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Allergology International
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a r t i c l e i n f o a b s t r a c t
Article history: Clinically and pathologically, the patients with hyper-IgE syndrome present similar skin manifestations
Received 28 May 2021 to common atopic dermatitis. The original hyper-IgE syndrome is characterized by diminished inflam-
Available online 18 August 2021 matory response, in combination with Staphylococcus aureus skin abscess and pneumonia followed by
pneumatocele formation. These immunological manifestations are frequently associated with skeletal
Keywords: and connective tissue abnormalities. We previously identified that major causal variants of the hyper-IgE
Atopy
syndrome are dominant negative variants in the STAT3.
IgE
In addition to the identification of new causative variants for the disorders similar to the original
Pathogenesis
Primary immunodeficiency
hyper-IgE syndrome, causative variants for new types of hyper-IgE syndrome centered only on atopy,
STAT3 high serum IgE levels, and susceptibility to infection, but not associated with diminished inflammatory
response, pneumatocele formation, and connective tissue manifestations, have been identified. Recent
discovery identified a novel zinc finger protein that regulates STAT3 transcription. Investigation of IL6ST
variants disclosed that IL6ST/IL6R cytokine receptor plays a crucial role for the signal transduction up-
stream of STAT3 in the pathogenesis of the original hyper-IgE syndrome. Even if the same IL6ST variants
are used for the signal transduction of IL-6 family cytokines, the signaling defect is more severe in IL-6/IL-
11 and milder in LIF. The fact that the non-immune manifestations of the gain-of-function mutations of
TGFBR1 and TGFBR2 are similar to the those of dominant negative mutations of STAT3 provide a clue to
elucidate molecular mechanisms of non-immune manifestations of hyper-IgE syndrome. Research on
this hereditary atopic syndrome is being actively conducted to elucidate the molecular mechanisms and
to develop new therapeutic approaches.
Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.alit.2021.07.007
1323-8930/Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
408 Y. Minegishi / Allergology International 70 (2021) 407e414
kinase 2 (TYK2)-LOF, (7) Serine Peptidase Inhibitor Kazal Type 5 It is considered that many of the clinical signs of STAT3-DN HIES
(SPINK5)-LOF, (8) Transforming Growth Factor Beta Receptor likely reflect defects of the diverse functions of STAT3 in vivo.
(TGFBR) 1/2-GOF, (9) Caspase recruitment domain-containing Most of the patients with STAT3-DN HIES suffer from recurrent
protein 11 (CARD11)-DN. This has more information compared to staphylococcal infections, beginning in infancy and predominantly
classical autosomal dominant (AD) and AR classification, and easier involving the skin and lungs. Staphylococcus aureus is the bacterium
to understand for non-specialists of PIDs. Because most of the pa- most frequently isolated from the patients, but Streptococcus
tients with phosphoglucomutase 3 (PGM3)-partial LOF displayed pneumoniae, Haemophilus influenzae, and enteric Gram-negative
impaired T-cell proliferation in response to PHA, anti-CD3, purified bacteria are occasionally isolated from the patients. Fungal in-
protein derivative (PPD), or tetanus toxoid (TT),14,15 I classified this fections, including mucocutaneous candidiasis and pulmonary
disorders into combined immunodeficiency (CID) category and will aspergillosis, are also common in STAT3-DN HIES. Eczema usually
not discuss in this article. begins during the neonatal period, earlier than the onset of com-
mon atopic dermatitis. Patients with HIES are usually free from
other allergic manifestations, such as allergic rhinitis, asthma, food
STAT3-DN allergy, and anaphylaxis.
STAT3-DN HIES is associated with non-immunological mani-
STAT3 is a transcription factor that binds to the STAT3- festations, including characteristic facial appearance, pneumato-
responsive elements in the promoters of various genes, including cele formation, fracture due to minor external force (pathological
acute-phase reaction proteins (Fig. 1).16,17 STAT3 plays a critical role fracture), osteoporosis, scoliosis, joint hyperextension, delayed loss
in responses to many cytokines and growth factors, including gc of deciduous tooth. There is an increased rate of malignancy, pre-
cytokines (IL-2, IL-7, IL-9, IL-15, and IL-21), GP130 cytokines (IL-6, dominantly malignant lymphoma. In most STAT3-DN HIES, the
IL-11, IL-27, IL-35, IL-39, cardiotrophin-1 (CT-1), cardiotrophin-like serum IgE levels are elevated, frequently higher than 2000 IU/ml.
