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REVIEW
URRENT
C
OPINION
Human IL-21 and IL-21R deficiencies: two novel
entities of primary immunodeficiency
Daniel Kotlarz a, Natalia Zie˛tara b, Joshua D. Milner c, and Christoph Klein a
Purpose of review
This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor
(IL-21R) deficiencies as novel entities of primary immunodeficiency.
Recent findings
We recently described the first patients with IL-21R deficiency who had cryptosporidial infections
associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent
respiratory tract infections. Immunological work-up revealed impaired B cell proliferation and
immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions.
Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21
gene. This patient predominantly manifested with very early onset inflammatory bowel disease and
recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired
B cell class-switch.
Summary
Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common
variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as
secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early
hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children.
Keywords
cryptosporidiosis, hematopoietic stem cell transplantation, inflammatory bowel disease, interleukin-21,
primary immunodeficiency
INTRODUCTION
Primary immunodeficiencies (PID) represent a
heterogeneous group of diseases leading to global
or selective susceptibility to infections [1,2]. More
than 200 monogenic defects of the human immune
system have been identified [3 ]; yet for many PID
the molecular cause remains unknown.
The common g chain (gc) cytokine family consists of the following members: interleukin-2 (IL-2),
IL-4, IL-7, IL-9, IL-15, and IL-21 [4]. These cytokines
play a fundamental role in the development, survival, proliferation, differentiation, and function of
the cells of the immune system, as highlighted by
the identification of immunodeficient patients with
mutations in IL2RG (TBþNK XSCID [5,6]), IL2RA
(severe immune dysregulation [7]), IL7R (TBþNKþ
SCID [8]), and JAK3 (TBþNK SCID [9,10]). To
date, no monogenic defects in IL4R, IL9R, IL15R,
or the respective cytokines have been reported.
Patients with deficiencies in gc-related cytokine
receptors suffer from life-threatening common
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and opportunistic infections and die within the first
year of life without effective treatment, such as
hematopoietic stem cell transplantation (HSCT) or
gene therapy [11,12]. In XSCID patients, defective
IL-7 and IL-15 signaling results in abrogated T and
natural killer (NK) cell development and function;
however, the cause of B cell deficiency remained
largely elusive [13]. Of note, it has been documented
that IL-21-mediated signaling may contribute to the
a
Department of Pediatrics, Dr. von Hauner Children’s Hospital, Ludwig
Maximilians University, Munich, bInstitute of Immunology, Hannover
Medical School, Hannover, Germany and cLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland, USA
Correspondence to Christoph Klein, MD, PhD, Dr. von Hauner Children’s
Hospital, Ludwig Maximilians University, Lindwurmstr. 4, D-80337
Munich, Germany. Tel: +49 89 4400 57701; fax: +49 89 4400
57702; e-mail: christoph.klein@med.uni-muenchen.de
Curr Opin Pediatr 2014, 26:704–712
DOI:10.1097/MOP.0000000000000160
Volume 26 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
IL-21 and IL-21R deficiencies Kotlarz et al.
KEY POINTS
IL-21 is a master regulator of function and homeostasis
of the immune system.
Human IL-21 and IL-21R deficiencies are life-threatening
PID, which may manifest with variable phenotypes,
including VEO-IBD, liver diseases, and susceptibility to
opportunistic infections.
HSCT may represent a potential curative therapeutic
strategy to prevent the fatal consequences of human
IL-21 and IL-21R deficiencies.
&
defective B lymphocyte function in children with
XSCID [14].
Recently, Kotlarz et al. [15 ] and Salzer et al. [16 ]
have identified mutations in the IL21R and IL21
genes, respectively, as novel causes of PID.
&
and activator of transcription (STAT) pathway [4].
