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Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis
Christoph Riethmuller1, Maeve A McAleer2, Sjors A Koppes3
1Serend-ip GmbH, Munster, Germany.
Background:
Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status.
Objective:
We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD.
Methods:
We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy.
Results:
We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = -0.80 and -0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients.
Conclusions:
NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations.
Insights
Loss-of-function mutations in the filaggrin gene (FLG) are linked to atopic dermatitis (AD). This study shows natural moisturizing factor (NMF) levels correlate with corneocyte morphology, explaining the skin barrier defect in FLG-mutated AD.
Area of Science:
- Dermatology
- Genetics
- Biophysics
Background:
- Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a significant risk factor for atopic dermatitis (AD), causing epidermal barrier defects.
- Patients with FLG LOF mutations often experience more severe and persistent AD, with increased risks of food allergies and eczema herpeticum.
- While abnormal corneocyte morphology, including villus-like projections (VP), is noted in AD, its relationship with FLG genotype and disease status requires systematic study.
Purpose of the Study:
- To quantitatively investigate the association between FLG genotype, natural moisturizing factor (NMF) levels, and corneocyte morphology in pediatric patients with AD.
- To elucidate the ultrastructural basis of the epidermal barrier defect in FLG-mutated AD.
Main Methods:
- Atomic force microscopy and scanning electron microscopy were used to analyze corneocyte conformation in 15 children with AD at presentation and after 6 weeks of therapy.
- A novel quantitative method assessed villus-like projections (VP) per corneocyte area, termed the Dermal Texture Index score.
- Corneocytes were examined in relation to FLG genotype and NMF levels.
Main Results:
- A strong negative correlation was observed between NMF levels and Dermal Texture Index scores in both acute and convalescent AD states (r = -0.80 and -0.75, respectively; P < .001 and P = .002).
- Villus-like projections (VP) predominantly contained corneodesmosin in homozygous/compound heterozygous FLG patients, and to a lesser extent in heterozygous and wild-type patients.
Conclusions:
- Natural moisturizing factor (NMF) levels are significantly correlated with corneocyte morphology in atopic dermatitis patients.
- These findings provide deeper insight into the filaggrin-deficient phenotype and the mechanisms underlying the epidermal barrier defect in FLG-mutated AD.
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