Allergic contact dermatitis: xenoinflammation of the skin
Highlights
► Target proteins for contact allergen modification in the skin are being identified. ► Contact allergens activate pattern recognition receptors via DAMPs. ► Nickel is a direct activator for human TLR4. ► Mast cells are important in contact hypersensitivity.
Introduction
Allergic contact dermatitis (ACD) is a highly prevalent T cell mediated inflammatory skin disease triggered by chemical allergens [1]. Low molecular weight organic chemicals or metal ions penetrate the skin and bind covalently or by complex formation to proteins. This may partly mimick conventional posttranslational protein modifications (PTM) or prevent those, thereby altering protein function and/or location. The protein reactivity of these haptens is essential for their action as contact allergens and serves two functions: the activation of the innate immune system and – via formation of T cell epitopes – the activation of the adaptive immune system.
Studies in the mouse model for ACD, the contact hypersensitivity (CHS) model, have revealed that pure chemicals can induce CHS in germ-free mice [2, 3••]. These findings highlight the peculiarity of these chemical allergens: they can cause sterile inflammation since they have autoadjuvant activity due to direct or indirect activation of the innate immune system in the absence of microbe (MAMPs) or pathogen associated molecular patterns (PAMPs) [4].
This review will focus on recent findings following the action of contact allergens from their entry into the skin, their interaction with skin proteins to their activation of innate and adaptive immune responses. New findings on mechanisms of immune regulation and tolerance induction to contact allergens are discussed.
Section snippets
Metabolic conversion and interaction of contact allergens with skin proteins
The penetration of chemical allergens through the skin barrier is facilitated by barrier defects such as mutations in filaggrin (FLG) that aggregates keratin filaments and is important for stratum corneum formation. Such mutations increase susceptibility to ACD as shown for nickel [5•], to chronic irritant contact dermatitis [6] and ACD prevalence in atopic individuals who often have FLG mutations [7]. Once in the viable epidermis or dermis the protein reactive electrophilic haptens modify
Innate immune response to contact allergens – chemicals mimicking infection
It has now been recognized that chemical allergens use mechanisms of innate immune system activation that are also used by microbes. One of the striking observations is, however, that CHS is normal in germ-free mice [2, 3••]. Therefore, the recently discovered triggering of TLR2 and TLR4 and the P2X7R dependent activation of the NLRP3 inflammasome in CHS can proceed independent of MAMPs/PAMPs suggesting a role for damage associated molecular patterns (DAMPs) [22]. One of the most important
Innate effector cells in allergic contact dermatitis
The role of innate effector cells of CHS and ACD has been addressed in more detail in several studies (Figure 1A). The early initiation phase of CHS involves the CD1d dependent activation of hepatic NKT cells by the accumulation of stimulatory lipids in the liver following contact allergen application to the skin [40]. By their IL-4 production and by the production of IL-33 by stromal cells and mast cells in the skin they activate B-1 B cells that seem to be involved both in the initiation and
Immune regulation of allergic contact dermatitis and the Langerhans cell puzzle
It is of great importance for the barrier function of the surfaces of the body such as skin and gut mucosa that the stromal and immune cells maintain an active tolerogenic milieu under steady state conditions. Therefore, it is not surprising that LCs are considered to be normally tolerogenic. Immune regulation in general is an active process that involves the interplay of different cell types such as DCs, Treg but also stromal cells such as keratinocytes. It can be envisioned as a car that is
Regulatory T cells in immunoregulation of CHS
Hapten application induces the interaction of T cells with endothelial cells. DNFB induced effector T cell recruitment into the skin in the elicitation phase of CHS was shown to depend on CXCL1/KC guided recruitment of Gr1+ neutrophils, and subsequent TNF-α mediated activation of endothelial ICAM-1 expression [28]. Interestingly, Treg cells prevent T cell interaction with endothelial cells by their CD39 and CD73 dependent degradation of ATP to adenosine [59]. Adenosine downregulates E-selectin
Mechanisms of tolerance induction to contact allergens
Ultraviolet B (UVB) irradiation induces the migration of immature LCs and induction of Treg and can thereby induce contact allergen specific tolerance. It was now clearly shown that LCs are required for tolerance induction [63] and that these LCs express OX40L and increased levels of IL-10 [64]. Langerin-DTR mice treated with diphtheria toxin did not develop Treg and tolerance to DNFB induced CHS. This phenotype was also observed when diphtheria toxin was given 10 days before UVB irradiation
Identification of the natural T cell epitopes
The molecular basis of T cell recognition of contact allergens and drugs is relatively well understood and there is great interest in using T cells as tools for the identification of contact allergens and drugs and for diagnostic purposes [4, 81] and possibly for the assessment of contact allergen potency [82]. However, it is still largely unknown which proteins are targeted by contact allergens in vivo for the production of T cell epitopes. Similar to studies leading to the first demonstration
Concluding remarks
Despite the strong progress in our understanding of the orchestration of the cellular and molecular immune response in CHS and ACD, many challenges lie ahead of us and problems have to be solved. Treatment of ACD may be improved by incorporating the recent findings on innate inflammatory mechanisms and on tolerance induction.
Given the seemingly contradictory results about the function of LCs it would certainly be very helpful to work in the CHS model with physiological contact allergen
Conflict of interest
The author declares no conflict of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I am grateful to Dr. Philipp R. Esser for discussions and for careful reading of the manuscript.
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