2018
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Frontiers website link:
o
www.frontiersin.org
P r Citation:
Hughes H, Mills_ko E, Rose D and Ashwood P(2018) Immune Dysfunction and Autoimmunity as
Pathological Mechanisms in Autism Spectrum Disorders. Front. Cell. Neurosci. 12:405.
doi:10.3389/fncel.2018.00405
Copyright statement:
© 2018 Hughes, Mills_ko, Rose and Ashwood. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction
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Frontiers in Cellular Neuroscience | www.frontiersin.org

Immune Dysfunction and Autoimmunity as Pathological Mechanisms
in Autism Spectrum Disorders
1 Heather K. Hughes1,2, Emily Mills Ko1,2, Destanie Rose1,2, Paul Ashwood1,2*

1
2 Department of Medical Microbiology and Immunology, University of California Davis, CA, USA
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3 MIND Institute, University of California Davis Medical Center, Sacramento, CA, USA.
4 * Correspondence:
5 Paul Ashwood
6 [email protected]
7 Keywords: autism, immune, dysregulation, autoimmunity, neurodevelopment, behavior.
8 Abstract
9 Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are
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highly variable and are clinically characterized by deficits in social interactions, communication, and
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stereotypical behaviors. Prevalence has risen from 1 in 10,000 in 1972 to 1 in 59 children in the
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United States in 2014. This rise in prevalence could be due in part to better diagnoses and awareness,
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13 however, these together cannot solely account for such a significant rise. While causative connections
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have not been proven in the majority of cases, many current studies focus on the combined effects of
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genetics and environment. Strikingly, a distinct picture of immune dysfunction has emerged and been
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supported by many independent studies over the past decade. Many players in the immune-ASD
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17 puzzle may be mechanistically contributing to pathogenesis of these disorders, including skewed
18 cytokine responses, differences in total numbers and frequencies of immune cells and their subsets,
19 neuroinflammation, and adaptive and innate immune dysfunction, as well as altered levels of
20 immunoglobulin and the presence of autoantibodies which have been found in a substantial number
21 of individuals with ASD. This review summarizes the latest research linking ASD, autoimmunity and
22 immune dysfunction, and discusses evidence of a potential autoimmune component of ASD.
23 1 Introduction
24 First defined as a distinct syndrome in 1943 by child psychiatrist Leo Kanner (Kanner, 1943), autism
25 spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are clinically
26 characterized by deficits in social interactions, communication, and stereotypical behaviors (Baio et
27 al., 2018). Recent prevalence of ASD has risen dramatically to 1-in-59 US children, with
28 preponderance toward males (Baio et al., 2018). Although increased awareness of the disorder and
29 changing diagnostic criteria have undoubtedly contributed to the increase in prevalence (King and
30 Bearman, 2009), researchers agree that these cannot solely account for such a significant rise in
31 occurrence (Hertz-Picciotto and Delwiche, 2009). While the cause of the majority of ASD remains
32 elusive, it likely involves a combination of genetic, epigenetic, and environmental factors. Twin
33 studies have found a high concordance rate among monozygotic twins, with a much lower rate
34 among dizygotic twins, implicating genetics as a factor; however, when combined, genetic
35 interactions/mechanisms account for only 10-20% of ASD cases (Abrahams and Geschwind, 2008),
36 this may suggest other heritable factors or shared genetic and environmental influences may be
37 involved. These genetic markers may also be present in healthy individuals, again suggesting other
Immune Dysfunction and Autoimmunity in Autism Spectrum Disorders
38 risk factors in the pathogenesis of most cases of ASD. The rate for dizygotic twins is higher than
39 non-twin siblings, and may suggest that shared prenatal environmental factors such an maternal
40 infection, diet, and household chemical exposures may play a significant role in the etiology of ASD
41 (Hallmayer et al., 2011). Environmental factors during pregnancy including maternal inflammation,
42 air pollution and pesticide exposure have been associated with an increased risk of developing ASD
43 and could be responsible for epigenetic changes identified in ASD (Loke et al., 2015); however, no
44 single etiological factor has risen to the forefront. Research in ASD is confounded by the fact that
45 these are highly heterogeneous disorders that likely have multiple etiologies and converging
46 pathophysiological pathways. There is a growing need to determine which factors might be involved
47 in the development of these disorders, as individuals with ASD and their families experience
48 increased stress and decreased quality of life (Estes et al., 2013;Kuhlthau et al., 2014), and the
49 increased prevalence of ASD has created a significant burden on health care (Lavelle et al., 2014)
50 with an economic impact projected to exceed $400 billion by 2025 (Leigh and Du, 2015).
51 Although the specific etiologies of ASD remain unknown, many hypotheses regarding causation of
52 ASD abound, including the potential involvement of the immune system. Just over a decade ago, we
53 hypothesized that ASD may in fact be an autoimmune disorder (Ashwood and Van de Water,
54 2004;Ashwood et al., 2006). At that time, immune studies were limited and results had been
55 somewhat inconsistent between various laboratories. Since then, a significant amount of research
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linking ASD and aberrant immune function has taken place, and although inconsistencies still exist, a
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clearer picture of the importance of immune involvement in ASD has emerged. This comprehensive
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review summarizes the latest research linking ASD and immune dysfunction, and discusses evidence
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59 of potential autoimmune mechanisms of ASD.
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Familial Autoimmunity
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Diverse autoimmune diseases within a nuclear family suggest familial autoimmunity (Anaya et al.,
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2007). Historically, studies have shown an increased prevalence of familial autoimmune disorders in
ASD. The first study to identify a connection was in 1971, where researchers found a child with ASD
who had several family members with multiple autoimmune disorders (Money et al., 1971). A later
study found that 46% of ASD families had two or more members with autoimmune disorders, and as
the number of autoimmune disorders within the family rose from one to three, the odds ratio for a
risk of a child with ASD increased from 1.9 to 5.5. This study found that autoimmune prevalence was
significantly increased in mothers and first-degree family members of ASD subjects, with type I
69 diabetes (T1DM), rheumatoid arthritis (RA), hypothyroid and systemic lupus erythematosis (SLE)
70 being the most common disorders found (Comi et al., 1999). A 2003 study also found a specific link
71 to hypothyroid/Hashimoto's thyroiditis and RA in parents with ASD offspring (Sweeten et al.,
72 2003a); however, others only found such an increase was paternally linked (Micali et al., 2004).
73 Since then, both self-reported and registry-based studies have shown additional links to
74 autoimmunity in the family of children with ASD. A study in 2006 found autoimmune thyroid
75 disease to be a significant risk factor, especially if the family member was the mother (Molloy et al.,
76 2006a). This and other self-reported studies have some limitations as they may include biased or
77 inaccurate recall. Utilization of health registries have allowed researchers to obtain larger datasets
78 from patients based on medical records in population based case-control studies. In 2007, Mouridsen
79 et al. found maternal ulcerative colitis and paternal T1DM were associated with infantile autism,
80 (Mouridsen et al., 2007). In addition, mothers with autoimmunity were more likely to have a child
81 with intellectual disability (ID), defined as an IQ of less than 50 (Mouridsen et al., 2007). In a large
82 nationwide study that included all children born in Denmark from 1993 to 2004 (689,196 children,
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83 3325 with ASD), researchers found that maternal RA and celiac disease increased risk of ASD in
84 offspring (RA incidence rate ratio (IRR): 1.70 [95% CI: 1.07–2.54]; celiac disease IRR: 2.97 [95%
85 CI: 1.27–5.75]), and an increased risk of infantile autism was found to be associated with family
86 history of T1DM in either parent [IRR:1.78; 95% CI:1.16 –2.61] (Atladottir et al., 2009). A further
87 study utilizing the Danish registries looked specifically at both maternal and paternal RA and risk for
88 ASD through 2007. Their data show that the risk of ASD increased by approximately 30% in cases of
89 parental RA (maternal: HR 1.31 and 95% CI 1.06-1.63; paternal: HR 1.33, 95% CI 0.97-1.82). They
90 conclude that a genetic component, specifically the Human Leukocyte Antigen - antigen D Related
91 (HLA-DR) B1*04 alleles found commonly in both RA and ASD, may be playing a significant role in
92 the development of ASD along with environmental factors (Rom et al., 2018). Registry-based studies
93 have also shown an almost 50% higher odds-ratio of a child having an ASD diagnosis by age 10 if
94 either parent had any autoimmune disease (maternal OR =1.6 [95% CI = 1.1–2.2]; paternal OR = 1.4
95 [95% CI = 1.0 –2.0]), with maternal T1DM, idiopathic thrombocytopenic purpura (ITP), myasthenia
96 gravis and rheumatic fever carrying the highest risks (Keil et al., 2010).
97 Confirming the link to autoimmune thyroid disorders previously found in case reports, a nested case
98 control study in Finland identified a significantly increased risk of developing ASD in children who
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99 were born to mothers positive for anti-thyroid peroxidase antibodies (TPO-Ab+) during pregnancy.
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This study looked at a population of children born in Finland between 1987 and 2005, which
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included 1132 confirmed cases of childhood autism. When compared to 967 matched controls, they
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found odds for developing ASD without ID were increased nearly 80% among children born to
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103 mothers who were TPO-Ab+ during pregnancy (OR= 1.78, 95% CI= 1.16–2.75). Interestingly, the
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104 odds were not increased for development of ASD with comorbid ID (Brown et al., 2015).
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These large population studies rely on medical reporting and abstraction of medical data, as well as
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only reporting past and present autoimmunity, therefore they may not cover younger mothers who
develop autoimmunity after the study period has ended. Nonetheless, a consistent pattern has
emerged, as multiple meta-analyses have confirmed the familial autoimmunity and ASD link. A 2016
meta-analysis of mainly cased-control studies found significant positive associations of ASD with
maternal autoimmunity during pregnancy (pooled OR: 1.34, 95% CI 1.23-1.56) and maternal
111 autoimmune thyroid conditions (pooled OR: 1.29, 95% CI 1.14-1.45) (Chen et al., 2016). Familial
112 T1DM and autoimmune thyroid disease were also associated with higher rates of regressive autism,
113 versus those with developmental delays evident during infancy (Scott et al., 2017). Overall,
114 combined family history of autoimmune disorders increased the risk of ASD by 28%, with most
115 significant increased risks associated with psoriasis 59%, RA 51%, T1DM 49%, and hypothyroid
116 64% (Wu et al., 2015)]
117 In summary, the results of these familial studies do not single out one autoimmune disease and risk
118 for ASD; however, a clear familial autoimmune component has emerged. The significant overlap of
119 autoimmunity within the family members of ASD subjects may suggest an involvement of inherited
120 immune factors. Maternal autoimmunity could also be playing a role in the gestational immune
121 environment that has been found to significantly influence neurodevelopment. Summary of these
122 studies can be found in Table 1.
123 3 Gestational Immune Influences
124 3.1 Maternal Autoantibodies
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125 The gestational environment is protected by the placenta, a selective barrier that allows for nutrient
126 uptake and waste elimination, and provides protection from pathogens while allowing protective
127 immune factors such as immunoglobulin-G (IgG) to cross into the amniotic fluid compartment
128 (Garty et al., 1994). This passage could be facilitating the transfer of maternal IgG that target fetal
129 brain antigens and could play an etiological role in ASD by blocking or activating proteins in the
130 fetal brain, or initiating a cascade of neuroinflammation. In addition to an increased prevalence of
131 familial and maternal autoimmunity in ASD, a subset of mothers of children with ASD (10-12%)
132 have been found to harbor autoantibodies with reactivity to fetal brain components (summarized in
133 Table 2), and these antibodies induce ASD-like pathology in animal models (Martin et al.,
134 2008;Braunschweig et al., 2012b;Bauman et al., 2013b).
135 The first evidence of such antibodies was found in 2003 in the serum of a mother with two children
136 on the autism spectrum. These antibodies were found to be reactive to Purkinje cells and other
137 neuronal proteins in rodent brain tissue (Dalton et al., 2003). Since then, several studies have
138 identified maternal antibodies with reactivity to various brain proteins of different molecular weights
139 in mothers of ASD subjects. For example, Zimmerman et al. found multiple patterns of reactivity to
140 rat brain proteins of low kilodalton (kDa) weight, and one at 250kDa (Zimmerman et al., 2007).
141 When measured by Western blot for reactivity to human and rodent fetal brain tissue, sera from ASD
142 mothers had significant reactivity to a 36 kDa protein present in both human and rodent fetal brain
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and dense banding at 61 kDa. (Singer et al., 2008). Braunschweig et al. observed immunoreactivity to
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proteins at approximately 37 and 73 kDa exclusively in the mothers of children with ASD, and found
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these to be associated with increased language deficits in the child. Additional reactivity to a pair of
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146 bands in the region of 39 and 73 kDa was associated with increased irritability and self-injurious
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147 behavior (Braunschweig et al., 2008;Braunschweig et al., 2012a). Multiple studies have since
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148 confirmed the presence of maternal autoantibodies (MAbs) with paired reactivity to 37 and 73 kDA
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proteins exclusive to mothers of children with ASD (Croen et al., 2008;Nordahl et al., 2013;Rossi et
al., 2013). Consistent with these studies, Piras et al. found that single (or combinations of) maternal
anti-brain antibodies correlated with severity of language and other behavioral impairments, and that
the presence of a specific autoantibody at 62kDa in the child correlated with the presence of
autoantibodies in the mother (Piras et al., 2014). Brimberg et al. confirmed that anti-brain antibodies
are significantly more prevalent in mothers of children with ASD than typically developing children,
and a majority of these women who harbor anti-brain antibodies also harbor anti-nuclear antibodies
156 common to autoimmune disorders (Brimberg et al., 2013). Although the presence of these maternal
157 autoantibodies were associated with risk of ASD in offspring, these studies are limited in that no
158 clear mechanism was identified, which limits our understanding of how they might contribute to the
159 etiology of ASD.
160 Animal models have allowed us to identify some pathogenicity of these autoantibodies (Table 3).
161 Passive transfer of anti-brain antibodies from mothers of children with ASD to animals during
162 gestation led to ASD-like pathology in both rodent (Singer et al., 2009;Braunschweig et al., 2012b)
163 and primate offspring (Martin et al., 2008;Bauman et al., 2013a), Target antigens to these maternal
164 autoantibodies have since been identified as lactate dehydrogenase A and B (LDH – 37 kDa band),
165 cypin (previously undetected 44 kDa band), stress-induced phosphoprotein 1 (STIP1 - upper 73 kDa
166 band), collapsin response mediator proteins 1 and 2 (CRMP1/2 - lower 70 kDa band) and Y-box-
167 binding protein (YBX1 – 39 kDa band), with individual and combinations of maternal autoantibodies
168 specific to these antigens increased in mothers of children with ASD. Increased stereotypical
