Fig. 6.1
a) Many immunological processes take part both in developing and maintaining the CNS. Microglia are the main contributor to many of these processes. As the resident phagocytic cell, microglia clear cellular debris and apoptotic neurons. They also further neural development by producing various growth factors and many cytokines that regulate neuronal survival and synaptogenesis. Microglia also respond to danger signals by producing reactive oxygen species and pro-inflammatory cytokines. Some of the cytokines that can affect the CNS include: IL-1β, TNF-α, IL-6 and TGF-β. These cytokines not only contribute to neuronal development but also play a role in learning and memory. b) Lymphocytes, part of the adaptive immune system have also been found to contribute to cognitive function. More specifically T cells have been demonstrated to contribute to visuospatial learning and enhance neurogenesis in the dentate gyrus. T cells important to cognitive function are believed to be found in the meningeal spaces where they produce cytokines; specifically IL-4 has been associated with visuospatial learning. c) Outside the CNS, neuro-immune interactions also take place. Many immune cells including macrophages express receptors for neurotransmistters. Some of these receptors include beta adrenergic, nicotine α-7, noradrenergic, metabotropic glutamate, neuropeptide and 5-hydroxytryptophan (5-HT) receptors. Signaling through these receptors can either enhance or suppress the immune response depending on the neurotransmitter and environmental conditions. Norepinephrine, for example, generally tends to have an inhibitory effect on pro-inflammatory cytokine production in macrophages but this can be reversed if other factors such as LPS are present. NGF nerve growth factor, BDNF brain derived neurotrophic factor, NT-3 neurotrophin-3, GDNF, Glial cell line-derived neurotrophic factor, IL interleukin, 5-HT 5-hydroxytryptophan
Other pro-inflammatory cytokines that are involved in spatial learning and memory include both IL-6 and Tumor necrosis factor (TNF)-α; however, these cytokines also have complex roles in shaping memory and learning and have reported beneficial and detrimental effects. A recent study showed that TNF-α signaling through the NFκB pathway lead to increased neural stem cell (NSC) proliferation. This proliferation was attributed to the activation of the IKK-β and NFκB pathway leading to up regulation of cyclin D1 (Widera et al. 2006). How cytokines affect the CNS is context dependent and environments surrounding the release of these cytokines play an equally important role in determining the ultimate effect than any single cytokine will play (Yirmiya and Goshen 2011). Transforming growth factor (TGF)-β, an important immune regulatory cytokine, is involved in signaling required for mouse mesencephalic progenitors to differentiate into tyrosine hydroxylase (TH) + dopaminergic neurons in vitro and in vivo (Roussa et al. 2006). When TGFβ2/TGFβ3 double knockout mice were examined it was found they have reduced numbers of TH+ neurons in the ventral mesencephalon, however, in the locus coeruleus TH+ neurons were not significantly different from controls indicating that while TGFβ signaling may be important in the ventral mesencephalon it does not seem to contribute to ventral midbrain dopaminergic neuron development (Roussa et al. 2006) .
6.1.2 Microglia
Microglia, the brain’s resident phagocytic cells, play a central role in CNS development and maintenance through regulating developmental neuronal death and the clearing of apoptotic neurons (Wakselman et al. 2008; Takahashi et al. 2005).They also phagocytose cellular debris and respond to ‘danger’ signals through production of reactive oxygen species (ROS) and inflammatory cytokines (Neumann et al. 2009; Ron-Harel et al. 2011). The significance of this function is illustrated through the depletion of microglia from murine neonatal cerebellar slice cultures. This specific elimination of microglia leads to increased Purkinje cell survival due to the reduction of phagocytosis of caspase-3-expressing Purkinje cells (Marin-Teva et al. 2004). More recently in vivo studies have shown that microglia regulate neurogenesis in the cerebral cortex of primates, rodents and human fetal tissues (Cunningham et al. 2013). Cunningham et al. (2013) show microglia enter and colonize the cortical proliferative zones near the end of neurogenesis and phagocytose neural precursor cells. Manipulation of microglia in rats either by suppressing microglia using doxycycline or activating them using injection of LPS resulted in increased and decreased numbers of neural precursors cells, respectively, further demonstrating the critical role microglia and the immune system play in regulating neuronal numbers in early brain development.
