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Expert Review of Clinical Immunology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20
Cellular mechanisms and clinical applications
for phenocopies of inborn errors of immunity:
infectious susceptibility due to cytokine
autoantibodies
Rui Sun, Yating Wang & Hassan Abolhassani
To cite this article: Rui Sun, Yating Wang & Hassan Abolhassani (2023): Cellular mechanisms
and clinical applications for phenocopies of inborn errors of immunity: infectious
susceptibility due to cytokine autoantibodies, Expert Review of Clinical Immunology, DOI:
10.1080/1744666X.2023.2208863
To link to this article: https://doi.org/10.1080/1744666X.2023.2208863
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REVIEW
Cellular mechanisms and clinical applications for phenocopies of inborn errors of
immunity: infectious susceptibility due to cytokine autoantibodies
Rui Sun
a
, Yating Wang
a
and Hassan Abolhassani
a,b
a
Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden;
b
Research Center for
Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
ABSTRACT
Introduction: With a growing knowledge of Inborn errors immunity (IEI), immunological profiling
and genetic predisposition to IEI phenocopies have been developed in recent years.
Areas covered: Here we summarized the correlation between various pathogen invasions, autoanti-
body profiles, and corresponding clinical features in the context of patients with IEI phenocopies. It
has been extensively evident that patients with anti-cytokine autoantibodies underly impaired anti-
pathogen immune responses and lead to broad unregulated inflammation and tissue damage.
Several hypotheses of anti-cytokine autoantibodies production are summarized here, including
a defective negative selection of autoreactive T cells, abnormal germinal center formation, mole-
cular mimicry, HLA class II allele region, lack of auto-reactive lymphocyte apoptosis, and other
possible hypotheses.
Expert opinion: Phenocopies of IEI associated with anti-cytokine autoantibodies are increasingly
recognized as one of the causes of acquired immunodeficiency and susceptibility to certain patho-
gen infections, especially facing the current challenge of the COVID-19 pandemic. By investigating
clinical, genetic, and pathogenesis autoantibodies profiles associated with various pathogens’
susceptibilities, we could better understand the IEI phenocopies with anti-cytokine autoantibodies,
especially for those that underlie life-threatening SARS-CoV-2.
ARTICLE HISTORY
Received 1 February 2023
Accepted 26 April 2023
KEYWORDS
Inborn errors of immunity;
primary immunodeficiency;
phenocopies; autoantibody;
interferons; cytokines;
interleukins; SARS-CoV-2
1. Introduction
Anti-cytokine autoantibodies (autoAbs) are present in most
healthy individuals and function regulatory in constraining
excessive immune responses to cytokines [1,2]. However,
high levels of neutralizing anti-cytokine autoAbs are pro-
duced in several pathological scenarios and lead to mani-
festations similar to those in IEI, such as ant-IL-17 A/F, anti-
IL-22 autoAbs in chronic mucocutaneous candidiasis (CMC),
anti-IFN-γ autoAbs in mycobacterial susceptibility, anti-IL-6
autoAbs in severe Staphylococcus spp. infection, anti-GM-CSF
autoAbs in Pulmonary alveolar proteinosis (PAP), and anti-
type I IFNs autoAbs in severe COVID-19 [3]. Anti-cytokine
autoAbs are of varied frequencies among different age
groups and associated with different infectious phenotypes,
together with anti-complement autoAbs and somatic gene
alterations as a separate entity termed ‘phenocopies of
inborn errors of immunity (IEI)’ based on the International
Union of Immunological Societies (IUIS) classification [3].
Anti-cytokine autoAbs are increasingly recognized as
the cause of acquired immunodeficiency and dysregula-
tion of the immune system, contributing to increased
susceptibility to the same viral, bacterial, and fungal
pathogens as germline mutations leading to inborn errors
of the corresponding cytokine, interleukins (ILs) and
interferons (IFNs), mainly in the context of immunocom-
petence [4,5]. In the past 3 years, the COVID-19 pandemic
affect the whole world, resulting in 760 billion reported
cases and 6.8 billion deaths. Currently, anti-type I IFNs
autoAbs have been widely confirmed to contribute to
severe COVID-19 pneumonia cases and caught increasing
attention to infectious susceptibility due to anti-cytokine
autoAbs. Moreover, de novo autoAbs elicited by SARS-CoV
-2 further contributed to the post-COVID-19 sequelae,
indicating an urgent need to improve the knowledge of
IEI phenocopies associated with various pathogen infec-
tions. This review provided a comprehensive overview of
clinical, genetic, pathogenesis and cytokine-autoAbs pro-
files associated with the recently identified phenocopies
of IEI.
2. Main hypotheses underlying de novo autoAbs
generation
Several hypotheses of cytokine-autoAbs production were
proposed including aberrant negative selection of autoreac-
tive T cells, HLA class II allele, abnormal germinal center
formation, molecular mimicry, and defective apoptosis
(Figure 1).
CONTACT Hassan Abolhassani hassan.abolhassani@ki.se Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute,
NEO, Blickagangen 16, Stockholm SE-14157, Sweden
Supplemental data for this article can be accessed online at https://doi.org/10.1080/1744666X.2023.2208863.
EXPERT REVIEW OF CLINICAL IMMUNOLOGY
https://doi.org/10.1080/1744666X.2023.2208863
© 2023 Informa UK Limited, trading as Taylor & Francis Group
2.1. Abnormal negative selection of autoreactive T cells
Autoimmune Regulator (AIRE) is thought to be responsible for
turning on the expression of genes coding tissue-specific
antigens in the thymus, thus playing an important role in
shaping the T-cell repertoire through a negative selection of
autoreactive T cells in the thymus [6]. This gene has also been
shown to be expressed in secondary lymphoid organs and
contributes to both central and peripheral tolerances [7,8].
The biallelic deleterious germline variants of the AIRE gene
lead to a rare but severe inherited IEI known as Autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED). APECED leads to damage of multiple internal
glands, mainly insulin-producing pancreatic islets, adrenals,
thyroid, and parathyroid glands and shows susceptibility to
fungal infections, particularly candidiasis [9–11]. The main
pathogenic mechanisms are believed to be T cell-mediated,
in which defective AIRE directly affects the deletion of auto-
reactive T cells in the thymus, and promotes a broad range of
autoAbs against various self-antigens, targeting endocrine and
other tissue antigens and cytokines, especially IFNs [12,13].
