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original article

Interleukin-36Receptor Antagonist
Deficiency and Generalized Pustular Psoriasis
Slaheddine Marrakchi, M.D., Ph.D., Philippe Guigue, Ph.D.,
Blair R. Renshaw, B.S., Anne Puel, Ph.D., Xue-Yuan Pei, Ph.D.,
Sylvie Fraitag, M.D., Jihen Zribi, M.D., Elodie Bal, Ph.D., Cline Cluzeau, Ph.D.,
Maya Chrabieh, M.Sc., Jennifer E. Towne, Ph.D., Jason Douangpanya, B.A.,
Christian Pons, M.Sc., Sourour Mansour, M.Sc., Valrie Serre, Ph.D.,
Hafedh Makni, M.D., Nadia Mahfoudh, M.D., Faiza Fakhfakh, Ph.D.,
Christine Bodemer, M.D., Ph.D., Josu Feingold, Ph.D.,
Smail Hadj-Rabia, M.D., Ph.D., Michel Favre, Ph.D., Emmanuelle Genin, Ph.D.,
Mourad Sahbatou, Ph.D., Arnold Munnich, M.D., Ph.D.,
Jean-Laurent Casanova, M.D., Ph.D., John E. Sims, Ph.D.,
Hamida Turki, M.D., Ph.D., Herv Bachelez, M.D., Ph.D., and Asma Smahi, Ph.D.

A bs t r ac t
From the Department of Dermatology
and the Laboratory of Immunology, Hedi
Chaker Hospital, Sfax University, Sfax,
Tunisia (S. Marrakchi, J.Z., H.M., N.M.,
F.F., H.T.); the Laboratory of Genetics,
INSERM Unit 781 (S. Marrakchi, P.G.,
S.F., E.B., C.C., S. Mansour, V.S., C.B., J.F.,
S.H.-R., A.M., A.S.) and the Laboratory of
Human Genetics of Infectious Diseases
(A.P., M.C., J.-L.C.), INSERM Unit 980,
Sorbonne Paris Cit Universit ParisDescartes, Hpital NeckerEnfants Malades;
the Department of Pathology, Hpital
NeckerEnfants Malades (S.F.); Institut
Pasteur, Unit de Gntique, Papillomavirus et Cancer Humain (C.P., M.F.);
INSERM UMRS 946, Institut Universitaire
dHmatologie (E.G.), and INSERM Unit
976, Assistance Publique Hpitaux de Paris
Hpital Saint-Louis (H.B.), Sorbonne Paris
Cit Universit ParisDiderot; and Fondation Jean Dausset, Centre dEtude du Polymorphisme Humain (M.S.) all in Paris;
the Department of Inflammation Research,
Amgen, Seattle (B.R.R., J.E.T., J.D., J.E.S.);
the Department of Biochemistry, University
of Cambridge, Cambridge, United Kingdom
(X.-Y.P.); and St. Giles Laboratory of Human
Genetics of Infectious Diseases, Rockefeller
University, New York (J.-L.C.). Address reprint requests to Dr. Smahi at Hpital Necker, INSERM U781, 149, Rue de Svres, 75015
Paris, France, or at asma.smahi@inserm.fr.
Drs. Marrakchi and Guigue contributed
equally to this article.
N Engl J Med 2011;365:620-8.
Copyright 2011 Massachusetts Medical Society.

