B R I E F R E P O R T
Interleukin-12 Receptor b1
Deficiency Predisposing to
Donald C. Vinh,1Brian Schwartz,2Amy P. Hsu,1David J. Miranda,1Patricia
A. Valdez,3Danielle Fink,4Karen P. Lau,4Debra Long-Priel,4Douglas
B. Kuhns,4Gulbu Uzel,1Stefania Pittaluga,5Susan Hoover,6John
N. Galgiani,6and Steven M. Holland1
1Immunopathogenesis Section, -Laboratory of Clinical Infectious Diseases,
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland;2Division of Infectious Diseases, University of California San
Francisco, San Francisco, California;3Bacterial Pathogenesis Unit, Laboratory of
Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda,and,4Neutrophil Monitoring Laboratory,
Clinical Services Program, SAIC-Frederick, and,5Laboratory of Pathology, National
Cancer Institute, National Institutes of Health, Frederick, Maryland; and6Valley
Fever Center for Excellence, The University of Arizona, Tucson
Coccidioidomycosisiscausedbythe thermallydimorphic molds
the semi-arid regionsofthe southwesternUnitedStates,Mexico,
and parts of South America. Symptomatic disease occurs in only
approximately one-third of exposed individuals, manifesting
primarily as a pneumonic process . Disseminated disease is
estimated to occur in ,5% of symptomatic individuals and
,1% of all infections, but the reasons are heretofore unknown.
Individuals of Filipino, African American, or Hispanic ancestry;
women in the third trimester of pregnancy; patients with ad-
vanced human immunodeficiency virus (HIV) infection; and
transplant recipients areatincreasedriskofdisseminateddisease
the control of Coccidioides species, and the ethnic associations
suggest significant genetic contributions to coccidioidomycosis
susceptibility. We recently described a young man with chronic
progressive coccidioidiomycosis and disseminated Mycobacte-
rium kansasii infection who had an 818del4 mutation in
IFNGR1, resulting in dominant partial deficiency of the in-
terferon (IFN)–c receptor . We report 2 related patients with
disseminated coccidioidomycosis with anovelmissense
mutation in the b1 subunit of the interleukin (IL)–12 receptor
(IL12RB1) C186Y. This confirms the importance of the IL-12/
IL-23/IFN-c pathway in the control of this fungal infection.
This 22-year-old woman presented in February 2008 with a 4-
day history of retrosternal discomfort, dysphagia, and odyno-
phagia, in addition to a 2-day history of subjective fevers and
chills. CT revealed mediastinal and right supraclavicular
lymphadenopathy. Coccidioides IgM and IgG serologic findings
then was lost to follow-up. She presented again in October 2008
with a 1-month history of fever, chills, non-productive cough,
and diffuse body aches. CT demonstrated lymphadenopathy in
the cervical, supraclavicular, hilar, mediastinal, retroperitoneal,
non-necrotizing granulomata with abundant coccidioidal
spherules (Figure 1A). She was treated with fluconazole
for ?1.5 years, with resolution and without recurrence.
The family originates from Palestine, and her parents are first
cousins. Her medical history is significant for a febrile illness at
age 11 years that developed while traveling in the Middle East
and was associated with cervical lymphadenopathy that pro-
gressively enlarged over a 1-month period. Lymph node biopsy
and repeated blood cultures yielded Salmonella serogroup D.
There was no other focus of infection (eg, osteomyelitis) by
imaging. Cure was eventually achieved after 6 weeks of in-
travenous antibiotic therapy.
The 18-year-old younger brother of patient 1 was born in
Phoenix, Arizona. At age 6 years, he was hospitalized with fever
and cough and received a diagnosis of ‘‘valley fever’’ (acute
coccidioidal pneumonia). He improved with fluconazole ther-
apy but was lost to follow-up. At 14 years of age and no longer
receiving fluconazole, he developed right supraclavicular
lymphadenopathy and a nasal lesion; spherules were seen on
biopsy. Fluconazole therapy was given until the age of 16 years.