In general, microglia activation increases expression of inflammatory cytokines and can have toxic effects on the surrounding cells; however, they are also vital for the down regulation of immune responses through autocrine feedback loops and production of anti-inflammatory cytokines (Garden and Moller 2006). Embryonic microglia are known producers of TNF-α and are key regulators of developmental apoptosis and synaptogenesis. Disrupting TNF-α signaling through use of anti-TNF-α antibodies or soluble TNF-α receptor (TNFR1) results in the decrease of AMPA-type glutamate receptors on hippocampal neurons and thereby modulate synaptic strength in these neurons (Beattie et al. 2002). TNF-α has been shown to upregulate expression of β3 integrins that help increase synaptic strength through stabilization of AMPARs (Cingolani et al. 2008). TNF-α is therefore suggested to have a central role for the homeostatic potentiation of synaptic strength during developmental synaptic refinement. Glial cells, in response to levels of activity in hippocampal cultures, have been shown to regulate TNF-α levels (Deverman and Patterson 2009).
Macrophage colony-stimulating factor (M-CSF) a growth factor for macrophages and microglia is necessary for proper development of certain areas of the brain. M-CSF mutant mice containing a null mutation in the M-CSF gene were shown to have auditory and visual processing impairment with failure of the newborn pups to respond to external cues and electrophysiologic abnormalities detected by intracortical recordings of brainstem auditory evoked potentials and visual evoked potentials (Michaelson et al. 1996). The effects of M-CSF are thought to be indirectly regulated by cytokine secreting microglia (Deverman and Patterson 2009). In addition to cytokines and chemokines, microglia produce many other regulatory and trophic factors promoting neuronal survival including: nerve growth factor (NGF) , brain-derived neurotrophic factor (BDNF) , neurotrophin (NT)-3, basic fibroblast growth factor, and glial-derived neurotrophic factor (GDNF) (Garden and Moller 2006). Microglia not only influence neuronal cells but can also be influenced by neuronal activity through neurotransmitter receptors such as glutamate receptors and by astrocytes through purinergic receptors such as P2X4, P2X7, P2Y2, P2Y6 and P2Y12 (Biber et al. 2007; Hung et al. 2010; Ferrari et al. 2006).
6.1.3 Cytokines, Immune Cells and Cognitive Function
Cytokines and immune cells are supportive in brain function including neurogenesis and cognitive functioning. Lymphocytes, for example, have been found to have a supportive role in cognitive functioning (Kipnis et al. 2012) . Experiments with severe combined immune deficient (SCID) mice, that do not have any T or B cells, display impairments in hippocampal dependent spatial learning and memory through analysis of the Morris water maze behavioral test (MWM) (Kipnis et al. 2004). Furthermore, nude mice (lacking only mature T cells) display similar impairments assessed by MWM which could be partially rescued with replenishment of T cells from wild-type mice, demonstrating the role of T cells more specifically in areas of visuospatial learning (Kipnis et al. 2004; Ron-Harel et al. 2008; Brynskikh et al. 2008). To provide further support of the role of T cells in learning and memory another study looked at rats that were either raised under normal environmental conditions or under enriched conditions in which neurogenesis was enhanced in the dentate gyrus. To confirm the role of T cells, mice were used in which monospecific T cells to either myelin basic protein (auto specific) (Tmbp) or ovalbumin (OVA) (non-CNS specific) (Tova) were used. Tmbp mice were found to have higher amounts of proliferating neurons compared with controls and preformed better in the MWM, while Tova had less proliferating neurons than controls (Ziv et al. 2006). To emphasize the importance of T cell/microglia interactions in neurogenesis the Tmbp mice were treated with a microglia blocking drug, minocycline, which significantly decreased neurogenesis in the dentate gyrus (Ziv et al. 2006). These findings support the role of T cells mediating neurogenesis and spatial learning through possible interaction with microglia .
