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520 ParT fOur Immunological Deficiencies

C. albicans IL-17A
IL-17F
IL-17RA
PRR
IL-17RC

CARD9 ACT1

RORyt

NF-κB MAPK
STAT-3 STAT1
IL-6R IFN-R

IL-6
IL-23
IL-23R IL-27R

Phagocytes, epithelial cells T lymphocytes
fIG 36.6 Genetic Etiologies Affecting the Interleukin (IL)-17 Pathway. Schematic representation
of IL-17 immunity and cooperation between cells recognizing Candida albicans (phagocytes and
epithelial cells) and cells producing IL-17 cytokines (T and innate [NK] lymphocytes). CMCD-causing
mutations (in blue) of IL-17F, IL-17RA, IL17RC, CARD9, and ACT1 impair IL-17 function or response.
CMCD-causing gain-of-function mutations (also shown in blue) in STAT1 impair the development
of IL-17–producing T cells.

Argentina displayed isolated CMC (see Fig. 36.6). A monoallelic and resulting in impaired T-cell tolerance, 88% of patients develop
mutation of IL17F was detected and found to have no impact CMC. High levels of neutralizing autoantibodies against IL-17A,
on protein production. However, this mutation greatly decreased IL-17F, and/or IL-22 have been detected in the serum of patients
the activity of homo- and heterodimers (IL-17F/IL-17F or IL-17A/ with APS-1. 50
IL-17F) by affecting binding of the complex to the receptor. AR complete ACT1 deficiency has been reported in two patients
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Another patient with a monoallelic mutation of IL-17F has been from a consanguineous family from Algeria. These two siblings
reported, but no cellular characterization was carried out. 17 developed CMC. However, one of them presented recurrent
AR complete IL-17RC deficiency has been reported in three episodes of folliculitis decalvans and bilateral blepharitis caused
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unrelated patients from Turkey and Argentina. All patients by S. aureus. Their cellular phenotypes are characterized by
suffered from CMC, and none presented invasive or recurrent impaired responses to IL-17A and IL-17F in fibroblasts and
bacterial infections. The clinical manifestations of infectious impaired responses to IL-17E in T lymphocytes. 19
diseases in this group of patients resembled those in patients with
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AD IL-17 deficiency. The three homozygous mutations identified, THEraPEuTIC PrINCIPLES
Q138X, R376X and R378X, confer a loss of IL-17RC protein Treatment of Chronic Mucocutaneous
expression in transfected HEK293T cells, with complete abolition Candidiasis (CMC)
of the response to IL-17A and IL-17 homo- and heterodimers. 18
Genome-wide approaches led to the discovery of heterozygous • A preventive antifungal treatment, (principally fluconazole) should be
STAT1 missense mutations in patients with CMC disease (D) administered in the long term, followed by other antifungal drugs,
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(OMIM 614162). These mutations, unlike the previously such as itraconazole or posaconazole.
reported mono- or biallelic STAT1 loss-of-function mutations • Antibiotic prophylaxis should be considered in selected patients with
cutaneous staphylococcal disease.
associated with susceptibility to mycobacterial, intracellular • Monthly prophylactic administration of intravenous immunoglobulin
bacterial, and viral infections, were shown to be gain of function should be considered in selected patients with recurrent pneumonia.
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(GOF). A recent study from the International STAT GOF group • Granulocyte–colony-stimulating factor (G-CSF), the JAK inhibitor
described 274 patients from 167 kindreds from 40 countries on ruxolitinib, or hemopoietic stem cell transplantation (HSCT) may also
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five continents. In total, 76 mutations of the STAT1 gene have be considered.
been identified and characterized in vitro. CMCD-causing STAT1
mutations enhance the responses of STAT1 to IFN-α/β, IFN-γ, AR complete ROR-γ/ROR-γT RORC deficiency has recently
and IL-27 and of the repressors of IL-17 T-cell development, been identified in three unrelated consanguineous families from
51
probably accounting for the low IL-17 T-cell counts in these Israel, Chile, and Saudi Arabia. RORC is a DNA-binding
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patients, resulting in CMCD. In AR APS-1 (APECED;)(OMIM transcription factor that plays an important role in thymopoiesis.
240300), caused by autoimmune regulator (AIRE) deficiency The patients suffered from an unusual combination of BCGosis