Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare primary immune disorder defined by mutations in the syntaxin binding protein 2 (STXBP2) alias MUNC18-2. Despite defective immunity and a hyper-inflammatory state, clinical findings such as neurological, gastrointestinal, and bleeding disorders are present in a significant number of patients and suggest an impaired expression and function of STXBP2 in cells other than cytotoxic lymphocytes.

PROCEDURE: We investigated four patients with FHL5 suffering from severe enteropathy and one of whom also had renal tubular dysfunction despite successful hematopoietic stem cell transplantation (HSCT). Gastrointestinal and renal biopsy specimens were analyzed by immunohistochemistry and electron microscopy.

RESULTS: Histopathology revealed an intracytoplasmatic accumulation of PAS-positive granules and an enlarged intracytoplasmatic CD10-positive band along the apical pole of enterocytes. Electron microscopy revealed short microvilli and granules filled with electro lucent material. In addition, we described mildly dilated renal tubules and electron micrographs displayed a higher number of cytoplasmic inclusions, electrodense lysosomal and electrolucent endosomal vesicles.

CONCLUSION: Mutations in STXBP2 do not only affect cytotoxic T lymphocytes but also cause changes in the intestinal and renal epithelium resulting in severe, osmotic diarrhea and renal proximal tubular dysfunction. These defects persist after successful treatment of hemophagocytic lymphohistocytosis by HSCT. Clinical manifestations in FHL5 patients despite successful HSCT may therefore be related to defective membrane trafficking in the gut and kidney.