On the Role of the Epidermal Differentiation Complex in Ichthyosis Vulgaris, Atopic Dermatitis and Psoriasis

S. Hoffjan; S. Stemmler

Disclosures

The British Journal of Dermatology. 2007;157(3):441-449. 

In This Article

Role of the Epidermal Differentiation Complex in the Pathogenesis of Atopic Dermatitis

AD is a chronic inflammatory skin disease that affects up to 15% of children in industrialized countries.[33] Symptoms include pruritus and chronic or relapsing eczematous lesions that are typically localized in the face and at the extensor sides of the extremities in children and at the flexural sides in adults.[33] AD belongs to the group of atopic disorders characterized by the development of IgE antibodies to ubiquitous, nonpathogenic allergens. Yet, only 60-70% of AD patients have elevated IgE levels (also called 'extrinsic AD'). A multifactorial background has been suggested for AD, with a complex interaction between genetic and environmental factors.[34]

The immune response in AD is dominated by production of T-helper (Th) 2 cytokines (such as interleukin [IL]-4, IL-5 and IL-13) and eosinophilia.[35] Based on these immunological findings, disturbed cytokine production and allergic dysregulation have been regarded as the central mechanisms for AD as well as asthma pathogenesis for a long time. Yet, the chromosomal regions most consistently linked to asthma or related phenotypes, including the cytokine cluster region on chromosome 5q and the major histocompatibility complex (in humans HLA) region on chromosome 6p, did not show substantial evidence for linkage to AD in genome-wide screens,[36] indicating that other genes might be important for susceptibility to AD. Very recently, the role of the epidermal barrier in preventing secondary allergic sensitization has come into focus as another, possibly key factor for disease inception. In a genome-wide linkage study in the British population, linkage of AD to chromosome 1q21, the region containing the EDC, was reported,[37] and it was first suggested that defective epidermal differentiation could predispose to AD.[38] Furthermore, microarray analysis of atopic skin lesions revealed altered expression of genes located within the EDC, in particular upregulation of S100A8 and S100A7 and downregulation of loricrin and filaggrin, compared with healthy control samples.[39] When filaggrin loss-of-function mutations were identified as causative for ichthyosis vulgaris (see above), this attracted attention to the fact that several affected members of the families with ichthyosis vulgaris also exhibited AD and, subsequently, analysis of the newly discovered FLG mutations in AD patients was performed. In a small cohort of 52 Irish paediatric AD patients, the combined allele frequency for the R501X and 2282del4 mutations was 33%, compared with only 4·3% in population controls, yielding a highly significant association with AD (P = 3 × 10-17).[40] The same group found the two mutations further associated with asthma in Scottish school children and with AD in a Danish birth cohort.[40]

Since this initial report in March 2006, surprisingly many replication studies have confirmed association of FLG mutations with AD. In a family-based association study in the German population, the R501X and 2282del4 mutations were associated with AD and in particular with the extrinsic type of the disease, characterized by high serum IgE levels and additional allergic sensitization.[41] In another German case-control cohort, the strongest association of FLG null mutations with AD was seen within the subgroup of patients with early onset of the disease.[42] Significant associations of these mutations with AD and concomitant asthma were also replicated in two large European cohorts.[43] Interestingly, neither allergic airway disease nor allergic sensitization were associated with the FLG mutations in the absence of AD in this study, suggesting that an impaired barrier function in AD in the first place might pave the way for subsequent allergic sensitization and asthma (the so-called 'atopic march').[43] Replication studies have also been performed in another cohort of northern German origin[44] and a British cohort.[45] This latter group found the FLG null alleles associated with a rather severe type of AD that starts in early childhood and persists into adulthood.[45] In yet another German case-control cohort, the combined FLG mutations were most strongly associated with the extrinsic type of AD and early onset before 2 years of age.[46] Analysis of two panels of European families recruited through a child with severe AD additionally revealed significant associations with AD, asthma and atopy.[47] Very recently, the first analysis of FLG loss-of-function mutations in a Japanese cohort was published. The R501X and 2282del4 mutations were undetectable in 143 Japanese AD patients; yet, the two novel null mutations (3321delA and S2554X) identified through sequencing of Japanese ichthyosis vulgaris families were significantly associated with AD.[32] Thus, although FLG loss-of-function mutations appear to be unique between different ethnic groups, they seem to represent significant predisposing factors for AD universally. Additional studies in non-European ethnic groups are warranted in order to confirm these results.

The results of the published association studies of FLG loss-of-function mutations with AD are summarized in Table 1 . Taken together, they provide highly significant evidence for a role of FLG variation in AD pathogenesis, and the FLG mutations are among the most consistently replicated associations for AD to date. This fact is especially striking because the initial report was published only a year ago. Notably, no negative association studies for the FLG mutations have been reported so far, which might be due to the bias of reporting only positive association results but still seems extraordinary compared with other association results.[48] Interestingly, however, when the original linkage peak on chromosome 1q21 was reinvestigated taking the FLG mutations into account, the LOD score fell from 3·57 to 2·03 but did not disappear completely, indicating that other genetic variations may be present influencing AD at this locus.[47]

So far, FLG mutations have not been associated with asthma in the absence of AD.[47,49] Further, filaggrin is not expressed in the bronchial muscosa[50] and therefore does not seem to influence asthma pathogenesis directly by regulating water and allergen permeability in the bronchial mucosa. On the other hand, an intact epidermal barrier is of great importance for preventing sensitization to allergens.[51] Thus, a heritable defect in the skin barrier could well facilitate transepidermal entry of allergens and promote secondary development of allergic disease, including extrinsic AD and asthma. The exact contribution of FLG mutations to AD as well as to concomitant clinical phenotypes such as asthma, allergic rhinitis and food allergy remains to be elucidated.

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