Autoimmune disorders cause a severe toll on human health. Despite improvements in treatment due to biologic drug therapy, the underlying etiology of autoimmunity is poorly understood. A major advance in our understanding of autoimmune pathogenesis came with the discovery of Th17 cells, a new class of CD4+ T helper cell subset. Th17 cells are dysregulated in many autoimmune settings, and antibodies against IL-17A (secukinumab) are effective in treating moderate-severe plaque psoriasis. Secukinumab is also being evaluated in other autoimmune conditions including multiple sclerosis (MS). Of the IL-17 family ligands, IL-17A is by far the best characterized. IL-17F is most closely related to IL- 17A, and is encoded on a linked genetic locus with conserved regulatory elements. IL-17A and IL-17F form homodimers, but also heterodimerize to form a signaling-competent ligand, IL-17AF. All forms of IL-17 bind a receptor of IL-17RA and IL-17RC. Consequently, these cytokines elicit qualitatively similar signals in target cells, but exhibit different signaling potencies, where IL-17A>IL-17AF>IL-17F. The existence of an IL-17AF heterodimer was demonstrated in 2007, but it is still unclear under what circumstances IL-17AF is expressed and the extent to which this isoform contributes to autoimmunity. Additionally, virtually nothing is known about its downstream signaling pathways, and particularly how they compare to those of IL-17A. Our overarching goal is to understand the role of IL-17AF in mouse models of organ-specific autoimmunity. Secukinumab treatment is associated with mucosal fungal infections, particularly with C. albicans. Candidiasis is also seen in mice treated with ?-IL-17A Abs. In addition, IL-17A protects against several serious pulmonary fungal infections; it is plausible that there is a risk for these infections when secukinumab use becomes more widely used in areas where such fungal pathogens are endemic. We recently showed that Abs against IL-17AF do not predispose to mucosal candidiasis in mice, in contrast to anti-IL-17A Abs. Therefore, blockade of IL-17AF may be a safer clinical approach with respect to susceptibility to fungal pathogens. In this proposal we will interrogate the role of IL-17AF in three models of autoimmune disease where IL-17A is known to be relevant: IL-23-dependent dermal inflammation (to model psoriatic skin inflammation), experimental autoimmune encephalomyelitis (to model MS) and experimental autoimmune glomerulonephritis (to model glomerular damage associated with lupus nephritis and Goodpasture's syndrome. We will evaluate the cellular source(s) of IL-17AF in each setting and assess downstream signaling in the IL- 17-responsive cell types that are most relevant in each disease model.
The immune system maintains a careful balance between protecting from infectious pathogens and causing collateral damage that arises as a result of over exuberant inflammation. Interleukin (IL)-17A is a key factor in protecting the host against fungal pathogens. However, an overabundance of IL-17A signalling contributes to the pathogenesis of autoimmunity. Antibodies that block IL-17A are now approved to treat psoriasis and may also be effective for other autoimmune diseases. However, blocking IL-17A poses a risk for opportunistic fungal infections. Another isoform of this cytokine is the IL-17AF heterodimer, which has weaker activity than IL-17A. To date its role in autoimmune disease pathogenesis is not understood, but preliminary data suggest blocking IL-17AF does not cause susceptibility to mucosal fungal infections. Our goal with this application is to determine the role of IL-17AF in three different animal models of autoimmune conditions where IL-17A is known to be important.
| Amatya, Nilesh; Childs, Erin E; Cruz, J Agustin et al. (2018) IL-17 integrates multiple self-reinforcing, feed-forward mechanisms through the RNA binding protein Arid5a. Sci Signal 11: |
| Bichele, Rudolf; Kärner, Jaanika; Truusalu, Kai et al. (2018) IL-22 neutralizing autoantibodies impair fungal clearance in murine oropharyngeal candidiasis model. Eur J Immunol 48:464-470 |
| Monin, Leticia; Gaffen, Sarah L (2018) Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. Cold Spring Harb Perspect Biol 10: |