169 behavior and overall impairment were observed in children of mothers who possessed combinations
170 of these autoantibodies (Braunschweig et al., 2013). Using structural magnetic resonance imaging
171 (MRI), Nordahl et al. showed enlarged brain volume in male children born to mothers harboring anti-
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172 brain antibodies (Nordahl et al., 2013). In rodents, maternal autoantibodies administered during
173 gestation were found to be able to migrate into the cortical parenchyma and alter coronal
174 development by binding to radial glial cells in the ventricular zone and increased the number of
175 neuronal precursor cells in the subventricular zone, increasing brain size and weight. Administration
176 of autoantibodies also led to decreased numbers of mature dendritic spines in the adult cortex of
177 mice, with STIP1 blockade being the likely culprit due to its importance in neuritogenesis, the
178 sprouting of neurites that later develop into dendrites (Martinez-Cerdeno et al., 2016;Ariza et al.,
179 2017). Mice exposed to maternal autoantibodies during the embryonic stage displayed ASD-like
180 behaviors including increased repetitive behaviors and altered social interactions (Camacho et al.,
181 2014). Generation of endogenous autoantibodies prior to gestation to the fetal brain epitopes
182 identified in ASD mothers also led to social deficits and increased repetitive grooming in adult
183 offspring mice (Jones et al., 2018).
184 Although the origin(s) of these autoantibodies are unknown, they are more frequent in mothers
185 carrying a functional variant of the Met Receptor Tyrosine Kinase (MET) promoter which leads to
186 reduced production of MET receptor tyrosine kinase, a receptor involved in immune regulation
187 (Heuer et al., 2011). Mothers carrying the variant MET allele had reduced interleukin (IL)-10, an
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188 important regulatory cytokine, suggesting that dysfunction in immune regulation may be driving the
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production of autoantibodies (Heuer et al., 2011). Understanding the development of these MAbs and
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the role of the proteins they target in neurodevelopment is important due to the substantial number of
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ASD cases found to involve these antibodies. Research in this area may lead to diagnostic tools that
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192 assess maternal risk, as well as possible treatments and early interventions for children with maternal
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193 autoantibody-related ASD.
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3.2
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Maternal Immune Activation (MIA)
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Maternal infection during pregnancy has been implicated as a potential environmental risk factor for
ASD [reviewed in: (Patterson, 2009)]. In case series reports, infections during pregnancy, such as
rubella, measles or toxoplasmosis, can negatively impact early neurodevelopment of the fetus. In
population based studies, viral and bacterial infections occurring in the first or third trimester,
respectively, or maternal fever during gestation pose an increased risk for later development of ASD
200 in offspring (Atladottir et al., 2010;Zerbo et al., 2013). Both rodent and non-human primate models
201 of maternal infection during gestation have supported epidemiological studies, showing alterations in
202 ASD-associated behaviors and immune dysregulation that persisted into adulthood in offspring born
203 to mothers exposed to viral or bacterial antigens during gestation (Schwartzer et al., 2013;Bauman et
204 al., 2014;Meyer, 2014;Onore et al., 2014;Choi et al., 2016;Rose et al., 2017). Maternal asthma during
205 pregnancy has also previously been linked with ASD (Croen et al., 2005;Lyall et al., 2014).
206 Furthermore, in a cohort of 220 children with ASD, those whose mothers had a history of allergies or
207 asthma during pregnancy displayed more severe social impairments (Patel et al., 2017). Animal
208 models of maternal gestational asthma have validated both behavioral and immune abnormalities in
209 offspring, including epigenetic alterations in methylation of immune pathway genes in microglia –
210 the resident immune cells of the brain (Schwartzer et al., 2015;Schwartzer et al., 2017;Vogel Ciernia
211 et al., 2018).
212 The driving mediators of MIA-associated ASD pathology are most likely elevations in maternal
213 cytokines and chemokines. In addition to their roles as immune-mediators, these signaling proteins
214 play important roles in central nervous system (CNS) development and are involved in migration of
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215 neuronal precursors, neuronal maintenance, synaptic pruning and plasticity, thus they need to be
216 tightly regulated (Deverman and Patterson, 2009). Cytokines that cross the placenta, such as IL-6 and
217 IL-4, have the potential to alter epigenetic regulation of gene transcription (Nardone and Elliott,
218 2016). Elevations of cytokines and chemokines in both maternal serum during gestation and amniotic
219 fluid are associated with increased risk of ASD in human subjects (Goines et al., 2011b;Abdallah et
220 al., 2012;Jones et al., 2016). Mechanistically, maternal cytokines such as IL-6 and IL-17 may be
221 mediating inflammation either at the placenta or directly in the developing fetal brain (Smith et al.,
222 2007;Hsiao et al., 2012;Choi et al., 2016). Moreover, it is possible that maternal inflammation may
223 be contributing to the development of maternal autoantibodies (Figure 1). As well as cytokine driven
224 responses, other downstream events occur that can effect immune and neuronal development. For
225 instances, in the LPS model of MIA trace metal levels are altered included the sequestration of zinc
226 in both the dams and offspring (Coyle et al., 2009); (Kirsten et al., 2015); (Kirsten and Bernardi,
227 2017) .
228 Recent evidence in a mouse model of MIA suggest that maternal microbiota composition may be
229 driving maternal inflammation to skew towards IL-17 production, inducing behavioral changes.
230 Dams lacking certain microbiota did not produce IL-17 and their offspring did not exhibit aberrant
231 behavioral phenotypes. IL-17 blockade was also effective in preventing behavioral abnormalities
232 (Choi et al., 2016;Kim et al., 2017). This is a notable finding considering our understanding of IL-17
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as a central driver of autoimmune disorders (Zhu and Qian, 2012). A better understanding of the role
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of IL-17 signaling during gestation and within the fetal brain may hopefully lead to therapeutics
targeting this cytokine.
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4.1
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Immune Findings in Individuals with ASD
Immune Mediated Co-morbidities
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238 Among the many immune findings in ASD, several recent large-scale studies have indicated that
239 individuals with ASD have frequent immune-mediated comorbid health issues that may progress or
240 predispose to later-life autoimmune conditions (Figure 2). Zerbo and colleagues found that allergies
241 and autoimmunity diagnoses were significantly more common in children with ASD, with odds ratios
242 of 1.22 and 1.36 respectively (Zerbo et al., 2015). Children with ASD, as surveyed in the National
243 Health Interview Survey, require higher health care use and have a higher prevalence of most
244 medical conditions defined in autoimmune areas, compared to those without developmental
245 disabilities (Schieve et al., 2012). However, as many autoimmune conditions do not manifest until
246 adulthood, the young age of most study populations is a limitation to finding associations between
247 ASD and autoimmunity. To determine significant pathogenic components of ASD, cluster analysis
248 found immune dysfunction to be the best-defined cluster for ASD. This study noted that immune
249 dysfunction underlined the majority of comorbidities observed in ASD (Sacco et al., 2012). Allergic
250 diseases are overrepresented in ASD, and in some individuals may influence behaviors and severity
251 of core behavioral deficits (Mostafa et al., 2008;Shibata et al., 2013). A large epidemiological study
252 found that asthma was 35% more common in children with ASD compared to typically developing
253 children (Kotey et al., 2014). This supports a previous study that found a significantly increased risk
254 of asthma in ASD subjects, with an odds ratio of 1.74 (Chen et al., 2013). Increased risk of type 1
255 diabetes, allergic rhinitis, atopic dermatitis, urticaria and a trend toward increasing comorbidity with
256 Crohn’s disease are also observed in subjects with ASD (Chen et al., 2013). The same group looked
257 specifically at asthma in a nationwide population-based prospective study over eight years and found
258 children with asthma in early life had an increased risk of developing ASD (adjusted hazard ratio:
259 2.01, 95% confidence interval: 1.19–3.40) (Tsai et al., 2014). An analysis of over 1500 adults with
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260 ASD showed significantly increased rates of medical conditions in individuals with ASD compared
261 to non-ASD controls, including but not limited to immune co-morbidities, gastrointestinal (GI)
262 disorders, diabetes, obesity, seizures and sleep disorders (Croen et al., 2015).
263 One of the most commonly reported comorbidities in ASD is the incidence of GI dysfunction and
264 inflammation in the GI tract (Figure 2). Assessment for GI dysfunction is often challenging in
265 individuals with ASD due to communication deficits. Reported prevalence of GI disturbances varies
266 widely, with ranges from 9 to over 90% in ASD subjects; however, the 2013 Interagency Autism
267 Coordinating Committee concluded that at least 50% of children with ASD had GI issues [discussed
268 in: (McElhanon et al., 2014)]. A 2014 assessment of 960 children enrolled in the Childhood Autism
269 Risks from Genetics and the Environment (CHARGE) study found that children with ASD had
270 significantly increased odds of having at least one GI symptom compared to typically developing
271 controls (OR 7.92 [4.89–12.85]) (Chaidez et al., 2014). Discrepancies in prevalence rates of GI
272 comorbidities in ASD are likely due to differences in defining criteria for symptoms, referral bias,
273 variations in samples sizes and sources of data, as well as the timing in which symptoms were
274 reported (Buie et al., 2010;Coury et al., 2012). Early studies examining intestinal dysfunction in ASD
275 showed increased monocytes, lymphocytes, NK cells, eosinophils and intraepithelial lymphocytes in
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276 duodenal biopsies, and autoantibody IgG and co-localized C1q complement bound to the basal
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membrane of GI epithelial cells (Torrente et al., 2002). This autoimmune phenomena – directed
against the gut lumen barrier - could be responsible for the increased intestinal permeability seen in
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individuals with ASD (de Magistris et al., 2010). Inflammatory immune cells were found to infiltrate
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280 the epithelium and lamina propria of the GI tract (Furlano et al., 2001;Torrente et al., 2002;Ashwood
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281 et al., 2003). Further, studies showing increased production of inflammatory cytokines and decreased
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282 regulatory IL-10 production by mucosal Cluster of Differentiation(CD)3+ T cells suggested the
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presence of increased inflammation and dysregulation of mucosal immune responses that could be
contributing to disruption of the intestinal barrier (Ashwood et al., 2004;Ashwood and Wakefield,
2006b). Mucosal gene profiling adds further support to these findings, with upregulation of cytokine
production, including IL-17 and increased immune activation in children with ASD who have
comorbid GI issues (Walker et al., 2013).
Increased inflammation and dysregulation of the GI tract in ASD is important as this compartment
289 comprises a significant percentage of immune cells in the body, and immune cells educated here
290 participate in immune function throughout the body. Cellular education and the maintenance of
291 regulatory immune cells in the mucosal GI compartment are strongly influenced by the community of
292 microbes that reside here, and this influences systemic immune homeostasis (reviewed in: (Wu and
293 Wu, 2012)). Additionally, if the intestinal barrier is disrupted, antigenic material from the lumen of
294 the gut may enter the periphery and initiate an immune response. Indeed, ASD subjects with GI
295 comorbidities have increased peripheral inflammation and lower production of regulatory cytokines
296 (Jyonouchi et al., 2001;Jyonouchi et al., 2005;Ashwood and Wakefield, 2006a;Jyonouchi et al.,
297 2011;Rose et al., 2018). Circulating antigens and bacterial metabolites could also directly influence
298 the brain if both the intestinal and blood-brain barriers are not sufficiently intact. This is one
299 proposed mechanism of how the microbiota-gut-brain axis may have pathological involvement in
300 neurological disorders (Cryan and Dinan, 2012). Interestingly, recent findings in post-mortem tissue
301 suggest that individuals with ASD have alterations in the blood-brain barrier and deficiencies in gene
302 expression of intestinal tight junction proteins (Figure 2) (Fiorentino et al., 2016). Several studies
303 have also indicated that individuals with ASD have dysbiotic alterations in gut flora and altered
304 bacterial metabolites (Figure 2) (Finegold et al., 2010;Williams et al., 2011;Gondalia et al.,
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305 2012;Williams et al., 2012;Kang et al., 2013;Tomova et al., 2015;Strati et al., 2017;Hughes et al.,
306 2018), including recent findings that children with ASD who exhibit GI symptoms have differences
307 in microbiota compared to children with ASD who have no GI dysfunction. Their microbiota also
308 differed from typically developing children with similar GI symptoms (Rose et al., 2018). These
309 studies suggest an ineffective immune response to bacteria in ASD, or production of inflammatory
310 mediators leading to preferential bacterial growth (Spees et al., 2013). It is unclear whether the
311 dysbiosis seen in ASD is driving the immune dysfunction and altered immune regulation, or is a
312 result of it and much more research is needed in this area.
313 It has been suggested that food allergy may play a role in GI dysfunction, and some parents of
314 children with ASD have seen behavioral improvements after implementing diets that eliminate
315 suspect antigens such as gluten and casein; however, the role of food allergies remains controversial.
316 Reports of IgE-mediated food allergies correlating with GI symptoms are inconclusive (Buie et al.,
317 2010), although, one group found a high incidence of non-IgE-mediated food allergy in younger
318 children with ASD (Jyonouchi et al., 2008). Celiac disease has also been reported to have an
319 association with ASD (Barcia et al., 2008;Ludvigsson et al., 2013). A recent Italian study looked at a
320 cohort of 382 preschoolers diagnosed with ASD, and found the prevalence of celiac disease among
321 the ASD cohort was significantly increased compared to the general pediatric population, with an
322 overall prevalence of 2.62% (Calderoni et al., 2016). This supports the earlier work by Barcia, et al.
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who found a 3.3% prevalence of celiac disease in ASD by exploring biopsied tissue (Barcia et al.,
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2008 ). As GI disturbances may exacerbate behavioral symptoms, better screening techniques that
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include identification of behaviors associated with GI distress may help to better elucidate the actual
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326 prevalence within this population.
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Additional research seeking to identify a genetic and molecular basis for the comorbidities plaguing
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individuals with ASD consistently found dysregulation of multiple innate signaling pathways by
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utilizing searches of curated gene pathways. Nine Kyoto Encyclopedia of Genes (KEGG) pathways
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were recently identified to overlap in ASD and other disease comorbidities common in ASD. For
example, three pathways involved in regulation of the immune response, the toll-like receptor (TLR),
nucleotide-binding and oligomerization domain (NOD) pathways, and chemokine signaling pathways
significantly overlapped with asthma and inflammatory bowel disease (Nazeen et al., 2016). Further
studies are needed to examine these pathways in ASD. However, it is important to note that not all of
these dysregulated pathways may exist in individuals with ASD (Campbell et al., 2013), but may be
dysregulated in those with immune comorbidities and help account for the wide heterogeneity and
337 conflicting results seen in some studies in ASD.
338 4.2 Autoantibodies in Individuals with ASD

