Filaggrin genotype does not determine the skin's threshold to UV-induced erythema

The local and systemic immunosuppressive effects of cis-UCA were initially demonstrated in murine models, and more recently, histidinemic mice deficient in cutaneous UCA because of a mutation in Hal, the gene encoding histidase, have been reported to show increased propensity to UVB-induced DNA damage.2 Mice deficient in caspase-14 (an enzyme in the profilaggrin-filaggrin proteolytic pathway) show accumulation of cyclobutane pyrimidine dimers in response to UVB radiation and increased apoptosis in the epidermis, indicating a role for caspase-14 in UVB scavenging within the stratum corneum.3 The immunosuppressive effects of cis-UCA have been demonstrated in human keratinocytes and leukocytes in vitro; knockdown of FLG in organotypic culture results in increased susceptibility of keratinocytes to UV-induced apoptosis.4 Loss-of-function mutations and copy number variation in FLG are known to result in lower levels of filaggrin breakdown products, including UCA, in human stratum corneum. [...]it has been postulated that FLG genotype might in part determine the photoprotective capacity of human skin (see Fig E1),1 but experimental evidence in vivo is lacking. Some epidemiologic data also suggest a higher incidence of multiple nonmelanoma skin cancers in subjects with a history of AD.8 Loss-of-function mutations in FLG are strongly associated with AD, and there is widespread downregulation of filaggrin expression in the skin of patients with atopic eczema, which has been demonstrated at the transcriptome level by means of direct RNA sequencing,9 and in the breakdown products of filaggrin in the stratum corneum, which was quantified by means of HPLC.10 A partial reduction in expression of filaggrin might result from the effect of circulating inflammatory cytokines, whereas a more profound deficiency results from loss-of-function mutations in FLG leading to near-complete absence of profilaggrin in the homozygous or compound heterozygous state. [...]it can be hypothesized that filaggrin deficiency contributes to the observed photosensitivity and/or reduced threshold to UVB-induced erythema in patients with AD.