Comèl-Netherton syndrome defined as primary immunodeficiency

Abstract

Background: Mutations in serine protease inhibitor Kazal-type 5 (SPINK5), encoding the serine protease inhibitor lympho-epithelial Kazal-type 5 related 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 patients with Comèl-Netherton syndrome has not been extensively investigated.

Objective: To define Comèl-Netherton syndrome as a primary immunodeficiency disorder and to explore the benefit of intravenous immunoglobulin replacement therapy.

Methods: We enrolled 9 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.

Results: All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but 1 reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% had recurrent gastrointestinal disease and failure to thrive. Mutations in SPINK5-including 6 novel mutations-were identified in 8 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 T(h)1 phenotype and elevated proinflammatory cytokine levels, whereas serum concentrations of the chemokine (C-C motif) ligand 5 and natural killer cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin resulted in remarkable clinical improvement and temporarily increased natural killer cell cytotoxicity.

Conclusion: 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 intravenous immunoglobulin therapy.

Figure 1. Immunological assessment of patients with Comèl-Netherton Syndrome

Panel A: Serum immunoglobulin levels measured before IVIG was started; arrows indicate 2SD below (↓) or above (↑) age matched control value.(30) (*) Patient #3 had a serum IgE level of 1119 IU/ml (2SD above age matched controls) at 6 years of age. Panel B: Decreased antibody responses following primary and secondary immunization with the neoantigen, bacteriophage phiX174, which was injected twice six weeks apart. Neutralizing antibody titres were determined in serially obtained serum samples and expressed as rate of phage inactivation or K value (Kv)²² plotted on a log scale (solid line in gray area, geometric mean and 95% confidence limit measured in 50 normal controls). The mean percentage of phage-specific IgG antibody in serum collected two weeks after the second immunization was identified as being resistant to treatment with 2-Mercaptoethanol (2-ME) (values of 50 normal controls: 48% +/− 23% 1SD). For patient #6, only one sample was collected post-secondary immunization. Panel C: NK cell cytotoxicity of ficoll-hypaque isolated PBMCs against K562 cells measured before IVIG treatment. The mean percent of lysis observed in at least three independent experiments preformed in each of the three patients studied (solid line in gray area, mean and +/− 2SD measured in 18 normal controls). Panel D: Median ± inter quartile ranges (IQR) of serum cytokine levels observed in eight patients with Comèl-Netherton syndrome (filled columns) are compared to those of sixteen age-matched normal controls (open columns); * p-values < 0.01. Median values of IL-4, IL-5, IL-7, IL-13, IL-15, IL-17, INF-α, INF-γ, and MIG [monokine induced by interferon gamma] were below detection limit in the majority of patients and control subjects (data not shown).

Figure 2

Toddler (patient #5) with Comèl-Netherton Syndrome before and three months after IVIG treatment.

Figure 3. Expression of LEKTI in different human tissues

Immunohistochemistry counterstained with hematoxylin shows LEKTI protein in red, if present. Panel detail: buccal mucosal cells of healthy individual (A) and patient #3 (B); skin biopsies of healthy child with LEKTI expression in superficial epidermal squamous layer (C) and patient #4 (D) lacking LEKTI; LEKTI expression in Hassall’s corpuscles (E) and tonsillar crypts (F) of normal controls.