339 In addition to antibodies targeting the GI epithelium, autoantibodies specific to self-proteins in the
340 brain, CNS and cellular components have been frequently reported in individuals with ASD (Figure
341 2 and Table 4). Autoantibodies are a common feature in autoimmunity, and their presence may be
342 predictive of the development of certain autoimmune disorders (Anaya et al., 2007;Lleo et al., 2010).
343 Presence of autoantibodies that react to components of the brain and CNS in individuals with ASD
344 have been identified since as early as 1988, when antibodies to neuron-axon filament proteins
345 (NAFP) were found in 10 out of 15 children with ASD (Singh et al., 1988). A year later, researchers
346 identified IgG and IgM antibodies that target cerebellar neurofilaments (Plioplys et al., 1989). Anti-
347 myelin basic protein (MBP) antibodies were identified in individuals with ASD in 1993 (Singh et al.,
348 1993) and later supported by additional studies (Singh 1998 and Connolly 2005). The anti-MBP
349 results have been replicated in additional studies, including a 2013 investigation that linked these
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350 autoantibodies to both severity of ASD as well as allergic manifestations (Mostafa and Al-Ayadhi,
351 2013). However, other studies have refuted these findings which underscores the wide variations of
352 immune phenotypes seen in ASD (Libbey et al., 2008).
353 More recent studies have found autoantibodies to the prefrontal cortex, caudate, putamen, cerebellum
354 and cingulate gyrus regions of the brain (Singer et al., 2006) and hypothalamus (Cabanlit et al., 2007)
355 in children with ASD. In 2009, researchers found that 21% of plasma samples from children with
356 ASD had intense immunoreactivity to Golgi neurons in primate cerebellum, with no reactivity
357 occurring in controls. These ASD autoantibodies reacted to a protein of a molecular weight of 52kDa
358 in human cerebellum (Wills et al., 2009). A follow-up study identified reactivity to interneurons in
359 other regions of the brain, including those in the superficial layers of the cortex. The target neurons
360 were identified as specifically GABAergic. GABAergic Golgi neurons and interneurons are
361 inhibitory, utilizing the neurotransmitter gamma-aminobutyric acid (GABA) to modulate nearby
362 excitatory synapses. It is unknown whether these antibodies are able to cross the blood-brain barrier
363 (Wills et al., 2011). However, if they are able to enter the brain and reach their target antigens, this
364 could potentially alter numbers or activity of inhibitory neurons, and contribute to the imbalance in
365 excitatory/inhibitory activity that has long been suggested to contribute to certain aspects of ASD
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366 (Rubenstein and Merzenich, 2003).
367
368
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86 children with ASD and 43 typically developing controls from the Autism Phenome Project, a
large multidisciplinary study conducted at the MIND Institute, were further assessed for these
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369 neuronal autoantibodies. Similar reactivity to cerebellar Golgi neurons and interneurons was found
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370 throughout the brain in some children with ASD; however, the results were not significantly different
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371 than controls, and in contrast to Wills 2009, some typically developing children also exhibited
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positive staining. Although these results did not support previous findings that these autoantibodies
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occur solely in ASD, this group did find a correlation between immunoreactivity and increased
scores on the Child Behavior Checklist (CBCL), indicating worsening behaviors with
immunoreactivity (Rossi et al., 2011). This finding that the autoantibodies are also present in
typically developing children suggests that in ASD, there may be some other pathological mechanism
that is allowing the autoantibodies to enter the typically “immune-privileged” brain, contributing to
ASD behaviors (Rossi et al., 2011). Using human protein extracts as antigenic targets the same
379 researchers found antibody reactivity to CNS proteins at two separate molecular weights (45 and 62
380 kDa) that correlated with worsening behaviors in children with ASD (Goines et al., 2011a).
381 Autoantibodies specific for a 45 kDa cerebellar protein were associated with a diagnosis of autism
382 disorder (Goines et al., 2011a) and cognitive impairment (Piras et al., 2014), while autoantibodies
383 directed towards the 62 kDa protein were associated with the broader diagnosis of ASD (Goines et
384 al., 2011a) and motor stereotypies (Piras et al., 2014). A Saudi Arabian cohort of children with ASD
385 also showed high levels of autoantibody reactivity to cerebellar neurons, the presence of which was
386 positively associated with ASD severity (Mostafa and Al-Ayadhi, 2012b). Increased serum
387 autoantibodies against human neuronal progenitor cell (NPC) proteins of 55kDA, 105kDa, 150kDa
388 and 210kDa molecular weights in ASD have also been identified, with the strongest reactivity noted
389 in neuronal progenitor cells expressing the mature neuronal marker Tuj1, as opposed to astrocytes
390 expressing Glial fibrillary acidic protein (GFAP) (Mazur-Kolecka et al., 2014). This group had
391 previously found that sera from ASD subjects suppressed differentiation and maturation of NPCs in
392 culture and provided a potential mechanism for aberrant neurodevelopment in ASD (Mazur-Kolecka
393 et al., 2007;Mazur-Kolecka et al., 2009;Mazur-Kolecka et al., 2014).
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394 Serum antibodies to ganglioside M1, the most abundant sialylated glycosphingolipid component of
395 neuronal membranes, were found to be significantly higher in children with ASD compared to
396 controls, with highest levels seen in the most severe cases of ASD (Mostafa and Al-Ayadhi, 2011).
397 Serum autoantibodies to gangliosides are frequently seen in autoimmune disorders associated with
398 neurological impairment, such as SLE and Guillain-Barré syndrome (Watanabe and Arimura,
399 2008;Mostafa et al., 2010b;Kusunoki and Kaida, 2011). Additional autoantibodies identified in
400 individuals with ASD include those reactive to cardiolipin, phosphoserine, and 𝛽2-glycoprotein 1
401 (Careaga et al., 2013), endothelial cells (Zhang et al., 2010;Bashir and Al-Ayadhi, 2015), myelin-
402 associated glycoprotein (Mostafa and Al-Ayadhi, 2012a;2013), double stranded DNA, nucleus and
403 nucleosomes (Al-Ayadhi and Mostafa, 2014;Mostafa et al., 2014) and mitochondrial DNA (Zhang et
404 al., 2010). Recently, folate receptor autoantibodies (FRA) have come to the forefront of autoantibody
405 studies in children with ASD. In 2013, Frye, et al. found FRAs to be prevalent in children with ASD
406 (75%), including blocking and binding FRAs, with 29% being positive for both FRAs (Frye et al.,
407 2013). This study additionally looked at supplementation of folinic acid, as FRA may be interfering
408 with folate transport across the blood-brain barrier, and found improvement in communication,
409 language, attention and stereotypic behaviors in treated children compared with non-supplemented
410 ASD controls (Frye et al., 2013). In support of these findings, a Belgium study found significantly
411 higher prevalence of blocking FRA in ASD compared to non-autistic individuals with developmental
412 delays (Ramaekers et al., 2013). Both studies also found a statistically significant increase in FRAs
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414
415
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among the parents of individuals with ASD, suggesting a relationship with familial autoimmunity.
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However, not all parents harbored these autoantibodies, and this suggests that in some instances there
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is postnatal acquisition of FRA (Frye et al., 2013;Ramaekers et al., 2013). 3-Chlorotyrosine, a marker
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416 of myeloperoxidase protein damage and inflammation, was significantly lower in those positive for
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417 blocking FRAs, suggesting that this group may have less inflammation than their counterparts
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positive for binding FRAs. Moreover, the presence of blocking FRAs in children with ASD was
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associated with less severe ASD symptoms compared to those who were negative for blocking FRA.
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(Frye et al., 2016). Further studies characterizing immune activation in the different FRA groups
could help clarify this relationship.
It is important to note that although the presence of autoantibodies are commonly found in
autoimmunity, they may not be specific to any single disorder and can be present to some degree in
424 healthy individuals, therefore they are not diagnostic without direct or indirect evidence (Rose and
425 Bona, 1993;Lacroix-Desmazes et al., 1998). It is currently unknown whether these autoantibodies
426 found in individuals with ASD play a causal role in the etiology of the disorder. The lack of
427 consistency in target antigens and wide heterogeneity of type and presence of these autoantibodies
428 suggest they may in fact be epiphenomenon in at least some cases of ASD due to general immune
429 dysregulation (Wills et al., 2009). Collateral damage can occur from unregulated or excessive
430 inflammatory responses, causing subsequent epitope spreading which leads to the development of
431 autoantibodies characteristically seen in autoimmunity (Vanderlugt and Miller, 1996).
432 4.3 Aberrant Innate Immune Responses

