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Advanced Neurology Role of immunosuppressants in autism

inflammation, and the glycolytic pathway. PPAR has incidence of apoptotic mononuclear cells than the
the ability to inhibit the activity of NF-κB, which, in untreated control group, suggesting that somehow this
turn, reduces inflammation [122,123] . Familial adenomatous pathway may be involved in the in vivo action of this
polyposis (FAP) is an autosomal dominant syndrome that medicine in this disease [134,137] .
increases an individual’s risk of developing colon cancer. Post-mortem analysis of ASD temporal lobes shows
The disorder is caused by mutations in the adenomatous an elevation in dendritic spine density and a decline
polyposis coli gene (APC) that are passed down from in developmental spine pruning in layer V pyramidal
generation to generation [124,125] . The APC gene, situated on neurons, as reported by Tang G, Gudsnuk K et al., In Tsc2+/
5q21–22 of chromosome 5, was reported to be mutated in ASD animals, where mTOR is constitutively overactive,
FAP patients [126,127] . There is an evidence that the APC gene these spine abnormalities coincide with hyperactivation
can inhibit the growth of tumors. Furthermore, the studies of mTOR and defective autophagy [110] . Group 1 innate
show that there is an association between the location of lymphoid cells (NK cells) are distinguished by their ability
the APC mutation and the phenotype in FAP patients.
Patients with FAP inherit a single germline mutation, to secrete cytokines and destroy target cells. Interferon-
and cancerous tumors form when cells sustain a second gamma is produced as a cytokine. Both viral infections
hit or lose the second allele of APC [128,129] . Endoscopic and aberrant immunological responses have been linked
examinations were used in clinical research on 24 patients to autism, and because NK cells function as the body’s first
with autism who had persistent gastroenterological line of defense against viral infection, it stands to reason
symptoms at Parma’s Paediatric Gastroenterology Unit. The that these cells would play a role in the development of
results provide a link between FAP and ulcerative colitis autistic symptoms. We discovered the significance of NK
that can act as a neurobehavioral disorder [130] . A single cells and their association with the nervous system in the
nucleotide polymorphism (SNP) in the 30-untranslated study of innate immunity and immunological control.
region of the APC gene that is substantially linked with Immune dysfunction leads to incorrect responses to
ASD was discovered. When comparing ASD cases and both internal and external stimuli, which can disrupt
controls, researchers found that the APC gene variant brain development in children [111] . A higher number of
was substantially more common in the former [131] . When NK cells, an increase in cytotoxicity in an unstimulated
PPAR ligand binds to the PPAR receptor, it activates the condition, and a decline in cytotoxicity in a stimulated
FAP gene, which causes activation of mTORC1, further condition, all have been seen among children with ASD.
leading to activation of NK cells that cause activation Reduced expression of HMGB3, NMUR1, and an altered
of HLA, causing elevation of IFN, due to which autism DAS of STAT4 are also associated with the genetic changes
occurs. However, azathioprine (AZA) negatively regulates of NK cells, along with overexpression of SPON2, IL2RB,
[29]
modulation of PPAR, which causes reduced activation of CX3CR1, and GZMB . Elevated NK cell counts, up to
[37]
AKT-mTOR signaling [110,132,133] . 40% higher, have been reported in people with ASD .
KIR and HLA are two types of receptors found on NK
6. Role of azathioprine in treatment of cells. Marçais et al. demonstrated that mTOR is critical
autism through mTOR and NK cell for the maturation of NK cells [112] . Activation of the Akt/
mTOR pathway was shown to be disproportionately high
Azathioprine is also known as Imuran and its chemical in reactive NK cells, as reported by Marçais et al. [112]
name is s-substituted 6-mercaptopurine. It is one of the Specifically, this was marked by an increase in the baseline
oldest pharmacologic immunosuppressive agents still in phosphorylation of direct and indirect targets of both
use today, and it was originally developed as a pro-drug mTOR complexes (mTORC1 and C2). The results revealed
that acts as a long-lasting form of 6-mercaptopurine. It that the modification of mTOR activity by external
has been used in various treatments, such as hematologic cytokines or pharmacological therapies was directly
malignancies, rheumatologic diseases, solid organ linked with NK cell activation. In addition, mTOR may
transplantation, and inflammatory bowel disease (IBD). control NK cell reactivity by incorporating cues other
This drug is a purine analogue whose mechanism of than NKIR ligands [112] .
action is at the level of DNA [134-136] . Gertrude B. Elion was
honored with the Nobel Prize in Medicine in 1988 for The PI3K-AKT-mTOR pathway is critical for
his work on “essential principles of developing drugs.” controlling immune cell growth, development, and
George Hitchings, who was a part of the team that both activation, including NK cells. Inducing NK cell
found 6-mercaptopurine and azathioprine, reported activation by IL-15 requires work from mTORC1. Mice
in vivo evidence and revealed that patients with bowel exposed to poly I: C or infected with MCMV exhibit
inflammation who were treated with AZA had a higher increased mTORC1 activity [116] . The adipogenesis in FAP

Volume 2 Issue 2 (2023) 14 https://doi.org/10.36922/an.391