Although T cells are not normally found in the CNS parenchyma under normal conditions, T-cell based support of behavioral plasticity is thought to take place in the meningeal spaces (Derecki et al. 2010; Schwartz and Shechter 2010). Depletion of T cells from the meningeal spaces results in impairments of learning and memory based on MWM results. Of the meningeal T cell population, CD4+ IL-4+ T cells were found to be the most important for spatial learning and memory as IL-4 deficient mice showed defects in MWM (Derecki et al. 2010). Other studies have also used T cell manipulations to demonstrate improved learning and memory (Ron-Harel and Schwartz 2009; Ron-Harel et al. 2008). Manipulation of T cells in aged mice through bone marrow transplantation improved spatial memory in these animals compared to young animals and was increased when compared with non treated aged animals (Ron-Harel et al. 2008). It has been suggested that assessing T cell immunity in old age could be used as a predictor of potential future memory loss and enhancing T-cell immunity could benefit age associated memory loss (Ron-Harel and Schwartz 2009) .
Major histocompatibility complex (MHC) molecules are important cell surface molecules that interact with T cells involved in host immunity. It was long thought that the neural cells were among the small list of cells that did not express this family of surface proteins; however, in the late 1990’s it was found that not only are these important immune molecules present on neurons but they actually influence synapse plasticity (Elmer and McAllister 2012). Mice with deficient signaling of class I MHC displayed impaired synapse plasticity (Huh et al. 2000). Peptides from within the cell are presented in MHC molecules and MHC I: peptide complexes, in an immunological context are scanned by cytotoxic T cells to detect abnormal conditions such as the presence of a viral infection or tumor. In the CNS it is thought that similar roles of MHC molecules are employed in presenting peptides in order to regulate normal developmental elimination of inappropriate synaptic connections, although the mechanism remains elusive (Boulanger 2009).
Communication between the immune system and CNS is not one way. Signaling is multidirectional and information can also pass from the CNS to the immune system. Norepinephrine (NE) released from sympathetic nerve terminals can signal to macrophages through beta adrenergic receptors (Kin and Sanders 2006). In general NE seems to have inhibitory effects on pro-inflammatory cytokine production such as TNF-α, IL-1β, and sometimes IL-6, based on data from splenic macrophages (Meltzer et al. 2004; Ignatowski et al. 1996; Nance and Sanders 2007). IL-6 production has been found to be both increased or decreased in response to NE depending on other signals and stimuli such as the presence of LPS (Nance and Sanders 2007). Other neuro-based receptors found on immune cells include noradrenergic receptors, nicotinic α-7 receptors, receptors for neuropeptides and hormones, metabotropic glutamate receptors (mGluRs) and receptors for monoamines serotonin and dopamine (Nance and Sanders 2007; Tracey 2002; Besedovsky and Rey 2007; Friedman and Irwin 1997; Pacheco et al. 2004). Signaling through these receptors can regulate and modulate immune function and may be important in response to stress and or in neuro-psychiatric disorders were imbalances in neuromodulators have been observed .
6.1.4 Neuroinflammation
While there are many beneficial roles of the immune system in CNS function, too much inflammation can be detrimental. Exposure to pathogens which activate immune responses to protect against infections can result in increased production of pro-inflammatory cytokines that contribute to sickness behavior, while both anxiety and depression have also been associated with inflammation (Irwin and Miller 2007). Pro-inflammatory cytokines including IL-1β, TNF-α and IL-6 can act on the brain causing sickness behaviors ranging from loss of appetite, lethargy to irritability (Dantzer et al. 2008). In addition to inflammation or as a result of infection, events causing stress, injury and ageing can also induce these same inflammatory mediators (Yirmiya and Goshen 2011). In experiments where IL-1β was injected intracerbroventricularly (i.c.v.) into the right lateral cerebral ventricle either 24 h or 1 h before training in the MWM, those rats injected for 1 h but not those injected 24 h before training showed impaired performance in spatial memory the next day (Oitzl et al. 1993) suggesting changes may be fast acting but also dose-dependent and transient. Furthermore, increased peripheral levels of IL-1β following infection with Legionella pneumophila or by direct administration of IL-1β daily also showed impaired spatial memory and learning in mice (Gibertini et al. 1995) suggesting there may be a conditioning effect with repeated prolonged exposure to cytokines. Transgenic mice that over express IL-1β show impairments in spatial memory that are particularly restricted to hippocampal dependent memory (Hein et al. 2010; Moore et al. 2009). Introduction of LPS also increases hippocampal IL-1 levels and induce similar impairments to special learning and memory (Nguyen et al. 1998). However, other study designs with different regimens of IL-1β administration did not show memory or learning impairments suggesting that the conditions and environmental factors contribute to memory and learning (Yirmiya and Goshen 2011). Additionally IL-1β associated neuroinflammation is linked in ageing and may play a role in age associated memory loss (Krabbe et al. 2004). Caspase-1 inhibitors when administered to aged mice over time reduced hippocampal IL-1β and helped to improve contextual memory (Gemma et al. 2005; Krabbe et al. 2004). In Alzheimer’s disease increased levels of TNF-α, IL-6 and IL-1β have been detected in the serum and cerebral spinal fluid (Akiyama et al. 2000; Shaftel et al. 2008). Activation of microglia have been found in Alzheimer and other neurological diseases such as Parkinson’s disease, multiple sclerosis and acquired immune deficiency syndrome dementia complex (Kim and de Vellis 2005). As stated above, the immune system orchestrates a vital and delicate balancing act necessary for the proper development and maintenance of the CNS. When there is imbalance in either direction, increased or decreased, appropriate functions of the CNS can become impaired.