IL-21 mainly activates STAT3 and STAT1, but also
transiently phosphorylates STAT5A and STAT5B [4]
(Fig. 1). The dominant activation of STAT1 and
STAT3 makes IL-21 distinctive among cytokines of
the gc family. The phosphorylation of STATs leads
to their dimerization and nuclear translocation,
subsequently inducing transcriptional activity of
the following genes: Cyclins a/b/e, Gzma, Gzmb,
Ifng, Cxcr3, Cxcr6, Bcl3, Jak3, Il10, Bim, Bcl6, Maf,
Prdm1, Rorgt, Eomes, Socs1, Socs3, Il21, and IL21r
[22 ,23–25]. Accordingly, IL-21 plays a critical role
in the regulation of cell cycle, cellular activation,
migration, cell survival, cytotoxicity, and its own
expression. In addition to the JAK-STAT pathway,
IL-21 can also transduce signals via the phosphoinositide-3-kinase/Akt [26] and rat sarcoma/mitogenactivated protein kinase pathways [25] (Fig. 1).
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INTERLEUKIN-21 AND INTERLEUKIN-21
RECEPTOR
The interleukin-21 receptor (IL-21R) was discovered
in 2000 by two independent groups [17,18]. These
studies showed that the IL-21R has a predicted open
reading frame with properties of a type I cytokine
receptor, such as a four-a-helical bundle structure
and an ‘up-up-down-down’ configuration. Furthermore, the extracellular domain of the IL-21R
includes the highly conserved WSXWS signature
motif that is common to type I cytokine receptors.
Subsequently, expression cloning of the IL-21R in
BaF3 cells has led to the identification of its ligand,
termed IL-21, which shares structural homology to
IL-2, IL-4, and IL-15 [19].
Recently, Hamming et al. [20] have reported the
crystal structure of the extracellular domain of
the human IL-21R complexed to IL-21. The authors
could demonstrate that the IL-21/IL-21R complex
has considerable structural resemblance to other
members of the gc family. Furthermore, the authors
highlighted that the WSXWS motif and N-linked
glycosylation of the IL-21R are critical for the
protein folding and localization at the plasma
membrane.
INTERLEUKIN-21-MEDIATED SIGNAL
TRANSDUCTION
IL-21 mediates signals via the heterodimeric IL-21R
complex that is composed of a unique a-chain of the
IL-21R and the gc [21]. Similar to the other gc-related
cytokines, IL-21 predominantly mediates signaling via the Janus kinase (JAK)-signal transducer
EXPRESSION AND PLEIOTROPIC
IMMUNOMODULATORY ACTIONS OF THE
INTERLEUKIN-21/INTERLEUKIN-21
RECEPTOR
Analysis of the tissue distribution of IL-21R demonstrated that it is primarily expressed in lymphohematopoietic cells, such as T, B, NK, and myeloid
cells [22 ]. The expression of IL-21R on cells of the
immune system is tightly regulated depending on
their activation status and environmental context.
Furthermore, expression of the IL-21R in nonhematopoietic cells has been documented in epithelial
cells [27–29], keratinocytes [29], and fibroblasts
[30,31].
In contrast to the wide expression of the IL-21R
on lymphoid and myeloid lineages, production of
IL-21 appears to be limited to T cell subsets, such
as NKT cells [32], CD8þ T cells [33], and activated
CD4þ T cells, in particular T helper 17 and T follicular helper cells [19,34].