433 4.3.1 Neuroinflammation
434 One of the major advancements in ASD research in the last ten years is evidence that active
435 neuroinflammation is a significant component of ASD, including chronically activated microglia
436 (Figure 2). Findings of increased microglial and astroglial activation in the cerebellum and various
437 regions of the cortices, specifically increased HLA-DR and GFAP via immunostaining (Vargas et al.,
438 2005) has prompted additional research in this area. These early findings included increases in
439 proinflammatory cytokines in the CSF and within several regions of the brain such as macrophage
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440 chemoattractant protein (MCP) -1, a cytokine important for monocyte recruitment. Findings also
441 included marked increases in CD68+ perivascular macrophages and monocytes, suggesting the
442 possibility of monocyte infiltration, which is one of the markers considered when autoimmunity is
443 suspected in MS and EAE models (van der Valk and De Groot, 2000;Vogel et al., 2013).
444 Additionally, a significant loss of Purkinje neurons in the cerebellum was noted in ASD subjects
445 compared with controls, and anti-inflammatory cytokines were associated with degenerative Purkinje
446 cells and cerebellar astroglia, suggesting an attempt to modulate inflammation in the presence of
447 damaged tissue (Vargas et al., 2005).
448 Microglia were later characterized in post-mortem brain samples of ASD subjects, revealing
449 alterations indicative of an activated microglia phenotype including increased somal volume,
450 increased density, and amoeboid presentation in 9 of 13 ASD cases (Morgan et al., 2010). These
451 alterations were not correlated with age and researchers found no co-localization of Interleukin 1
452 receptor, type I (IL-1R1) with the monocyte/microglia marker ionized calcium binding adapter
453 molecule 1 (Iba-1). IL-1R1 is upregulated rapidly during acute inflammation, therefore this lack of
454 increased co-localization suggests this is not an acute inflammatory event, rather a long-standing
455 alteration in the brains of ASD subjects (Morgan et al., 2010). This group later found increases in
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456 spatial clustering of microglia to neurons in these brain samples, suggesting neuron-directed
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recruitment of microglia in ASD subjects (Morgan et al., 2012). Considered the resident innate
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immune cells of the brain, microglia colonize the brain during the early embryonic period and are
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essential to neurodevelopment, including involvement in angiogenesis (Fantin et al., 2010;Rymo et
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460 al., 2011), regulation of astrocytic differentiation from neuronal precursor cells (Nakanishi et al.,
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461 2007), synaptic pruning (Paolicelli et al., 2011) and clearance of newborn neuronal precursors
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462 destined for apoptosis (Sierra et al., 2010). When activated to an inflammatory phenotype, microglia
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secrete inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), IL-1β and IL-6 and
produce nitric oxide synthase (iNOS) [Reviewed in: (Smith et al., 2012)]. Although some microglia
activation is required for productive neurodevelopment (Cunningham et al., 2013), chronic activation
is associated with disease states (Smith et al., 2012). Furthermore, excessive activation can lead to
cell death and abnormal or reduced connectivity (Rodriguez and Kern, 2011).
To gain a more specific picture of the pro-inflammatory cytokine milieu in the brains of ASD
469 subjects, Li et al. 2009 further investigated cytokines associated with inflammatory responses in post-
470 mortem tissue and found significantly increased pro-inflammatory cytokines including interferon
471 gamma (IFNγ) associated with NK cells and T helper (TH)-1 activation (Li et al., 2009). In support of
472 altered immune regulation and function in the brains of ASD subjects, recent transcriptome analyses
473 of the superior temporal gyrus and cerebral cortex of postmortem samples indicated upregulation of
474 genes involved in immunity and inflammation, including markers of activated microglia and
475 pathways of innate immunity (Garbett et al., 2008;Voineagu et al., 2011) More recent transcriptome
476 analyses of multiple cortical areas of ASD brains support and add to these findings. Large scale RNA
477 sequencing revealed that the dysregulated co-expression module found in the brains of ASD subjects
478 by Voigneau et al. was enriched for activation specific to the microglia, and showed increased
479 expression of ‘immune-response’ genes (Gupta et al., 2014). Correlating well with these findings,
480 methylation studies have identified that immune-response genes in frontal cortex of individuals with
481 ASD have hypomethylated CpG sites, causing increased transcription of inflammatory genes such as
482 TNF-α, integrin and complement genes, and genes that encode transcription factors involved in
483 microglial development (Nardone et al., 2014).
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484 To allow for in-vivo study of individuals with ASD, Suzuki and colleagues utilized positron emission
485 tomography (PET) analysis to assess binding values of the [11C](R)-PK11195 radiotracer that binds
486 selectively to the mitochondrial 18 kDa translocator protein (TSPO), specifically targeting activated
487 microglia. They found significantly increased binding values in several regions of the brain compared
488 to controls, suggesting increased microglia activation in all regions analyzed compared to controls,
489 including the cerebellum, several regions of the cortex, and the corpus callosum (Suzuki et al., 2013).
490 These in-vivo findings support studies of increased microglia activation in post-mortem tissue;
491 however, it is important to note that 1) the sample sizes were small and only included individuals
492 with high-functioning ASD, 2) significant non-specific binding can occur with the [11C](R)-PK11195
493 radiotracer, and 3) researchers were unable to normalize binding values due to lack of a microglia-
494 free reference region (Suzuki et al., 2013). These findings warrant additional in-vivo studies with
495 larger sample sizes/additional ASD phenotypes, and ideally a more-specifically binding radiotracer.
496 4.3.2 Peripheral Innate Immune Dysfunction

497 Aberrant innate immune responses are not restricted to the brain and CNS in individuals with ASD,
498 alterations in circulating monocytes, dendritic cells and NK cells have also been identified (Figure
499 2). Early studies found increased number of monocytes in the peripheral blood of children with ASD
500 (Denney et al., 1996;Sweeten et al., 2003b), and elevated production of IFNγ, IL-1RA, and a trend
for elevated IL-6 and TNF-α in whole blood cultures, suggesting increased activation of monocytes
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502 in individuals with ASD (Croonenberghs et al., 2002a). In support of these finding, a recent study
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503 found increased CD95, a marker of activation on monocytes in the peripheral blood of children with
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504 ASD (Ashwood et al., 2011a). Sweeten and colleagues also found elevated plasma neopterin, a
505 pyrazinopyrimidine compound produced by monocytes and macrophages in response to IFNγ
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stimulation, indicating increased cellular immune activation (Murr et al., 2002;Sweeten et al.,
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2003b). Additionally, after TLR2 and TLR4 stimulation, upregulation of inflammatory cytokines and
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the HLA-DR activation marker was seen in monocytes from children with ASD versus typically
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509 developing children (Enstrom et al., 2010a). Dendritic cell numbers were also increased in children
510 with ASD and associated with bigger amygdala size and more aberrant behaviors (Breece et al.,
511 2013).
512 An early study investigating induced responses of immune cells in children with ASD found
513 increased production of the innate cytokines: TNF-α, IL-1β and IL-6 after stimulation of peripheral
514 blood mononuclear cells (PBMC) with the TLR-4 ligand lipopolysaccharide (LPS), from children
515 with ASD when compared to typically developing children (Jyonouchi et al., 2001). To improve
516 understanding of differential innate responses to varied TLR stimuli in ASD, investigators measured
517 innate responses to several environmentally relevant pathogen-associated molecular patterns
518 (PAMPs). The outcome of this study demonstrated elevated cytokine production after exposure to
519 several innate immune ligands. Stimulation of isolated monocytes with TLR2 ligand lipoteichoic acid
520 (LTA) produced a significant increase in production of TNF-α, IL-1β and IL-6 in children with ASD
521 versus typically developing controls, supporting earlier works. TLR4 stimulation with LPS also
522 produced increased IL-1β. Moreover, increased production of IL-1β after LPS stimulation was found
523 to be associated with worsening behaviors (Enstrom et al., 2010b). Recently, Nadeem et al. identified
524 increases in the IL-17RA receptor on circulating monocytes in children with ASD. IL-17RA is the
525 receptor for IL-17A, a cytokine associated with autoimmunity and implicated in rodent models of
526 ASD (Choi et al., 2016). Increased expression of the nuclear transcription factor NFkB and inducible
527 nitric oxide synthase (iNOS) were also noted in ASD groups. Cells treated with IL-17 increased
528 expression of iNOS/NFkB and blockade of IL-17 reversed this inflammatory profile (Nadeem et al.,
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529 2018). These data may suggest a link between adaptive arm of the immune system and innate
530 immune dysfunction in people with ASD.
531 Significant increases in cytokines associated with innate inflammation have also been found in
532 phytohemagglutinin (PHA) stimulated PBMC of children with ASD, including TNF-α and GM-CSF
533 (Ashwood et al., 2011b). Excessive production of pro-inflammatory cytokines initiated by the innate
534 immune system could have downstream consequences including over-activation of the adaptive arm,
535 leading to autoimmune sequelae. Abnormal innate cytokines have also been identified in the plasma
536 and sera of individuals with ASD. Significant increases in plasma levels of IL-1β, IL-6, and TNF-α
537 suggest increased activation of the innate arm (Emanuele et al., 2010;Ashwood et al., 2011b;Suzuki
538 et al., 2011;Ricci et al., 2013) and are consistent with the dynamic responses seen previously in
539 stimulated monocytes (Enstrom et al., 2010b;Ashwood et al., 2011c). Other innate-associated
540 cytokines reported to be elevated in the plasma or sera of individuals with ASD when compared to
541 typically developing controls include IL-12p40 and the chemokines IL-8, MCP-1, regulated on
542 activation, normal T cell expressed and secreted (RANTES), eotaxin and C-X-C motif chemokine 5
543 (CXCL5) (Ashwood et al., 2011b;Suzuki et al., 2011;Mostafa and Al-Ayadhi, 2015). While there
544 have been a few contradictory reports regarded plasma/sera cytokine concentrations individuals with
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545 ASD, a recent meta-analysis of plasma cytokines showed significant evidence of abnormal
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548
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cytokine/chemokine profiles in individuals with ASD versus healthy controls, including elevated IL-
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1β, IL-6, IL-8, IFN-γ and MCP-1, and reduced concentrations of the anti-inflammatory cytokine
transforming growth factor beta 1 (TGFβ1) (Masi et al., 2015). Further characterization of ASD
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549 subjects found that circulating plasma levels of pro-inflammatory cytokines associated with increased
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550 innate immune activation correlated with worsening behaviors, which suggests that ongoing
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551 inflammation likely contributes to the severity of behaviors (Ashwood et al., 2011b). Leukocyte
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adhesion molecules have also been investigated in children with ASD, and were found to be reduced,
indicating dysfunctional immune-endothelial cell interactions that could have implications for the
migration of innate immune cells into the CNS (Onore et al., 2012).
NK cells are important early responders of the innate immune system. They specifically target virally
infected cells and play important roles in both tumor surveillance and protection of the fetus during
pregnancy. As early responders, they can initiate a cascade of immune responses and if dysfunctional
558 these important signals may be missing or altered (Mandal and Viswanathan, 2015). A significant
559 increase of total numbers of NK cells, identified as CD56+CD3-, was observed in children with
560 autism with both high and low IQ (Ashwood et al., 2011a). Cytokines produced by NK cells
561 expressing high levels of CD56 can significantly influence the cytokine milieu. Upregulation of
562 mRNA responsible for expression of receptors including killer-cell immunoglobulin-like receptors
563 [KIRs] and increased cytokine, perforin and granzyme B production was observed at resting levels in
564 NK cells from 2-5 year old children with ASD (Enstrom et al., 2009b). The cytolytic function of NK
565 cells is important for immune regulation, as they can remove persistently activated immune cells
566 (Cook et al., 2014). Interestingly, when stimulated, significantly decreased cytotoxicity and lower
567 production of effector molecules (granzyme, perforin and IFNγ) were seen in children with ASD
568 compared to controls (Enstrom et al., 2009b). Decreased cytolytic activity was seen previously in a
569 large subgroup of children with ASD (Vojdani et al., 2008). This pattern suggested that NK cell
570 activation may be “maxed-out” in vivo, and the cells may be unable to respond to further stimuli.
571 Similar patterns of increased CD56+ NK cells but impaired cytolytic activity have been seen in the
572 peripheral blood of patients with autoimmune disorders such as MS, T1DM, SLE and RA (Fogel et
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573 al., 2013), again adding evidence of an autoimmune component/lack of immune regulation in
574 individuals with ASD.
575 4.4 Aberrant Adaptive Immune Responses