6.1.5 Neuroinflammation in ASD
Recent studies have suggested that neuroinflammation occurs in individuals with ASD . Inflammation in post mortem brain specimens of a wide range of individuals with ASD age 4–45 years old have been observed, specifically, the cerebellum , anterior cingular gyrus and the midfrontal regions of the brain (Vargas et al. 2005). Neuroglial activation and presence of increased levels of inflammatory cytokines such as IFN-γ, IL-1β, IL-6, TNF-α and chemokines CCL-2 were found in brain tissue and CSF (Li et al. 2009; Morgan et al. 2010; Vargas et al. 2005). Additionally postmortem brain samples of patients with ASD were also found to have increased levels of glial fibrillary acidic protein (GFAP) in the frontal, parietal and cerebellar cortices (Laurence and Fatemi 2005). GFAP is expressed in activated astrocytes and is also a sign of inflammation. The cerebellum in particular showed the most prominent histological changes and microglial activation in individuals with ASD. In addition, some of the cerebellar tissues from individuals with ASD, but none of the control tissues had accumulation of perivascular macrophages and monocytes and deposition of complement membrane attack complexes which suggest that the neuroinflammation seen may be primarily driven by innate immune responses (Vargas et al. 2005) . Furthermore, researchers found increases in Th1 with no differences in Th2 cytokines suggesting that ASD patients have increased neuroinflammatory immune response through the Th1 pathway (Li et al. 2009). Increases in Th1 cytokines such as IFNγ were not compensated by increases in IL-10 also suggesting a failure in immune regulation (Li et al. 2009). In addition to increases in cytokines, post-mortem temporal cortex samples from ASD and general population controls were assessed for transcriptome differences and increases in expression of immune related genes were found in the ASD population (Garbett et al. 2008). In particular cytokine signaling and immune regulatory genes were altered, which included genes from the NFκB, IL-1r, Toll, IL-6, Caspase, Th1/Th2 and FAS pathways. Interestingly, the ASD samples had higher variability in transcriptome differences when compared to controls (Garbett et al. 2008) . Furthermore, activation of microglial cells and perivascular macrophages measured by increased MHC II expression was seen in the cortical regions, white matter and most prominently in the cerebellum of patients with autism. This microglial and astroglial activation in the cerebellum was associated with degenerating purkinje cells, granule cells, and axons (Vargas et al. 2005). Altered microglial profiles found in post mortem brain samples of ASD patients showed an increase in average microglial somal volume and increase in microglial density in white and grey matter respectively and activation ranged from severe to mild in ASD brain specimens (Morgan et al. 2010). The data also suggested that microglial activation maybe particularly prominent in younger individuals, though more samples are needed to verify this (Morgan et al. 2010) .