620

Background

Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is

characterized by sudden, repeated episodes of high-grade fever, generalized rash, and
disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis.
Methods

We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the
effect of mutations on protein expression and conformation, stability, and function.
Results

We identified significant linkage to an interval of 1.2 megabases on chromosome

2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra
suggests that the proline at position 27 affects both the stability of interleukin-36Ra
and its interaction with its receptor, interleukin-1 receptorlike 2 (interleukin-1 receptorrelated protein 2). Biochemical analyses showed that the L27P variant was poorly
expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from
the patients.
conclusions

Aberrant interleukin-36Ra structure and function lead to unregulated secretion of

inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence
Nationale de la Recherche and Socit Franaise de Dermatologie.)
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Interleukin-36Receptor Antagonist and Psoriasis

soriasis is a chronic inflammatory

skin disease affecting 2 to 3% of persons of
European descent.1 Psoriasis vulgaris, the
most common form of the disease, accounts for
80% of cases and has a strong, albeit complex,
genetic component.2 Numerous chromosomal loci
have been implicated in genomewide association
studies, but analyses of these loci have yielded
only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses.3-5 The disease follows mendelian
transmission in a small minority of families.
Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are
characterized by a diffuse, erythematous, pustular
rash combined with high-grade fever, general
malaise, and extracutaneous organ involvement.6-9
Age at onset is variable. Generalized pustular psoriasis has been included within the spectrum of
psoriasis because it is often observed in conjunction with psoriasis vulgaris and because it involves
the recruitment of T cells and neutrophils.6-8,10-12
The purpose of this study was to identify genetic
abnormalities responsible for familial generalized
pustular psoriasis.

means of GeneScan, version 3.7, and genotyping

software. Parametric multipoint linkage analysis
was performed with the use of Merlin software,
version 1.1.2, assuming a full recessive model. The
age of the most recent common ancestor of the
patients who carried the mutation for generalized
pustular psoriasis was estimated with the use of
the ESTIAGE program.13 See the Supplementary
Appendix, available with the full text of this article at NEJM.org., for details regarding sequencing, quantitative real-time PCR analysis, human
interleukin-36receptor antagonist (interleukin36Ra) L27P modeling, construction of interleukin-36Ra plasmids and their expression of in human embryonic kidney [HEK] 293T cells and HaCat
cells, keratinocyte culture and immortalization,
measurement of interleukin-8 by enzyme-linked
immunosorbent assay (ELISA) in the patients serum and supernatants of stimulated keratinocytes, generation of recombinant human interleukin-36 proteins and an interleukin-36responsive
Jurkat reporter cell line, and immunohistochemical analyses.

R e sult s
Clinical Characteristics of the Patients

Me thods
Affected Families

Members of nine Tunisian multiplex families with

autosomal recessive generalized pustular psoriasis
participated in the study, which was approved by
the ethics committee at Hpital Necker. All patients
or their parents provided written informed consent
to take part in the study.
Genetic Analysis

We carried out a whole-genome scan with the use

of an Affymetrix GeneChip Human Mapping 10K
2.0 Array (Atlas Biolabs). DNA was extracted from
patients blood leukocytes with the use of the
Illustra DNA extraction kit Nucleon BACC3 (GE
Healthcare), according to the manufacturers instructions. Microsatellite DNA markers from chromosome region 2q12-q13 (UCSC Genome Browser)
were amplified by means of a polymerase-chainreaction (PCR) assay, with primers labeled with
fluorescent dye, and were analyzed by means of
electrophoresis on a 310 Genetic Analyzer (Applied Biosystems); genotypes were determined by

The pedigrees of the nine families that agreed to

participate in this study are shown in Figure 1A; the
pattern of inheritance was consistent with autosomal recessive disease. Table S1 in the Supplementary Appendix provides details of the clinical
features of the 16 affected family members. All
families originated from southern Tunisia and
reported varying degrees of consanguinity, with the
exception of Family 5, in which the parents reported no consanguinity. All affected persons fulfilled
the clinical and biologic criteria for generalized
pustular psoriasis (Fig. 1B, and Table S1 in the Supplementary Appendix), defined by repeated flares
of sudden onset, with the typical combination of
signs: a diffuse, erythematous skin eruption characterized by rapid coverage with pustules, along
with high-grade fever (40 to 42C), asthenia, marked
leukocytosis, and elevated serum levels of C-reactive protein. In the aggregate, the families reported five deaths after septicemia. Disease developed
in 12 of the affected persons during childhood
(between 1 week and 11 years of age) and in 4 affected persons after they reached adulthood; 2 of
these 4 had generalized pustular psoriasis dur-