However, little is known about the role of T cell defects on
B cell stimulation and autoAbs production in APECED patients.
The abnormal negative selection also underly the autoAbs
production in thymoma and myasthenia gravis (MG associated
Article highlights
●More than 1200 reported IEI phenocopy cases with at least one type
of anti-cytokine autoAbs were summarized from the perspectives of
genetic, clinical manifestation and pathogen susceptibility.
●As an expanding universe, studies of phenocopies of human inborn
errors of immunity provided us with forecast pathogenesis, clinical
phenotypes, and possible therapy strategy when infectious diseases
widely spread. Insight into autoimmune diseases (including APECED,
Thymoma, SLE, RA), several main hypotheses illustrated the possible
mechanisms of abnormal autoAbs generation.
●IEIs patients with impaired cytokines pathway (including IFN-γ, IL-6,
IL12, IL17A/F, IL22, Type I IFN, and GM-CSF) due to single genetic
defects revealed mechanisms of cytokines in the host defense.
Various anti-cytokines autoAbs had been associated with several
pathogens, including bacteria, viruses, and fungi.
●aAbs-IFN-γ positive patients have a broad infectious spectrum of
bacteria (especially on Mycobacteria, Salmonella), viruses (mainly
VZV), and fungi. aAbs-IL-6 positive cases present higher severe bac-
terial infection (mainly Streptococcus spp., Staphylococcus spp.). aAbs-
IL17A/F and/or aAbs-IL-22 show higher susceptibility to the virus
(mainly VZV, HSV and SARS-CoV-2) and fungi (mainly C. albicans).
AutoAbs against type I IFN are the basis of severe viral infection
including SARS-CoV-2, VZV, HSV, CMV, IVA, IVB, YFV-17d vaccine.
●aAbs-GM-CSF positive individuals associated with higher susceptibil-
ity to bacteria (Nocardia spp. and Mycobacteria spp.) and fungi
(Candida spp.). Insight of associations of pathogen and autoAbs
profiles highlighted susceptibility to infectious risk factors, clinical
management, pre-diagnose strategies and prognostic estimation of
these patients with IEI phenocopies due to anti-cytokine autoAbs.
Figure 1. Infectious susceptibility due to cytokine autoantibodies. Preexisting anti-cytokine/interleukine autoantibodies lead to susceptibility to pathogen invasion,
followed by broad unregulated inflammation and tissue damage. During this process, abnormal negative selection in the thymus, aberrant germinal center
formation, molecular mimicry, dysregulation of cell apoptosis, and dysfunctional immune clearance further contributed to de novo autoantibodies generation and
following autoimmune complications from head to toe.
2R. SUN ET AL.
with Good’s syndrome), this IEI is also featured with a high
level of anti-type I IFN autoAbs production, but the underlying
germline genetic cause has not been yet identified [14,15].
Besides MG, thymoma is highly related to autoimmune ence-
phalitis [16,17], acquired neuromyotonia [18,19]. Among these
clinical conditions, MG is the single most common thymoma-
associated neurological autoimmune disease (~30–40%)
caused by autoAbs against neuromuscular-associated pro-
teins. One explanation regarding the dysfunctional negative
selection can be attributed to abnormalities of the thymus, in
which immature thymocytes are dysregulated during their
maturation toward CD4+ or CD8+ T cells, thus contributing
to the failed central tolerance and development of a variety of
autoimmune symptoms [20]. Moreover, both thymoma and
AIRE mutations seem to lead to a severer and broader range
of autoAbs profiles than that of the local tissue-specific auto-
immune diseases, this could be explained by the irreplaceable
central negative selection role of thymus T cells on B cell
immunoglobulin (Ig) production and autoAbs de novo
generation.
2.2. HLA class II allele
The human leukocyte antigen (HLA) molecules present self-
or non-self-peptides to the surface of antigen presentation
cells (APCs) for the following recognition of T cell receptors.
The HLA allele polymorphism has been reported to be
related to autoimmune diseases and pathogen susceptibility
[7,21,22]. Possible molecular mechanisms of HLA variation
on autoimmune diseases have been identified in recent year
studies. For example, HLA-DR4 associated with Rheumatoid
arthritis due to abnormal post-translational modification
results in citrullination of in RA patients autoantigens
[23,24]. Also, HLA risk variants could result in systemic
lupus erythematosus patients with high HLA-DR and HLA-
DQ protein expression by altering the binding of transcrip-
tion factors (such as IRF4 and CTCF) [25]. Similarly, a strong
association of HLA class II region can be observed in both
high anti-IFN-γ autoAbs individuals in Southeast Asia [26]
and high anti-GM-CSF autoAbs among the Japanese popu-
lation [21].
2.3. Abnormal germinal center formation
Germinal center (GC) is where high affinity, class-switched
antibodies are generated for humoral immunity. The strictly
regulated germinal center is crucial for maintaining self-
tolerance. GC formation starts from naïve B cells get acti-
vated by antigens carried by FDC in the follicle, then by
presenting antigens via MHC II molecule to CD4+ T cells,
B cells survive, and then migrate to GC where they experi-
ence somatic mutations, class-switch recombination, posi-
tive selection and differentiate into plasmablast or memory
B cells [27–29]. During this process, the low affinity or
autoreactive B cells go apoptosis and are removed.
Abnormal GC presents without immunization and detect-
able pathogen invasion [30–32]. The role of abnormal GC
formation has been described in several autoimmune diseases
including the defective exclusion of autoreactive B cells that
are supposed to be anergic after BCR stimulation during the
early stage of GC [33] and major blood B cell subset alterations
(e.g. reduction of mature B cell and increased frequency of
pre-GC B cells in the blood of children) [34] in system lupus
erythematosus (SLE) patients, ectopic GC, and B cell-T cell
aggregations that lacks FDC in the synovial tissues in rheuma-
toid arthritis patients (RA) [35,36], Fas mutation-related lym-
phocyte apoptosis deficiency in autoimmune
lymphoproliferative syndrome (ALPS) [37,38], the ectopic GC
in the salivary gland and subsequent development in the
spleen in Sjogren’s syndrome (SS) [39,40], and ectopic expres-
sion of neuromuscular molecules in MG-type thymoma [41]. In
current acute COVID-19 cases, extrafollicular B cell responses
are also reported. Together with mounted Bcl-6 expressing
T follicular helper cell loss, absence of germinal centers, and
the expanded plasmablasts. Also, the autoantibody profiles
and the B cell responses resemble SLE flares [42]. The abnor-
mal germinal center formation may relate to the limited dur-
ability of humoral immunity [43]. Though we can not exclude
abnormal germinal center formation as a potential factor in IEI
phenocopy autoAbs generation, limiting evidence supports
the aberrant germinal center formation contributed to anti-
cytokine autoantibodies in IEI phenocopies and still requires
further demonstration.
