Genetic Mutation Impairs Immunity in Candidiasis and Mycobacteriosis

Human inborn errors of immunity mediated by the cytokines interleukin-17A/F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease.

These 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. The inborn errors of human IFN-γ 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.


An international team of scientists led by those at Hiroshima University (Japan) and the Rockefeller University (New York, NY, USA) identified bi-allelic mutations in RAR-Related Orphan Receptor C (RORC), which encoded RORγ and RORγT, in seven patients from three families of diverse ethnic origins, with an unusual combination of candidiasis and mycobacteriosis. RORγT is a well-known key transcription factor of Th17 cells, which produce IL-17 and IL-22.

The team used a variety of techniques including genome-wide linkage analysis with Genome-wide Human Mapping arrays (Affymetrix; Santa Clara, CA, USA); whole-exome sequencing where genomic DNA extracted from the patients’ blood cells was sheared with a Covaris S2 Ultrasonicator (Covaris; Woburn, MA, USA); and quantitative polymerase chain reaction (qPCR) on extracted ribonucleic acid (RNA) was performed with the Light Cycler 480 Probes Master mix (Roche; Basel, Switzerland).

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, the scientists focused on IFN-γ immunity and identified pathological mechanisms underlying host susceptibility to mycobacteria. Leukocytes from RORC-/- patients showed impaired IFN-γ production in response to a mycobacterial challenge, and this defect is attributable to the functional impairment of γδT cells, CD4+CCR6+CXCR3+ ab Th1* cells, or both. These findings also suggested that IFN-g treatment may be beneficial for RORC-/- patients.

The authors concluded that their results demonstrate that human RORC play a surprising dual role in host defense. These findings are clinically, immunologically, and genetically robust, as they were consistent in seven patients, from three ethnic groups, homozygous for three different RORC mutations that are loss-of-function for both isoforms. Human RORC is essential not only for the development of IL-17A/F-producing lymphocytes protecting the mucocutaneous barriers against Candida, but also for the activation of IFN-γ-producing T cells, and for systemic protection against Mycobacterium. The study was published on July 9, 2015, in the journal Science.

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Hiroshima University
Rockefeller University
Covaris