576 4.4.1 T Cells
577 Over the last ten years, researchers have found significant abnormalities of the adaptive arm of the
578 immune system in people with ASD, including altered numbers of lymphocytes, dysregulation of T
579 and B cell activation, and altered adaptive cytokine production (Figure 2). Increased total numbers of
580 T cells and skewed ratios of CD4 to CD8 lymphocytes have been associated with decreased
581 executive function in people with ASD (Han et al., 2011). Several studies have also shown altered
582 cytokine production in T cells. Molloy et al. found a shift to a TH2 phenotype with significant
583 increases in IL-4, IL-5 and IL-13 after stimulation in vitro (Molloy et al., 2006b). Altered surface
584 markers of T cell activation have also been seen. Specifically, the T cell activation markers HLA-DR
585 and CD26 were found to be increased in children with ASD (Ashwood et al., 2011a). CD5, a
586 transmembrane protein associated with T cells and found to be elevated in autoimmunity (Sigal,
587 2012), was recently found to be significantly elevated in plasma of ASD subjects, and is associated
588 with worsening severity of ASD (Halepoto et al., 2017). In response to stimulation, T cells from
589 children with ASD also showed increased CD134 and increased cellular proliferation associated with
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worsening behaviors (Ashwood et al., 2011b). CD134 (also known as OX40) is a co-stimulatory
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molecule expressed on activated T cells, including memory T cell subsets (Webb et al., 2016) that is
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required for optimal activation of naïve T cells and is important in survival and maintenance of
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593 memory T cells.
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Significant alterations in cytokines associated with the adaptive arm have been found in children with
ASD versus controls, including IL-5, IL-13, IL-17 (Suzuki et al., 2011), IL-23 and IL-12 (Ricci et al.,
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596 2013), IL-21 and IL-22 (Ahmad et al., 2017a). Two recent studies found altered cytokine profiles in
597 neonatal blood spots, suggesting early immune dysregulation. Increased IL-4 at birth was associated
598 with increasing severity of ASD, and increased IL-1β with milder versions of ASD (Krakowiak et al.,
599 2017). Zerbo et al. observed increased MCP-1 and decreased RANTES at birth in children with ASD
600 (Zerbo et al., 2014). It is noteworthy to mention that various reports of T cell skewing in ASD does
601 not necessarily implicate a specific polarization associated with the disorder, rather it supports the
602 suggestion that a lack of regulation may be at play. A recent study clustered subjects into immune
603 endophenotypes based on T cell polarization after stimulation with PHA, and found that both TH1
604 and TH2 responses were associated with worsening behaviors and increased severity of core ASD
605 symptoms (Careaga et al., 2015). Transcription factors associated with inflammatory T cell
606 activation, and different T cell subsets, namely T-box transcription factor (Tbet), GATA binding
607 protein 3 (GATA3) and retinoid-acid receptor-related orphan receptor gamma t (RORyT) are all
608 increased in children with ASD (Ahmad et al., 2017b). These studies support the notion of distinct
609 clusters of ASD phenotypes characterized by immune dysfunction (Sacco et al., 2010;Sacco et al.,
610 2012).
611 Aberrant T cell responses or decreased removal of activated T cells can lead to autoimmune
612 pathology (Joller et al., 2012). CD95 is the first apoptosis signal (Fas) receptor, which initiates
613 apoptosis of activated T cells when they are repeatedly exposed to antigen. It has critical importance
614 in tolerance and regulation, and alterations in Fas signaling may play a role in the development of
615 autoimmunity (Siegel and Fleisher 1999). Reduced CD95 expression on T cells from ASD subjects
616 compared to controls is suggestive of decreased apoptosis of potentially overactive T cells in ASD
617 (Engstrom et al., 2003).
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618 4.4.2 Regulatory T cells

619 One of the most important immune components in the prevention of autoimmunity is regulation, and
620 regulatory T cells (Tregs) play a key role in immune regulation and homeostasis (Sakaguchi, 2004).
621 Humans that carry mutations in the transcription factor forkhead box P3 (FoxP3) or have depletion in
622 Tregs develop severe autoimmunity (Sakaguchi et al., 1995;Miyara et al., 2005;Toubi et al.,
623 2005;Long and Buckner, 2011;Fujio et al., 2012). Tregs have been found to be critical for preventing
624 autoimmunity in murine models (Sakaguchi et al., 1995) and a deficiency of Tregs may play a role in
625 the development of autoimmune disorders, including RA (Toubi et al., 2005) and SLE (Miyara et al.,
626 2005). Autoimmune pathology can occur when immune regulation breaks down, disrupting tolerance
627 and homeostasis, and leading to an aberrant attack on self (Lourenço and La Cava, 2011). Typically
628 in autoimmunity, a breakdown in tolerance will lead to the production of destructive autoantibodies
629 by plasma cells and self-reactive T cells with a deficit in number or activity of Tregs (Sakaguchi,
630 2004). Notably, several studies have found that Tregs or their regulatory effector molecules are
631 decreased in some individuals with ASD (Figure 2) (Okada et al., 2007;Ashwood et al.,
632 2008;Mostafa et al., 2010a). For example, plasma TGFβ1 was significantly reduced in adult males
633 with Asperger’s syndrome (Okada et al., 2007) and in children with ASD (Ashwood et al., 2008).
Reduced TGFβ1 was associated with increased ASD severity and lower adaptive and cognitive
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635 behaviors (Ashwood et al., 2008). Furthermore, microRNAs (miRNAs) involved in controlling
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636 TGFβ1 signaling pathways show differential expression in the cortex and serum of individuals with
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637 ASD (Mundalil Vasu et al., 2014;Ander et al., 2015;Huang et al., 2015). Additionally, circulating
638 CD4+CD25high Tregs were found to be significantly decreased in children with ASD, with reduced
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frequency correlating with severity of the disorder (Mostafa et al., 2010a). Several studies have also
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shown decreased IL-10 production after stimulation of CD4+ T cells (Jyonouchi et al.,
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2001;Jyonouchi et al., 2005;Ashwood and Wakefield, 2006a;Jyonouchi et al., 2014).
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4.4.3 B cells
Antibody production of high specificity to various antigens is the primary role of B cells, in order to
neutralize and help eliminate pathogens. Despite the growing number of studies identifying
autoantibodies in subjects with ASD, the B cells responsible for antibody production have been
poorly studied. Irregularities in B cell populations and antibody production have been identified in a
small number of ASD studies, although with conflicting results. A 2011 study found increased
648 numbers of total (CD20+) and activated (CD38+) B cells in children with ASD compared to age-
649 matched controls. No differences were seen in naïve (CD5+) B cells, thus the increase in total cells
650 was likely due to increased activated cells, suggesting increased immune activation overall (Ashwood
651 et al., 2011a). Higher numbers of CD19/CD23 B lymphocytes were also found in children age 3-6
652 recently diagnosed with regressive autism, supporting the previous findings (Wasilewska et al.,
653 2012). However, Heuer et al. found no differences in total numbers of B cells, and B cell responses to
654 stimulation were not different among ASD subjects compared to controls (Heuer et al., 2012).
655 Differences in study design and markers used (CD20 and CD19, respectively) could account for the
656 contradictory results. Neither marker is comprehensive for individual B cell subsets as their
657 expression is decreased as B cells mature and differentiate into antibody-secreting plasma cells
658 (Tedder, 2009). CD38 expression increases significantly upon maturation, therefore this marker may
659 be a better indicator of the population of effector cells that may be responsible the production of
660 specific autoantibodies. Additional research is needed to further characterize these cells, including
661 identifying populations of positive regulators and B-regulatory cells (Bregs), as these cells secrete IL-
15
662 10, have recently been found to play a role in the induction of Tregs (Fujio et al., 2013), and play an
663 important role in the acquisition of tolerance during pregnancy (Rolle et al., 2013).
664 In addition to significant levels of autoantibodies found in individuals with ASD, atypical antibody
665 production has been frequently seen in ASD serum and plasma with correlations to behaviors.
666 Results vary and are often contradictory – these inconsistencies may be due to small sample sizes and
667 improper controls such as “population standard” versus age-matched controls residing in the same
668 locale, and lack of adjusting for seasonality. Comparing immunoglobulin levels across a broad age
669 range can produce inconsistencies, thus it is critical to have age-matched controls. For example, an
670 early report found decreased circulating IgA associated with HLA-DR antigens in a subset of ASD
671 subjects (Warren 1997), and a 2012 study supported these findings (Wasilewska et al., 2012);
672 however, other studies showed no change in IgA (Heuer 2008). Ages varied widely in the Warren
673 study (from ages 5-31) and may account for discrepancy because IgA does not reach adult levels
674 until around age 10 (Aksu et al., 2006) whereas the later studies were age-matched. Decreased IgA in
675 children with regressive ASD did not fulfill the criteria for either partial or full IgA deficiency in the
676 study by Wasilewska and colleagues, and likely reflects immune dysfunction in a subset of patients
677 (Wasilewska et al., 2012). Heuer et al. found that decreased plasma IgG/IgM negatively correlated
678 with worsening behaviors as assessed using the Autism Behaviors Checklist (ABC) (Heuer et al.,
679 2008). Researchers also found a significant increase in IgG4 in ASD subjects, with a trending
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increase in IgG2 subtype (Croonenberghs et al., 2002b;Enstrom et al., 2009a). IgG4 is a blocking
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antibody, produced under conditions of chronic antigen exposure and class switch to IgG4 is
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dependent on TH2 cytokines (IL-4/IL-13) (Aalberse et al., 2009). This is consistent with the dynamic
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683 T cell responses found by later by Ashwood et al. (Ashwood et al., 2011c). These correlations
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684 support an association with immune dysfunction and potentially a lack of immune regulation in
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685 individuals with ASD.
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Improvement of symptoms with the use of immune-modulating drugs and supplements
P
Several clinical trials have shown the efficacy of immunosuppressive drugs for improving behaviors
in individuals with ASD. The first study to show this relationship used corticosteroid treatment in a
6-year-old boy with language regression at 22 months who received a diagnosis of PDD at age 3-1/2.
After several weeks of this treatment, the boy experienced significant gains in expressive language
691 and responsiveness to communication to nearly age-appropriate levels, and reduction in stereotypical
692 echolalia (Stefanatos et al., 1995). Since then, improvements have been seen in language ability,
693 behaviors and motor development in several case studies and clinical trials using corticosteroids and
694 immunosuppressive drugs (Mott, 1996;Chez et al., 1998;Shenoy et al., 2000;Mordekar et al., 2009)
695 including a recent study that showed improvement in language-specific electrophysiological brain
696 function after treatment with corticosteroids (Duffy et al., 2014). The effectiveness of the anti-
697 psychotic medication risperidone in improving stereotyped behaviors and social withdrawal in
698 individuals with ASD was increased with the addition of celecoxib, a cyclooxygenase-2 (COX-2)
699 selective nonsteroidal anti-inflammatory drug (Asadabadi et al., 2013). Human cord blood
700 mononuclear cell transplantation, alone and in combination with umbilical mesenchymal stem cell
701 transplantation significantly improved behaviors in children with ASD compared to controls. These
702 transplanted cell types are known to have profound immune-regulatory capabilities, suggesting that a
703 possible mechanism of improvements seen may be immune-modulation (Lv et al., 2013). These trials
704 and cases studies, although small and specific to select groups of ASD subjects, suggest that in some
705 children with ASD, immune abnormalities may be driving certain behaviors.
16
706 Nutritional or supplemental approaches may be helpful in modulating immune function in people
707 with ASD. Several studies have found children with ASD to be deficient in serum levels of vitamin D
708 (25‐hydroxycholecalciferol), and serum levels were found to be negatively associated with language
709 and behavioral scores on the ABC and the Childhood Autism Rating Scale (CARS) (Desoky et al.,
710 2017;Saad et al., 2018), (Feng et al., 2017). Serum vitamin D levels also negatively correlated with
711 the presence of anti-myelin-associated glycoprotein autoantibodies (Mostafa and Al-Ayadhi, 2012a).
712 This fat-soluble vitamin has important immunomodulatory and neuroprotective functions (Aranow,
713 2011;Wrzosek et al., 2013), and deficiency may be contributing to immune and behavioral
714 abnormalities in people with ASD. Daily supplementation with Vitamin D, not to exceed
715 5000IU/day, was found to significantly improve behavioral outcomes and lowered elevation of CD5
716 expression in children with ASD, supporting a role for Vitamin D in modulating the immune system
717 (Desoky et al., 2017;Feng et al., 2017;Saad et al., 2018). As previously discussed, children with ASD
718 have altered T cell profiles, perhaps due to altered transcriptional activity (Ahmad et al., 2017b).
719 Similar T cell alterations have been seen in the inbred BTBR mouse model of ASD, and a recent
720 study showed modulation of this transcriptional activity through the administration of the antioxidant
721 resveratrol, a nutritional component found in various fruits, legumes and grape juice. Resveratrol
722 increased mRNA expression of FoxP3 in spleen and brain tissues, and increased the number of
723
724
725
n al
FoxP3+ T regulatory cells in the periphery of BTBR and B6 mice. Resveratrol also decreased
expression of transcription factors associated with inflammatory T cells, including TH17 cells.
o
Additionally, the nutritional compound decreased ASD associated repetitive behaviors in BTBR mice
si
726 (Bakheet et al., 2017). These studies, offer support that immune dysfunction is driving at least some
i
727 of the pathological outcomes in subsets of people with ASD. As our understanding of how immune
v
728 dysregulation is contributing to the pathogenesis of ASD grows, more treatments can be targeted
729
730
731
732
6
r o
specifically to these mechanisms.
P
Outstanding questions & conclusion
The evidence that immune dysfunction likely plays a role in the etiology/pathophysiology of ASD is
733 becoming substantial. Familial autoimmunity is a common risk factor, and maternal autoantibodies
734 and inflammation during gestation significantly increase the risk of having a child with ASD.
735 Furthermore, individuals with ASD have significant immune dysfunction and inflammation. They
736 also suffer from immune-mediated co-morbidities much more often than the typically developing
737 population, including GI dysfunction and dysbiosis. The presence of autoantibodies in individuals
738 with ASD is increased, and evidence of neuroinflammation has been substantiated both in vivo and in
739 post-mortem brain tissue. Although the plethora of evidence identifying a connection between
740 autoimmunity, immune dysfunction and ASD (summarized in Figure 3) is tantalizing, it still leaves
741 many mechanistic questions regarding the impact of immune system dysfunction on the development
742 of ASD.
743 The most outstanding question remaining from these studies is whether the immune dysfunction is
744 causal or rather sequelae of the larger disorder. The origin of the immune dysfunction seen in many
745 individuals with ASD and the role it plays in the aberrant behaviors is still unknown, although many
746 of these studies discussed throughout this review support an association of worsening behaviors
747 associated with altered immune function. Gestational influences, including maternal immune
748 activation and the presence of maternal autoantibodies may be contributing to altered early
17
749 neurodevelopment and immune dysfunction in offspring, and these are supported by preclinical
750 animal models of both maternal immune activation and passive transfer of autoantibodies.
751 Interactions between the different immune cells leading to inflammation and altered cytokine
752 production in people with ASD may be directly contributing to abnormal brain development and
753 signaling, and the ever expanding knowledge of neuro-immune cross-talk may eventually elucidate
754 some of the mechanisms involved in the pathogenesis of ASD.
755 To date, categorizing ASD and immune dysfunction has been a difficult task due to the heterogeneity
756 of the disorder and the changing diagnostic criteria; however, the recent focus on clustering
757 phenotypes may provide a clearer picture to help elucidate the different factors involved in the
758 etiologies of these complex disorders. The immune dysfunction driving the development of
759 autoantibodies and overall immune abnormalities in people with ASD remains unknown, however,
760 recent insights into dysbiosis causing aberrant immune system education could be a plausible
761 mechanism as to the origin of immune dysfunction. Prenatal immune influences could be driving
762 direct and/or epigenetic changes in gene expression responsible for altered neurodevelopment. As
763 future studies improve our understanding of these complex and interconnected systems, it will allow
764 for development of new therapies that target immune dysfunction in ASD. Future research could
765 focus on interventions that improve immune parameters to help identify mechanisms involved in
766 development and exacerbation of ASD symptoms. As our understanding of the involvement of the
767
768 pathological mechanisms involved.
o n l
immune system in ASD grows, it can shape future hypotheses and research to better identify the
a
si
769 7 Conflict of Interest
770
771
o vi
The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
r
772
773
774
775
8
P
Author Contributions
HH wrote the first draft of the manuscript; EMK, DR and PA wrote sections of the manuscript. All
authors contributed to manuscript revision, read and approved the submitted version.
9 Funding
776 This material is based upon work supported by the National Science Foundation Graduate Research
777 Fellowship under Grant No. 1650042; Autism Speaks Foundation (Grant #7567), NIH grants
778 #R21HD086669, R21ES025560, R21MH116383, RO1HD090214, R01ES015359, P30ES23513,
779 U54HD079125, and P01ES011269; National Science Foundation, Jane Botsford Johnson
780 Foundation, Jonty Foundation and NARSAD Foundation.
781 10 Acknowledgments
782 We would like to thank the participants and their families for their participation in immunological
783 studies and the staff of the University of California Davis M.I.N.D. Institute for their technical
784 support. We would also like to thank Judy Hughes for her edits on comments on this manuscript.
785
786 11 Figure legends
18
787 Figure 1: Maternal immune influences during gestation increase risk of ASD. Infection and immune-
788 mediated/autoimmune disorders in the mother are known risk factors that increase the chances of a
789 child developing ASD. These inflammatory factors as well as altered maternal microbiota may be
790 contributing to increased inflammatory cytokines and/or autoantibodies that react to fetal brain tissue.
791 These factors alter the immune profile and neurodevelopment of the child and are linked to
792 behavioral abnormalities seen in ASD including repetitive behaviors, stereotypies, anxiety, and
793 impaired social behaviors.
794
795 Figure 2: Aberrant Immune Findings in Individuals with ASD. Evidence of immune dysfunction in
796 ASD has grown substantially in recent years. Individuals with ASD commonly have immune-
797 mediated comorbidities such as allergies and gastrointestinal (GI) dysfunction that may be
798 contributing to the aberrant behaviors seen in ASD. Although research in this area is occasionally
799 contradictory, the vast majority of immune studies in individuals with ASD have shown immune
800 dysfunction and dysregulation. Several studies have found elevations in inflammatory cells and
801 cytokines, both in the peripheral as well as within post-mortem brain tissue. A variety of
l
802 autoantibodies targeting various tissues and cellular components throughout the body have been
803
804
sio n a
identified in subsets of subjects with ASD. Individuals with ASD also have fewer regulatory T cells.
805
806
807
o vi
Figure 3: Summary of Immune Evidence in ASD – is Immune Dysregulation Causing or
Contributing to these Disorders? Immune findings in individuals with ASD have grown from a few
r
scant early studies to a plethora of extensive and varied research showing immune dysfunction that
P
808 contributes to worsening behaviors. Familial autoimmunity is a common finding within families
809 affected by ASD. In addition, individuals with ASD have significant immune dysregulation that
810 contribute to altered behaviors. These individuals also suffer more so than the general population
811 from immune-mediated comorbidities such as allergies, asthma and gastrointestinal (GI)
812 disturbances. Mechanistically, studies have shown that the gestational immune environment must be
813 delicately balanced, and without such balance neurodevelopment can be altered. Whether these
814 immune characteristics are causal or just sequelae of the overarching disorders remain to be
815 determined; however, the evidence is building that the dysregulated immune response may be
816 pathologically contributing to ASD.
817
818
819
820
821
822
823
19
824 Table 1| Studies identifying association of familial autoimmunity and ASD
Subject Details Methods Summarized Findings References