2.4. Molecular mimicry
Some external pathogens express antigens that resemble
self-proteins like cytokines, this phenomenon is called
‘molecular mimicry’ [44]. Thus, such structures from patho-
gen or host do not necessarily have to be identical, it is
sufficient that they are similar enough to be recognized by
the same antibody. And cross-reactivity between foreign
molecules on pathogens and self-molecules leads to anti-
self-responses and autoimmune disease [45]. For example,
myelin basic protein (MBP) self-peptides T cells of Multiple
sclerosis patients proposed cross-react with EBV nuclear
antigen 1 (EBVNA1) [46,47]; hypocretin neuron protein man-
nosyltransferase 1 (POMT1) is a promising autoantigen
recognized by T and B cells of narcolepsy type 1 patients,
which cross-react with influenza H1N1 viral epitope [48];
also, the similarity between the Noc2 protein of Aspergillus
spp. and the epitope cross-react by the aAbs-anti-IFN-γ as in
patients with the mycobacterial disease [49].
2.5. Defective apoptosis of auto-reactive lymphocytes
As mentioned above, immune tolerance in central and per-
ipheral inhibit the overproduction of autoantibodies to self-
antigens. One of the possible hypotheses of tolerance
breakdown is autoreactive T-cell escape enhancement due
to defective apoptosis [50,51]. BCL-2 family proteins are the
key elements of cell apoptosis processes in the hematopoie-
tic system, including B and T lymphocytes [52,53]. After
recognition of strong signals by self-antigens, various pro-
teins including BCL-2 homology domains can initiate apop-
tosis via BCL-2, BCL-XL, MCL1, BAX, and BAK. BAX/BAK
pathway, furthermore, leads to mitochondrial outer mem-
brane permeabilization (MOMP) and second mitochondria
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 3
apoptotic molecules release. Both cytochrome C and mito-
chondria-derived activators of caspases (SMAC) release can
activate several downstream pathways, including caspase-
dependent cell death pathways in auto-reactive immune
cells [54,55].
Autoimmune lymphoproliferative syndrome (ALPS) is an
inborn immune regulatory disorder due to mutations in
FAS (tumor necrosis factor receptor superfamily member 6)
and other genes characterized by lymphoproliferation and
autoimmunity [56]. B cell differentiation is frequently
altered in ALPS-FAS. The mice model study showed an
absence of apoptosis in non-selected clones and subse-
quently impaired germinal center reaction allowed survival
of dysregulated autoreactive B cells [56,57]. Also, dysregu-
lation between Bcl-2 or FAS apoptotic pathways is found in
SLE because of the significantly high expression of BCL-2 in
peripheral blood B and T lymphocytes which can change
the function of antigen-presenting cells (APCs) [58].
Germline genetic defects on FAS cause dysregulation in
extrinsic apoptosis and have been verified as the reason
for the autoimmune lymphoproliferative syndrome (ALPS
or Canale-Smith syndrome), which is associated with CD4-T
cells autoAbs over production lead to the accumulation of
double negative T cells (DNTCs) [59].
3. Common cytokine auto-abs production in IEI
phenocopies
3.1. Autoantibodies against IFN-γ
Interferon-γ, one of the pleiotropic cytokines that belong to the
type II IFN family, is mainly produced by activated T helper cells
(Th cells/CD4+ cells) and NK cells (Figure 2). Single gene defects
of IEIs have been demonstrated to lead to one specific infec-
tious disease, which also can be observed with defective type II
IFN immunity [7,60]. Inborn errors of human IFN-γ characterize
the genetic basis of Mendelian susceptibility to mycobacterial
diseases (MSMD), which are caused by recurrent Mycobacterium
spp. or Salmonella spp. as well as Talaromyces spp. Infections
[61]. In patients with IL12B, IL12RB1, IL12RB2, IL23R, TYK2, IKBKG,
RORC, TBET genetic defects lead to impaired IFN-γ production
[3,62,63]. Moreover, patients with IFNGR1, IFNGR2, IFNG, JAK1,
STAT1, IRF8, CYBB, SPPL2A, and ISG15 genetic defects present
the dysfunction of cellular responses to IFN-γ [7,64–67], as
above mentioned genes are all critical to IL-12/23-IFN-γ
immune pathway. After a confrontation with various pathogens
such as Mycobacteria (including both slowly-growing and
rapidly-growing non-tuberculous environmental mycobacteria
[NTM] and M. tuberculosis [MT]), Salmonella (mainly S. Typhi)
and Talaromyces (mainly T. marneffei), phagocytes (neutrophils
Figure 2. IEI phenocopies related to anti-cytokines autoAbs function and role of cytokines in host defense against different pathogens. IFNAR1/2: interferon-α
receptor; aAbs: autoantibodies.
4R. SUN ET AL.
and monocytes) produce IL-12 (p40&p35 heterodimer) and IL23
(p40&p19 heterodimer) production. This could activate NK cells
and T cells by IL12 receptor (encoding by IL12RB1 and IL12RB2)
or IL23 receptor (encoding by IL23R) and generate IFN-γ. IFN-γ
receptor (encoding by IFNGR1 and IFNGR2) recognizes IFN-γ,
stimulates JAK/STAT1 downstream pathway via TYK2, and reg-
ulates IRF8, SPPL2A, ISG15 expression to induce anti-microbial
process and control these pathogens [68].