Consistent with the broad cellular distribution
of the IL-21R, IL-21 exerts its biological effects on
essentially all cells of the innate and adaptive
immune system. In particular, it has been documented that IL-21 supports the following immunomodulatory actions: proliferation and survival of
CD4þ T cells [19], differentiation and immunoglobulin class-switch of B cells [14,35,36], proliferation, expansion, survival, and cytotoxicity of
CD8þ T cells [25,37–41], development of T follicular
helper cells and germinal center formation [42–49],
differentiation of T helper 17 cells [50–52], survival,
proliferation, granular morphology, cytotoxicity,
and cytokine production of NKT cells [32], proliferation, differentiation, and cytotoxicity of NK
cells [53,54], suppression of regulatory T cells [55],
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Allergy, immunology and related disorders
IL-21
γc
IL-21R
JAK3
JAK1
P
P
P
Cytoplasm
P
P
STAT5
STAT1
MAPK
PI3K
P
STAT3
STAT3
P
P
STAT3
Target genes
Nucleus
FIGURE 1. Interleukin-21 (IL-21)-mediated signal transduction. Binding of IL-21 to the heterodimeric receptor complex
consisting of the interleukin-21 receptor (IL-21R) and common gamma chain leads to activation of JAK1 and JAK3. These
kinases phosphorylate STAT1, STAT3, and STAT5 leading to STAT dimerization and translocation to the nucleus with
subsequent binding to target gene regulatory elements. In addition to the JAK/STAT pathway, IL-21 activates also PI3K and
MAPK pathways. JAK, Janus kinase; MAPK, mitogen-activated protein kinases; PI3K, phosphoinositide-3-kinase; STAT, signal
transducers and activators of transcription. Adapted and modified from [22 ].
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antigen presentation and apoptosis of dendritic cells
[56], phagocytosis of macrophages [57], and autocrine regulation of its own expression [23].
The pleiotropic immunomodulatory effects of
IL-21 are summarized in Fig. 2.
LOSS-OF-FUNCTION MUTATIONS IN THE
INTERLEUKIN-21 RECEPTOR GENE AS A
NOVEL CAUSE OF PRIMARY
IMMUNODEFICIENCY
Using whole exome and targeted sequencing based
on cellular screening assays, Kotlarz et al. [15 ] have
recently identified novel loss-of-function mutations
in the human IL21R gene in two unrelated consanguineous families with two affected siblings each.
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Clinically, the patients manifested with recurrent
respiratory and gastrointestinal infections. In
particular, all patients showed cryptosporidial infections associated with chronic cholangitis and liver
disease. Detailed demographic, genetic, clinical, and
immunological information for the individual
patients are provided in Table 1. Of note, the index
patient 1 and patient 2 had originally been diagnosed with ‘idiopathic liver fibrosis’ and were
referred for liver transplantation. The underlying
PID had not been clinically recognized in
patient 1. He had to undergo liver transplantation
because of end-stage liver disease but died shortly
after the procedure due to infectious complications
and multiorgan failure. A critical clinical review of
both cases revealed the presence of Cryptosporidium
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IL-21 and IL-21R deficiencies Kotlarz et al.
Cytotoxicity
Proliferation
Survival
Cytokines
Differentiation
Expansion
Differentiation
GC firmation
TH 17
TFH
NKT
Cytotoxicity
Proliferation
Survival
IFN-γ
Perforin
CD8
Proliferation
Differentiation
Cytotoxicity
Resistance to Treg supp.
CD4
IL-21
DC
Mϕ
ag presentation
Phagocytosis
NK
Treg
Cytotoxicity
Maturation
Differentiation
Survival
B
Proliferation,
Plasma cell differentiation
lg class-switch
lg production
Apoptosis
FIGURE 2. Pleiotropic actions of interleukin-21 (IL-21) on the immune system. The major sources of IL-21 are CD4þ T cells,
including T follicular helper cells (TFH) and TH17 cells, as well as NK T cells and CD8þ T cells. IL-21 can act in autocrine
fashion on these populations or can have multiple effects on other lymphoid [NK cells, B cells, regulatory T (Treg) cells] as well
as myeloid lymphoid [NK cells, B cells, regulatory T cells (Treg) cells] as well as myeloid (DC, dendritic cells; Mw,
macrophages) cells. Other known cellular targets of IL-21 include epithelial cells, fibroblasts, and keratinocytes (not depicted).
Immunomodulatory effects of IL-21 on each population are listed. Adapted and modified from [22 ].
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species in the bile duct system and duodenum of
both patients, triggering an extensive immunological workup in patient 2.
