Immunity and his role crucial in ASD

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects communication, social interaction and behavior of people who suffer from it. Although ASD has traditionally been associated with alterations in the nervous system, there is increasing evidence suggesting the involvement of the immune system in the pathophysiology of this condition.

Autism spectrum disorder, also known as ASD, is usually diagnosed in early childhood. It is a complex heterogeneous developmental disorder that involves the early appearance of behavioral abnormalities, social deficiencies, and communication deficits. ASD can present at various levels of severity, from mild to severe, and has a male preponderance, with up to four males diagnosed per female; however, this may be changing due to our changing understanding of the differences between male and female presentation of ASD. 

The prevalence of ASD has increased substantially in recent decades, reaching 1 in every 36 children, due to new knowledge and advances in genetics, immunology, and testing and examination protocols to enable early diagnosis. While the etiology of ASD remains unknown, several risk factors are associated with the development of ASD, including genetic and environmental risk factors.

Rare inherited or de novo variants have also been identified that carry substantially increased risk; However, these may only account for a small percentage of ASD cases, as may monogenic disorders such as fragile X syndrome. Therefore, no single gene or common set of genes has been identified in most cases of ASD, and recent studies have identified environmental exposures implicated in ASD risk. These exposures may be exacerbated by gene-environment interactions and epigenetic mechanisms.

Several environmental risk factors have been clinically identified, most of which occur during pregnancy. In support of these findings, animal models of maternal immune activation with various immune primers have revealed ASD-relevant behaviors and provided evidence of innate immune activation in the offspring generated by Maternal Immune Activation (MIA), suggesting that Early exposure to maternal inflammation may be inadequately priming the fetal immune response and may lead to future dysfunction of this arm of the immune system.

The network of cellular and chemical components that make up the immune system confers protection against invaders through an intricate system designed to identify the "self" from the "other." Sentinel cells of the innate immune system include neutrophils, monocytes, and their tissue counterparts, macrophages.

Cytokines and immunity

Cytokines are key chemical mediators of the immune response produced by cells when activated by exposure to an antigen or immunogen. They are fast-acting cell signaling molecules that require proper regulation to maintain a balance between pro-inflammatory and anti-inflammatory responses. This balance is especially critical during neurodevelopment, as cytokines and their receptors are also expressed by neurons, and are intricately involved in the proper development of the central nervous system. 

Immune cells play a crucial role in defending the body against pathogens and regulating the inflammatory response. In ASD, immune dysfunction characterized by a chronic inflammatory response and alterations in the composition and function of immune cells has been observed. Studies have shown that patients with ASD have elevated levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-).α) and interleukin-6 (IL-6), as well as an increase in the activation of microglial cells and astrocytes in the brain.

Early studies in ASD cytokine research identified increases in inflammatory cytokines in TLR4-stimulated whole blood cultures and peripheral blood mononuclear cells. Activation of TLR4 in innate immune cells, including monocytes, initiates a proinflammatory cascade and the production of cytokines such as TNF-α, IL-1β and IL-6. 

In a recent study, people with ASD had increased serum inflammatory cytokines, including IL-1β, IL-6, IL-12, IL-23, and TNF-α, providing additional evidence of peripheral innate immune activation. We recently characterized a cohort of children with ASD based on PBMC responses to lipopolysaccharide stimulation and found that those with higher innate inflammatory responses or greater T cell activation had more behavioral alterations.

Chemokines are cytokines that mediate chemotaxis and the recruitment of immune cells to sites of inflammation. Several chemokines associated with innate immune activation are elevated in ASD. Furthermore, neonatal blood spots from children with ASD were found to have increased MCP-1. Elevation of MCP-1 in amniotic fluid was also associated with an increased risk of having a child with ASD. However, this study used ASD siblings as controls. 

ASD is a highly heritable disorder, and families can widely show immune dysfunction in all members; Therefore, using peers as controls can be problematic.

Furthermore, evidence of dysregulation in the innate and adaptive immune response has been found in individuals with ASD. For example, a decrease in the number of natural killer (NK) cells and an alteration in the proportion of T lymphocyte subpopulations have been observed in the peripheral blood of patients with ASD. These alterations could contribute to the susceptibility of individuals with ASD to infections and the presence of associated medical comorbidities.

