Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined

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Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.