The specific inducer of microglia activation in ASD is unknown and whether dysfunction in immune pathways leads to neuroinflammation or if CNS impairments in ASD lead to immune dysregulation, or in fact an interplay between the two systems, is yet to be fully elucidated. Both environmental and genetic risk factors are thought to play a role in ASD. Genetic contributions to ASD were first suggested in the 1980’s after investigation of co-occurrences of rare syndromes and chromosomal disorders were observed with ASD (Blomquist et al. 1985). Moreover the increased occurrences of ASD in families shown in twin and sibling studies further provided evidence for a genetic component to ASD (Kates et al. 2004; Bailey et al. 1995; Constantino and Todd 2000; Steffenburg et al. 1989; Jorde et al. 1991). Candidate gene association studies and whole-genome linkage studies have been used to identify loci of interest and assess copy number variation. Even with a long list of putative contributing genetic mutations and syndromes associated with ASD, these only account for 10–20 % of cases (Abrahams and Geschwind 2008). Genetic risk factors for ASD include genes that affect both CNS and immune pathways. Immune related genes associated with ASD include: phosphoinisitide–3 kinase (PI3K) pathway proteins such as MET, PTEN, TSC1 and 2, as well as MHC II, complement 4B, and macrophage inhibitory factor (MIF) (Onore et al. 2012) .
6.2 Maternal Immune Activation and ASD
6.2.1 Infection During Pregnancy
In addition to genetic contributions, environmental factors are also thought to play a role in ASD. Maternal immune activation (MIA) during pregnancy is one potential environmental factor that may increase the risk for developing ASD (Patterson 2009). Studies investigating viral and bacterial infections during pregnancy have shown associations with maternal infection and increases in ASD, including in 1964 when a rubella outbreak was connected with increased cases of autism (Chess et al. 1978). Other viruses that have been linked to congenital infection and associated with ASD include the herpes viruses: herpes simplex virus, cytomegalovirus, varicella and the paramyxovirus mumps (Libbey et al. 2005). The study of data from the Danish Medical Birth Register investigated 10,133 ASD diagnoses from children born from 1980 to 2005 looking at mothers who were hospitalized during pregnancy and found evidence to support association of viral infection during the first trimester and bacterial infection during the second trimester with increased risk of the child developing ASD (Atladottir et al. 2009). It is possible that genetically predisposed or susceptible individuals who encounter a prenatal infection may develop ASD due to high levels of cytokines or initiation of autoimmune processes resulting in increased maternal inflammation which could affect the developing fetal brain (Libbey et al. 2005). Additional evidence to infer maternal immune involvement in autism is data showing increased rates of autoimmunity in families with ASD (Croen et al. 2005; Atladottir et al. 2009). In support of a role of MIA , one study showed that mid-gestational findings of increased IFNγ, IL-4 and IL-5 in maternal serum significantly increased the risk of ASD (Goines et al. 2011).
6.2.2 Other Inflammatory Processes
In addition to increased frequencies of autoimmunity among families with individuals with ASD some reports have also identified fetal specific autoantibodies in the mothers of children with autism (Braunschweig et al. 2008; Croen et al. 2008). IgG maternal antibodies can cross the placenta and persist for up to 6 months after birth (Heininger et al. 2006). Antibodies with autoreactivity to fetal brain proteins were found at 37 kDA and 73 kDa molecular weights in approximately 12 % of mothers with an autistic child but no mothers of typically developing children or children with developmental delays other than ASD (Braunschweig et al. 2008); later another band with a molecular weight of 39 kDa was also found to be associated with ASD (Croen et al. 2008). Maternal antibodies are present in detectable levels at 18 weeks in the developing fetus and reach levels comparable to the mothers by 38 weeks of gestation (Croen et al. 2008). To further test the role these autoantibodies are playing in ASD, several studies have injected serum or purified IgG from mothers of children with ASD and mothers of controls into various animal models mid gestation. In one study pregnant mouse dams were intraperitoneally injected with purified IgG from mothers of children with autism disorders (MCAD) or from mothers of typically developing children. Injections were given daily during embryonic days 13–18, resulting in adolescent offspring from MCAD injected dams which displayed long-term behavioral differences compared with controls (Singer et al. 2009). In another study non-human primate, rhesus macaques were injected with purified IgG from mothers of children with ASD and from those of typically developed children. Animals were found to have higher amounts of stereotypical behaviors and increased motor activity than controls (Martin et al. 2008). These data suggest that dysfunction of the maternal immune system may play an active role in the pathology of some children who develop ASD.
