Filaggrin and atopic march

Abstract

There is an increasing number of experimental, genetic and clinical evidence of atopic dermatitis expression as a pre-condition for later development of other atopic diseases such as asthma, food allergy and allergic rhinitis. Atopic dermatitis is a heterogeneous, recurrent childhood disease, also present in the adult age. It is increasingly attributed to systemic features and is characterized by immunological and skin barrier integrity and function dysregulation. To maintain the protective function of the skin barrier, in particular the maintenance of pH, hydration and antimicrobial functions, the filaggrin, among others, plays a significant role. Filaggrin is a multifunctional, histidine-rich, insoluble protein. The lack of filaggrin is associated with various cutaneous (e.g. ichthyosis vulgaris, allergic contact dermatitis) and non-cutaneous (e.g. diabetes, inflammatory conditions of the gastrointestinal tract) diseases and may be a result of genetic, immunological factors combined with environmental factors. In this review we summarised (emphasized) recent findings in understanding the role of filaggrin in atopic dermatitis and other diseases, participants in the atopic march.

Keywords: atopic dermatitis; atopic diseases; filaggrin.

Figure 1

Atopic march. AD – atopic dermatitis. Modified according to (6).

Figure 2

The mechanisms of atopic march. Inherited or acquired filaggrin deficiency results in immune and inflammatory changes. In addition, inflammatory and immune changes may result in filaggrin deficiency. Therefore, there is a positive feedback loop. Skin barrier impairment caused by deficiency of filaggrin; reduced filaggrin function leads to increased activity of TSLP, which through dendritic cells acts to promote both Th2 cell adaptive immune responses and Th2 innate immune cell response (marked as 1). Allergen uptake and presentation to dendritic cells in a Th2 context (marked as 2). Th2 cell expansion and activation (marked as 3). B cells activation and IgE switch (marked as 4). Neutrophil recruitment and activation (marked as 5). Eosinophil recruitment and mediators’ release (marked as 6). Immunoglobulin E binding to the high-affinity IgE receptor (FcεRI), on mast cell and basophil receptors (marked as 7). Th – T helper. IL – interleukine. IgE – immunoglobulin E. TSLP - thymic stromal lymphopoietin.

Figure 3

The relationship between itching, skin barrier abnormalities and immune dysregulation. Scratching due to itching may aggravate skin damage. Dry skin stimulates itching by increasing the density of epidermal nerve fibres. Scratching also promotes Th2 chemokines, eosinophil recruiting chemokines, and TSLP. Obviously, the immune response can induce itching through the secretion of numerous cytokines that can act as a pruritogens. FLG – filaggrin. TSLP – thymic stromal lymphopoietin. Th – T helper. IL – interleukine. SC – stratum corneum. Modified according to (35).