Genes and immune proteins underlying CMC disease discovered

In the early 1960s, severe infections of the normally harmless Candida albicans were spotted on the skin, nails, mouth or genitals in some people with otherwise normal immune systems. Initial clinical investigations found the condition, chronic mucocutaneous candidiasis (CMC), is either a milder autosomal dominant (AD) genotype or the rarer autosomal recessive (AR). But little more was learnt about how or why a person could be susceptible to this single microbe and what genetic or immunological dysfunctions were at play.

Now international teamwork involving laboratories in Rockefeller University in New York, Paris Descartes University in Paris and King Saud University in Riyadh, have pinpointed the genetic mutations carried by both forms of the condition. In doing so, they uncover what parts of the immune system are broken to allow the fungus to overcome our T-cell immunity.

The team selected a child born to Moroccan first cousins and diagnosed with the AR type of the disease and an Argentinean family carrying the AD form. They sequenced seven genes that encode various interleukins (IL) suspected of causing similar narrow range diseases and publish their results today in Science.

The recessive type is caused by a nonsense mutation to the gene for IL-17RA that prevents cells of the immune system from responding to Interleukin-17 (IL-17) signals triggered by extracellular pathogens, such as C. albicans. Whereas the dominant form is caused by a missense mutation to IL-17F, which disrupts how the protein binds to other cytokines, thereby blocking an effective response.

"This is a real proof-of-principle that CMC is a distinct condition that results from an inborn deficiency in IL-17. It is also the first to demonstrate the role of IL-17 in yet another disease resulting from a narrow infection range," says Jean-Laurent Casanova of Rockefeller University in New York, the principal investigator of the study.

Now that the causes are known, it might be possible to test treating the condition with a recombinant form of IL-17. Saleh Al-Muhsen, the team leader at King Saud University is continuing to work with the other labs on a larger cohort of CMC patients to discover if any other genes or immune proteins are involved. Casanova says this should "open the door for more potential discoveries related to genetic susceptibility to infectious diseases in human."

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