Autoantibodies against (aAbs-IFN-γ) are also present in
most healthy individuals, which can be predicted by their
biological role in IFNγ activity regulation. Characterization of
healthy individuals showed aAbs-IFN-γ cutoff titers was ~6500
ng/ml while patients with MSMD phenocopies have abnormal
aAbs-IFN-γ titers which can reach ~32500 ng/ml (~5 times
higher than healthy populations) [69]. Similarly, a high titer
of neutralizing aAb-IFN-γ leads to severe bacterial infections,
especially mycobacterial infections due to inhibition of IL-12/
IFN-γ pathway [70–72]. Possible genetic susceptibility to aAb-
IFN-γ production has been reported in recent years; HLA class
II DRB1 × 16:02 and DQB1 × 05:02 alleles have a high preva-
lence of aAb-IFN-γ patients in the Southeast Asian patients’
cohort [73]. Another hypothesis of aAb-IFN-γ production is
molecular mimicry, which means when a patient infected by
NTM and MT (or other pathogens with high similarity with
ribosome assembly protein sequence), falsely cross-reactive
with nucleolar complex protein 2 (NOC2) and leads to the
stimulation of aAb-IFN-γ production. The similarity of aAb-
IFN-γ target dominant B cell epitope has been described
[49]. Partially aAb-IFN-γ (P121–131/P123–135) epitope
sequences have high similarity with NOC2, which is conserved
in the majority of the species (including NTM and MT) [49,69].
Surprisingly 40% reduction of binding affinity of aAb-IFN-γ to
IFN-γ can be achieved by replacing the aAb-IFN-γ (amino acids
121–127) epitope sequence [49] (Table 1).
3.2. Autoantibodies against IL6
IL-6 is the central cytokine of multiple inflammatory conditions
with an effector function on T cell development/proliferation
and antibody stimulation, which could be produced by various
types of cells, including monocytes, macrophages, infected/
injured cells (Figure 2). Uptake pathogens infection with IL6
production, ligand-binding protein IL-6 R and signal-
transducing protein gp130 (encoding by IL6ST) can recognize
IL-6 and lead downstream JAK/STAT3 pathway (via IL-6R) or
MAPKs pathway (via gp130 and help of active kinase IRAK4).
ZNF341 as a transcription factor can bind the STAT3 promoter
to regulate its expression inside the nucleus [74]. As a result,
this process will lead to the expression of IL-6-induced genes,
as well as C-reactive protein (CRP), one of the most important
acute-phase biomarkers in the context of IL-6-dependent
inflammation [75].
Studies on specific IEI patients with hyper IgE syndrome
have revealed that one of the major cellular and genetic basis
of severe staphylococcal diseases can be attributed to the
impaired cellular responses to IL-6 pathway [76,77]. Patients
with germline genetic defects on IL6RA [78], IL6ST [79,80],
STAT3 (loss-of-function) [81,82], ZNF341 [74] and IRAK4 [83]
lead to the impaired IL-6 signaling pathway [78,84].
Generally speaking, IL-6/STAT3 pathway is essential for naïve
T cell to T helper cell 17 (Th17) differentiation, thus patients
with impaired IL-6 related IEIs present low Th17 cells.
Immunoglobulin (IgG, IgA, and IgM) levels reduced slightly
while serum IgE level is high, with a diminished number of
switched memory B cells and without evaluated CRP level [85].
Therefore, these patients present complex clinical symptoms
including eczema, recurrent infection (especially
Staphylococcus aureus and fungal infection), as well as other
syndromic skeletal and orthopedic clinical manifestations
[78,80,86].
Also, high titer of IL-6 specific neutralizing autoAbs (aAb-IL
-6s) lead to the phenocopies of dysfunctional IL-6 reaction,
and even exists in a certain proportion of the healthy popula-
tion. A study of the aAb-IL-6s evaluation level showed that
0.1% of the healthy population had a high titer of aAb-IL-6s
while lacking neutralizing ability due to low affinity. Patients
with a high level of aAb-IL-6s result in IEI phenocopy of hyper
IgE syndrome with increased susceptibility to severe bacteria,
mainly Staphylococcal spp. infection. Although the exact
mechanism of aAb-IL-6s with corresponding phenotype is
unclear, the similarity of aAb-IL-6s patients and impaired IL-
6/STAT3 related IEI patients may provide some clues. So far,
four aAb-IL-6s cases with neutralizing capacity reported severe
Table 1. Summary of hypothesizes of IEI phenocopies related AutoAbs generation.
aAbs
Dominant Immunoglobulin
types HLA region Possible functional epitope Hypothesis
aAbs-IFN-γ IgG (IgG1 and IgG4) HLA class II DRB1 ×
16:02
HLA class II DQB1 ×
05:02
IFN-γ Amino acid 125–133
AAKTGKRKRSQML
Molecular mimicry;
HLA Class II region;
aAbs-IL-6 IgG (IgG1) IL-6 Trp157 Helix D
LTKLQAQNQWLQDMT
Cross-reactive antigen;
Multiple step break immune tolerance;Molecular
mimicry;
TH17 related
aAbs
IgG Central T-cell tolerance impairment;
aAbs-Type I IFN IgG HLA-B × 40:01
HLA-B × 40:02
HLA-B × 35:01
IFN-α amino acid 103–119
GVGVTETPLMKEDSILA
IFN-ω amino acid 127–144
VGEGESAGAISSPALTLR
HERV-W-env amino acid 248–262
NSQCIRWVTPPTQIV
Molecular mimicry;
HLA Class II region;
aAbs-GM-CSF IgG (IgG1 and IgG2) HLA-DRB1 × 08:03 HLA Class II region;
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 5
bacterial (including S. aureus, Escherichia coli, Haemophilus
influenzae) infection, all cases can release IL-6 normally but
show normal CRP levels [86]. The majority of these patients (3/
4, 75%) recovered after antibiotics treatments [87–89].
Notably, one 56-year-old female patient present CRP positive
4 years prior to the age of onset, which means aAb-IL-6 was
produced later in life [87]. The delayed autoAbs production
might attribute to the exposure to cross-reactive antigens and
need multiple steps to break immune system tolerance.
Another 29-month infant male patient was not only infected
by bacteria but also suffered from various virus infections,
including poliovirus and Varicella-zoster virus (VZV) [89].
