Comel‐Netherton syndrome: A local skin barrier defect in the absence of an underlying systemic immunodeficiency

Abstract

Background: Comel-Netherton syndrome (NS) is a rare autosomal disease, characterized by severe skin disease, hair shaft defects, atopic diathesis, and increased susceptibility for skin infections. Since patients with NS suffer from recurrent infections, it has been hypothesized that an underlying immunodeficiency attributes to this. Here, we studied clinical and immunological characteristics of the cohort of NS patients in the Netherlands in order to identify whether potential immunodeficiencies result in the increased risk of infectious complications. Methods: Phenotypes were scored for severity of skin condition, specific hair shaft defects, atopy, and recurrent infections. Patients' blood samples were collected for quantification of serum immunoglobulin (Ig) levels, specific antibodies against Streptococcus pneumoniae, and allergen-specific IgE, as well as detailed immunophenotyping of blood leukocyte and lymphocyte subsets by flow cytometry. Results: A total of 14 patients were included with age range 3-46 years and varying degrees of skin involvement. All patients presented with atopic symptoms (food allergy, n = 13; hay fever, n = 10; asthma, n = 7). Recurrent skin infections were common, particularly in childhood (n = 12). Low levels of specific antibodies against S pneumoniae were found in 10 of 11 evaluated patients. Detailed immunological analysis was performed on 9 adult patients. Absolute numbers of lymphocyte subsets and serum immunoglobulin levels were all within normal ranges. Conclusion: Multidisciplinary evaluation of our national cohort showed no evidence for a severe, clinically relevant systemic immunodeficiency. Therefore, we conclude that in Dutch NS patients the increased risk of infections most likely results from the skin barrier disruption and that increased allergen penetration predisposes to allergic sensitization.

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

“…40 Therefore, the skin barrier defect is likely to trigger an immune response in NS patients with no evidence for an immunodeficiency, as previously suggested. 14 Of note, the inflammatory properties of IL-17 and IL-36 pathways are enhanced by their capacity to mutually regulate each other. [41][42][43] Studies have shown that IL-36 cytokines are the most upstream mediator of skin inflammation in murine models of psoriasis.…”

“…16,24 NS patients also displayed an enrichment in circulating lymphocytes expressing IL-17 and IL-22, 25 suggesting that NS could be a T H 17-driven disorder resulting from skin barrier impairment. 14 The involvement of the T H 17 axis in NS pathogenesis is supported by the successful treatment of NS patients with anti-IL-17A antibodies. [26][27][28] Although anti-IL-17A therapy results in a significant clinical benefit, we recently reported that improvement could not be durably sustained, suggesting that other biological pathways are likely to contribute to NS pathogenesis.…”

“…The presence of immune system abnormalities remains debated. 13,14 Histologic analyses of NS skin shows stratum corneum detachment, parakeratosis, reduced granular layer 15 with epidermal hyperplasia, and hyperpapillomatosis with increased expression of proliferation markers such as keratin (KRT) 16. 16 Differentiation markers such as involucrin, loricrin, and filaggrin are diffuse in NS upper epidermal layers with a reduction of desmosomal components, 5 which contribute to the skin barrier defect.…”

Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review

“…In a majority of patients, the erythroderma present at birth gradually evolves into ichthyosis linearis circumflexa with typical ‘double-edged’ scales ( 30 ). Although symptoms can vary widely, most patients experience extensive pruritus and recurrent skin infections ( 24 , 29 , 31 ). Furthermore, NS is considered an immunodeficiency, based on previous studies that showed defects in immune cell function ( 29 , 32 , 33 ).…”

“…Furthermore, NS is considered an immunodeficiency, based on previous studies that showed defects in immune cell function ( 29 , 32 , 33 ). However, a recent study suggests a local skin barrier defect in the absence of an underlying systemic immunodeficiency ( 24 ).…”