cytokine factor 1 (CLCF1), oncostatin M (OSM), and leukemia However, there are cases with only mildly elevated IgE and the IgE
inhibitory factor (LIF), ciliary neurotrophic factor (CNTF)), type 1 can fall into the normal range. Specific IgE against S. aureus and
and type 2 IFNs (IFNa, IFNb, and IFNg), IL-10 family cytokines (IL-10, Candida albicans is elevated, and it is thus considered that antigen-
IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29), receptor tyrosine specific IgE production is enhanced in this disorder. Eosinophilia is
kinases (epidermal growth factor (EGF), fibroblast growth factor present in about 90% of the patients, and the number of eosinophils
(FGF), fms like tyrosine kinase 3 (Flt3) ligand, growth hormone in the peripheral blood was mostly higher than 700/ml.
(GH), insulin-like growth factor 1 (IGF1), macrophage colony- The other immunoglobulins levels are generally normal, and
stimulating factor (M-CSF), and platelet-derived growth factor antibody responses to vaccination are impaired at least some of the
(PDGF), as well as IL-5, IL-12, IL-23, granulocyte-colony stimulating HIES patients.20,21
factor (G-CSF), leptin, and platelet activating factor (PAF). A null STAT3 mutations are localized mostly to the DNA binding, SH2,
mutation in the STAT3 gene in mice demonstrated that STAT3 was and transactivation domain (Fig. 2). Mutations are in most part
essential for the survival of the embryo around the time of im- missense mutations and some small in-frame deletions. So far, there
plantation.18 The mice with tissue-specific deletions of STAT3 have is no convincing report that STAT3 haploinsufficiency can cause this
shown STAT3 to play a crucial role in cell proliferation, survival, syndrome. STAT3 protein is present and can dimerize with wild type
migration, apoptosis and inflammation in various tissues, organs STAT3 protein, but inhibit STAT3 signaling of wild-type allele, i.e.
and cells, including skin, respiratory epithelium, thymic epithelium, function as dominant negative. The number of Th17 cells and
liver, mammary glands, neurons, lymphocytes, and macrophages.19 memory B cells in peripheral blood is decreased. STAT3 signal
Fig. 1. Signal transduction of IL6-IL6R-IL6ST. IL6 binds to IL6R with low affinity, which is not sufficient for signal transduction. IL6-IL6R complex binds to IL6ST to initiate signaling.
Soluble IL6R can be produced by alternative splicing or proteolytic cleavage, which can also initiate signaling. Hexameric IL6-IL6R-IL6ST complex induces phosphorylation of JAKs,
then JAKs phosphorylate tyrosine residues in the cytoplasmic domain of GP130, leading to the recruitment and activation of STAT1, STAT3, and, STAT5. Phosphorylated STATs
dimerize and translocated into the nucleus to the IL6-responsive elements identified in the promoters of various acute-phase protein genes. IL-6 signaling is disrupted by the
mutations of the IL6R, IL6ST, and STAT3 genes.
Y. Minegishi / Allergology International 70 (2021) 407e414 409
Fig. 2. Structure and mutations of STAT3. Structure and mutations of STAT3 is shown. Most of the mutations are located in the DNA binding, SH2, and transactivation domain. There
are three hot spots for the mutations, i.e. R382, V463, and V637, shown with red arrows. Approximately 60% of the mutations are located in the hot spots.