Human IL-6 consists of 212 amino acids and two IL6s
molecules can sequentially ensemble as IL-6 signaling hex-
amer complex with two IL-6Rs (via IL-6 helix D) and two
gp130 (via IL-6 helix A and C or helix D) [90]. To characterize
human aAb-IL-6s, the epitope of patients’ aAb-IL-6 can
strongly bind to a specific peptide sequence which contains
the critical residue in Trp157 Helix D for binding with gp130
[87,90] (Table 1). This identified epitope not only provides the
molecular mechanism of IL-6 dysfunctional activity by aAb-IL-6
in the patients but also provides a promising drug target on
IL-6/STAT3 signaling pathway-related diseases [91,92].
3.3. Autoantibodies against Th17-related cytokines
(IL17A/F and/or IL22)
Different pathogens activate dendritic cells and macrophages
to produce IL-12 or IL-23, suggesting two different signal
specificities. Candida spp. can be recognized by myeloid cell
C-type lectin receptors and will stimulate CARD9/BCL-10/
MALT1 complex to produce IL-23 and lead to a downstream
signaling pathway [93]. Naïve CD4+ T cells differentiate to
Th17 with the stimulation of IL-23, together with transforming
growth factor-β (TGFβ), IL-1β, IL-21, and IL-6. As described
above, transcription factors retinoid-related orphan receptor-
γt (RORγt), STAT3, ZNF341 promote/STAT1 inhibits Th17 and
γδT (γδT17) cells to regulate IL-17A/F and IL-22 production
[94]. IL-17A/F is responsible for inflammation regulation
expressed on both tissue cells and immune cells and IL-22
works on tissue re-generation expressed only on tissue cells
[95], indicating their distinct functional spectra. By recognizing
IL-17A/F with IL-17 receptors (encoding by IL17RA and IL17RC),
cytoplasmic adaptor protein ACT1 (nuclear factor-kappaB [NF-
κB] activator 1, encoding by TRAF3IP2) regulate IL-17 receptors
stimulation to MAPK pathway (including JNK1, MAPK8) [96]. As
above mentioned, AIRE is responsible for controlling autoanti-
gen expression during the negative selection of autoreactive
T cells by lymphotoxin regulation [97]. Abnormal expression
and function of the AIRE gene can make autoreactive T cells
escape deletion and falsely active to self-antigens and could
be the genetic reason for APECED [6].
Moreover, IEI patients with germline impaired Th17-related
cytokines pathways present with CMC. Revealed pathogenesis
of CMC includes genetic defects on CARD9, IL17RA, IL17RC,
TRAF3IP2, STAT1 (gain-of-function), STAT3 (loss-of-function),
ZNF341, JNK1, RORC, MAPK8, as well as AIRE. Candidiasis is
located ~60–70% of healthy individuals on the oral, gastro-
intestinal system surface, skin, and female lower genital tract,
which has high susceptibility to becoming opportunistic
pathogen when people have low Th17 immunity. The elucida-
tion of the pathogenesis of CMC diseases in IEIs provides
possibilities to understand the clinical implications of pheno-
copy in patients suffering from CMC because of autoAbs
against Th17-related cytokines (IL-17A/F, IL-22). Since Th17-
related cytokines are to recruit phagocytes to the site of
Candida infection and produce antifungal peptides to protect
mucosal surfaces from fungal invasion [93].
Auto-Abs against IL-17A/F (aAb-IL-17) and/or IL-22 (aAb-IL
-22) can be classified in two situations to discuss: Unknown
genetic reason with aAb-IL-17/22; and aAb-IL-17/22 due to
AIRE mutations. So far, there are no specific HLA II alleles/T
and B cell epitopes reported with aAb-IL-17/22 production. In
most published studies, the incomplete penetrant association
between aAb-IL-17/22, CMC, and APECED has been shown.
The correlation between the presence of aAb-IL-17/22 and
CMC is ~70%. The correlation between APECED and CMC is
more than 80% [98]. And more than 90% of reported APECED
patients carried aAb-IL-17/22 [99]. APECED has a higher pre-
valence in a specific population, such as Finnish (>80% with p.
R257×), Sardinians (>90% with p.R139×), and Iranian Jews
(with unique variant p.Y85C) with incidences of ∼1/25000,
∼1/14500, and ∼1/9000, respectively [100–103]. Certain types
of autoAbs and CMC clinical manifestation can be observed in
unique AIRE mutations, including p.R257× (CMC+, aAb-IL-22+,
aAb-IL-17F+), p.G228W (aAb-type I IFNs+, aAb-IL-22-, aAb-IL
-17F-), c.967_979del13 (CMC+, aAb-IL-22+, aAb-IL-17F+) and
c.1064–1068dupCCCGG (extremely high titer of aAb-IL-22)
[104]. Also, in the patients with thymoma aAb-IL-17/22 and
CMC infectious manifestation can be observed [105]. Both
primary (AIRE genetic mutation) and secondary (thymoma)
defects correlated with abnormal autoAbs production indicate
the hypothesis of central T-cell tolerance impairment: such as
autoreactive T cell escape deletion, mTECs (medullary thymic
epithelial cells) antigen presentation failure, negative selection
failure, and unbalanced Treg cells differentiation [106]
(Table 1).
3.4. Autoantibodies against GM-CSF
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
is important for alveolar macrophages to maintain cholesterol
efflux and surfactant clearance at alveolar-air-liquid interface.
Primary pulmonary alveolar proteinosis (PAP) is caused by
germline genetic defects in CSF2RA and CSF2RB, which are
encoding GM-CSF receptors [107]. GM-CSF signaling can be
blocked also by GM-CSF autoAbs (aAb-GM-CSFs) as IEI pheno-
copy, which can result in a reduced ability of surfactant clear-
ance and forming of the foam cells at the alveolar air-liquid
interface. The existence of aAb-GM-CSFs not only is the reason
for PAP, but also can be identified in life-threatening neurolo-
gical sequelae, severe pulmonary/extrapulmonary, and crypto-
coccal meningitis. Of note, the lung and brain are the main
organs with higher susceptibility to getting an infection
[108,109]. Autoimmune phenocopy of PAP takes accounts for
90% of all cases. A genome-wide association study of auto-
immune PAP patient cohort showed that HLA-DRB1 × 08:03
could be the genetic reason for the individuals predisposing
6R. SUN ET AL.
aAb-GM-CSF production, especially among in Asian popula-
tion (~5–10%) but rare in other populations. AutoAbs against
GM-CSFs have been characterized as polyclonal IgG (mainly
IgG1 and IgG2) targeting multiple non-overlapping epitopes
of GM-CSF [21]. Also, it has been demonstrated that aAb-GM-
CSF-specific memory B cells back to germinal centers with the
help of T cells to experience multiple times of somatic hyper-
mutations and affinity selection could improve the pathogeni-
city of aAb-GM-CSF [110].