Innate immune cells

Cytokines that are repeatedly seen in ASD, such as IL-1β, IL-6, and TNF-α, are produced during the activation of the innate arm of the immune system. This arm is responsible for the first line of defense against foreign antigens. When host physical or chemical barriers are breached, innate arm cells called monocytes act as sentinels, which are recruited to attack tissues by chemokines released at sites of infection. 

Here, these cells join their tissue-resident counterparts to become macrophages. A hallmark of macrophages is their plasticity. These cells lean toward a spectrum of phenotypes that depend on exposure to the microenvironment. In vitro, they are polarized to a classic “M1” inflammatory phenotype through stimulation with LPS plus IFN or TNF-α

This stimulation leads to the production of the canonical proinflammatory cytokines IL-1β, IL-6, and TNF and helps drive T helper cell -1 differentiation. For example, Enstrom et al. found altered cytokine production after TLR activation in peripheral CD14 monocytes isolated from children with ASD, with increases in the canonical innate inflammatory cytokines TNF-, IL-1β, and IL-6 after TLR2 activation. IL-1β was also increased after TLR4 activation with LPS, and IL-1β concentrations were positively correlated with behaviors associated with ASD, including impaired social interactions and non-verbal communication.

More recently, in a study they were grouped based on the ratios of monocyte production of IL-1β and IL-10 after stimulation of various TLRs. The IL-1β/IL-10 ratio groups differed significantly in monocyte expression of miRNAs and mitochondrial respiration. When probed with β-glucan, monocytes in the high-ratio group responded with increased proinflammatory responses, while the low-ratio group responded with increased anti-inflammatory responses. 

They also found dysregulated gene expression of the translation machinery in monocytes from children with ASD compared to typically developing controls, which may be contributing to increased inflammatory responses in a subset of these children as a failure to dampen a response. Prolonged immune response through regulation of translation. 

Furthermore, they identified increased IL-6 production in LPS-stimulated monocytes from children with ASD. In subsequent studies, ASD children with gastrointestinal problems had significantly increased infiltration of monocytes, eosinophils, and neutrophils in duodenum, colon, and terminal ileum biopsies. Furthermore, a significant increase in the number of NK Lymphocytes was observed in children with ASD compared to controls. Transcriptional profiling of whole blood from children with ASD also revealed increased expression of genes belonging to the KEGG pathway of NK cells.

Another relevant aspect is the relationship between the immune system and the nervous system in ASD. The existence of bidirectional communication between both systems has been proposed through signaling molecules, such as cytokines, which could influence brain development and function. In fact, the theory of “neurogenic inflammation” has been postulated as a potential mechanism in the etiology of ASD, in which chronic activation of the immune system could affect synaptic plasticity and neuronal connectivity.

Neuroinflammation and innate immune cells in the brain

Neuroinflammation is an inflammatory process that occurs in the central nervous system, involving the activation of brain immune cells, such as microglia and astrocytes, as well as the infiltration of peripheral immune cells in response to pathological stimuli. This phenomenon may play an important role in various neurological and psychiatric diseases, including Autism Spectrum Disorder (ASD).

In the context of ASD, it has been proposed that chronic neuroinflammation could contribute to the development and expression of symptoms associated with this condition. Activation of microglia and astrocytes, as well as an increase in the production of proinflammatory cytokines, have been observed in the brains of individuals with ASD. These changes could alter neuronal homeostasis, synaptic plasticity, and brain connectivity, which in turn could influence the behavior and cognitive functions of people with ASD.

Microglia are specialized macrophages that reside in the brain and CNS. They play a fundamental role not only in neurodevelopment, but also in CNS homeostasis throughout life. During neurodevelopment, microglia are responsible for phagocytosing excess neuronal precursor cells to regulate neurogenesis by restricting cell production. 

They also play a role in supporting neuronal survival while limiting axon growth. Production of brain-derived neurotrophic factor by microglia promotes the survival and differentiation of neurons, the regulation of synaptic formation and transmission, and synaptic plasticity is essential for memory and learning. 