Routine immunological analyses of peripheral
blood lymphocytes revealed normal numbers of T,
B, and NK cells in all patients. However, the index
patient 2 showed reduced immunoglobulin classswitched IgDCD27þIgGþ B cells and increased
naı̈ve IgMþIgDþ B cells [15 ]. Similarly, patient 3,
patient 4, and two unpublished patients (patient 5
and patient 6) exhibited a significant reduction of
CD20þCD10CD27þ memory B cells and elevated
frequencies of IgMþIgDþ B cells [58 ,59 ], indicating
a deficiency in immunoglobulin isotype classswitch in IL-21R-deficient children. Moreover, all
published patients showed elevated IgE levels and
reduced IgG levels were detected in patient 2,
patient 4, and patient 6 [15 ]. It has been previously
shown that IL-21-induced STAT3 signaling is critical
for activation of PRDM1, a master regulator of
isotype class-switch and B cell differentiation [60].
As an adjunctive mechanism in IL-21-induced B cell
differentiation, Berglund et al. [61 ] have recently
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shown that IL-21R-mediated STAT3 activation induces CD25 (IL-2Ra) expression on naı̈ve B cells, thus
sensitizing their responsiveness to IL-2.
Detailed experimental studies confirmed aberrant IL-21-mediated activation of STAT signaling
resulting in impaired IL-21-related functions of lymphoid cells. The IL-21R-deficient patients 1–4 were
characterized by B cell defects (proliferation and
immunoglobulin class-switch), T cell deficiency
(reduced T cell proliferation in response to specific
antigens, specific antibody responses to immunization, and cytokine production), and variable dysfunctions of NK cell cytotoxicity (Table 1).
In contrast to deficiencies in other gc-related
cytokines, such as IL2RG [5,6] and IL7R [8], lossof-function mutations in the IL21R gene appear
to be not associated with severe combined immunodeficiency. However, IL-21R-deficient patients
exhibited increased susceptibility to infections
and multiorgan complications with high morbidity
and mortality in childhood. Accordingly, patient 1
had to undergo orthotopic liver transplantation
because of progressive chronic cholangitis, biliary
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707
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708
Sex
M
F
M
M
Patient
Pat 1a
Pat 2b
Pat 3
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Pat 4c
Latin
American/
Hispanic,
Colombia
Latin
American/
Hispanic,
Colombia
Lebanese,
Lebanon
Lebanese,
Lebanon
Ethnicity,
Country
of origin
Yes
Yes
Yes
Yes
Consanguinity
8
13
n/a
n/a
Age of
diagnosis
(years)
IL21R, c.240_
245delCTGCCA,
p.Cys81_His82del
IL21R, c.240_245
delCTGCCA,
p.Cys81_His82del
IL21R, c.G602T,
p.Arg201Leu
IL21R, c.G602T,
p.Arg201Leu
Mutation
(Gene;
Genotype)
4
7
4
2
Age of
onset
(years)
Recurrent otitis media, multiple
episodes of pneumonia
(Pseudomonas aeruginosa,
Pneumocystis jirovecii,
Streptococcus pneumoniae);
cryptosporidiosis associated
with liver disease, chronic
diarrhea; failure to thrive;
other infectious
complications (persistent
norovirus infection, several
episodes of bacteremia,
hematogenous dissemination
of Mycobacterium
massiliense, systemic
Candida albicans infections)
Recurrent otitis media, multiple
episodes of pneumonia
(Pseudomonas aeruginosa,
Pneumocystis jirovecii);
cryptosporidiosis associated
with liver disease
Recurrent pneumonia and
sinusitis; cryptosporidiosis
associated with liver
disease/fibrosis, chronic
cholangitis, chronic