6.2.3 Rodent Models of MIA
Other models that investigate the role of MIA include rodent models of immune activation of pregnant dams. IL-6 is an important cytokine involved in maternal immune influence of fetal development (Hsiao and Patterson 2011) . Injecting IL-6 in the absence of other immune stimulus at embryonic day 12.5 is sufficient to cause behavioral changes in the offspring, particularly in measurements of prepulse inhibition of adult offspring (Smith et al. 2007). Other pro-inflammatory cytokines such as IL-1β, TNF-α and IFN-γ did not cause any changes in behaviors. Likewise, injection of neutralizing anti IL-6 antibodies administered when MIA was induced prevented development of behavioral abnormalities. IL-6 knockout mice also exhibited resistance to in utero MIA induced behavioral changes (Smith et al. 2007). Pregnant mice infected with the human influenza virus on embryonic day 9.5 had offspring who as adults displayed behavioral defects in prepulse inhibition and acoustic startle response (Shi et al. 2003) . Additionally when polyinosinic –polycytidylic acid (poly I:C), a viral mimic, was injected into dams at embryonic day 12.5 the offspring had similar behavioral defects as the influenza infected offspring suggesting that the behavioral abnormalities are indeed due to activation of the maternal immune system not the virus itself (Shi et al. 2003). Recent studies with poly IC induced MIA in mice show behavioral changes in three areas relevant to those seen in ASD which include impairments in communication, social interactions and repetitive behaviors (Malkova et al. 2012; Schwartzer et al. 2013). Male offspring of MIA mice were found to produce less ultrasonic vocalizations (a murine form of communication) in different social situations compared with controls. In addition, the offspring were also found to spend less time with novel mice and more time with a novel object when compared to saline controls indicating a difference in social interactions and finally the MIA offspring displayed more repetitive behaviors as measured by time spent self grooming and time spent burying marbles compared with controls (Malkova et al. 2012) . In addition to poly I:C models, the use of the bacterial component lipopolysaccaride (LPS) as a mid-gestational activator of the maternal immune system has been tested and results in behavioral changes in offspring similar to those observed using poly I:C (Patterson 2009). In the latter model neuroglial activation and increased cytokine production has been shown that likely results in permanent elevation of cytokines in the brain that affect postnatal behaviors (Patterson 2009) . These models together with epidemiological data of human infection during pregnancy demonstrate that the immune status of the mother is important for the developing fetus (Patterson 2009). Since not all mothers who are infected with a pathogen have offspring with ASD it is likely that genetic background acts as a factor to enhance ASD risk. Gene—environment interactions are thought to play a major role in ASD. One study examined these interactions by testing MIA in mice heterozygous for the tuberous sclerosis 2 (Tsc2) gene. Offspring of dams injected with poly I:C exhibited increased asocial behavioral abnormalities more than MIA alone suggesting a double hit of genetic and environmental factors results in severe behavioral defects (Ehninger et al. 2012). In addition to alteration in fetal neurodevelopment it is also possible that MIA alters peripheral immune responses as well. In one study of MIA, a Th17 skewing of T cells were seen in poly I:C maternally exposed mice compared with controls (Mandal et al. 2011) .
6.3 Systemic Immune Activation in ASD
6.3.1 Peripheral Cytokines and Chemokines in ASD
Immune abnormities in ASD have been reported since 1977 (Stubbs and Crawford 1977) . Since that initial report there have been a number of immune related problems described with some conflicting findings likely reflecting the heterogeneity of ASD . Elevated pro-inflammatory cytokines have been found in plasma of children with ASD aged 2–5 years old including IL-1β, IL-6, IL-8 and IL-12p40 (Ashwood et al. 2011b). Elevated amounts of chemokines MCP-1, RANTES and eotaxin were also found in children with ASD (Ashwood et al. 2011d). In both studies these elevated inflammatory mediators were associated with more impaired or aberrant behaviors. Other reports of inflammatory cytokines found elevations of IFNγ (Singh 1996), MIF (Grigorenko et al. 2008) and platelet derived growth factor BB (PDGF-BB) in plasma of children with ASD (Kajizuka et al. 2010). Both MIF and PDGF correlated with behavioral scores as well. In addition to increases in pro-inflammatory cytokines, decreases in TGFβ, a regulatory cytokine, were also found in children with ASD which were associated with worsening behavioral scores (Ashwood et al. 2008). In addition to plasma cytokine differences, there have also been reports of differences in immunoglobulin levels. One study reported that children with autism have reduced levels of plasma IgG and IgM which also correlated with increased behavioral severity (Heuer et al. 2011). Other studies have reported increases in serum proteins attributed mostly to increases in albumin; however, IgG, specifically IgG2 and IgG4 were also seen elevated in individuals with ASD and these increases in immunoglobulin correlated with behavioral abnormalities (Croonenberghs et al. 2002; Enstrom et al. 2009a). Autoantibodies to various and diverse targets have been reported in children with autism and could point to cellular damage that may be involved in increasing inflammation , revealing antigens otherwise hidden and/or epitope spreading (Onore et al. 2012) .
