Theme Editorial
Introducing a New Epoch in Inborn Errors of
Immunity
Peter D. Arkwright, MD, PhDa, and Jolan E. Walter, MD, PhDb,c Manchester, United Kingdom; St Petersburg, Fla; and Boston,
Mass
The last 2 decades have ushered in a new Epoch in our un-
derstanding, diagnosis, and management of inherited immune
disorders. The long-held belief in malalignment of the stars as a
cause of disease has been replaced by a detailed understanding of
the constellation of nucleotides that make up our genetic uni-
verse. Identification of more than 400 genetically defined new
inherited disorders of immunity, presenting with not only clin-
ical features of immune deficiency but also autoimmunity/
autoinflammation, malignancy, or a combination of all 3, has led
to the umbrella term “primary immunodeficiencies (PID)” being
replaced by “inborn errors of immunity (IEI).”1 Diagnosis of IEI
is typically based on stringent genetic criteria confirmed by
functional analyses of pathogenic variants.
The transformation of the field has been driven by advances in
genomic and proteomic technology and has opened the oppor-
tunity of mechanism-based targeted therapies. The futuristic
vision is that population-based genetic screening programs will
circumvent the need to wait until the patient develops overt
clinical disease.2 This is already part-reality in countries using T-
cell receptor excision circles newborn screening for severe com-
bined immunodeficiencies.3 Similar screening programs are now
being piloted for other IEI.4,5
The exponential progress in genomics has exposed new vul-
nerabilities, inadequacies, and challenges in the “wholly trinity”
facing clinicians managing the patient, laboratories providing
functional immune tests, and genomic facilities involved in the
diagnosis and management of patients with IEI, as highlighted in
the review by Abraham and Butte6 in this issue (Table I). Some
of the challenges are summarized below:
1. Inherent shortcomings of current genomic diagnostics:
Ongoing inadequacies in modern genomics include diffi-
culties identifying di- and multigenic disorders, mosaics, and
somatic and epigenetic disease-causing variants. Examples
include the inability to identify monogenetic variants in most
a
Lydia Becker Institute of Immunology and Inflammation, University of Manchester,
Manchester, United Kingdom
b
Pediatric Allergy/Immunology, University of South Florida & Johns Hopkins All
Children’s Hospital, St Petersburg, Fla
c
Pediatric Allergy/Immunology, Massachusetts General Hospital for Children,
Boston, Mass
Conflicts of interest: The authors declare no conflicts of interests.
Received for publication November 4, 2020; accepted for publication November 4,
2020.
Corresponding author: Peter D. Arkwright, MD, PhD, Department of Paediatric
Allergy and Immunology, Royal Manchester Children’s Hospital, University of
Manchester, Oxford Rd, Manchester, UK. E-mail: peter.arkwright@nhs.net.
J Allergy Clin Immunol Pract 2021;9:660-2.
2213-2198
Ó 2020 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaip.2020.11.022
660
patients with common variable immunodeficiency, and the
importance of selecting an appropriate cellular source to
effectively detect somatic mutations causing autoimmune
lymphoproliferative syndrome type 1a (CD4 CD8 double-
negative T lymphocytes) and RAS-associated autoimmune
leukoproliferative disease (bone marrow). Furthermore, pre-
dicting incomplete and variable clinical penetrance of genetic
variants, particularly for IEI caused by haploinsufficiency, is
sometimes challenging.
Bioinformatic interpretation of genomic libraries lags behind
hard-core sequencing, and is an area needing further work. Ad-
vances in bioinformatic algorithms and machine learning are
required to improve the diagnostic accuracy, speed of reporting,
and differentiate disease-causing variants from variants of un-
certain significance.
There is also a knowledge gap of physicians and other health
care providers in the proper interpretation of genetic findings.
Therefore, only a few practicing allergists/immunologists initiate
genetic testing for even complex noninfectious phenotypes.7
There is an unmet need to educate clinicians regarding the po-
wer of genetics in diagnosis in IEI.
2. Inability to access targeted diagnostic immune functional
tests: Finding novel gene variants needs to be complemented
by in vitro laboratory tests to provide direct evidence of
abnormal expression and/or functional activity. Routinely
available screening tests of immune function, such as
lymphocyte subsets, serum immunoglobulins, vaccine anti-
body responses, CH50 and AH50, and neutrophil oxidative
burst tests, are not pathognomonic in many patients with life-
threatening IEI, such as signal transducer and activator of
transcriptions and dedicator of cytokinesis 8 deficiencies.
Access to targeted in-depth laboratory tests is limited mainly
to clinicians working in academic research institutes. Reporter
gene assays, using, for instance, luciferases that are easily
detectable by bioluminescence, provide high-throughput
technology for assessing signal transduction and gene
expression. These assays are increasingly being used to study
immune dysfunction in IEI, 1 example being signal trans-
ducer and activator of transcription 3 gain of function.8
3. Clinical competence and confidence: It remains the remit of
the physician to interpret and evaluate the significance of the
results and manage the patient’s disease. Clinical implications
of the disease need to be considered, and treatment options
provided not only for the patient but also for other affected
family members. Detailed knowledge and good communica-
tion skills are critical. The specific needs of individual patients
and their families often require a personalized approach to
care. Individualized care of patients with rare IEI will run
J ALLERGY CLIN IMMUNOL PRACT ARKWRIGHT AND WALTER 661
VOLUME 9, NUMBER 2