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A
Family 2

Family 1
I

Family 3

I
1

I
1

II

II
1

II
1

III

III
1

IV
1

IV

V
1

Family 4

Family 5

I
2

I
1

II

II
1

Family 6

I
1

II

III

2 3

III
1

IV

34

5 6

IV
1

34

5 6

V
1

Family 7
1

IV

IV
3

III

IV

III
1
2

II

III

Family 9

II

II
2

Family 8
I

622

III
1

IV

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10

Interleukin-36Receptor Antagonist and Psoriasis

Figure 1 (facing page). Pedigrees of Nine Families

Affected with Generalized Pustular Psoriasis and
Clinical Characteristics of Affected Family Members.
The pedigrees shown in Panel A suggest autosomal recessive segregation in the nine families affected with
generalized pustular psoriasis. Solid symbols indicate
affected family members, open symbols unaffected
members, squares male family members, circles female
family members, slashes deceased family members,
and double lines consanguinity. Panel B shows representative clinical features in patients with generalized
pustular psoriasis. Subpanels a, b, and c show diffuse
erythematous and pustular eruptions on the trunk in patients from Families 1, 7, and 3, respectively; subpanel d
shows a more localized, erythematosquamous plaque
on the forearm of a member of Family 1, which persisted between attacks. Subpanel e shows the superficial
desquamating stage in the legs, which follows the initial
erythematous and pustular eruption, in a member of
Family 6. Subpanels f and g show crusted erythematous
and pustular lesions of the leg and scalp, respectively, in
two patients (from Families 2 and 6, respectively) who
also had psoriasis vulgaris. Subpanel h shows the erythrodermal form of generalized pustular psoriasis in a pregnant woman from Family 8 in whom impetigo herpetiformis was also diagnosed. Subpanels i and j show chronic
flexural psoriatic lesions in two patients from Family 2.
Subpanel k shows, in a member of Family 1, benign migratory glossitis mixed with the pustular lesions of generalized pustular psoriasis a mixture that was observed in
most of the patients. Subpanel l shows, in a member of
Family 5, acral pustular lesions of the digits with partial
nail destruction, representative of the acrodermatitis
continua form of generalized pustular psoriasis.

ing pregnancy and received a diagnosis of im

petigo herpetiformis. The frequency of flares was
highly variable from one person to another, with
some having chronic involvement, manifested as
erythematous chronic plaques without pustules.
Flares were associated with viral or bacterial infections in 12 patients, withdrawal of retinoid therapy in 7, menstruation in 6, and pregnancy in 2.
Histopathological studies performed in 8 patients
showed typical spongiform pustules, acanthosis
with elongation of rete ridges, and parakeratosis in
the stratum corneum (Fig. S1 in the Supplementary
Appendix). Immunostaining showed infiltration of
the skin by CD8 T cells, CD3 T cells, and macrophages (Fig. S1 in the Supplementary Appendix).
Linkage Analysis and Screening
of Candidate Genes

We genotyped chromosomal markers in the members of Family 1 and identified an 11-megabase

Figure 2. Molecular Modeling of Normal and Mutant Interleukin-36Receptor

Antagonist (Interleukin-36Ra).
Panel A shows a model of human wild-type interleukin-36Ra (white) superimposed on the L27P variant (blue). Panel B shows a close-up view of the
mutated region with L27P and H22 in stick presentation. Panels C, D, and
E show the surface presentation of the distribution of the electric charge of
mouse interleukin-36Ra, human wild-type interleukin-36Ra, and the human
L27P variant, respectively. Arrows point to the regions in which the charge
distribution is altered.

