Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of Comèl-Netherton syndrome patients has not been extensively investigated.
To define Comèl-Netherton syndrome as a primary immunodeficiency and to explore the benefit of IVIG replacement therapy.
We enrolled nine patients with Comèl-Netherton syndrome, sequenced SPINK5, and analyzed LEKTI expression by immunohistochemistry. Immune function was assessed by measuring cognate immunity, serum cytokine-levels and natural killer cell cytotoxicity.
All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but one reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% suffered from recurrent gastroenteritis and failure to thrive. Mutations in SPINK5 – including six novel mutations- were identified in eight patients. LEKTI expression was decreased or absent in all patients.
Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax® and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed TH1-phenotype and elevated proinflammatory cytokine levels, while serum concentrations of the chemokine RANTES and NK cell cytotoxicity were decreased.
Treatment with intravenous immunoglobulin substitution resulted in remarkable clinical improvement and temporarily increased NK cell cytotoxicity.
These data provide new insights into the immunopathology of Comèl-Netherton syndrome and demonstrate that this multisystem disorder, characterized by lack of LEKTI expression in epithelial cells, is complicated by cognate and innate immunodeficiency that responds favorably to IVIG therapy.