Genome-wide search for inborn errors of IL-17 immunity underlying chronic mucocutaneous candidiasis

Project Summary
Chronic mucocutaneous candidiasis (CMC) is characterized by lesions of the nails, skin, and oral and genital
mucosae by the fungus Candida albicans. Autosomal recessive (AR) IL-17RA, IL-17RC, and ACT1 deficiencies,
and autosomal dominant (AD) IL-17F deficiency underlie ‘isolated CMC’, while AR CARD9, ROR-g/gT, ZNF341,
IL-12p40, and IL-12Rβ1 deficiencies, AD STAT3, IL6ST/GP130, and JNK1 deficiencies, and AD STAT1 gain-of-
function (GOF) underlie ‘syndromic CMC’. Cells with IL-17RA, IL-17RC, ACT1, or JNK1 deficiency respond poorly
to IL-17A and IL-17F. Cells with IL-17RA or ACT1 deficiency also respond poorly to IL-17E (IL-25). Patients with
ROR-g/gT, ZNF341, STAT3, IL6ST, or JNK1 deficiency, or STAT1 GOF, display low proportions of IL-17A/IL-17F
(IL-17A/F)-producing T cells. Since 2008, we have made major contributions to these discoveries that causally
connected inborn errors of IL-17 immunity with CMC. Three outstanding enigmas are (i) the mechanisms by which
STAT1 mutations can be GOF and by which they impair the development of IL-17 T cells, (ii) the mechanisms by
which inborn errors of STAT3 that impair IL-17 production underlie CMC, while inborn errors of STAT3-activating
cytokines IL-6, IL-21, and IL-23 apparently do not, and (iii) the genetic etiology of about half of the patients with
isolated or syndromic CMC. We first intend to test the hypotheses that (a) STAT1 GOF mutations impair the
dephosphorylation of nuclear STAT1 by disrupting the formation of antiparallel dimers, thereby preventing the
accessibility of specific phosphatases, and that (b) excessive responses of T cells to IFN-a, IFN-g, and IL-27
collectively impair the development of Th17 cells. We then intend to analyze the production of IL-17 cytokines by
leukocytes from patients with IL-6R, IL-21R, or IL-23R deficiency, in comparison with known etiologies of CMC,
testing the hypothesis that the isolated disruption of IL-6, IL-21, or IL-23 only weakly impairs the development of
Th17 and related IL-17-producing lymphocytes. We finally intend to discover novel CMC-causing genes using
genome-wide (GW) approaches, based on GW linkage (GWL), and whole-exome or whole-genome sequencing
(WES/WGS). On the three fronts, we have exciting preliminary results. We found (i) that all STAT1 variants tested
are GOF due to impaired dephosphorylation by the tyrosine phosphatases TC-PTP and PTP1B, by disruption of
antiparallel dimers formation; and the concomitant addition of STAT1-dependent cytokines IFN-a/b, IFN-g, and
IL-27 inhibits the development of IL-17 T cells from naïve CD4+ T cells with STAT1 GOF; (ii) patients with AR IL-
6R or IL-23R deficiency and CMC, implying incomplete penetrance; and (iii) patients with syndromic CMC and
mutations of cRel, RelB, MAP3K6 (also known as ASK2), ZNF375 (zDHHC5), or UBASH3B (TULA-2). From a
biological standpoint, this research will provide new insights into the mechanisms of mucocutaneous immunity to
fungi, while dissecting the molecular and cellular control of human IL-17. From a clinical angle, this work will
provide new molecular diagnoses for patients and genetic counseling for families, while paving the way for new
cytokine-based approaches in patients with CMC.

Grant Number: 5R01AI127564-10
NIH Institute/Center: NIH
Principal Investigator: Jean-Laurent Casanova