(Mb) region of homozygosity on chromosome

2q13-q14 (Fig. S2 in the Supplementary Appendix).
Subsequently, we observed cosegregation of the
disease and a common haplotype of 1.2 Mb (contained within the 11-Mb region) in the other eight
families, suggesting a founder effect (Zmax=13 at
=0) (Fig. S2 and Table S2 in the Supplementary
Appendix). Nine genes encoding members of the
interleukin-1 family reside at this locus. Because
these genes encode proteins known to have a role
in the innate immune response in the skin,14,15
we sequenced their exons and exonintron boundaries. We identified a homozygous variant in
IL36RN that was predicted to result in the substitution of proline for leucine at amino acid position
27 (L27P) of the interleukin-36Ra protein (Fig. S3
and Fig. S4 in the Supplementary Appendix) and
was present in all affected persons whom we analyzed (Fig. 1A). We did not observe mutations in
the other eight genes (see the Supplementary Appendix) on sequencing DNA and also complementary DNA obtained by reverse transcription of RNA
(i.e., we analyzed both genes and their messenger
RNA [mRNA] transcripts). On the basis of the size
of the homozygous region in each of the families,
we estimated that the most recent common ances-

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Figure 3 (facing page). Functional Effects of the L27P Mutation in the Interleukin-36Receptor Antagonist Gene.
Panel A shows the expression of interleukin-36receptor antagonist (interleukin-36Ra) variants in HEK 293T cells as assessed by Western blot analysis. Myc-tagged ectodysplasin-A receptorassociated adapter protein (Edd) was used as an internal control and was cotransfected with Myc-tagged interleukin-36Ra. Two points are shown for each variant. The expression of the interleukin-36Ra L27P variant is severely impaired, as compared with the wild-type, L27R, and L27A variants. The
same results were observed in HaCat cells. Panel B shows the inhibition of interleukin-36 by wild-type and mutant interleukin-36Ra. Truncated human interleukin-36 protein (5 ng per milliliter) was used to stimulate a cell line that overexpresses the interleukin-36 receptor (interleukin-1 receptorlike 2) and carries a reporter plasmid in which the luciferase gene is
driven by the interleukin-8 promoter. Inhibitor on the x axis refers to the concentration of each form of interleukin-36Ra
used. The y axis shows the light output from the luciferase encoded by the reporter plasmid, expressed in relative light
units (RLU). Interleukin-36Ra (previously known as huIL-1F5) and interleukin-36RaL27P (previously known as huIL-1F5L27P)
are the wild-type and mutant forms of human IL-1F5, respectively. The half-maximal inhibitory concentrations (IC50) were
0.074 and 0.64 g per milliliter for wild-type and mutant interleukin-36Ra, respectively. Panel C shows the thermal stability
of interleukin-36Ra proteins. Wild-type interleukin-36Ra and mutant interleukin-36Ra (100 g per milliliter in phosphatebuffered saline) were heated for 15 minutes at the indicated temperatures, chilled on ice, and then added to a reporter assay similar to the one described for Panel B at their IC90 concentrations. The graph shows a loss of antagonistic activity
with increasing temperature. These results are representative of two independent experiments in which two separate
batches of interleukin-36Ra protein were used. The graph on the left in Panel D shows interleukin-8 production, which was
assessed by means of an enzyme-linked immunosorbent assay (ELISA) with the use of immortalized keratinocytes from
two patients (Patient V.2 from Family 1 and Patient III.4 from Family 2) and from four age-matched controls, which were
stimulated with 50 ng of truncated human interleukin-36, interleukin-36, or interleukin-36 cytokines per milliliter for
24hours. The graph on the right in Panel D represents interleukin-8 production after the stimulation of keratinocytes from
patients and controls with 2.5 ng of polyinosinicpolycytidylic acid (poly[I:C]) per milliliter and 10 ng of interleukin-1 per
milliliter for 24 hours. The mean (SD) values are shown from three independent experiments in which each stimulation
was performed in triplicate. Panel E shows the production of interleukin-8, assessed by means of ELISA, in blood samples
from five patients during inflammatory flares, as compared with four controls. Panel F shows the results of immunohistochemical studies in one of four patients with generalized pustular psoriasis who underwent such studies. There is strong
and diffuse cytoplasmic staining of interleukin-36, specifically in epidermal keratinocytes (subpanel a). No staining is
observed in the neutrophils filling the pustules (subpanel b). The expression of interleukin-36 is very low in a specimen
of control epidermis (subpanel c), as well as in tissue samples of inflammatory skin disorders, lichen planus (subpanel d),
and erythema multiforme (subpanel e). DE denotes dermis, and EP epidermis.