61 ASD Self-reported questionnaire: known AI 46% ASD families had 2+ members with AI (Comi et al., 1999)
l
46 TD within family ↑ ASD odds ratio (1.9 to 5.5) as number of family members with AI ↑ from 1-3
a
↑ T1DM, RA, hypothyroid and SLE in ASD mothers and 1st degree relatives
101 ASD
101 AI
101 HC
i
Self-reported questionnaire: which 1st &
2nd degree relatives have AI
sio n ↑ frequency of AI in ASD families compared to AI and TD families

↑ AI including hypothyroid/Hashimoto's thyroiditis and RA in ASD parents
(Sweeten et al., 2003a)
v
79 ASD Self-reported questionnaire: ASD with No significant relationship of AI in ASD vs. DD (Micali et al., 2004)
o
61 DD familial AI and psychiatric history 31.5% of ASD fathers vs 18.2% control had AI
r
No difference found in mothers.
P
153 ASD Telephone interview: AI in 1st and 2nd ASD with regression ↑ in families with 1st or 2nd degree AI relatives (Molloy et al., 2006a)
155 regressive ASD degree relatives. ↑ risk with familial AI thyroid diagnoses, especially maternal family members
111 ASD Registry based: Danish National Hospital ↑ risk of ASD with maternal UC and paternal T1DM (Mouridsen et al., 2007)
330 TD Registry Mothers with AI more likely to have child with ID (IQ <50)
3325 ASD (1089 Registry based: All children born in ↑ risk of ASD with maternal RA and celiac disease (Atladottir et al., 2009)
"infantile autism") Denmark 1993-2004 ↑ risk of infantile autism associated with family history of T1DM, both parents.
1227 ASD, Registry based: Three Swedish registries ↑ risk of ASD with AI in both parents (Keil et al., 2010)
30,675 TD ↑ risk of ASD with maternal T1DM, ITP, myasthenia gravis and rheumatic fever
967 ASD Nested case–control design: prospectively ↑ risk of ASD with maternal TPO-Ab presence during pregnancy (Brown et al., 2015)
967 TD drawn maternal sera samples with registry-
based ASD diagnoses from FiPS-A
11 studies Systematic review and meta-analysis ↑ risk of ASD with family history of all AI (Wu et al., 2015)
↑ risk of ASD with familial hypothyroidism, RA, and psoriasis
10 studies Systematic review and meta-analysis ↑ risk of ASD with maternal AI developed during pregnancy (Chen et al., 2016)
↑ risk of ASD with maternal thyroid disease
206 ASD Medical chart review of ASD diagnosis and ↑ risk of regressive ASD with familial AI (Scott et al., 2017)
33 regressive ASD familial AI association Regressive ASD associated with familial T1DM and autoimmune thyroiditis
ASD: autism spectrum disorders; TD: typically developing; AI: autoimmunity; T1DM: Type 1 diabetes mellitus; RA: rheumatoid arthritis; C: SLE: systemic lupus erythematosus; healthy control; BAP: broad
autism phenotype; IBD: inflammatory bowel disease; UC: ulcerative colitis; ID: intellectual disability; ITP: idiopathic thrombocytopenic purpura; FiPS-A: Finnish Prenatal Study of Autism; TPO-Ab: thyroid
peroxidase antibody
825
826 Table 2 | Studies identifying presence of anti-brain autoantibodies in mothers of children with ASD
Mother with 2 IHC of sera binding to rodent brain. Pilot study - maternal sera had reactivity to rodent Purkinje cells in cerebellum and large (Dalton et al., 2003)
l
ASD children brain stem neurons.
11 ASD mothers
10 TD mothers
Serum reactivity to prenatal, postnatal,
and adult rat brain proteins by
immunoblotting
sio n a
↑ reactivity to prenatal rat brain in multiple patterns of low kDa weight, and one
significantly higher at 250 kDa
No reactivity to postnatal or adult rat brain
(Zimmerman et al.,
2007)
r o
100 TD mothers
v
100 ASD mothers
i Serum reactivity to human and rodent

fetal and adult brain tissues, GFAP, and
MBP by immunoblotting
↑ reactivity at 36 kDa in both human fetal and rodent embryonic brain tissue.
↑ reactivity at 61 kD in human fetal brain tissue.
↑ reactivity at 36 and 39 kDa against human fetal brain in mothers whose children had
(Singer et al., 2008)
P
regressive ASD.
61 ASD mothers Plasma reactivity to human fetal ↑reactivity to 73kDa and 37kDa to human fetal brain correlated with regressive ASD (Braunschweig et
62 TD mothers and adult brain proteins by Reactivity to 37 kDa was higher in ASD mothers compared with TD and DD mothers. al., 2008)
40 DD mothers immunoblotting No reactivity with TD plasma to either tissue type.
84 ASD mothers Mid-pregnancy plasma reactivity to fetal ↑reactivity at 39 kDa in ASD compared to DD and TD (Croen et al., 2008)
49 DD mothers brain protein by immunoblotting Reactivity at both 39 kDa and 73 kDa seen only in early-onset ASD
160 TD mothers
202 ASD mothers PCR for MET rs1858830 allele genotyping. Presence of C allele associated with reactivity at 37 and 73-kDa to fetal brain proteins. (Heuer et al., 2011)
163 TD mothers Measured MET protein and cytokines by Presence of C allele associated with ↓ MET protein expression and ↓ IL-10
Luminex from stimulated maternal
PBMCs. Previous study results used for
the associations to presence of auto-Abs
277 ASD (70 BAP) Maternal plasma reactivity to Rhesus ↑ reactivity to many including proteins with MW of 42, 49, 60, 80, and 100 kDa in plasma (Goines et al.,
189 age-matched macaque fetal brain protein medleys by from ASD mothers 2011a)
TD (2-5 years) and immunoblotting, child plasma reactivity No correlation with reactivity found in children
their mothers to Rhesus macaque cerebellum protein Child results listed in Table 4.
medley.
204 ASD mothers Maternal plasma reactivity to Rhesus ↑ paired reactivity at 37 and 73 kDa combined in ASD, not seen in TD (Braunschweig et
71 BAP mothers macaque brain at 3 gestational ages by ↑ paired reactivity at 39 and 73 kDa in ASD and BAP compared to TD and DD al., 2012a)
102 DD mothers immunoblotting Paired reactivity at 37 and 73 kDa associated with language deficits.
183 TD mothers Paired reactivity at 39 and 73 kDa associated with increased irritability
Reactivity to 39 kDa (alone or paired with 73 kDa) associated with BAP
21