Two monthsafterdiscontinuation, he developed right knee pain
and weight loss without fever or night sweats. A lesion in the
right proximal tibia showed granulomatous osteomyelitis with
spherules; cultures grew Coccidioides species. Itraconazole led to
improvement. He has no other history of infection.
Received 6 August 2010; accepted 7 December 2010.
Correspondence: Steven M. Holland, MD, Laboratory of Clinical Infectious Diseases,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg
10CRC, Rm B3-4141 MSC 1684, Bethesda, MD 20892 (firstname.lastname@example.org).
Clinical Infectious Diseases
Published by Oxford University Press on behalf of the Infectious Diseases Society of
d CID 2011:52 (15 February)
Both patients tested negative for HIV on multiple occasions;
demonstrated no quantitative abnormality in peripheral blood
CD141monocytes, CD31T cells and subsets, CD201B cells,
and CD161natural killer (NK) cells; and had no evidence of
elevated serum IgM level or hypogammaglobulinemia.
Because of extra-intestinal salmonellosis and subsequent ex-
trathoracic coccidioidomycosis in patient 1, an immunological
deficiency involving IL-12 was pursued. Peripheral blood
mononuclear cells (PBMCs) demonstrated significantly reduced
production of IFN-c after stimulation with phytohemagglutinin
(PHA) and failure to augment production in response to PHA
with IL-12, suggesting a defect involving the IL-12 receptor.
Sequencing of IL12RB1 confirmed homozygous 557G . A
transition, resulting in a cysteine to tyrosine substitution at
amino acid position 186 (C186Y). A distinct pathologic muta-
tion at this same amino acid position (C186S) resulting in
salmonellosis but variablesusceptibility toMycobacterium bovis–
bacilli Calmette Gue ´rin has been previously reported .
Epstein Barr virus–transformed B cells and T lymphocytes
activated with PHA and IL-2 from patient 1 lacked IL12Rb1 on
the cell surface with use of commercially available antibodies
(BD Pharmingen, clone 2.4E6; R&D, clone 69310) (Figure 1B
and D), althoughprotein was detectable onintracellular staining
with use of 2.4E6 (data not shown). Despite the presence of
intracellular IL12Rb1, the patient’s cells failed to respond to
escalating doses of IL-12, as demonstrated by the absence of
phosphorylationof signaltransducer and activatorof
transcription–4, confirming a complete functional deficiency of
the IL-12 receptor (Figure 1C, and E).
Buccal cells from patient 2 demonstrated the same homozy-
gous mutation as that in patient 1, and both unaffected parents
were heterozygous. The unaffected sibling was not tested.
It has long been appreciated that disseminated coccidioidomy-
cosis occurs in only a small minority of those at risk. These 2
cases are typical of disseminated disease. In conjunction with
our previous report of disseminated coccidioidomycosis in
a patient with a dominant IFN-c receptor mutation, this shows
the centrality of the IL-12/IL-23/IFN-c axis to human control of
Early work established that IFN-c was required for mac-
rophage killing of phagocytosed Coccidioides species and that
this process was potentiated by IL-12 [5, 6]. Subsequently, IL-
12 and IFN-c responses of human PBMCs stimulated in vitro
with coccidioidal antigens were found to distinguish immune
(delayed type hypersensitivity–positive) from nonimmune
(delayed type hypersensitivity –negative) donors . Specif-
ically, PBMCs from nonimmune donors with disseminated
coccidioidomycosis produced significantly less IFN-c than
did those from healthy immune donors. Furthermore, al-
though IFN-c production by PBMCs from immune donors
could be dramatically increased by IL-12, no increase was seen
Offset histograms showing progressive STAT4 phosphorylation in response to added IL-12 (isotype control [bottom], 0, 2.5, 5, and 10 [top] ng/mL,
respectively). D, Activated T lymphocytes from patient 1 failed to express IL-12Rb1 on the cell surface. E, Phosphorylation of STAT4 is absent in
lymphocytes from patient 1 at the same IL-12 doses used in C.
A, Abundant Coccidioides species spherules in lymph node. B, Normal activated T cells showing robust cell surface display of IL12Rb1. C,
d CID 2011:52 (15 February)
d BRIEF REPORT
in patients with disseminated coccidioidomycosis, and this
hypo-responsiveness to exogenous IL-12 in nonimmune pa-
tients was associated with impaired activation of STAT4 .