tor of family members carrying the L27P mutation

lived 13 generations ago (95% confidence interval,
7 to 29).13 The mutation does not seem to affect the
stability or rate of degradation of IL36RN mRNAs
(data not shown).
We observed the L27P mutation, in the heterozygous state, in 3 of 287 unaffected persons from
Sfax, Tunisia, indicating a carrier prevalence of approximately 1% and an allele prevalence of 0.52%
in this population. We did not detect this mutation
in 500 unaffected Europeans, nor did we detect it
in available databases (dbSNP, Ensembl Genome
Browser).
Effect of L27P Substitution

The region of interleukin-36Ra protein surrounding

amino acid position 27 is highly conserved across
species, and leucine at position 27 is absolutely
conserved across mammalian species (Fig. S4),
suggesting that it is critical to biologic fitness. We
created a three-dimensional model of human interleukin-36Ra based on the crystal structure of
mouse interleukin-36Ra16 and suggest that the
L27P mutation reduces both the stability of the in624

terleukin-36Ra protein and its affinity for the interleukin-1Rrp2 receptor (Fig. 2, and the Supplementary Appendix). Consistent with this hypothesis
is the observation that very little mutant (L27P)
interleukin-36R is expressed, as compared with
nonmutant interleukin-36Ra, in HEK 293T and
HaCat cells on transfection of these cells with the
relevant construct; for example, transfection with
a construct encoding an arginine or an alanine at
position 27 resulted in levels of interleukin-36Ra
that were similar to those generated by the nonmutant gene (Fig. 3A).
To better evaluate the effect of the mutation on
protein stability and antagonist function, we generated recombinant mutant and nonmutant interleukin-36Ra proteins and tested their abilities to
inhibit signaling by interleukin-1 receptorlike 2
(interleukin-1RL2, also known as interleukin-1 receptorrelated protein 2), on stimulation with
interleukin-36. The L27P mutant protein was substantively less able to inhibit interleukin-1RL2
signaling than was nonmutant interleukin-36Ra
(Fig. 3B). We subjected the L27P mutant protein
to brief incubation at increasing temperatures and

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Interleukin-36Receptor Antagonist and Psoriasis

Ra

Ra
Ed
d
W + In
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Ty rle
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Myc-Tagged Edd
Myc-Tagged Interleukin-36Ra

C
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Inhibition by Interleukin 36Ra

(%)

30
Interleukin-36RaL27P
20
Interleukin-36Ra

103

102

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Interleukin-8 Promoter Activity

(RLU; millions)

Temperature (C)

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Inhibitor (g/ml)

E
Patient 1

12,000

600

Patient 2
50,000

500

45,000
10,000

Interleukin-8 (pg/ml)

40,000
35,000

8,000

30,000
6,000

25,000
20,000

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400

300

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Interleukin-8 Level in Keratinocytes (pg/ml)

Controls
(N=4)