37 ASD and TD IHC for plasma reactivity to rhesus Reactivity at 37 and 73 kDa or 39 and 73 kDa found only in ASD mothers (Rossi et al., 2013)
mothers macaque brain tissue. Immunoblot No significant differences in reactivity seen in ASD children vs. TD.
and their children reactivity to fetal and adult rhesus
ages 3-13 years macaque brain proteins.
l
Preschool aged MRI scan (during sleep) to evaluate total ↑ abnormal brain enlargement in ASD, both groups (Nordahl et al.,
a
males: 131 ASD brain volume and compare maternal ASD children with 37/73 kDa IgG+ mothers had more extreme abnormal brain enlargement 2013)
n
(10 with 37/73 auto-Ab positive group to maternal auto- compared to Ab negative ASD and TD groups, specifically in the frontal lobe.
o
kDa IgG+ mothers) Ab negative groups
si
50 TD, all negative
i
for auto-Abs
v
246 ASD mothers Plasma reactivity to fetal macaque brain 6 brain proteins that has plasma reactivity were identified: lactate dehydrogenase A and B (Braunschweig et
o
149 TD mothers verified by immunoblotting. Protein (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins al., 2013)
r
enrichment via PlasmPrep cell protein 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein (YBX1)
P
fractionation, 2-D electrophoresis and Reactivity to any alone or in combination significantly was associated with ASD outcome
mass spectrometry. ↑ stereotypical associated with reactivity to LDH, and combined reactivity to LDH/STIP1 or
LDH/STIP1/CRMP1
↑ overall impairment associated with reactivity to LDH and CRMP1
2431 ASD Plasma IHC reactivity to mouse brain ↑ presence of brain-reactive auto-Abs in ASD mothers compared to control women (Brimberg et al.,
mothers, 653 Presence of brain-reactive auto-Abs associated with anti-nuclear autoantibodies and 2013)
controls of child- increased prevalence of autoimmune diseases, especially RA and SLE.
bearing age
333 ASD mothers Child and mother plasma reactivity to Reactivity at 37, 39 and/or 73 kDa anti-brain auto-Abs associated with impaired language (Piras et al., 2014)
355 ASD Rhesus macaque brain tissue and human development, neurodevelopmental delay and sleep/wake cycle disturbances.
142 SIB adult cerebellum by immune-blotting Presence of the 62 kDa autoAb in the child associated with maternal reactivity at 39 and/or
73 kDa.
Child results listed in Table 4.
ASD: autism spectrum disorders; IHC: immunohistochemistry; TD: typically developing; kDa: kilodalton; GFAP: glial fibrillary acidic protein; MBP: myelin basic protein; DD: non-ASD
developmentally delayed; PCR: polymerase chain reaction; BAP: broader diagnosis of autism spectrum disorder; IgG: immunoglobulin G; MRI: magnetic resonance imaging; 2-D: two
dimensional; auto-Abs: auto-antibodies; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SIB: typically developing sibling
827
22
828 Table 3 | Preclinical studies of maternal autoantibodies and ASD-like pathology

Pre-clinical Model Details Summarized Findings References
Mouse model ASD-sera exposed offspring exhibited: (Dalton et al., 2003)
l
Sera from 1 ASD mother (auto-Ab+) and 4 TD mothers injected into ↓ reflexes
a
pregnant MF1 mice at varied time points. Offspring behaviors and ↓ exploration
n
cerebellar chemistry measured with standard behavioral tests and ↓ spatial orientation
o
MRS ↓ creatine and choline concentrations in cerebellum
si
No impairments in memory
i ASD-IgG exposed offspring exhibited: (Martin et al., 2008)

Non-human primate model
v
Purified IgG from separately pooled from 21 ASD and 7 TD maternal ↑ whole-body stereotypies
o
sera, measured for presence of auto-Abs. 4 Rhesus macaques were ↑hyperactivity
r
injected IV with auto-Ab+ IgG from ASD maternal sera and 4 were No significant differences seen in social behaviors
P
injected with auto-Ab- IgG from TD maternal sera at GD 27, 41, and 55.
Behaviors assessed at preweaning and postweaning time points.
Mouse model ASD-IgG exposed offspring exhibited: (Singer et al., 2009)

Purified IgG from separately pooled from 63 ASD and 63 TD maternal ↑ anxiety, startle, and hyperactivity
sera, injected IP into 26 pregnant C57Bl/6J mice total, 13 dams per ↑ Iba1 staining indicating microglia activation in E18 embryos
group, at E13-E18. Offspring from untreated and from saline injected ↑ BDNF at adolescence
mice included as negative controls. Several behavioral and Social deficits seen at adulthood
neurodevelopmental outcomes measured. IL-12 detectable in E16 embryos
Mouse model ASD-IgG exposed offspring exhibited: (Braunschweig et al.,

Purified IgG from pooled from 3 ASD maternal sera positive for 37 kDa ↓ weight and body length 2012b)
and 73 kDa fetal brain protein reactivity. Purified IgG also pooled from ↓ sensory and motor development prior to weaning
3 TD maternal sera absent of reactivity. Single IV injection of purified ↑ anxiety
IgG per group given to pregnant C57Bl/6J mice at GD 12, saline given ↑ vocalizations during separation-induced stress in males at PND8
as negative control. Offspring assessed for behavioral abnormalities Social deficits trended in males but did not reach significance
and alterations in neurodevelopment. No differences seen in stereotypical behaviors
No differenced seen in numbers of CA1 hippocampal neurons
Non-human primate model ASD-IgG exposed offspring exhibited:

Purified IgG from ASD maternal sera positive for 37 kDa and 73 kDa ↑ maternal protectiveness during pre-weaning stage (Bauman et al., 2013b)
autoAbs and purified IgG from TD maternal sera absent of reactivity ↑ inappropriate and frequency of social approach in juveniles
injected IV into two groups of pregnant Rhesus macaques at GD 30, 44, ↑ brain volume in males compared with controls, mainly white matter and most
58, 72, 86, and 100. profoundly in the frontal lobes.
23
Pre-clinical Model Details Summarized Findings References

Mouse model ASD-IgG injected adult offspring exhibited: (Camacho et al., 2014)
Purified IgG from ASD maternal sera positive for autoAbs or from TD ↑ grooming
maternal sera absent of reactivity was injected directly into cerebral ↑ marble burying
ventricles of E14 embryonic Swiss Webster mice. Behaviors measured No differences in social approach, however ASD-IgG mice had↑ time spent with
with battery of behavioral assays novel object compared to mice injected with TD-IgG
Mouse model
n
Biotinylated IgG from ASD maternal sera positive for 37 kDa and 73
o al Brain from ASD-IgG injected embryos exhibited:

Reactivity to RG cells (neural stem cells) in VZ
(Martinez-Cerdeno et
al., 2016)
si
kDa fetal brain protein reactivity or from TD maternal sera absent of ↑proliferative Pax6+ RG cells in the SVZ
reactivity was injected directly into cerebral ventricles of E14 or E16 ↑mitotic precursor cells in the SVZ of the ganglionic eminence (a
i
embryonic Swiss Webster mice. Brain reactivity and quantification neurodevelopmental structure that guides cell and axon migration)
v
assessed with IHC and stereology. RG cells translocated much earlier than control mice
o
↑ brain weight and rostro-caudal length
r
↑somal volume in neurons
P
Mouse model
Purified IgG from ASD maternal sera positive for 37 kDa and 73 kDa
fetal brain protein reactivity or from TD maternal sera absent of
reactivity was injected directly into cerebral ventricles of E14
embryonic Swiss Webster mice. Changes in dendritic arbor and spine
population assessed with Golgi method and Neurolucida.
Adult brain from ASD-IgG injected embryos showed:
↓ length and volume of dendritic spines on neurons of the frontal cortex
↓ total number of spines on neurons in frontal cortex
↓ total number of spines on neurons in occipital cortex
↓ spine density of apical dendrites, and ↓ number of mature spines on basal and
apical dendrites in occipital cortex
(Ariza et al., 2017)
Mouse model Epitope-specific antibodies were successfully produced and persisted in dams (Jones et al., 2018)
Mixtures of 21 synthesized epitopes of LDH-A, LDH-B, STIP1, and through end of lactation
CRMP1 (fetal brain target peptides) plus adjuvant were injected SC 5 MAR-ASD offspring exhibited:
times into dams prior to mating (MAR-ASD). Control females injected ↑ weight and head width
SC with saline plus adjuvant. Maternal sera tested for verification of ↑ repetitive behaviors
endogenous autoAb production. Offspring behaviors measured with ↓ social behaviors, including male-female social interactions
behavioral assays
ASD: autism spectrum disorder; autoAb:: autoantibody; MRS: magnetic resonance spectroscopy; IgG: immunoglobulin G; TD: typically developing; IV: intravenous; GD: gestational day;
IP: intraperitoneal; Iba1: Ionized calcium binding adaptor molecule 1; E13: embryonic day 13; BDNF: brain derived neurotrophic factor; IL-12: interleukin-12; IHC: immunohistochemistry;
RG cells: radial glial cells; VZ: ventricular zone; SVZ: subventricular zone; LDH: lactate dehydrogenase, STIP1: stress-induced phosphoprotein 1; CRMP1: collapsin response mediator
protein 1; SC: subcutaneous
829
830
24
831 Table 4 | Studies identifying presence of autoantibodies in individuals with ASD
Subject details Methods Summarized Findings References
48 autism (5.9 ± 3.9 years) Serum ELISA measurements of BDNF, IgG/IgM auto-Abs ↑ BDNF in ASD, CDD compared to HC and NNI (Connolly et al.,
19 CDD (7.0 ± 2.4 years)
14 PDD-NOS (4.8 ± 3.9 years)
9 LKS (7.4 ± 2.3 years)
n al
to BDNF, endothelial cells, MBP, and histones
Note: Subject numbers indicate total included in study.
o
↑ anti-BDNF IgM and IgG in autism, CDD and epilepsy compared to HC
↑ IgM to endothelial cells in autism, CDD, PDD-NOS, and epilepsy compared to
HC and NNI
2006)
si
37 epilepsy (5.9 ± 3.8 years) Actual numbers varied slightly depending on assay ↑ IgG to endothelial cells in autism and PDD-NOS compared to HC
29 HC (4.3 ± 2.0 years) ↑ IgM and IgG to MBP in autism, CDD, PDD-NOS, and epilepsy compared to
i
21 NNI (4.2 ± 2.6 years) both HC and NNI, LKS not elevated
P r o v
29 ASD (3-12 years)
9 SIB (4-8 years)
13 TD (9-17 years)
63 ASD (2-15 years)

63 TD (2-14 years)
25 SIB (1-13 years)
21 DD (2-5 years)
Serum ELISA and Western blot reactivity to human brain ↑ reactivity to 100 kDa epitope in caudate putamen and prefrontal cortex in
Western blot of plasma reactivity to adult human

hypothalamus and thalamus protein extracts
ASD
↑reactivity to 73 kDa epitope in cerebellum and cingulate gyrus in ASD and SIB
↑ reactivity to 52 kDA thalamus and hypothalamus proteins in ASD

