The eczemas comprise a family of inflammatory skin diseases that have as hallmarks itch, epidermal spongiosis, and disruption of the stratum corneum barrier. Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are among the most common and widely studied of the eczemas. In the spring of 2006 a revealing new light focused on AD, firmly associating that disease with ichthyosis vulgaris and loss-of-function mutations in the filaggrin (FLG) gene (Palmer et al., 2006), and subsequent studies have confirmed that finding (Irvine, 2007). This insight gave molecular support to long-standing predictions that AD might be caused by an epidermal barrier defect allowing penetration of irritants, microbes, and protein antigens (Wood et al., 1992).
Those revelations led naturally to the question of whether FLG barrier defects might also predispose to ACD by allowing greater penetration of chemical haptens. In this issue, Novak and collaborators in Germany provide evidence that the answer may be yes (Novak et al., 2008). These investigators looked for two common FLG mutations in a cross-sectional population that had been studied and patch tested with common chemicals in the KORA Allergy Study from 1994 to 1995 (Schäfer et al., 2001). They selected 1,537 subjects equally weighted for the presence of specific IgE and for a history of atopic diseases. Subjects were stratified by age and sex, and the investigators properly distinguished between patch tests showing only contact sensitization and history of actual, relevant allergy with dermatitis caused by nickel or fragrances. Results indicated associations of FLG mutations with nickel sensitization and with reactions to jewelry. Somewhat puzzling was the lack of an association with sensitization to other common haptens. Certainly the frequency of sensitization to preservatives and fragrance chemicals in skin-care products might be expected to be higher in the presence of a diminished barrier. It may be that the sample size in the present study was simply inadequate to provide statistically significant associations with other chemicals. Also, sensitization to such products often occurs through skin areas such as the axilla (e.g., from deodorants) or the face, which can have increased absorption, even with an intact barrier. Oddly, nickel allergy is often associated with skin piercing, which rends even the normal epidermis. Perhaps the simplistic assumption of increased nickel sensitization due to barrier impairment should be questioned and examined further in the future.
It is worth considering that the exclusive FLG association with nickel allergy in this study might reflect mechanisms that are more complex than the simple lack of an adequate physical barrier. Nickel and other metal ions differ from classical haptens in their capacity to activate T cells through a wide range of molecular mechanisms, some of which are dependent on antigen processing and others that are independent (Gamerdinger et al., 2003; Thierse et al., 2005). Nickel may bind to various proteins ranging from serum albumin to enzymes, chaperones, and heat shock proteins (Spiewak et al., 2007). Such complexes not only may ensure transport through epidermal interstices but also may have functional effects on keratinocytes and dendritic cells (Thierse et al., 2005). Protein binding by nickel might be enhanced by a preferential peptide availability caused by FLG mutations. Interestingly, nickel can also bind and activate calcineurin to upregulate nuclear factor of activated T cells (NFAT) in keratinocytes (Al-Daraji et al., 2002), possibly initiating inflammation that enhances allergic sensitization. For many years we have followed the well-defined concept that antigenic messages are transmitted by Langerhans cells, but we have tended to ignore possible contributions from other epidermal cells to contact sensitization until relatively recently. Studies have increasingly focused on the role of the keratinocytes in priming for eczematous inflammation (Li et al., 2006).
FLG mutations are associated with higher frequencies of sensitization to nickel but not to other haptens.
Nickel may have unique antigenic properties through differing associations with a variety of cells during induction of sensitization. Nickel ions, too small for antigenic recognition, are highly reactive in combining with extracellular proteins and altering spatial conformation to become allergenic. The nickel-induced changes in tertiary structure allow for dendritic cell (DC) presentation of haptenic complexes in the context of major histocompatibility complex (MHC) class II molecules to T-cell receptors (TCRs) on CD4+ lymphocytes (Spiewak et al., 2007). Alternatively, nickel's reactivity with intracellular proteins can provide for processing and presentation, in association with MHC class I molecules, to CD8+ T lymphocytes. A third, metabolism-independent pathway allows direct linkage of nickel to dendritic cell MHC and to TCRs, analogous to superantigen T-cell activation (Gamerdinger et al., 2003). Nickel may also have direct effects on DCs to enhance maturation, trigger signaling pathways, and increase expression of chemokines and costimulatory molecules (Aiba et al., 2003). Hypersensitivity reactions to nickel have been reported to be represented by both T-helper 1 (Th1) and Th2 cells, although results have varied, and this dual profile has been reported for reactions to other antigens as well (Spiewak et al., 2007; Ohmen et al., 1995). Overall, nickel has unique features as a contact allergen, and these may lead to a better understanding of the association with FLG mutations.
Another aspect relates to the complex interaction spectrum of atopy, AD, nickel sensitivity, and allergic contact reactivity. Novak et al. (2008) confirmed previous reports demonstrating associations between FLG mutations and AD and respiratory allergy (Irvine, 2007). Past studies of contact sensitivity have struggled with the paradoxical situation of impaired experimental sensitization in AD, the frequently noted association with nickel allergy (Rajka, 1989), and the higher frequency of positive patch tests in atopy and AD (Klas et al., 1996). Contradictory conclusions are often noted (Spiewak, 2005), and many studies have been compromised by inconsistent definitions of atopy and AD and by concerns about irritant reactions mistaken for contact allergy (Heine et al., 2004). Patients with respiratory allergies or AD have lower thresholds for irritants, possibly reflecting both barrier impairment and greater inflammatory reactivity (Nassif et al., 1994). Novak and colleagues do not present data for nickel allergy in their atopic vs. nonatopic subjects but note that the association of FLG mutations with nickel was not related to greater sensitization in atopic individuals, referencing recent European studies (Spiewak, 2005; Heine et al., 2004). The initial report of contact allergy data in this subject population showed a nonsignificant tendency toward a higher frequency of sensitization in the small subpopulation with AD (Schäfer et al., 2001). It is possible that an increased risk of sensitization occurs only in AD individuals with FLG mutations or coexisting ichthyosis.
The report by Novak et al. provides a fresh perspective on the issues of contact allergy, nickel sensitization, and stratum corneum defects. Individuals with FLG mutations appear to have an increased risk of nickel sensitization. The questions of nickel sensitivity in atopics probably cannot be clarified definitively without large prospective studies of well-characterized subjects with AD, with and without ichthyosis. Most likely, similar associations will eventually be seen for some other contact allergens. Other metal sensitivities will be an interesting area to examine. The clinical implications for ichthyosis and other barrier defects will also warrant our attention as this story unfolds.
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