Editors' ChoiceSKIN DISEASE

March to the beat of adaptive immunity

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Science Translational Medicine  23 Sep 2015:
Vol. 7, Issue 306, pp. 306ec163
DOI: 10.1126/scitranslmed.aad3622

Patients with atopic dermatitis (AD) early in life are more likely to develop subsequent allergic diseases such as asthma and allergic rhinitis as they age, a progression termed the atopic march. Loss-of-function mutations in the human filaggrin gene are a major genetic predisposing factor for AD development. Although AD is often the earliest expression of the atopic march, how its development primes the atopic march progression is not known. To address this issue, Saunders and colleagues generated Filaggrin mutant mice on the proallergic BALB/c background to assess for spontaneous AD-like lesions and subsequent changes in pulmonary function. The authors assessed differences in clinical disease and mechanisms of cellular inflammation in these mice compared with wild-type (WT) mice.

The authors discovered that Flgft/ft mice had attenuated profilaggrin expression in the epidermis and absent functional filaggrin monomer, similar to FLG-null patients. Starting at 8 weeks, Flgft/ft mice developed significant eczematous-like dermatitis, with overt dermatitis by 12 weeks. Skin findings were similar to human AD, with eosinophilic and lymphocytic infiltration, increased transepidermal water loss, and upregulation of IL-4, IL-17, IFN-g, and IL-25 levels (but not IL-33 or TSLP), even in nonlesional skin. The authors then sought to determine the cellular source of these cytokines and using several reporter mice, found that the Flgft/ft mice demonstrated significantly increased TH2, TH17, and natural type 2 innate lymphoid cells (nILC2) compared with WT mice. Importantly, these mice demonstrated spontaneous pulmonary inflammation with increased airway hyper-responsiveness, including increased levels of TH2 and TH17 cytokines in lung homogenates. Thus, these mice mimic human AD including the atopic march phenomenon. To assess the comparative roles of innate and adaptive immune processes, the authors used Rag1–/–Flgft/ft mice and demonstrated that these mice continued to have eczematous lesions, with eosinophil and neutrophil infiltration in the dermis, and increased IL-1B and IL-25 levels, but without changes in TH2 or TH17 levels in the skin. Notably, these mice demonstrated elevated nILC2 expansion but did not develop lung inflammation compared with Rag1–/– mice. B and T cell reconstitution allowed progression to secondary lung inflammation.

Together, these data suggest that spontaneous dermatitis caused by filagrin deficiency is mediated by innate immune responses, including the up-regulation of nILC2s and the cytokines IL1-B and IL-25. Additionally, adaptive immune responses of T and B cells, including TH2 and TH17 cytokines, are required for the development of more severe skin pathology and progression to lung inflammation in the atopic march. This work provides exciting insight into how the atopic march might progress and provides a model to further investigate mechanisms and therapies to halt the progression of further allergic disease development after atopic dermatitis.

S. P. Saunders et al., Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammatoin of the atopic march requiring adaptive immunity. J. Allergy Clin. Immunol. 10.1016/j.jaci.2015.06.045 (2015). [Full Text]

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