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Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32 Page 282

JAK inhibitors have also become increasingly popular for treating various autoimmune conditions,
including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), atopic dermatitis, etc. The actions
of a new generation of JAK inhibitors are more selective for specific JAKs, as opposed to the 1st generation
JAK inhibitors. In ASD subjects in whom type 1 IFN-induced neuroinflammation plays a role in their
behavioral symptoms or cognitive dysfunctions, orally available JAK inhibitors may provide an additional
treatment option. Interestingly, multiple open-label studies have reported the beneficial effects of baricitinib
for severe COVID-19 . With the increase in reports of the favorable effects of baricitinib, the FDA issued
[79]
an EUA (emergency use authorization) for its use as an adjunct treatment, with remdesivir, for hospitalized
COVID-19 patients older than 2 years of age. In ASD patients who have a risk of more significant
neuroinflammation following COVID-19, baricitinib may also offer another treatment option for
controlling post-COVID inflammation.

Immunodeficiency affecting PI3K/Akt/mTOR pathways
PI3k/Akt/mTOR pathways are crucial for immune functions, especially differentiation of Th17 vs. Treg cell
pathways, but these pathways are also crucial for neuronal cell activation and neuronal plasticity, as shown
[80]
in patients diagnosed with tuberous sclerosis (TS) . Dysregulation of these signaling pathways caused by
multiple pathogenic gene variants including TS complex 1/2 are now categorized as activated PI3Kinase
[81]
delta syndrome with highly variable clinical features . As expected, apart from the immune system, this
condition affects the nervous system, frequently exhibiting neurodevelopmental delay and learning
disabilities along with autoimmune and autoinflammatory complications [81-83] .

Class IA PI3kinase (PI3K) molecules consist of a p110 catalytic subunit and a regulatory subunit, and
catalyze phosphatidylinositol 4.5 bisphosphate to the phosphatidylinositol 2,3,4 trisphosphate (PIP3), which
[84]
serves as a secondary messenger for cell proliferation, activation, and differentiation . Its catalytic unit
(p110) is coded by genes PIK3CA, PIK3CB, and PIK3CD. PIK3CD is predominantly expressed in
[84]
leukocytes . Its regulatory subunits are coded by PIK3R1, PIK3R2, and PIK3R3 . AD, GOF mutations of
[84]
PIK3CD (Activated PI3Kinase delta syndrome (APDS) 1) or AD, LOF mutations of PIK3R1 (APDS2) can
cause overactivation of PI3K and downstream Akt/mTOR pathways in immune cells and other lineage cells.
This results in complex clinical features of immunodeficiency and autoimmune/autoinflammatory
symptoms, illustrating the importance of balanced activation in this signaling pathway in immune cells [81,85] .
These patients present with clinical features overlapping with both type 1 interferonopathies and
CAPS [81,85,86] . Regulatory proteins for PI3K activation also affect this signaling pathway and pathogenic
variants coding for such regulatory molecules cause clinical features resembling APDS: such conditions are
often referred to as APDS-like syndrome. LOF PTEN pathogenic variants are best known for causing
APDS-like syndrome .
[85]
(1) APDS1 and APDS2: As described above, the clinical features of APDS1/APDS2 are highly variable.
However, in general, these patients present with combined immunodeficiency with evidence of impaired
humoral and cellular immunity. Impaired humoral immunity is typically suspected when they suffer from
recurrent sinopulmonary infection caused by community-acquired organisms covered by infant vaccines
[83]
(Prevnar and Hib). Ocular infection is reported to be frequently seen in APDS patients . Impaired
immunity exerted by T cells and innate immune cells is also impaired, as evidenced by an increase in the
frequency of viral and opportunistic infection: asymptomatic viremia of CMV and EBV is common , as is
[83]
persistent or recurrent herpes infection . Chronic viral infection may lead to benign lymphadenopathy and
[87]
hepatosplenomegaly [83,86] . In addition to symptoms associated with immunodeficiency, APDS patients also
manifest autoimmune conditions typically after the first decade of life: cytopenia and glomerulonephritis
are common, along with an increase in the risk of malignant complications . Since both APDS1/APDS2
[88]