TABLE I. Examples of current inadequacies and challenges impeding optimal management of patients with IEI
Category Specific Solution
Inherent inadequacies of  Variants of uncertain significance  Advanced bioinformatic algorithms, progressive
current genomic  Mosaicism, somatic mutations, digenic diseases, machine learning, and extended database
diagnostics skewed lyonization  Correct cellular source, clinical review
 Incomplete and variable clinical expression  Clinical review
Inaccessibility of targeted  Limitations of routinely available laboratory tests  Streamlined, focused functional testing, eg, reporter
diagnostic immune gene assays
functional tests
Clinical competence and  Individual nonspecialists and specialists have  Multidisciplinary partnership between clinical and
confidence insufficient breadth or depth of knowledge to manage laboratory team approach to patient care
the complex medical problems
Societal/ethical concerns of  Ethical concerns regarding implications of genomic  Clear discussion of pros and cons, patient choice to opt
genomic testing diagnosis and incidental findings on the patient and out of personal therapies, without impeding care for
family members other family members
Therapeutics  Toxicity associated with conditioning for HCT  Reduced intensity, targeted conditioning protocols
 High cost and noncurative nature of biologics  Replacement by genetic editing and repair, eg, HCT
 Infection risk and toxicity of systemic and gene therapy
immunosuppressants  Focus on scientific evidence-based therapies
 Lack of a robust clinical evidence base for treating the
disease

CURRENT PRACTICE FUTURE VISION

DIAGNOSTICS
Reaconary diagnosis of sick Limited preempve newborn Universal preempve
paents largely using roune eg newborn
lab tests and panels TREC screening for SCID genomic screening

Reaconary symptomac
treatment of sick paents with
anmicrobials, immune
modulators & biologics
THERAPEUTICS
Limited preempve HCT and Universal preempve genec
gene therapy for life- eding and therapy
threatening IEI aer TREC
screening and where FH

Paent-focused rights of
confidenality
ETHICS
Limited override of paent rights
of confidenality where potent
for life-disability disease in
others
Universal paent responsibility to
ensure that health informaon is used
to promote not only individual health,
but that of family & community

FIGURE 1. Futuristic vision of diagnosis, management, and ethics pertaining to IEI. FH, Family history; SCID, severe combined immu-
nodeficiency; TREC, T-cell receptor excision circle.