3.5. Autoantibodies against Type I IFNs
By characterization of type I IFNs, including 13 IFNα subtypes,
IFNβ, and others (IFNɛ, IFNτ, IFNκ, IFNω, IFNδ, and IFNζ) on
both innate and adaptive immunity, their critical roles for
human defense against viruses are evident [111] (Figure 2).
Several studies have indicated that patients with germline
genetic defects of type I IFNs pathway underlie severe viral
infection diseases, including lethal SARS-CoV-2 infections,
influenza virus infection, herpes simplex virus 1 (HSV-1) and
severe side effects on attenuated viral vaccine including yel-
low fever virus vaccine (YFV-17D) and Measles, Mumps, and
Rubella (MMR) vaccine [112–115].
TLR3, TLR7, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2 genetic
defects individuals have been reported which are correlated
with severe COVID-19 pneumonia [112,116–122]. SARS-CoV-2
(ssRNA) sensed by single-strand RNA sensor TLR7 and double-
strand RNA sensor TLR3, subsequently activated IFN-
regulatory factor 3 and/or 7 (IRF3/IRF7) via TANK-binding
kinase 1 (encoding by TBK1) and inhibitor of NF-κB kinases
(encoding by IKK) to regulate type I IFN production and primes
antiviral mechanism via interferon receptors (encoding by
IFNAR1/IFNAR2) and JAK1-STAT1/2 [123].
Not only impaired type I IFNs caused by genetic defects
individuals suffered from a severe viral infection, but also
neutralizing auto-Abs against type I IFN can generate pheno-
copy of IEI with severe viral infection [124]. Among the healthy
population, aAb-IFN-I (neutralizing 100 pg/ml IFN-α2 and/or
IFN-ω) can be observed only in 0.17% of individuals below 70-
year-old. Several other studies demonstrated that the popula-
tion with type I IFN autoAbs increased by age from 4% after
70 years to 7% between 80 and 85 years [12,117,124].
However, this ratio dramatically increased in patients with life-
threatening SARS-CoV-2. About 10%–15% of patients with
aAb-IFN-I (neutralizing IFN-α2 and IFN-ω) can be observed in
severe COVID-19 pneumonia patients and it can be reached
20% in patients >80 years [12,123]. Also, the preexistence of
aAb-IFN-I suggested being the reason APECED patients suf-
fered from life-threatening COVID-19 [12,125]. Furthermore,
aAb-IFN-I could be the reason individuals developed adverse
events after yellow fever live attenuated vaccination (YFV-17D)
[126]. In a selected group of patients who suffered from life-
threatening influenza (such as IVA, IVB) presence of patho-
genic aAb-IFN-I has been evident [13].
The molecular mimicry hypothesis of the abnormal aAb-IFN
-I production in patients infected by SARS-CoV-2 has been
suggested and may lead to the loss of tolerance [127]. For
example, the SARS-CoV-2 S1/S2 cleavage site (amino acid 683–
690) is mimicking a FURIN-cleavable peptide on human
epithelial sodium channel α-subunit (ENac-α), which might
contribute to autoimmune responses [128]. HLA-B × 40:01,
HLA-B × 40:02, and HLA-B × 35:01 regions have been reported
with 8-mer/9-mer peptides mimicked by SARS-CoV-2 [129].
Meanwhile, three epitopes from HERV (Human endogenous
retrovirus)-W-env (amino acid 248–262), IFN-α (amino acid
103–119), and IFN-ω (amino acid 127–144) correlated with
the severity of patients infected by SARS-CoV-2 (Table 1).
Although the correlation between HERV-W-env epitopes and
aAb-IFN-I is supported by the animal model [130], they still
need to be further identified [131]. In another study, charac-
terized the de novo anti-Ang II antibodies in a group of
hospitalized COVID-19 patients, autoAbs interfere with angio-
tensin II (AngII) processing by Angiotensin-converting enzyme
2 (ACE2) and signaling to its receptors, leading to the dysre-
gulated vascular tension and worsening the disease. Such
antibodies showed cross-reactivity between AngII and the
spike protein, suggesting that the immune epitope homology
between these molecules contributes to autoimmunity
against self-antigens [132,133].
4. IEI phenocopies in the context of COVID-19
complications
The presence of type I IFN autoAbs in the context of COVID-19
patients has been observed in two situations. One is type I IFN
autoAbs preexisted before SARS-CoV-2 infection; another
occasion seems to be the SARS-CoV-2 triggered (post-
expoure, newly generated) autoAbs production.
4.1. Contribution of preexisting type I IFN autoAbs on
COVID-19 severity
Patients with APECED featured by neutralizing antibodies
against type I IFNs are more prone to developing severe
hypoxemic COVID-19 pneumonia [12,125]. Almost all (95%)
of APECED patients display autoAbs against IFN-ω and IFN-α
[6,104]. Notably, the presence of anti-IFN-α and anti-IFN-ω
neutralizing antibodies was detected in all Finnish and
Norwegian APECED patients [13]. These anti-IFN autoAbs
were triggered early on during the development of the dis-
ease and persist for years [6,134]. Aligned with this observa-
tion, in a study among 22 APECED patients from seven
countries infected with SARS-CoV-2 aged from 8 to 48 years,
21 patients tested had autoAbs neutralizing IFN-α subtypes
and/or IFN-ω. Strikingly, 19 out of 21 patients (86%) were
hospitalized for virus infection, including 15 (68%) admitted
to the intensive care unit (ICU), 11 (50%) aided with mechan-
ical ventilation, and 4 (18%) died. Besides, similar levels of
autoAbs before and after COVID-19 in patients were observed,
indicating preexisting autoAbs neutralizing type I IFNs in
APECED patients underlay a high risk of life-threatening
COVID-19 pneumonia at all ages, in this case, the virus infec-
tion seems not to further trigger the production of autoAbs
[12]. In another study indicating a likely preexisting IFN-
autoAbs, the autoAbs against type I IFNs were the first princi-
pal contributor to disease severity. To validate the roles of
autoAbs in vivo, IEI phenocopy-related autoAbs against
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 7
IFNAR, IL-18 (IFN-γ inducing factor), IL-1β (IL-17 inducing fac-
tor), IL-21 R (IL-17 inducing factor) and GM-CSF were treated
on mice infected with SARS-CoV-2, all the autoAbs contributed
to disease severity in the mice model [135].