F
a

b
EP

c EP

EP

e
EP

EP
DE

DE
DE

DE

DE

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found that it was more readily denatured by heating than was the nonmutant protein (Fig. 3C).
Keratinocytes from two patients who were homozygous for the L27P mutation produced much
higher levels of interleukin-8 than keratinocytes
from controls in response to the proinflammatory
cytokines (interleukin-36, interleukin-36, and
interleukin-36) as well as to interleukin-1 and
polyinosinicpolycytidylic acid (poly[I:C]), a synthetic ligand specific for toll-like receptor 3 that is
involved in responses to viral infections (Fig. 3D).
Accordingly, we found that interleukin-36 is overproduced after the stimulation of keratinocytes
with interleukin-1 and poly(I:C) (Fig. S5 in the
Supplementary Appendix). The overproduction of
interleukin-8 probably results from the impaired
inhibitory activity of interleukin-36Ra that is caused
by the mutation, because an antibody against interleukin-1RL2 blocked interleukin-8 production
by normal keratinocytes, on exposure to interleukin-36 cytokines (Fig. S6 in the Supplementary
Appendix). Consistent with this interpretation are
the results of plasma cytokine measurements with
the use of multiplex ELISA in six of the affected
persons at the time of an acute flare: interleukin-8
levels were substantively increased, as compared
with the levels in unaffected persons (Fig. 3E).
Finally, to gauge the extent to which the interleukin-36interleukin-36Ra signaling pathway was
stimulated in affected persons, we performed immunohistochemical analyses of skin lesions from
four affected persons who were homozygous for
the L27P mutation. The results suggest that all
three proinflammatory cytokines interleukin36, interleukin-36, and in particular, interleukin36 were overexpressed in the skin lesions from
persons who were homozygous for the mutation,
as compared with the expression levels in skin
samples from unaffected controls and in skin lesions from patients with inflammatory skin diseases other than psoriasis, such as lichen planus
and erythema multiforme (Fig. 3F).

Discussion
Our study shows that generalized pustular psoriasis is an autoinflammatory disease resulting from
excessive expression of interleukin-1 family proteins in the skin and disinhibition of the signaling
pathway that these proteins activate (Fig. 4).14,15,17
We identified a homozygous mutation in
IL36RN, the gene encoding interleukin-36Ra (also
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known as interleukin-1F5), an antagonist of three

cytokines belonging to the interleukin-1 family
interleukin-36, interleukin-36, and interleu
kin-36 (also known as interleukin-1F6, interleukin-1F8, and interleukin-1F9, respectively).18-21
These cytokines activate several proinflammatory
signaling pathways, such as the nuclear factor-B
and mitogen-activated protein kinase pathways.22,23
The interleukin-36Ra antagonist and the three
agonists interleukin-36, interleukin-36, and in
terleukin-36, as well as interleukin-1RL2, are
highly expressed in epithelial tissues such as the
skin, trachea, and esophagus.20 Moreover, we have
shown that the expression of interleukin-36 agonist can be strongly induced in keratinocytes after
treatment with immunostimulating agents such as
interleukin-1 and poly(I:C). These data suggest
that this pathway may play a role in the innate immune response to pathogens. The interleukin-1
family consists of 11 members (interleukin-1,
interleukin-1, interleukin-1receptor antagonist
[interleukin-1Ra], interleukin-18, interleukin-33,
interleukin-36, interleukin-36, interleukin-36,
interleukin-36Ra, interleukin-37, and interleukin1F10). They are encoded by highly conserved genes
and probably arose from the duplication of a common ancestor gene.24 Interleukin-36Ra shares 44%
homology with interleukin-1Ra, which negatively
regulates both interleukin-1 and interleukin-1.
The crucial role of innate immune pathways in tissue inflammation and protective immunity is supported by the identification of several genetically inherited defects involving either impaired
or enhanced interleukin-1 immunity and inflammation.25-27
However, mutations in genes that encode the
cytokines, their receptors, or their inhibitors have
been ascribed to only two pathologic conditions.
The first is a form of X-linked mental retardation
associated with mutation of IL1RAPL1, which encodes the interleukin-1 receptor accessory protein
like protein.28 Deficiency of interleukin-1receptor
antagonist (DIRA), the second condition, is associated with excessive activity of interleukin-1.29,30
DIRA is characterized by pustular eruptions and
osteoarticular, bone, and central nervous system
defects. The third condition, described in this article, is associated with a mutation in a gene encoding another member of the interleukin-1 family,
interleukin-36Ra. The mutation results in a reduction of interleukin-36Ra activity; we propose that
the resulting disease be called DITRA (deficiency

