Abstract
BackgroundNetherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete.ResultsWe analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19+) and naïve B cells (CD27−, IgD+) were high while memory B cells (CD27+) and switched memory B cells (CD27+IgM−IgD−), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21low, CD38low) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4+ T cells was reduced significantly and the proportion of CD8+ T central memory significantly elevated. An increased proportion of CD57+ CD8+ T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16+ and CD27− NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity.The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L+ T cells, naïve CD4+ and CD27+ CD8+ T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8+ cells and decreased the proportion of activated B cells and plasmablasts in three patients studied.ConclusionsThis study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.
Highlights
Netherton syndrome (NS, Online Mendelian Inheritance In Man (OMIM) 266500) is a severe autosomal-recessive ichthyosiform genodermatosis with atopic manifestations, neonatal failure to thrive and recurrent skin infections
For NK cell phenotyping, CD45, CD3, CD14, CD19, CD56, CD16, CD57, CD62, CD27 and CD45RA markers were used as reported earlier (27). 50,000 CD45+ cells were acquired with FACSAria (BD Biosciences, San Diego, CA, USA) and analyzed with FlowJo (Version 10.0.8r, TreeStar) [9]
The proportion of CD19+ B cells was above the reference value in 3/11 (27%) patients and within the highest quartile of reference values in 4/11 (36%) (Fig. 1, i)
Summary
Netherton syndrome (NS, OMIM 266500) is a severe autosomal-recessive ichthyosiform genodermatosis with atopic manifestations, neonatal failure to thrive and recurrent skin infections. NS is caused by mutations in SPINK5, encoding an epidermal serine protease inhibitor LEKTI (lympho-epithelial Kazal-type-related inhibitor) [1]. NS patients have a selective antibody deficiency to bacterial polysaccharides [2], elevated serum IgE and IgG4 levels, low numbers of NK cells [3, 4] and increased levels of proinflammatory and Th17 pathway cytokines (IL-1β, IL-12, TNFα, IL-2, IL-19) both in serum and in skin [5, 6]. Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