dysfunction impairs IL-6 response in the liver, thus impairing patients are middle east origin and clinically similar to STAT3-DN
elevated acute phase protein such as C reactive protein (CRP). HIES patients, suffering from eczema, mucocutaneous candidiasis,
Therefore, it is desirable to use an earlier marker such as IL-6 as a and elevated serum IgE levels. The patients, however, showed
severity marker in the early stage of infection. In addition, when a stronger inflammatory responses and fewer non-immunological
child suffers from an early stages of severe infection, it is charac- manifestations compared to STAT3-DN HIES. ZNF341 is a previ-
teristic that the feeling of seriousness is lacking. Thus, it is necessary ously unexplored putative transcription factor containing 12C2H2
to pay close attention when you follow up this HIES patients, and it is zinc finger (ZF) domains (Fig. 3). The mutations in ZNF341 are ho-
recommended that the patients to be followed by PID specialists. mozygous nonsense or frameshift mutations that induce truncation
If suspected with newborn rash in combination with S. aureus of the ZNF341 protein, but interestingly, nonsense mediated mRNA
infections and high serum IgE levels, in theory, we could diagnosis decay does not operate in this gene and truncated ZNF341 protein
STAT3-DN HIES in newborn period. Early definitive diagnosis and can be expressed at least some of the patients. ZNF341 proteins do
start of prophylaxis might be able to prevent pneumatocele for- not interact with wild-type ZNF341 even after stimulation, and two
mation to improve quality of life of the HIES patient. But in practice, of the mutant proteins (Q195X and R302X) are retained in the
because of the rarity of this syndrome, it is difficult to diagnose this cytoplasm, suggesting these mutants are complete LOF. Chromatin
disorder in the neonatal period. Prophylactic antibiotics and anti- immunoprecipitation-sequencing (ChIP-seq) analysis with the
fungals are given in most cases of STAT3-DN HIES.22,23 As an anti- anti-ZNF341 mAb identified that strongest ZNF341-binding site
bacterial agent against S. aureus, trimethoprim/sulfamethoxazole is was located in the STAT3 promoter region and strong ZNF341
generally used. It is relatively difficult to be resistance to the drug binding was also observed in the STAT1 promoter and ZNF341
even when used for a long period of time. In addition, penicillinase- intron 1. There are two isoforms in ZNF341 protein, both isoforms
resistant penicillin antibiotic flucloxacillin and macrolide azi- induced expression from the STAT1 and STAT3 promoters by re-
thromycin may be administered. Since S. aureus is resident on the porter assays. Three of the five mutants induced no luciferase ac-
skin at a high rate, reduction of the amount of S. aureus by a bleach tivity, confirming that the Q195X, R302X and K355fs mutant alleles
bath may improve atopic dermatitis. Prophylactic administration of were complete LOF. By contrast, the Y542X mutant, which can bind
anti-fungal agents such as itraconazole, voriconazole, and pos- to the canonical motif on Electrophoresis Mobility Shift Assay
aconazole, which are sensitive to Aspergillus, is also recommended. (EMSA) and in pulldown assay. The mutant yielded intermediate
Long term use of these drug is associated with adverse effects.24 levels of luciferase activity, suggesting that it is partial LOF, at least
Periodical blood chemistry and careful monitoring of drug serum when overexpressed.
levels are a critical component of this prophylaxis. In some patients The patients had decreased Th17 cells, and lower central
with STAT3-DN HIES, surgical removal of the pneumatocele may be memory CD4þ and CD8þ T cells, higher proportions of naive CD4þ
considered, but the frequency of complications is high, and it is T cells, but had normal proportions of Treg cells, gd T cells, and
necessary to carefully consider the surgical indication.23 Immuno- invariant NKT cells. The lymphocyte subset of ZNF341-LOF closely
globulin replacement therapy is recommended for children with resembles that of STAT3-DN HIES. However, by closely looking at
this disease because of the deficiency in the production of specific the cellular phenotype of the ZNF341 deficiency, the pathogenesis
antibodies. of this HIES might be more complex than originally conceived.
As a curative treatment, hematopoietic stem cell transplantation Immortalized cell lines, including EBV-LCL, SV40 transformed fi-
(HSCT) has not been performed much because of the symptoms of broblasts, and Herpesvirus saimiri (HVS) immortalized T cell lines,
non-hematopoietic tissues in STAT3-DN HIES, but impaired differ- from the patients displayed no major STAT3-DN phenotype.
entiation of Th17 cells is involved in the development of bacterial Furthermore, ZNF341 deficient monocytes are not functionally
and fungal infections. Therefore, hematopoietic stem cell trans- impaired in STAT3 signaling, although the expression levels of
plantation is being considered in cases where it is difficult to con- STAT3 is lower compared to wild-type ZNF341. Interestingly, STAT3
trol lung infections with antibiotics. Application of HSCT to STAT3- activity is impaired in ZNF341-deficient B cells and STAT3 auto-
DN HIES is still controversial and future studies are needed. Organic induction is impaired in ZNF341-deficient naïve CD4þ T cells,
changes in the lungs (bronchiectasis and pneumatocele) are
important factors in the prognosis of the patients, and regular
follow-ups including chest computed tomography (CT) are rec-
ommended. Vaccination, including live vaccines, are well tolerated,
with the exception of the pneumococcal polysaccharide vaccine,
which might induce severe necrotic reactions.25
ZNF341-LOF
Fig. 3. Structure and mutations of ZNF341. Structure and mutations of ZNF341 is
shown. Each shaded box indicates zinc finger (ZF) domain. Nuclear localization signal
Homozygous mutations in the ZNF341 gene were reported in 19 (NLS) is located in ZF2-ZF3 and ZF10-ZF11. LOF mutations in the ZNF341 are shown in
patients from 10 families as a new type of HIES.26,27 Most of the red.