diarrhea; failure to thrive;
other infectious
complications (Helicobacter
pylori-associated gastritis,
esophageal candidiasis)
Chronic upper respiratory
infections; cryptosporidiosis
associated with chronic
cholangitis, biliary fibrosis,
end-stage liver disease
Clinical manifestations
IVIG (at age of 7 years)
IVIG (at age of 11 years)
IgE "", IgG #; memory CD20þ
CD10CD27þ B cells #,
IgDþIgMþ B cells ", antibody
responses to immunization
(DTT, TT, PPSV23) #; T cell
proliferation (TT) #; defective
augmentation of CD8þ T cell
proliferation; B cell
proliferation and Ig classswitching #
IgE slightly increased, IgG #;
CD8þ T cells #; memory CD20þ
CD10CD27þ B cells #,
IgDþIgMþ B cells "; antibody
response to immunization
(PPSV23) #; T cell proliferation
(PHA, ConA, TT, Candida) #;
defective augmentation of
CD8þ T cell proliferation; B cell
proliferation and Ig classswitching #; NK cell
cytotoxicity #
HLA-identical HSCT (died
because of infectious
complications, multiorgan
failure, and graft rejection
on day þ84)
Liver transplantation at the age
of 4 years (died because of
infectious complications and
multiorgan failure on day
þ542)
Treatment
IgE ", lgG below-normal; classswitch CD19þIgDIgGþ
CD27þ B cells #, IgDþIgMþ B
cells "; antibody responses to
immunization (DTT, TT, Hib) #;
T cell proliferation (DTT, TT,
Candida) #; T cell effector
cytokine production #; B cell
proliferation and Ig classswitching #; NK cell
cytotoxicity #
IgM ", IgE "; CD19 B cells "
Immunological findings
Table 1. Synopsis of the clinical and immunological phenotypes of IL-21-deficient and IL-21R-deficient patients
Kotlarz et al.
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[15 ]
Kotlarz et al.
&
[15 ]
Kotlarz et al.
&
[15 ]
Kotlarz et al.
&
[15 ]
Reference
Allergy, immunology and related disorders
Volume 26 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1040-8703 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
M
M
F
Pat 6d
Pat 7
Pat 8
Palestinian,
Israel
Turkish, Turkey
Turkish, Turkey
n/p
Yes
Yes
Yes
n/p
8
10
20
15.5
IL21R, c.G602A,
p.Arg201Gln
IL21, c.T147C,
p.Leu49Pro
IL21R, c.153-1G>T
(splice site)
IL21R, p.Trp138Ser
2
4
6
n/p
Recurrent otitis media and
pneumonia (Pneumocystis
jirovecii, interstitial)
Recurrent upper and lower
respiratory tract infections;
VEO-IBD with persistent
nonbloody diarrhea, failure
to thrive, and recurrent oral
aphthous ulcers
Pulmonary tuberculosis;
hepatic steatosis,
hepatosplenomegaly;
lymphadenopathy; discoid
lupus/chronic inflammatory
skin disease with T-cell
infiltrate; other infectious
complications (invasive
fungal infection, CMV
keratoconjunctivitis/retinitis)
n/p
HSCT (at the age of 8 years)
IVIG, trimethoprimsulfamthoxazole,
mesalazine, enteral nutrition
IgE ", IgG #; isohemagglutin #;
circulating CD19þ #, marginal
zone CD19þIgDCD27þ #,
class-switch
CD19þIgDCD27þ B cells #,
transitional CD19þCD38hi
CD23 B cells "; T cell
proliferation (TT) #; antibody
responses to immunization
(HepB, BCG) #
IgG #, IgM "; B cell proliferation
and Ig class-switching #
IVIG, Bactrim prophylaxis,
HSCT at age of 20 years
(died soon after post-HSCT
complications)
n/p
Leukopenia; IgG, IgA #, IgM
above-normal; B cells #;
class switch B cells #
Full phenotype not reported
except: memory CD20þ
CD10CD27þ B cells #,
IgDþIgMþ B cells ";
defective augmentation of
CD8þ T cell proliferation
K. Warnatz,
personal
communication
Salzer et al.
&
[16 ]
J. Milner and I.
Barlan,
personal
communication
Deenick et al.
