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Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32 Page 284

Phenocopies of IEI
Recent progress in IEI research has revealed the conditions that mimic the IEIs summarized in previous
sections. For example, somatic mutations in NLRP3, TNSRSF6, KRAS, NRAS, and STAT5B revealed
clinical features of autoinflammatory syndromes resembling those caused by inherited or de novo germline
[9]
mutations of the above-described genes . In patients with late-onset autoinflammatory syndrome without
identifiable germline pathogenic variants, the possibility of somatic mutation may need to be considered.
Likewise, the production of autoantibodies against key mediators of inflammation, usually cytokines, may
also create phenocopies of the IEIs described above . In ASD subjects with late-onset deterioration, the
[9]
possibility of phenocopies of IEIs with the above-described mechanisms should be considered when
exploring treatment options.

VEXAS syndrome
Among autoinflammatory syndromes caused by somatic mutation, Vacuoles, E1 enzyme, X-linked,
Autoinflammatory, Somatic (VEXAS) syndrome is just recently described as an adult-onset monogenic
autoinflammatory disease caused by somatic mutations of the UBA1 gene. This condition is characterized
by severe adult-onset chronic inflammation associated with hematological disorders, most commonly
myelodysplasia syndrome . Despite the fact that this syndrome was only recently described, a fair number
[101]
of VEXAS syndrome patients have been described, indicating that this condition may not be
uncommon . UBA1 encodes one of the two E1 enzyme isoforms and E1 enzyme is crucial for
[101]
ubiquitylation, which is one of the cellular functions to terminate enzymatic actions. In the immune system,
this mutation results in uncontrolled activation of immune responses, resulting in autoinflammatory
[101]
syndrome . Multiple organs are affected, as is seen in patients with autoinflammatory syndrome caused by
germline mutations. The nervous system is also affected, manifesting symptoms of headache,
[102]
cerebrovascular accidents, serous meningitis symptoms, and sensory neuropathy . As for treatment,
biologics targeting IL-1, IL-6, and JAK have been used along with hematopoietic stem cell transplant
(HSCT) in severe cases . When dealing with difficult cases with negative genetic workup results in ASD
[101]
subjects, the possibility of somatic mutations may need to be considered, as illustrated in VEXAS syndrome.

Anti-cytokine autoantibodies
[9]
Anti-cytokine autoantibodies have also been recognized as phenocopies of IEIs . These autoantibodies are
thought to differ from anti-idiotypic agonistic antibodies that regulate immune balance for the prevention
of autoimmune conditions . For example, the production of antagonistic autoantibodies against IL-17 and
[103]
IL-22 has been implicated in the pathogenesis of chronic mucocutaneous candidiasis, since both IL-17 and
IL-22 are key cytokines produced by Th17 cells, exerting major defense against fungi [104,105] . Antagonistic
autoantibodies against IL-6 predispose affected subjects to pyogenic infection, with clinical features
resembling STAT3 deficiency or AD hyper IgE syndrome . During the era of the COVID pandemic, the
[105]
production of antagonistic autoantibodies against type 1 IFNs has been shown to be associated with an
increased susceptibility to severe COVID-19 in the elderly . However, such anti-cytokine autoantibodies
[63]
[106]
are also detectable in asymptomatic individuals and clinical manifestations are highly variable . In severe
COVID-19 cases, the presence of anti-IFN autoantibodies is detrimental in the absence of immune
[106]
memory, which generally exerts other arms of immune defense against viral infection . In addition, the
presence of anti-IFN autoantibodies may cause dysregulated immune responses and could lead to long-term
sequelae of COVID-19, now often referred to as long COVID. We have treated several ASD subjects with
long COVID. It is our experience that pre-existing difficult ASD behaviors make it challenging to diagnose
and treat long COVID symptoms in a timely manner. ASD subjects with components of IEIs described in
this review are likely more prone to produce such autoantibodies following potent immune stimuli such as