↑ reactivity to 3 hypothalamus proteins (42–48 kDa MW)
(Singer et al.,
2006)
(Cabanlit et al.,
2007)
11 ASD 72-hour neuronal culture analyzed for effect of ASD sera Treatment with ASD sera: (Mazur-Kolecka
9 SIB on differentiation of NPCs by immunoblotting, ↓ NPC proliferation et al., 2007)
(>6 years) morphometry, and immunocytochemistry ↑ cell migration
↑ small cells with processes
↑ length and number of processes
↑ synaptogenesis
33 ASD (7.3 ± 3.0 years) Plasma ELISA and Western blot reactivity to MBP ↑ auto-Abs to MBP found in regressive autism compared to classic (infantile) (Libbey et al.,
26 regressive autism (6.7 ± autism and Tourette syndrome subjects. 2008)
2.7 years)
25 TD (8.9 ± 3.4 years)
24 Tourette syndrome (10.0 ±
2.6 years)
63 ASD (2-15 years) Western blot of plasma reactivity to human cerebellar ↑ auto-Abs to 52 kDa cerebellar protein in ASD (Wills et al.,
63 TD (2-14 years) protein extracts. Cerebellar-specific auto-Abs detected ↑ "intense immunoreactivity" to Golgi cells of the cerebellum in ASD, 2009)
25 SIB (1-13 years) by IHC of Macaca fascicularis monkey cerebellum. associated with auto-Abs to 52 kDa cerebellar protein
21 DD (2-5 years)
25
37 ASD (1-12 years) Measured effect of ASD sera on cell response to Oxidative stress reduced proliferation in differentiating NPCs treated with TD (Mazur-Kolecka
37 TD (1-14 years) oxidative stress via immunoblotting, morphology, sera. Effect was not as prominent with ASD sera, indicating an altered response et al., 2009)
immunofluorescence, apoptosis and proliferation to oxidative stress.
assays.
20 ASD (3.0 ± 0.4 years) Taqman Real time PCR to detect serum mtDNA. Serum ↑ extracellular mtDNA in ASD (Zhang et al.,
l
12 TD (3.0 ± 1.2 years) ELISA analysis to detect mtDNA antibodies ↑ anti-mtDNA auto-Abs (type 2) in ASD 2010)
277 ASD (70 BAP)

189 TD
(2-5 years)
macaque cerebellum protein medley
si n a
Western blot for child plasma reactivity to Rhesus
o
↑ auto-Abs to 45 kDa protein in ASD
↑ auto-Abs to 62 kDa protein in BAP
Increases in either auto-Ab was associated with lower adaptive and cognitive
(Goines et al.,
2011a)
i
scores, increased aberrant behaviors.
54 ASD
54 TD
P r
(4 - 11 years)
o v
86 ASD (2.0-5.6 years)
43 TD (2.3-4.7 years)
Serum anti-ganglioside M1 Abs were measured by ELISA ↑ antiganglioside M1 auto-Abs in ASD, especially in severe compared to mild or (Mostafa and
moderate autism. Al-Ayadhi,
2011)
IHC for plasma reactivity to sections of macaque monkey No differences in rate of plasma immunoreactivity to cerebellar Golgi neurons (Rossi et al.,
brain (methods similar to Wills 2009), results compared and other neural elements in ASD vs. TD, however immunoreactivity associated 2011)
to behavioral assessments. with worsening behavior and higher multiple CBCL scores.
7 ASD with reactivity (2.5 to IHC: follow up of subgroup of ASD children from Reactivity seen in previous study identified as GABAergic interneurons (based (Wills et al.,
7 years) previous study (Wills 2009) with reactivity to cerebellar on co-localization of staining to calcium-binding proteins). 2011)
7 ASD with no reactivity 52-kDa protein and to Golgi cell region of the Reactivity extended to other regions of the brain with slight preponderance to
6 TD with no reactivity (2.5 to cerebellum. IHC to detect plasma immunoreactivity in superficial layers of the cortex.
8 years) the maqaque and male mouse brains.
80 ASD Indirect immunofluorescence used to measure serum ↑ anti-neuronal auto-Abs in ASD, associated with increased severity of autism (Mostafa and
80 TD anti-neuronal antibodies and seen more frequently in females ASD (90% vs 53.3%, P=0.001). Al-Ayadhi,
(6-12 years) 2012b)
50 ASD Serum ELISA measurements of 25-hydroxy vitamin D and ↓ 25-hydroxy vitamin D in ASD (Mostafa and
30 TD anti-MAG autoAbs ↑ anti-MAG auto-Abs in ASD Al-Ayadhi,
(5-12 years) 25-hydroxy vitamin D levels negatively correlated with CARS scores and anti- 2012a)
MAG auto-Abs
54 ASD Plasma ELISA measurements of anti-cardiolipin, anti- ↑ auto-Abs to cardiolipin, phosphoserine, and 𝛽2-glycoprotein 1 in ASD (Careaga et al.,
22 DD phosphoserine, and anti-𝛽2-glycoprotein 1 auto-Abs compared to TD and DD controls, significantly associated with worsening 2013)
33 TD behaviors.
(2-5 years)
26
42 ASD Serum ELISA measurement of human anti-MBP Abs. ↑ auto-Abs to MBP and MAG in ASD, regardless of allergies. (Mostafa and
42 TD Severity of ASD and manifestation of allergic/asthma Severity of autism was also found to be associated with increased allergies. Al-Ayadhi,
(6-11 years) symptoms compared to results. 2013)
93 ASD
(2.9 – 17.4 years)
n al
Patented process of identifying FRA: incubated serum ↑ prevalence of FRA in ASD sera.
with folate receptors then added radio-labeled folic acid. Blocking FRA correlated with CSF 5-MTHF concentrations in 16 children.
o
(Frye et al.,
2013)
si
HPLC measurement of 5-MTHF in the CSF. Treatment with folinic acid improved attention, language and communication,
and repetitive behaviors, with "moderate to much" improvement seen in 1/3 of
i
children treated.
P r o v
75 ASD (2-22 years)
30 DD (1-18 years)
20 ASD (1.4-5 years)

18 TD (1.4-4.4 years)
Patented process of identifying FRA: incubated serum
Immunoblotting and immunocytochemistry to detect

serum auto-Abs against differentiating NPCs
↑ prevalence of FRA in ASD vs DD
with folate receptors then added radio-labeled folic acid. ↑ prevalence of FRA in parents of ASD vs DD, suggesting familial autoimmune
component to ASD
↑ auto-Abs against human neuronal progenitor cell proteins of 55 kDA, 105

kDa, 150 kDa and 210 kDa molecular weights in ASD subjects compared to
controls. Strongest reactivity noted in NPCs expressing Tuj1.
(Ramaekers et
al., 2013)
(Mazur-Kolecka
et al., 2014)
100 ASD ELISA measurement of serum anti-ds-DNA Abs. ↑ anti-ds-DNA and anti-nuclear auto-Abs in ASD (Mostafa et al.,
100 TD Immunofluorescence measurement of serum Presence of anti-ds-DNA auto-Abs positively associated with a family history of 2014)
(4-11 years) antinuclear Abs. autoimmunity.
355 ASD Western blot plasma reactivity to homogenized Rhesus Plasma reactivity at 45 and 62 kDa brain proteins associated with autism (Piras et al.,
142 SIB macaque brain tissue and human adult cerebellum severity and larger head circumference. 45 kDa reactivity associated with 2014)
(2-47 years, mean age: 9.06) cognitive impairment/lower VABS scores while 62 kDa reactivity associated with
stereotypies.
60 ASD ELISA measurement of serum anti-nucleosome-specific ↑ anti-nucleosome-specific auto-Abs in ASD, associated with family history of (Al-Ayadhi and
60 TD antibodies. autoimmunity. Mostafa, 2014)
(3-12 years)
55 ASD (3-12 years) ELISA measurement of plasma levels of anti-endothelial ↑ anti-endothelial cell auto-Abs in children with autism compared to healthy (Bashir and Al-
25 TD (4-12 years) cell antibodies controls, associated with autism severity. Ayadhi, 2015)
62 ASD (4-11 years) ELISA measurement of serum ENA-78 and anti-neuronal ↑ anti-neuronal auto-Abs in ASD (Mostafa and
62 TD (5-12 years) auto-antibodies ↑ ENA-78 (neutrophil-recruiting chemokine CXCL5) associated with increases Al-Ayadhi,
in anti-neuronal auto-Abs 2015)
27
40 ASD/FRAA- Measured redox, methylation, vitamins and immune ↓ 3-Chlorotyrosine (a marker of inflammation) was in those positive for (Frye et al.,
(7.0 ± 3.3 years) biomarkers using various assays and compared to blocking FRAs 2016)
16 ASD/FRAA blocking+ behavioral assessments Presence of blocking FRAs in ASD associated with less severe ASD symptoms
(6.4 ± 3.0 years) compared to ASD negative for these FRAs
48 ASD/FRAA binding+
l
(7.3 ± 3.1 years)
sio n a
ASD: autism spectrum disorders; CDD: childhood disintegrative disorder with regression after age 2 years; PDD-NOS: pervasive developmental disorder-not otherwise specified; LKS:
Landau-Kleffner syndrome; HC: healthy children; NNI: children with non-neurologic illnesses; ELISA: enzyme-linked immunosorbent assay; BDNF: brain-derived neurotrophic factor; MBP:
myelin basic protein: SIB: typically-developing sibling; TD: typically developing child; kDa: kilodalton; DD; non-ASD developmentally delayed; NPCs: human neuronal progenitor cells; MEF:
i
myelin-enriched fraction of the brain; AEF: axolemma-enriched fraction of the brain; IHC: immunohistochemistry; auto-Abs: autoantibodies; PCR: polymerase chain reaction; mtDNA:
v
mitochondrial DNA; BAP: broader diagnosis of autism spectrum disorder; CBCL: The Child Behavior Checklist; MAG: myelin-associated glycoprotein; FRA: folate receptor antibodies; 5-
o
MTHF: 5-methyltetrahydrofolate; CSF: cerebrospinal fluid; Tuj1: neuron-specific Class III β-tubulin; ds-DNA: double-stranded DNA; VABS: Vineland Adaptive Behavior Scales; ENA-
r
78:Epithelial cell-derived neutrophil-activating peptide-78; CXCL5: C-X-C motif chemokine 5
832 P
28
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Immune Dysfunction and Autoimmunity as Pathological

Mechanisms in Autism Spectrum Disorders

Frontiers in Cellular Neuroscience | www.frontiersin.org

1 Heather K. Hughes1,2, Emily Mills Ko1,2, Destanie Rose1,2, Paul Ashwood1,2*

123 3 Gestational Immune Influences

124 3.1 Maternal Autoantibodies

Immune Mediated Co-morbidities

338 4.2 Autoantibodies in Individuals with ASD

432 4.3 Aberrant Innate Immune Responses

496 4.3.2 Peripheral Innate Immune Dysfunction

575 4.4 Aberrant Adaptive Immune Responses

618 4.4.2 Regulatory T cells

786 11 Figure legends

Subject Details Methods Summarized Findings References

sio n ↑ frequency of AI in ASD families compared to AI and TD families

i Serum reactivity to human and rodent

Subject Details Methods Summarized Findings References

828 Table 3 | Preclinical studies of maternal autoantibodies and ASD-like pathology

i ASD-IgG exposed offspring exhibited: (Martin et al., 2008)

Mouse model ASD-IgG exposed offspring exhibited: (Singer et al., 2009)

Mouse model ASD-IgG exposed offspring exhibited: (Braunschweig et al.,

Non-human primate model ASD-IgG exposed offspring exhibited:

Pre-clinical Model Details Summarized Findings References

o al Brain from ASD-IgG injected embryos exhibited:

831 Table 4 | Studies identifying presence of autoantibodies in individuals with ASD

Subject details Methods Summarized Findings References

Note: Subject numbers indicate total included in study.

63 ASD (2-15 years)

Western blot of plasma reactivity to adult human

↑ reactivity to 52 kDA thalamus and hypothalamus proteins in ASD

Subject details Methods Summarized Findings References

277 ASD (70 BAP)

Subject details Methods Summarized Findings References

20 ASD (1.4-5 years)

Immunoblotting and immunocytochemistry to detect

↑ auto-Abs against human neuronal progenitor cell proteins of 55 kDA, 105

Subject details Methods Summarized Findings References

Pkaleidoscope of autoimmunity: multiple autoimmune syndromes and familial autoimmunity.

957 Winter, H. (2010). Evaluation, diagnosis, and treatment of gastrointestinal disorders in

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