&
[58 ]; Ives
&
et al. [59 ]
BCG, Bacillus Calmette–Guérin; ConA, concanavalin A; DTT, diphtheria toxoid; F, female; HepB, hepatitis B; Hib; haemophilis influenza type B; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell
transplantation; IVIG, intravenous immunoglobulin replacement; M, male; n/a, not applicable; n/p, not published; Pat, patient; PHA, phytohaemagluttinin; PPSV23, Pneumococcal Polysaccharide Vaccine, 23-valent; tbc,
to be confirmed; TT, tetanus toxoid; VEO-IBD, very early onset inflammatory bowel disease.
a
Died because of infectious complications and multiorgan failure on day þ542 after orthotopic liver transplant at the age of 5 years.
b
Died because of infectious complications and multiorgan failure on day þ84 after HLA-identical HSCT at the age of 11 years.
c
Died because of infectious complications, progressive fulminant liver failure, and hepatorenal syndrome at the age of 8 years.
d
Died because of HSCT-related complications at the age of 20 years.
n/p
Pat 5
IL-21 and IL-21R deficiencies Kotlarz et al.
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Allergy, immunology and related disorders
fibrosis, and end-stage liver disease. He died because
of severe infectious complications and multiorgan
failure on day þ542 posttransplant. In view of the
refractory course and suspected immunodeficiency,
an allogeneic HSCT was performed in patient 2 prior
to genetic diagnosis. She developed multiple complications associated with reactivation of viral infections and fulminant cryptosporidiosis. She required
a second HSCT due to graft rejection but died shortly
after the procedure suffering from multiorgan
failure. Patient 4 died of infectious complications,
progressive fulminant liver failure, and hepatorenal syndrome. Patient 6 succumbed because of
HSCT-related complications at the age of 20 years.
LOSS-OF-FUNCTION MUTATION IN THE
INTERLEUKIN-21 GENE
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Salzer et al. [16 ] have recently identified a homozygous loss-of-function mutation in the IL21 gene in
patient 7 from a consanguineous Turkish family.
Similar to the identified IL-21R-deficient patients,
laboratory examinations demonstrated increased
IgE levels and reduced IgG levels (Table 1). Immunological analysis revealed reduced numbers of circulating (CD19þ), marginal zone-like (CD19þIgDþ
CD27þ), and class-switched memory (CD19þIgD
CD27þ) B cells, whereas transitional (CD19þCD38hi
CD23) B cells were increased. Patient 7 showed
normal T cell proliferation upon stimulation with
various stimuli, but not in response to tetanus
toxoid. The immunological findings in patient 7,
in particular the defective B cell development, are
reminiscent of common variable immunodeficiency
(CVID). Of note, IL21 has been already considered as
a candidate gene for patients with CVID or selective IgA deficiency [62]. Borte et al. [62] demonstrated that stimulation of B cells from CVID and
IgA-deficient patients with IL-21, IL-4, and antiCD40 could prevent apoptosis and induce isotype
class-switch. On the basis of these findings, they have
performed Sanger sequencing of IL21 in a cohort of
16 unrelated CVID patients; however, no mutation in
the coding region of IL21 was detected. Therefore,
targeted gene sequencing of IL21 may be considered
in a larger cohort of CVID patients.
Of note, IL-21 deficiency was associated with
severe very early onset inflammatory bowel disease
(VEO-IBD) in the first year of life. Patient 7 showed
recurrent and severe upper and lower respiratory
tract infections, indicative for PID, that may have
been masked by severe VEO-IBD in his two deceased
siblings lacking genetic diagnosis [16 ]. Furthermore, patient 7 showed no signs of cholangitis
and was negative for Cryptosporidium species in
feces. In contrast, only two IL-21R-deficient patients
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(patient 2 and patient 4) had a history of mild
chronic diarrhea that may also been triggered by
gastrointestinal infections, such as cryptosporidiosis. As IBD represents a complex and multifactorial
disorder, the IBD-like phenotype in patient 7 may be
attributed to environmental factors or differences in
the intestinal microbiota [63,64]. In accordance
with IL-21 deficiency, a number of monogenetic
immunoregulatory disorders have been already
associated with IBD-like phenotypes, such as
Wiskott–Aldrich syndrome, immunodysregulation
polyendocrinopathy enteropathy X-linked syndrome, chronic granulomatous disease, and X-linked
lymphoproliferative syndrome, as reviewed in [65].