Current studies indicated that SLE patients are frequently
treated with immunosuppressive agents and cytotoxic drugs
to control abnormal immune responses and are prone to be
vulnerable to SARS-CoV-2 infection and develop more severe
manifestations [136–138] Another study showed preexisting
IFNα autoAbs were recently identified in 4/10 (40%) SLE
patients who were later infected with SARS-CoV-2 [139].
However, a comparison of the outcomes between 26
patients with neutralizing type I IFN autoAbs and 192 patients
without autoAbs who were hospitalized for COVID-19 showed
IEI phenocopy patients with type I IFN autoAbs had an
increased risk of admission to ICU together with a delayed
time to viral clearance, but the survival was not adversely
affected by the type I IFN autoAbs [140]. A possible explana-
tion might be the potential role of humoral and cellular adap-
tive immune responses in anti-viral responses [141], the cohort
size and ages also differ between studies. To recap, the con-
troversial debates indicate a questionable role of the autoAbs
and potential compensatory immune mechanisms in mediat-
ing the progression of the disease [6,134].
4.2. SARS-CoV-2 triggered anti-cytokine auto-Abs in
COVID-19 patients
It is clear that SARS-CoV-2 is highly associated with the emer-
gence of self-reactive antibodies. However, the origin, breadth,
and resolution of the autoAbs, and their connection with the
de novo antiviral responses remained unclear. A puzzle
regarding anti-type I IFN autoAbs is that the production of
autoAbs and their neutralizing capacity can be triggered by
viral infection. A study reported a transient increase of anti-IFN
-α2 autoAbs in two patients with preexisting IFN-α2 autoAbs
(neutralizing capacity comparable to or marginally higher than
controls). Higher antibody levels (complete abolish STAT1
phosphorylation of 10 ng/ml IFN-α2) were observed during
COVID-19 compared to pre-COVID-19, then the antibody levels
started to decline 6–12 weeks after SARS-CoV-2 infection [142].
Consistent with this study, another experimental observation
also confirmed the binding levels and neutralization activity of
autoAbs to type I IFNs were highest during the acute phase of
COVID-19 infection and decreased afterward [143]. The most
frequent defected autoAbs in this phenomenon are against
IFN-α2 (45%). AutoAbs toward other self-antigen levels were
comparable to or even exceeded those observed in patients
with APECED, PAP, and atypical mycobacterial infections.
Notably, a subclass of anti-IFN-α, anti-IFN-ε and anti-IL-22
autoAbs were induced to a high level, suggesting that
COVID-19 may play a role in breaking self-tolerance and
induce a broad range of autoAbs other than aAb-IFN-α2,
which contribute to impaired virus protection [144].
It worth noting that not only anti-cytokine autoAbs are
abnormal in life-threatening COVID-19 patients, other various
autoAbs had a broad range of self-antigen defects such as
new-onset anti-IgG autoAbs [144,145], ANA autoAbs [144],
could be the reason for respiratory disease, which affects
organs, mainly the immune, digestive, nervous, and cardiovas-
cular systems [145]. Despite the surging of autoAbs in COVID-
19 patients, the autoimmune phenomenon is not equivalent
to autoimmune disease. Although they may be pathogenic in
some, not all situations [146], stressing the need for continued
follow-up of these patients to understand the long-term impli-
cations and pathogenic function of these autoAbs.
5. Expert opinion on pathogens and clinical
manifestations of IEI phenocopies-review of
literature
We reviewed more than 1200 reported cases with at least one
type of autoAbs, including aAbs-IFN-γ, aAbs-IL-6, aAbs-IL12,
aAbs-IL17A, aAbs-IL17F, aAbs-IL22, aAbs-IFN-α (incl. 13 sub-
types), aAbs-IFN-ω, aAbs-IFN-β and aAbs-GM-CSF
(Supplementary Table. S1). Within these cases, except 215
cases with un-identified gender in the original paper, 552
(45.1%) of them are male and 456 (37.3%) are female. The
correlations between pathogens and auto-antibodies profiles
have been evaluated (Table 2).
Patients with aAbs-IFN-γ had a broad infection spectrum in
bacteria, viruses and fungi. The bacterial infection can be observed
in both Genus Mycobacteria (species including M. kansasi,
M. avium complex, M. abscessus complex, M. fortuitum,
M. abscessus, M. chelonae, M. tuberculosis, M. scrofulaceum, NTM,
Mycobacteria spp (s)) and Genus Salmonella (species including
S. enteritidis, Salmonella spp.), which is very similar to the observa-
tions in previous studies [72,147,148]. This group of patients also
had higher susceptibility to VZV infections (n = 37, 18.5%) while
few of them presented infections with Epstein-Barr virus (EBV, n =
2, 3.6%), and Cytomegalovirus (CMV, n = 4, 4.7%). Similarly, VZV
infection history also showed in previous studies from 14.5% to
21.1% in patients with aAbs-IFN-γ [72,73].
So far, there were four cases with aAbs-IL-6 present with
severe bacterial infections (offending pathogens were likely
S. intermedius, S. aureus, S. pneumoniae) have been reported
[87–89]. Patients with autoAbs against Th17-related cytokines
(aAbs-IL17A, aAbs-IL17F, aAbs-IL22) have a higher susceptibil-
ity to the virus (VZV, HSV and SARS-CoV-2) and Fungi (mainly
C. albicans). Of note, no bacterial infection susceptibility can
be observed in our study. The individuals who present anti-
IL22 antibodies were susceptible to VZV infection (100%) and
HSV infections (42.9%) indicating the important antiviral func-
tion of Th17-related cytokines. Higher susceptibility of
C. albicans leads to CMC due to defective anti-fungal immunity
in these patients [124].
