IL-17 Cytokine Signaling and Biology in Autoimmunity

Inflammatory mediators called cytokines are responsible for coordinating the inflammatory events that prevent infections. However, when dysregulated, they can trigger bystander inflammation that is a major contributor to autoimmune diseases. Many successful drugs used to treat auto.immunity act by reducing the activity of such cytokines.

The discovery of the cytokine IL-17 and its corresponding receptors as a unique family of inflammatory cytokines in the 1990s opened up many exciting avenues of research for investigators examining the scientific basis of autoimmune diseases. Sarah L. Gaffen, PhD, professor of Rheumatology and holder of the Gerald P. Rodnan Endowed Chair, has made a career of studying IL-17 and its signaling mechanisms, using molecular and biochemical approaches as well as mouse models of IL-17-dependent diseases. Her laboratory's long-term objective is to better define the role of IL-17-mediated signals in driving immune responses and disease pathogenesis. Understanding these molecular processes is expected to provide the foundation for targeted intervention for clinical benefit.

Dr. Gaffen and her lab were one of the first groups to take on the challenge of dissecting the biology of IL-17, starting in 1999 when she established her independent laboratory. "In fact, when IL-17 was first discovered and sequenced, it was not immediately apparent that it was a cytokine because of its unusual structure. It did not look like other cytokines, such as IL-6 or tumor necrosis factor (TNF). I became interested in IL-17 because of these differences and the possible implications for autoimmune diseases," says Dr. Gaffen. "I proceeded with the assumption--or at least the hope--that elucidating IL-17- driven molecular events would not only help us determine how the immune system operates but also enable us to find better ways to intervene."

Accordingly, the persistent theme in Dr. Gaffen's research is answering the following questions: What does IL-17 do in the immune system, for good or for bad? What are the molecular pathways that the IL-17 receptor activates? How do different cell types interpret the presence of IL-17 in different circumstances? Clinically, all of this is important because IL-17 pathways could potentially be altered or harnessed to suppress destructive hyper-active signals leading to inflammation and autoimmunity.

Indeed, in 2016, drugs to block IL-17 were approved for treatment of psoriasis and psoriatic arthritis, and are under evaluation for other autoimmune conditions as well. "Of course, IL-17 did not evolve to give us autoimmune disease," points out Dr. Gaffen. "Any time you use drugs to suppress part of the normal immune system, you run the risk of infection. It is only recently that we've come to appreciate that IL-17's main function appears to be to control certain kinds of fungal infections."

2017 NIH MERIT Award Recipient

Oral thrush is an opportunistic infection caused by a fungal member of the commensal microbiota called Candida albicans. Oral thrush is a common infection associated with HIV infection, where T cells are depleted to dangerously low levels. IL-17 is primarily manufactured by T cells, specifically "type 17 T helper" (Th17) cells. Dr. Gaffen's lab was the first to show a connection between IL-17 and oral thrush. Her student Dr. Heather Conti (now an assistant professor at the University of Toledo) infected mice genetically engineered mice to lack the IL-17 receptor and found them very susceptible to infection with Candida albicans; in other words, the mouse equivalent of human oral thrush. Humans were later discovered with chronic oral thrush not due to HIV; some of these individuals carried mutations in the IL-17 receptor, demonstrating that the immune events discovered by Dr. Gaffen's group in mice accurately mirrored human disease.

A key conundrum, however, remained. Most humans never develop oral thrush, so what is the fungal trigger that causes the immune system to produce IL-17 in order to prevent oral thrush from developing? One reason that Candida albicans is able to establish opportunistic infections is its ability to convert from a single cell yeast form to a multi-cellular filamentous "hyphal" state. Only hyphae are able to penetrate the surface epithelial cells of the mouth. Candidalysin is a peptide toxin secreted by Candida albicans only in its hyphal state, and was discovered in 2016 by Drs. Julian Naglik of King's College London and Bernhard Hube of Friedrich Schiller University Jena in Germany. Dr. Gaffen spent her sabbatical in Dr. Naglik's lab in London in order to define this connection. Dr. Gaffen and some of her Pittsburgh team, led by postdoctoral fellow Dr. Akash Verma, showed that the Candidalysin toxin played an essential role in stimulating IL-17 production during the initial immune response, and therefore served as the missing Candida-derived IL-17 trigger. Additional experiments showed that IL-17 and Candidalysin behave in a synergistic manner to further amplify antifungal signals in the oral cavity. These studies thus revealed some of the essential circuitry that maintains Candida albicans as a commensal organism in the mouth even in the face of a normal immune system.

In 2017, Dr. Gaffen and Dr. Naglik received a prestigious NIH "MERIT" (Method to Extend Research In Time) Award for their research into the IL-17 signaling pathway and its relationship with oral candidiasis. Dr. Gaffen is one of only a handful of researchers at the University of Pittsburgh to have received a MERIT Award from the NIH, and one of only six people to have received one from NIDCR. Dr. Gaffen and her group are continuing their research into how Candida albicans interacts with the immune system. The long-term goal of Dr. Gaffen's MERIT award is to understand how Candidalysin generates the IL-17 signaling response in oral immunity from a biochemical and molecular standpoint.

Current Grant Support

Dr. Gaffen's research is currently supported by the following NIH-funded grants:

Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis. Project Number: R37-DE022550. Funding Body: National Institute of Dental and Craniofacial Research. Principal Investigator: Sarah L. Gaffen.

Negative Control of IL-17R Signaling: Implications for Fungal Immunity. Project Number: R01-AI107825. Funding Body: National Institute of Allergy and Infectious Diseases. Principal Investigator: Sarah L. Gaffen.

IL-17 Isoforms in Organ Specific Autoimmunity. Project Number: R21-AI128991. Funding Body: National Institute of Allergy and Infectious Diseases. Principal Investigator: Sarah L. Gaffen.

IL-23/STAT3 Mediated Regulation of Immunity to Oral Candidiasis. Project Number: R01-DE023815. Funding Body: National Institute of Dental and Craniofacial Research. Principal Investigator: Sarah L. Gaffen.

References and Further Reading

1. Monin L, Gudjonsson JE, Childs EE, Amatya N, Xing X, Verma AV, Coleman BM, Killeen M, Mathers A, Ward NL, Gaffen SL. MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-dependent Skin Inflammation. J Immunol. 2017; 198: 767-775.

2. Amatya N, Garg AV, Gaffen SL. The Yin and the Yang of IL-17 Signaling. Trends Immunol. 2017; 38(5): 310-322.

3. Verma AH, Richardson JP, Moyes DL, Ho J, Huppler AR, Ramani K, Coleman BM, Kane LP, Biswas PS, Hube B, Naglik JR, Gaffen SL. Oral Epithelial Cells Orchestrate Innate Type 17 Responses to Candida Albicans Through the Virulence Factor Candidalysin. Sci Immunol. 2017; 2: eaam8834.

4. Conti HR, Gaffen SL. IL-17 Mediated Immunity 1to the Opportunistic Fungal Pathogen Candida Albicans. J Immunol. 2015; 195(3): 780-788.