counter to the modern evidence-based medicine, because
there is often no clinical trial or even case series evidence.
Therapeutic decisions thus need to be based on a robust
understanding of disease pathogenesis.
The clinical complexity of many IEI is now beyond the expertise
of most individual nonspecialists and specialists alike.6 Non-
specialists strain to keep up with the latest advances, while super-
specialists may focus on treating specific-organ malfunction with
the latest immune modulators and biologics to the detriment of
infective and neoplastic complications, for instance, in cytotoxic T-
lymphocyteeassociated protein 4 deficiency. A multidisciplinary
partnership between clinicians with a spectrum of expertise and
colleagues working in genomic and immunology laboratories will
increasingly become the criterion standard of care.
4. Ethical concerns: The inevitable roll out of broad genomic
screening programs raises bioethical concerns. This is partic-
ularly the case where a definitive diagnosis, in, for instance,
ataxia telangiectasia picked up by newborn screening for se-
vere combined immunodeficiency,9 may not translate into
better patient outcome. The risk-benefit ratio of identifying
incidental, genetic diseases such as BRAC1 gene variants also
need to be considered. The anxiety and potential financial
penalties of private health care insurance systems need to be
weighed against the benefits of preventative measures that
662 ARKWRIGHT AND WALTER
avert premature death of the patient and potentially other
family members.
The realization that an individual’s health is intimately
entwined with that of their family and the rest of the community
is no better illustrated than with the current coronavirus disease
2019 pandemic. Our survival depends on understanding that
human rights and freedoms cannot be allowed to override human
responsibilities to others. In relation to IEI, patients and ethicists
need to grasp the fact that an individual patient’s disease can
seriously impact the health of other family members, as well as
lead to major discoveries in our field. Just as optimal manage-
ment of IEI requires that lone practitioners give way to multi-
disciplinary teams, current ethical regulations that prevent
sharing of (semi)-anonymized scientific and clinical data need to
give way to unobstructed access to this information for the
benefit of humanity, if it is not to die with the patient.
Advances in therapeutics have provided physicians with
choices that were not previously available. Widening choices
come with difficult decisions as to the optimal treatment for
patients with IEI as highlighted in the review by Cooper et al.10
For severe combined immunodeficiency, replacing the defective
hematopoietic stem cells either by transplantation (HCT) or in
some cases gene therapy has always been the treatment of choice.
For Wiskott-Aldrich syndrome, chronic granulomatous disease,
and hyper-IgM syndrome, understanding long-term outcome
and impact on patient’s quality of life over the years has shifted a
previous conservative treatment approach using prophylactic
antimicrobials and immunoglobulin replacement to definitive
HCT. For recently discovered IEI with variable penetrance and
less clear natural history, such as primary immune regulatory
disorders (eg, cytotoxic T-lymphocyteeassociated protein 4, LPS
responsive beige-like anchor protein, nuclear factor kappa B
subunit 1, and phosphoinositide 3-kinase deficiencies), there is
uncertainty regarding the risk-benefit ratio of curative options
such as hematopoetic stem cell transplantation or gene therapy
versus conservative therapies with biologics. Short-term risks of
HCT and gene therapy need to be continually balanced against
the practicality, cost, efficacy, and toxicity of symptomatic
therapies, such as modern biologics. An example of the dia-
metrically different therapeutic approaches is in management of
agammaglobulinemia in different parts of the world. In the West,
life-long immunoglobulin replacement is the norm, whereas on
the Indian subcontinent where there is hot tropical climate and
lack of suitable storage of the serum is difficult, HCT is offered as
a more practical and definitive solution.11 Progress in genomic
editing technology may well mean that symptomatic drug ther-
apy is in the future increasingly used as a bridge pending
definitive curative treatment (Figure 1).
J ALLERGY CLIN IMMUNOL PRACT
FEBRUARY 2021
In addition to the diagnostic and therapeutic challenges in
managing patients with IEI are the conceptual hurdles of under-
standing the intricacies of what constitutes optimal human im-
munity to environmental microbes. Immature adaptive response
of young children’s immune system has often been viewed as an
immune vulnerability. Shaw and Su12 in their review in this issue
discuss the price of robust adaptive immunity in terms of potential
bystander inflammatory complications associated with common
infectious diseases, such as EBV infection, dengue fever, and severe
acute respiratory syndrome coronavirus 2 infection, where naivety
has advantages over maturity.12
The review articles in this issue herald in a new Epoch in our
understanding of IEI. The extraordinary progress in immunology
and biotechnology has furnished us with the tools to not only fix
our inflammasome driven-carburetor, replace or repair the
hematopoetic stem cells of our immune engine, but also predict
and redefine our immune destiny by star-gazing inwardly at our
genomic constellation.
REFERENCES
1. Notarangelo LD, Bacchetta R, Casanova JL, Su HC. Human inborn errors of
immunity: an expanding universe. Sci Immunol 2020;5:eabb1662.
2. Murray MF, Giovanni MA. Bringing monogenic disease screening to the clinic.
Nat Med 2020;26:1172-4.
3. van der Burg M, Mahlaoui N, Gaspar HB, Pai SY. Universal newborn screening
for severe combined immunodeficiency (SCID). Front Pediatr 2019;7:373.
4. Dezfouli M, Bergström S, Skattum L, Abolhassani H, Neiman M, Torabi-
Rahvar M, et al. Newborn screening for presymptomatic diagnosis of comple-
ment and phagocyte deficiencies. Front Immunol 2020;11:455.
5. Collins CJ, Yi F, Dayuha R, Whiteaker JR, Ochs HD, Freeman A, et al.
Multiplexed proteomic analysis for diagnosis and screening of five primary
immunodeficiency disorders from dried blood spots. Front Immunol 2020;11:
464.
6. Abraham RS, Butte M. The new “wholly trinity” in the diagnosis and management
of inborn errors of immunity. J Allergy Clin Immunol Pract 2021;9:613-25.
7. Farmer JR, Uzel G. Mapping out autoimmunity control in primary immune
regulatory disorders. J Allergy Clin Immunol Pract 2021;9:653-9.
8. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Neimela JE, et al.
Early-onset lymphoproliferation and autoimmunity caused by germline STAT3
gain-of-function mutations. Blood 2015;125:591-9.
9. Barmettler S, Coffey K, Smith MJ, Chong HJ, Pozos TC, Seroogy CM, et al.
Functional confirmation of DNA repair defect in ataxia telangiectasia (AT) in-
fants identified by newborn screening for severe combined immunodeficiency
(NBS SCID). J Allergy Clin Immunol Pract. 2021;9:725-34.
10. Cooper MA, Zimmerman O, Nataraj R, Wynn RF. Lifelong immune modulation
versus hematopoietic cell therapy for inborn errors of immunity. J Allergy Clin
Immunol Pract 2021;9:628-39.
11. Vellaichamy Swaminathan V, Uppuluri R, Patel S, Melarcode Ramanan K,
Ravichandran N, Jayakumar I, et al. Treosulfan-based reduced toxicity he-
matopoietic stem cell transplantation in X-linked agammaglobulinemia: a cost-
effective alternative to long-term immunoglobulin replacement in developing
countries. Pediatr Transplant 2020;24:e1362.
12. Shaw ER, Su HC. The influence of immune immaturity on outcome after viral
infections. J Allergy Clin Immunol Pract 2021;9:641-50.