410 Y. Minegishi / Allergology International 70 (2021) 407e414
IL6ST-partial LOF
infection. No viral or fungal infections were reported. Serum IgG, impaired IL-12 signaling, Th2 biased differentiation might be more
IgA, and IgM levels were mildly reduced and IgE levels was elevated easily obtained under certain circumstances. Genetic modifier
in both patients, but in one patient the increase was very modest genes are also a possibility, because of the difference in the IL-6
for HIES; 787 kU/liter (normal range 0e100 kU/liter). signaling between the two TYK2-LOF patients with atopic mani-
One mutation in the patients was a homozygous frameshift, festations, but so far we were not successful to pin point a genetic
G183Efs, and the other was a homozygous missense, I279N, modifier gene.
causing normal protein expression, but impaired function. Neither
was found in the genome Aggregation Database (gnomAD). Pa- SPINK5-LOF
tient T cells showed impaired IL6-mediated phosphorylation of
STAT3 and STAT1, which was restored by the introduction of wild- Comel-Netherton syndrome is an AR PID characterized by ich-
type IL6R. The patients had an increased proportion of Forkhead thyosiform erythroderma, trichorrhexis invaginata (bamboo hair),
box P3 (FOXP3) þ regulatory T cells, with increased expression of and atopic manifestations. In 1949, Comel reported this disorder is
FOXP3 protein. characterized by erythroderma associated with itchymosis.41 In
Based on these findings, it is hypothesized that the disruption of 1958, Netherton reported that this disorder is associated with
cellular responses to IL-6 alone can underlie most of the features of characteristic bamboo hair.42 The molecular cause of this disorder is
the original HIES.36 Although this is a fascinating hypothesis due to LOF mutation of Serine protease inhibitor, Kazal type 5 (SPINK5),
its simplicity, but negative data against this hypothesis is that pa- mainly expressed in skin and mucosa.43 The identification of this
tients having neutralizing autoantibodies against IL-6 present with disorder revealed that the serine protein inhibitor plays a critical
the similar symptoms as IL-6R LOF with respect to reduced in- role in the pathogenesis of PID and formation of normal hair shape.
flammatory response but not with atopic manifestations. More Due to SPINK5-LOF mutations, serine protease activity increases
studies are need, especially to identify a molecular mechanism how in the stratum corneum, resulting in increased exfoliation and
IL-6 and/or other signaling molecules regulate atopic manifesta- epidermal barrier dysfunction and immune disorders. Immune
tions in STAT3-DN HIES and related disorders. abnormalities were originally considered to be secondary to the
excessive invasion of allergens due to abnormal epidermal barrier
function. But more recently, intrinsic immune abnormalities in
TYK2-LOF
SPINK5 deficiency was reported.44 Immediately after birth, ich-
thyosis begins on the face and spreads throughout the body.
TYK2 is a member of the Janus kinase family (JAK1, JAK2, JAK3,
Bamboo hair presents with invaginated hair fissures, twisted hairs,
and TYK2) that plays a crucial role in the signaling of subset of
or nodular hair splits. In severe cases, SPINK5-LOF is life-
cytokine receptors including. IFN-a/b, IL-10, IL-12, and IL-23.
threatening, and even in mild cases, it presents with systemic
Binding of the ligand to these cytokine receptor induces confor-
features including failure to thrive., aminoaciduria, susceptibility to
mational changes and activation of the JAKs kinases via phos-
infection, defect in thermoregulation, and dehydration.
phorylation. The JAKs phosphorylate the intracellular part of the
Atopic manifestations include food allergies, cedar pollinosis,
receptor which create a docking site for the STATs. STATs are sub-
bronchial asthma, and atopic dermatitis. Laboratory examination
sequently phosphorylated and translocated to the nucleus to acti-
shows an increase in total IgE and an increase in various allergen-
vate the transcription of the target genes.