6.3.2 Adaptive Responses in ASD
Adaptive immune responses in children with ASD also show increased cytokine production . Peripheral blood mononuclear cells (PBMC) isolated from the blood of children with ASD ages 2–5 were stimulated and compared to age matched controls. Unstimulated cells from children with ASD produced higher amounts of IL-8 when cultured overnight. After stimulation with phytohemagglutinin (PHA), cells from individuals with ASD produced larger quantities of GM-CSF, IL-13 and TNF-α (Ashwood et al. 2011c). A number of these increased cytokines also correlated to behavioral abnormalities. Increased production of TNF-α and IFN-γ were associated with more stereotyped behaviors. Increased impaired communications were associated with higher IFN-γ and IL-8 production. IL-12p40, a subunit of IL-12, correlated with worsening speech and increased hyperactivity (Ashwood et al. 2011c). This data suggest that perhaps an increased Th1 response may worsen behaviors. Both increases in IL-10 and IL-5 may help to improve behaviors—IL-10 increases were associated with better expressive language while increased IL-5 production correlated with improved fine motor skills. Besides increased production of cytokines, PBMC differences were also seen in T cell activation markers suggesting an altered activation of T cells which may contribute to the differences in cytokines produced (Ashwood et al. 2011c). Other studies have also looked at CD4 and CD8 T cells and have found a shift in Th1 and Th2 cytokines (Gupta et al. 1998) .
Adhesion molecules play an important role in leukocyte migration and are involved in modulating immune—CNS connections via passage of T cells through epithelial barriers. Soluble adhesion molecules such as sPECAM, sL-selectin, and sP-selectin were found in lower amounts in high functioning ASD individuals when compared to controls (Iwata et al. 2008; Tsuchiya et al. 2007). Reports of improved behaviors during febrile outbreaks in children with ASD have also been described; these changes in behavior are transient and may be attributed to increased up-regulation of adhesion molecules allowing for more T cell-CNS interactions (Onore et al. 2012; Curran et al. 2007) .
6.3.3 Innate Responses in ASD
Changes in innate immune responses have been described in children with ASD. Natural killer (NK) cells, normally involved in killing atypical host cells, have been found to have reduced ability to kill K562 target cells (an immortalized myelogenous leukemia cell line) in children with ASD (Warren et al. 1987; Enstrom et al. 2009b; Vojdani et al. 2008) . Factors that may contribute to decreased NK cell activity may be attributed to production of lower amounts of perforin, granzyme B and IFN-γ following stimulation conditions in children with ASD (Enstrom et al. 2009b). Increased numbers of circulating monocytes have also been reported in ASD (Sweeten et al. 2003). Moreover, increased expression of activation markers on these monocytes suggest that these cells are in an activated state (Ashwood et al. 2011a). Indeed these cells have been found to have released increased inflammatory cytokines such as IL-1β, TNF-α and IL-6 in response to TLR2 and TLR4 stimulus. Increased production of IL-6 and IL-1β correlated with increased impairment of social behaviors in children with ASD (Enstrom et al. 2010). Monocytes under certain conditions can give rise to other myeloid cells such as dendritic cells, tissue macrophages and microglia (Djukic et al. 2006; Geissmann et al. 2010). Altered activation and responses in myeloid cells, therefore, have many implications for inflammation in both peripheral and CNS systems .
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