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Interleukin-36Receptor Antagonist and Psoriasis

Figure 4. Disinhibition of the Signaling Pathway Activated by Interleukin-1 Family Proteins in Generalized Pustular
Psoriasis.
Interleukin-36, interleukin-36, and interleukin-36 exert their actions by binding to the interleukin-36 receptor,
interleukin-1 receptorlike 2. Ligand binding to this receptor enables the recruitment of the interleukin-1receptor
accessory protein, leading to signal transduction involving activation of nuclear factor-B (NF-B) and mitogenactivated protein (MAP) kinases. The interleukin-36receptor antagonist (interleukin-36Ra) also binds to the interleukin-36 receptor, which blocks binding by the agonist ligands but fails to recruit accessory protein and therefore
does not lead to biologic activity. Interleukin-36Ra antagonizes their action and inhibits downstream inflammatory
signaling (NF-B and MAP kinases), avoiding exacerbated inflammatory responses. DITRA denotes deficiency of
interleukin-36receptor antagonist.

of interleukin thirty-sixreceptor antagonist). Fewer organ systems seem to be affected in DITRA

(which primarily involves the skin) than in DIRA.
But persons with DITRA, in contrast to those with
DIRA, have a very high-grade fever and general
malaise during an attack. We found that keratinocytes from patients with a deficiency of interleukin36Ra (i.e., those with DITRA) have overproduction
of interleukin-8 not only in response to inter
leukin-36, interleukin-36, and interleukin-36
but also after poly(I:C) stimulation possibly explaining the role of common infections in triggering pustular flares in all our patients. The mouse
interleukin-36interleukin-36Ra pathway has been
implicated in skin inflammation. Indeed, skinspecific overexpression of interleukin-36 in mice
results in a psoriasis-like phenotype with pustu-

lar lesions,19,31 which can be exacerbated by a

concomitant deficiency in interleukin-36Ra.19
Moreover, the psoriatic phenotype apparent in
human skin lesions transplanted onto immunodeficient mice is normalized by treatment with
an antihuman interleukin-1RL2 antibody.19
The interfamilial variation in the age at disease
onset in our study may be related to modifying
genes, epigenetic factors (including environmental factors), or both. During the course of generalized pustular psoriasis, patients may present
with various subtypes of psoriasis,2,12 suggesting
common pathophysiological mechanisms. For instance, impetigo herpetiformis is a rare pustular
dermatosis of unknown cause that typically occurs in pregnant women. It is considered by most
authors to be a generalized pustular psoriasis of

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627

Interleukin-36Receptor Antagonist and Psoriasis

pregnancy.32 Our study supports this conclusion, dysregulation of the interleukin-36interleukin-36Ra

since generalized pustular psoriasis during preg- signaling pathway may confer a predisposition to
nancy (initially diagnosed in two patients as im- common forms of psoriasis.
petigo herpetiformis) occurred in the same paSupported by grants from the Agence Nationale de la Rechertients in whom generalized pustular psoriasis was che and the Socit Franaise de Dermatologie.
also triggered by other, classic factors. ApproxiDisclosure forms provided by the authors are available with
mately 30% of patients with generalized pustular the full text of this article at NEJM.org.
We thank all the study families for their participation and
psoriasis present with the lesions of psoriasis Maxime Battistella and Manuelle Viguier for their critical read33
vulgaris, supporting our hypothesis that putative ing of the manuscript.
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