specific IgE, and eosinophilia. Markedly high trypsin-like enzyme
TYK2-LOF is a rare molecular origin of PID, which was described
activity in the stratum corneum, attenuation of SPINK5 protein
in 10 patients from eight unrelated families.37e40 The first case is a
expression by immunostaining in the epidermis. Mouse models
Japanese boy, living in Tokyo metropolitan area with westernized
lacking the Spink5 also have the similar clinical features as humans,
life style, suffering from mycobacterial and skin viral infections
such as abnormal epidermal detachment and abnormal hair shape.45
associated with hyper IgE phenotype.37 Later, Dr. Casanova's group
identified five families with TYK2 deficiency. The patients live in
TGFBR1/2-GOF
Turkey, Morocco, Iran and Argentina. The patients presented with
mycobacterial and viral disease without hyper IgE phenotype.37 In
TGF-b plays an important role in normal development and ho-
addition, another TYK2-LOF patient with features of hyper IgE
meostasis. TGFBR1 and 2 are serine/threonine and tyrosine kinases.
phenotype was reported in 2016.39 Common features of all the
Canonical TGF-b signaling ignites when TGFB1/2/3 binds to
patients are intracellular bacterial infections including Mycobac-
TGFBR2, which recruits and phosphorylates TGFBR1. Then, acti-
terium and Salmonella and various viral infections including herpes
vated TGFBR1 phosphorylates mothers against decapentaplegic
simplex virus infection and molluscum contagiosum. Only two
homolog 2 (SMAD2) and SMAD3, which further recruit SMAD4 and
patients, however, present hyper-IgE phenotype. In these two pa-
translocate to the nucleus where it regulates the transcription of
tients, the mutations are C70HfsX21 and P216RfsX14, it is
TGF-b target genes.46 Loeys-Dietz syndrome (LDS), caused by the
unlikely that the phenotypic difference is caused by the
GOF mutations of TGFBR1/2, is characterized by the triad of arterial
genotypeephenotype relationship (Fig. 5). Environmental factors
tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft
might be associated with this phenotypic difference. Because TYK2-
palate.47 Most of the mutations are heterozygous missense muta-
LOF patients have defects in Th1 cell differentiation due to the
tions, located in cytoplasmic protein kinase region of the receptors
(Fig. 6). The patients have craniofacial involvement consisting of
cleft palate, craniosynostosis, and hypertelorism. Most of these
non-immunological manifestations overlap with those of STAT3-
DN HIES.
Atopic diseases of LDS include asthma, food allergy, atopic
dermatitis, allergic rhinitis, and eosinophilic gastrointestinal dis-
ease, therefore, atopic manifestations are not limited to the skin.
Fig. 5. Structure and mutations of TYK2. TYK2 is a non-receptor tyrosine kinase,
In immune organs, TGFBR1/2-GOF HIES patients show excessive
consisting of FERM, SH2, pseudokinase, and kinase domain. The locations of homo- nuclear accumulation of phosphorylated Smad2 in the thymus
zygous LOF mutations are shown in red. compared to age-matched unaffected individuals. Additionally,
412 Y. Minegishi / Allergology International 70 (2021) 407e414
CARD11-DN
Fig. 7. Signal transduction pathway and structure and mutations of CARD11. CBM complex is located in the downstream signal transduction pathway of TCR and BCR, which
transmit a signal to mTOR and NF-kB pathway. N-terminal CARD domain of CARD11 and BCL10, coiled-coil domain of CARD11 and CASP domain of MALT1 interact each other to
form a CBM complex. Most of the disease-causing mutations are missense DN mutations, shown in red, are located in the CARD, coiled-coil, and GUK domain.
Y. Minegishi / Allergology International 70 (2021) 407e414 413
interactions with MALT1. Unlike CARD/CC-associated GOF muta- which definition is adopted, elucidation of the etiology and path-
tions found in patients with BENTA, these mutations did not drive ophysiology of HIES is helpful for elucidation of the human immune
constitutive NF-kB activation in the absence of antigen receptor system, mechanism of atopic diseases, and the development of new
stimulation. therapeutic approaches.