These studies unequivocally established IL-12 and IFN-c as
key mediators of cellular immunity to Coccidioides species,
and the cases that we report prove that mutations in the IL-12/
IL-23/IFN-c axis can confer susceptibility to disseminated
coccidioidomycosis. It will be interesting to determine
whether functional polymorphisms in genes of this axis may
account for the ethnocentric vulnerability described in epi-
Coccidioides species share the essential property of thermal
dimorphism with only a select few other human pathogenic
fungi, namely, Histoplasma capsulatum, Paracoccidioides brasi-
liensis, Blastomyces dermatitidis, Penicillium marneffei, and
Sporothrix schenkii. Despite differences in phylogeny, biology,
and almost certainly in pathogen-associated molecular patterns,
human immunological responses converging on the IL-12/IL-
23/IFN-c axis appear to be fundamentally necessary for pro-
tection from some of these dimorphic moulds, because muta-
tions in this pathway have also been identified in cases of
disseminated histoplasmosis and paracoccidioidomycosis [8, 9].
Of interest, disseminated coccidioidomycosis and histoplasmo-
sis have been described in patients with autosomal dominant
hyper-IgE (Job) syndrome due to mutations in STAT3. Al-
though the mechanism conferring susceptibility remains un-
defined, STAT3 is critical for IL-23 signaling, and IL-23 may be
. Collectively, these genetic immunodeficiencies illustrate
the importance of this axis to control these dimorphic fungi. As
a corollary, patients with refractory or disseminated disease with
these dimorphic fungi should be evaluated for functional defects
in these pathways.
The cases described here are distinct because of their pre-
dominant presentations with deep mycoses. Defects in the
IL-12/IL-23/IFN-c axis have been collectively referred to as
Mendelian susceptibility to mycobacterial disease (MSMD),
based on the seminal discoveriesthat individuals harboring such
mutations were susceptible to these pathogens . However,
the susceptibility phenotype of these genetic disorders continues
to expand and now includes thermally dimorphic fungi. In
contrast to previous MSMD reports, neither of the patients here
has developed mycobacterial infection. Because nontuberculous
mycobacteria are thought to be ubiquitous, it is unclear whether
this absence represents a regional variation or an effect of this
particular mutation predisposing selectively to moulds. The
variability in susceptibility to mycobacteria associated with
mutations in IL12Rb1 has been well described , presumably
because IL12 is somewhat redundant in protective immunity
against mycobacteria. However, the episode of salmonellosis in
patient 1 is characteristic of her IL12Rb1 defect.
Studies of primary immunodeficiencies have defined critical
components of natural human immunity to pathogens. Re-
cently, the features of human immunity to fungi have been in-
creasingly characterized. Defects in the phagocyte nicotinamide
adenine dinucleotide phosphate oxidase system, which cause
chronic granulomatous disease, predispose to infection with
Aspergillus species and other nondimorphic hyalohyphomycetes
(eg, Fusarium species, Paecilomyces species, and Penicillium
species). Impairment of the IL-17/IL-22 axis, seen in STAT3
deficiency and autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy, manifests with mucocutaneous candidi-
asis [12–14]. It is clear from this and previous reports that the
IL-12/IL-23/IFN-c axis is critical to the control of thermally
dimorphic fungi [3, 8, 9]. These primary immunodeficiencies
demonstrate that the occurrence of severe fungal disease is not
random but can reflect a discrete immune defect. These dis-
orders suggest the immunologic pathways that may be useful to
understand susceptibility to invasive fungal disease in at-risk
The content of this publication does not necessarily reflect the views or
policies of the Department of Health and Human Services, nor does
mention of trade names, commercial products, or organizations imply
endorsement by the US Government.
Financial support.This work was supported by the National Cancer
Institute, National Instututes of Health (NIH; HHSN261200800800001E);
Canadian Institutes of Health Research (to DCV); and Division of Intra-
mural Research, National Institute of Allergy and Infectious Diseases, NIH.
Potential conflicts of interest. All authors: no conflicts.
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