Elucidating the Role of the Skin Barrier Protein Filaggrin in the Adaptive Immune Response to Commensals

Abstract

Atopic dermatitis (AD), commonly known as eczema, is a chronic inflammatory skin disease affecting millions of Americans. Disruption of skin barrier physiology is central to its pathogenesis. Mutations in the gene encoding filaggrin are present in up to 40% of patients and predispose patients to severe and early‐onset AD as well as systemic atopy (asthma and allergic rhinitis). Filaggrin, expressed in the upper layers of the skin epithelium, is a protein critical to the structural integrity of the epidermis and its key physiological functions of maintaining proper skin moisturization and pH. The epidermal barrier also plays a central role in the skin’s response to bacteria. In AD, disease flares are accompanied by skin microbial dysbiosis, specifically increased abundance of Staphylococcus epidermidis (S. epi), a common skin commensal, and Staphylococcus aureus, a pathobiont. Whereas the role of S. aureus in AD is relatively well‐studied, comparatively little is understood about the impact of impaired skin epithelial barrier function (e.g. flg mutations) on the immune response to commensal bacteria and how this might contribute to skin and systemic inflammation in atopy. I hypothesize that early life deficiency of skin barrier function alters the quality of the commensal‐specific T cell response, which contributes to later pro‐inflammatory responses to these bacteria. Using a novel system allowing me to track CD4+ T cells specific for S. epi I have found that mice lacking filaggrin (flg−/−) differ from wildtype (wt) littermates in their immune response to this commensal. Our lab has previously shown that wt mice colonized early in life develop immune tolerance to S. epi via enrichment of antigen‐specific regulatory T cells (Tregs), an immune cell population that controls inflammation. In contrast, S. epi colonization of flg−/− mice elicits reduced antigen‐specific Tregs and increased numbers of antigen‐specific CD4+ effector T cells (Teffs). Ongoing studies are focused on elucidating the mechanistic basis of this key finding and determining its contribution towards propensity for skin and systemic type‐2 inflammation. In summary, our work suggests that skin barrier physiology significantly impacts the quality of the commensal‐specific CD4+ response early in life, which may have enduring consequences for skin immune homeostasis.Support or Funding InformationAmerican Physiological Society: Porter Physiology Development Fellowship