Atopic disease was the prominent feature in most patients with At present, distinguishing HIES patients from common atopic
CARD11-DN (89%), most frequently presenting with atopic disorders, especially early in life, is not an easy task. Consultation
dermatitis (73%) but also including asthma (55%), food allergies with the PID specialists is recommended, however, even for PID
(32%), and eosinophilic esophagitis (7%). However, atopy was mild specialists, it is difficult to distinguish the HIES from common
or absent in at least 10% of the patients, with no discernible dif- atopic disorders. In this setting, a detailed family history and clin-
ferences in CARD11 signaling function. Furthermore, unrelated ical course associated with specific laboratory tests for HIES is
patients with the same mutation and even family members essential. From a clinical standpoint, early exclusion of CID is
harboring identical mutations demonstrated differences in the especially important, because the number of CID patients with high
variety and severity of manifestations. These observation suggests serum IgE levels is relatively large and earlier and curative treat-
that environmental factors or genetic modifiers might be associ- ment might be crucial for the prognosis of the patients. Eventually,
ated with the development of atopic disorders in CARD11-DN HIES. HIES can be distinguished from common atopic disorders by
Insufficient humoral responses, such as low IgM levels, appear to be observing the clinical course, usually the development and recur-
a common in impaired CARD11 signaling with or without increased rence of unusual infectious episodes or the association of non-
IgE levels. A number of families presented with more severe hu- immunological manifestations. If there is enough evidence to
moral defects resembling common variable immunodeficiency indicate that the patients are different from common atopic dis-
(CVID), which may be contributed by intrinsic defects in B-cell and eases, genetic testing panels for the causative genes of HIES is the
extrinsic defects in T cells. method of definitive diagnosis.
Cutaneous viral infections, including molluscum contagiosum There are challenges in elucidating the pathogenesis and
and herpes simplex virus 1 infections, were also common to the pathophysiology of HIES. Regarding IL-6R-LOF HIES, the discussion
CARD11-DN HIES patients. Impaired CD8þ T-cell immuno- was based on the clinical and laboratory findings of only two pa-
surveillance could be a causal factor. Interestingly, patients with tients. At present, it is technically difficult to completely rule out
BENTA carrying CARD11-GOF mutations often present with mol- the possibility that modifier genes may affect the phenotype of
luscum contagiosum and Epstein-Bar virus infections. Both these HIES patients. Especially, if the number of the patients is
CARD11-GOF and CARD-DN mutations resulted in similar skin viral limited and there are some discrepancies in the phenotype of the
infections. patients, such as severe and mild atopy. Strong regional bias of the
HIES patients is also a concern for the interpretation of patho-
Other PIDs with high serum IgE levels genesis of HIES, because it is well known that environmental fac-
tors are deeply involved in the pathogenesis of atopic disorders.
Several other PIDs mainly from the CID category are characterized Although PID research has witnessed many examples of the same
by high serum IgE levels and susceptibility to infections. The PIDs, genetic abnormality has different phenotypes between humans
including WiskotteAldrich syndrome, DOCK8 deficiency, PGM3 and mice, but it is still necessary to make good use of mouse
deficiency, and Omenn Syndrome, are all characterized by decreases models for the understanding of PID pathogenesis. More new ge-
in T-cell numbers and an impairment in T-cell proliferation. Causa- netic causes of HIES are likely to be identified in the near future.
tive genes of Omenn syndrome include Recombination-activating Many new patients with HIES are likely to be identified by
gene (RAG)1, RAG2, IL2RG, IL7R, DNA ligase 4 (LIG4), DNA cross-link worldwide application of recently developed genetic technologies.
repair 1C (DCLRE1C), RNA component of mitochondrial RNA process- These advances are certain to help HIES research to elucidate the
ing endoribonuclease (RMRP), adenosine deaminase (ADA), protein ki- understanding of human immunology and the development of
nase, DNA-activated, catalytic (PRKDC). The high serum IgE levels may treatments for atopic disorders.
result from weak TCR signaling insufficient to induce Treg cells, and/
or an imbalance in the Th1/Th2 differentiation. Immune- Acknowledgements
dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
syndrome is caused by the LOF mutations in the FOXP3 gene, is also This work was supported by AMED under grant numbers
one of the PID with high serum IgE levels. This indicates that the lack JP19ek0109218 and JP16ek0109014, and KAKENHI under grant
of regulatory T cells alone is sufficient to induce high serum IgE levels numbers 21H0288210, Research Cluster Program and Industry-
in the patient. It is necessary to exclude these disorders/genes to Academia Collaboration Grant of Tokushima University.
diagnose HIES.
Conflict of interest
Concluding remarks The author has no conflict of interest to declare.
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