These researchers also found no evidence of acute inflammation, suggesting that microglia have long-standing activation. Furthermore, the same group later found greater spatial proximity of microglia to neurons in the dorsolateral prefrontal cortex of the ASD brain, with microglial processes frequently surrounding the somal bodies of neurons in ASD samples. 

Increased microglia density has also been identified in two separate regions of the cortex in the ASD brain compared to controls. NF-B is increased in the postmortem ASD brain, with localization in glial and neuronal cells, and an enzyme complex that activates NF-B is also elevated in the ASD brain.

More recently, cells from the adaptive arm of the immune system were shown to increase in the postmortem brain of ASD and accumulate near blood vessels, further supporting evidence of neuroinflammation in ASD.

Furthermore, measurement of microglial TSPO activation may also introduce variability. While TSPO is expressed by activated microglia, endothelial cells during homeostasis and astrocytes in a disease context can also express TSPO. 

Finally, in a study by Suzuki and colleagues, they did not identify whether their research subjects had TSPO gene polymorphisms, since polymorphisms can influence radiotracer binding. Additional PET studies using microglia-specific proteins, correctly identifying subjects with high and low TSPO binding affinity, and analyzing both binding affinity and total volume distribution will help clarify the above-mentioned findings.

Transcriptomic analyzes of several brain regions support findings of increased immune responses in the ASD brain, with enrichment in specific immune system genes observed in several studies.

Preclinical studies relevant to ASD have also identified dysregulation of innate inflammatory responses and activation of macrophages and microglia. For example, in the MIA model, MIA drove increased production of inflammatory cytokines by bone marrow-derived macrophages obtained from offspring. 

Neuroinflammation in ASD has also been associated with dysregulations in the excitatory/inhibitory balance in the brain, which could contribute to neuronal hyperexcitability and the emergence of symptoms such as sensory hypersensitivity and difficulties in sensory integration in individuals with ASD. Furthermore, it has been postulated that neuroinflammation could be involved in the appearance of common medical and psychiatric comorbidities in people with ASD, such as gastrointestinal disorders, epilepsy, and sleep disorders.

The study of neuroinflammation in ASD has aroused growing interest in the scientific community, as it could offer new therapeutic opportunities to address the underlying mechanisms of this condition. Strategies aimed at modulating the inflammatory response in the brain, such as the use of anti-inflammatory drugs or therapies that promote neuroprotection, could represent innovative therapeutic approaches for ASD.

Neuroinflammation emerges as a relevant process in the pathophysiology of ASD, with significant implications in the development and expression of the symptoms of this condition. The study of the interaction between the immune system and the nervous system in the context of ASD could open new avenues to better understand this complex disease and develop more effective and personalized therapeutic strategies for affected people.

In an LPS-based MIA study, MIA offspring exhibited an increase in peripheral IL-1β and IL-6 throughout growth. Peripheral inflammation further increased after re-exposure to LPS at 8 weeks, along with substantial increases in inflammatory cytokines, chemokines, and cell adhesion molecules in the brain. 

Another recent study using a two-hit model of MIA plus prenatal hypoxia found infiltrating monocytes and neuroinflammation in the brain. When monocyte entry was blocked, neuroinflammation was enhanced. Supporting the hypothesis that inflammation plays an important role in aberrant behavior, in the MIA model, increased plasma innate inflammatory cytokines in adulthood were associated with significantly impaired social behavior compared to those who did not exhibit this inflammatory response. 

Other animal models have also documented associations between innate inflammatory cytokines and behavioral impairment. These offspring also presented changes in the intestinal microbiota and alterations in the microbial metabolites produced by the microbiota that were associated with worse behavior. 

These behaviors were corrected with the addition of the commensal Bacteroides fragilis, suggesting that MIA-induced changes in the gut microbiota may be contributing to the behaviors.

The composition of the maternal microbiota was also found to be a critical component for pathological outcomes in MIA: if mothers lacked a certain commensal bacteria responsible for driving responses to IL-17, the offspring did not exhibit typical behavioral manifestations. of mine .

An alteration in the number of myeloid cells was also observed in this model. Intestinal dysfunction is common in ASD and the composition of the microbiota is often altered.

Bibliography

Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD)

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