Type I IFN (aAbs-IFN-α and aAbs-IFN-ω) as the key element
of antiviral function can be observed wide susceptibility infec-
tion spectrum of the virus. For aAbs-IFN-α, higher virus infec-
tion proportion showed in SARS-CoV-2 (n = 80%), VZV (56%),
HSV (45%), CMV (23%), human papillomavirus (HPV,14%), viral
hemorrhagic septicemia virus (VHSV) genotypes IVA and IVB as
well as YFV-17d and MMR vaccines. Similarly, within 7 patients
who suffered life-threatening SARS-CoV-2 with aAb-IFN-I, 5
(71%) individuals were infected with CMV, and 6 (86%) indivi-
duals were infected with HSV-1/2; In COVID-19 patients with-
out aAb-IFN-I the percentage is 31% and 24%, respectively.
The result indicates a higher susceptibility of aAb-IFN-I
8R. SUN ET AL.
patients to herpesvirus family infections [149]. Also, high-titer
neutralizing autoAbs against type I IFN, especially IFN-ω can
be detected in most APECED patients. Probably, therefore,
APECED patients have been described as having recurrent
infection of HSV and VZV (~15%) [98] and life-threatening
SARS-CoV-2 infection [124].
Among patients with aAbs-GM-CSF, no specific virus spe-
cies was observed, while higher predisposition to bacteria
(Nocardia spp. and Mycobacteria spp.) and fungi (Candida
spp., Aspergillus spp., Cryptococcus spp., Histoplasma spp.,
Penicillium spp., and Zygomyces spp.) were documented.
The clinical manifestations of these IEI phenocopy cases
and autoAbs profile is summaggrized in Table 3. Of the
349 cases with aAbs-IFN-γ, 140 cases (40%) present clinical
manifestations with mycobacteria infection (mainly disse-
minated nontuberculous mycobacteria infection) and 75
Table 2. Associations of various pathogens and autoAbs profiles in IEI phenocopies.
Genus Species
aAbs-IFN
-γ
aAbs-IL
-6
aAbs-
IL12
aAbs-
Il17A
aAbs-
Il17F
aAbs-
IL22
aAbs-IFN-α (incl. 13
subs)
aAbs-IFN
-ω
aAbs-IFN
-β
aAbs-GM-
CSF
Bacteria
Streptococcus S. pneumoniae 1/1 1/1
S. intermedius 1/1
Haemophilus H. influenzae 1/1
Staphylococcus S. aureus 1/1 2/2
Escherichia E. coli 1/1
Legionellosis Legionellosis spp. 1/1
Enterobacter E. cloacae 1/55
Acinetobacter A. baumannii 1/55
Klebsiella K. pneumoniae 3/55
Burkholderia B. cepacia 1/55
Aeromonas A. veronii 1/55
Nocardia N. asteroides 19/68
N. brasiliensis 1/68
N. farcinica 1/68
Nocardia spp. 11/68
Mycobacteria M. kansasi 2/32 4/68
M. avium
intracellulare
3/68
M. avium complex 29/34
M. abscessus
complex
3/31
M. fortuitum 8/116
M. abscessus 51/88
M. chelonae 4/86
M. tuberculosis 39/141 24/69
M. scrofulaceum 2/2
NTM 11/59
Mycobacteria spp.
(s)
15/96 5/223
Salmonella S. enteritidis 6/6
Salmonella spp. 30/99
Virus
Varicellovirus VZV 37/200 1/1 2/2 1/1 43/43 66/117 2/2
Simplexvirus HSV 18/42 24/53 6/9
Enterovirus PLV 1/1
Cytomegalovirus CMV 4/86 6/31 6/26
Lymphocryptovirus EBV 2/55
Betacoronavirus SARS-CoV-2 3/3 3/3 4/4 206/260 136/136 1/1
Papillomavirus HPV 10/71
Alphainfluenzavirus IVA 22/22 17/17 3/3
IVB 1/1 1/1
YFV-17d vaccine 3/3 3/3
Fungi
Candida C. albicans 3/55 3/3 4/4 7/7 12/12 60/61 69/71 1/1
Aspergillus Aspergillus spp. 1/55 11/293
Cryptococcus C. deuterogattii 12/12
C. neoformans 10/43
C. gattiim 2/2
Cryptococcus spp. 5/68
Histoplasma H. capsulatum 7/43 4/68
Penicillium P. marneffei 23/67
Zygomyces Zygomyces spp. 1/68
In each cell: x/y = n of pathogen-infected cases/n of the total number of auto-abs positive cases; Mycobacteria spp (s) include following sub-species: M. mantenii;
M. colombiense; M. genavense; M. perigrinum; M. intermedium; M. gordonae; M. terrae; slow-grower mycobacteria; fast-grower mycobacteria.
IFN-a subtypes include: IFN-α1,-α2,-α4,-α5,-α6,-α7, -α8, -α10, -α13, -α14, -α16, -α17, -α21; VZV: Varicella-zoster virus; HSV: Herpes simplex virus; PLV: Poliovirus; CMV:
Cytomegalovirus; EBV: Epstein – Barr virus; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; IVA: Influenza A virus; IVB: Influenza B virus; HPV: Human
Papillomavirus.
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 9
cases (21.5%) had severe T. Marneffei infections.
Meanwhile, 40 (11.5%) of these cases carried opportunistic
infections and 13 (3.7%) with lymphadenitis. APECED is the
most common clinical manifestation in ~91% of the
patients with aAbs-IL17A/F and/or aAbs-IL-22, also, thymic
neoplasm (2%) and CMC (6%) can be observed in these
patients. Of note, patients with aAbs-type I IFN (aAbs-IFN-α
and/or aAbs-IFN-ω) frequently present clinical manifesta-
tions of critical/severe SARS-CoV-2 infection (36.7%),
APECED (22.9%), SLE (15%), critical/severe influenza pneu-
monia (5%), unspecified-pneumonia (5%), enteropathy
(5%), hepatitis (5%). The majority of the patients with
aAbs-GM-CSF had a clinical diagnosis of PAP (94.8%), and
few of them also had cryptococcal meningitis (n = 9, 3%)
and life-threatening neurological sequelae manifestations
(n = 4, 1.3%).
Funding
This work was supported by Anna-Greta Crafoords foundation
Declaration of interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Hassan Abolhassani http://orcid.org/0000-0002-4838-0407
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