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Bi-Alllelic Mutations in RORC Gene Impair Human Immunity to Both Candida and Mycobacterium

The discovery of bi-allelic mutations in the RORC (retinoic-acid-related orphan receptor C) gene in patients with candidiasis and mycobacteriosis has revealed the pivotal role of RORC in mucocutaneous immunity to Candida and in systemic immunity to Mycobacterium in humans. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis (CMC), which is characterized by chronic or recurrent infections of the skin, nails, and oral and genital mucosae by Candida albicans, and inborn errors of human IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital disorder characterized by susceptibility to infections by poorly virulent intracellular pathogens such as non-tuberculosis Mycobacterium. Five genetic etiologies of CMC and eighteen genetic etiologies of MSMD have been reported so far. Only a few patients were affected by both candidiasis and mycobacteriosis, including some patients with IL-12p40 and IL-12R-beta-1 deficiencies that impair both IFN-gamma immunity and IL-17 immunity. The new study was published online on July 9, 2015 in Science. The article is titled “Impairment of Immunity to Candida and Mycobacterium in Humans with Bi-Allelic RORC Mutations.” In an international collaboration study with St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University in New York City, researchers at Hiroshima University identified bi-allelic mutations in RORC, which encoded RORgamma (image) and RORgammaT, in seven patients from three kindreds of diverse ethnic origins, with an unusual combination of candidiasis and mycobacteriosis. RORgammaT is a well-known key transcription factor of Th17 cells, which produce IL-17 and IL-22. Therefore, as predicted by the mouse model, the lack of the functional RORgammaT (and RORgamma) protein prevented the development of IL-17-producing T cells, which accounts for the patients' chronic candidiasis. Consistent with the phenotype of Rorc-/- mice, these patients presented with mild T cell lymphopenia, small thymus, lack of palpable axillary and cervical lymph nodes, and absence of MAIT and type 1 NKT cells.

Severe infection episodes associated with mycobacteria were observed in patients with an unexpected phenotype compared to that observed in previous studies on Rorc-/- mice. To explain this unexpected phenotype, researchers focused on IFN-gamma immunity and identified pathological mechanisms underlying host susceptibility to mycobacteria. Leukocytes from RORC-/- patients showed impaired IFN-gamma production in response to a mycobacterial challenge, and this defect is attributable to the functional impairment of gamma-delta T cells, CD4+CCR6+CXCR3+ alpha-beta Th1* cells, or both.

These findings also suggested that IFN-gamma treatment may be beneficial for RORC-/- patients. Moreover, this phenotype does not seem to be human-specific, as the researchers also found that mice deficient in Rorc were susceptible to mycobacterial infection.

"We expected these patients to be susceptible to candidiasis, but their susceptibility to mycobacterial disease was unanticipated" said the article’s lead author Dr. Satoshi Okada at Hiroshima University and the article’s senior author Professor Jean-Laurent Casanova at The Rockefeller University.

They finally discovered that human RORC is essential not only for the development of IL-17-producing T cells against Candida but also for the activation of IFN-gamma-producing T cells and for systemic protection against Mycobacterium.

[Press release] [Science abstract]