These PID emphasize that a variable penetrance of
the IBD-like phenotype can be observed under
conditions of immunodeficiency and that gene–
environment interactions play a critical role in the
manifestation of IBD. Therefore, the identification
of additional patients is required to define the full
phenotype of IL-21-deficient patients and to determine the penetrance of VEO-IBD.
PERSPECTIVES
IL-21 and IL-21R deficiencies are life-threatening PID
that may manifest with variable phenotypes, such as
liver disease (IL-21R deficiency) and VEO-IBD (IL-21
deficiency). Interestingly, another IL-21R-deficient
patient (patient 6) has recently been identified with
yet more unique features, including liver disease in
the absence of detectable cryptosporidiosis, lymphoproliferation, fungal disease, and inflammatory skin
disease (J. Milner and I. Barlan, personal communication). Furthermore, an additional IL-21R-deficient
patient (patient 8) with a missense mutation, affecting the same codon of IL21R as in patient 1 and
patient 2, has been recently discovered (K. Warnatz,
personal communication). The clinical findings predominantly included pneumonia and recurrent otitis
media, but notably no cryptosporidial infections or
liver disease could be detected. Therefore, further
studies and identification of additional patients are
required to define the full phenotype of both IL-21
and IL-21R deficiencies.
The studies highlighted in this review indicate
that early diagnosis is of critical importance for
IL-21-deficient and IL-21R-deficient patients to prevent life-threatening infections and multiorgan
complications. In view of the critical role of IL-21
in modulating immune homeostasis, HSCT may be
advocated as a therapeutic option. However, future
studies are required to assess the potential and consequences of this strategy. In cases of IL-21
deficiency, administration of recombinant IL-21
may be considered as an alternative, especially
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IL-21 and IL-21R deficiencies Kotlarz et al.
when the clinical status of the patient is incompatible with HSCT. Several preclinical studies and
clinical trials have already documented the feasibility and safety of the administration of recombinant IL-21 in the treatment of solid tumors and
hematological malignancies (reviewed in [22 ]),
thus providing basic knowledge on established
dosing regimens.
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CONCLUSION
PID are a heterogeneous group of rare, chronic
disorders that affect the development and function
of the immune system. Advances in immunology
and genetics have resulted in the identification of
more than 200 PID. Previous studies on PID have
provided fundamental insights into key factors controlling immune homeostasis in a natural ecosystem. A better understanding of the underlying
pathomechanisms is critical to make a rational
choice of the available therapeutic strategies for
children with intractable diseases. Furthermore, this
knowledge will improve diagnostic processes and
may help to develop new genetic-tailored therapies
to cure affected children.
The characterization of IL-21 and IL-21R
deficiency highlights that PID can manifest with a
multitude of clinical presentations, making it
difficult to diagnose the underlying immunodeficiency. As exemplified by the identification of
IL-21-deficient and IL-21R-deficient patients, nextgeneration sequencing, in particular whole exome
sequencing, serves as an unbiased and powerful
technique that may be implemented in routine
clinical diagnostics in the near future.
Both IL-21 and IL-21R deficiencies must still be
completely characterized with respect to the clinical
and immunological phenotype. Therefore, we hope
that this review will raise the awareness of the
medical and scientific community for PID caused
by mutations in IL21 or IL21R genes.
Acknowledgements
We thank the interdisciplinary medical teams involved
in the care of the described patients. Furthermore, we are
grateful to all patients and their families for participating
in genetic studies. In particular, we thank Drs. Isil
Barlan, Polina Stepensky, and Klaus Warnatz for their
personal communication on newly identified IL-21R
patients.
This work was partially supported by grants from the
DFG (KFO250, SFB914, Gottfried-Wilhelm-Leibniz
Program), BMBF (PID-NET), and Reinhard-Frank
Stiftung (fellowship to D. Kotlarz). This work was sponsored in part by the intramural research program of the
NIAID, NIH.
Conflicts of interest
There are no conflicts of interest.
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