Fas (APO-1/CD95) in inflammatory CNS diseases: intrathecal release in bacterial meningitis
Introduction
Apoptosis is a genetically encoded process of cell deletion in physiological and pathological conditions. Neutrophils, eosinophils, monocytes and lymphocytes are constitutively programmed to undergo apoptosis, which limits their pro-inflammatory potential and leads to rapid, specific, and non-phlogistic recognition by mononuclear phagocytes (Savill, 1997). Fas (CD95), a cell surface receptor belonging to the tumor-necrosis-factor superfamily, signals apoptosis after binding to the Fas-ligand (Itoh et al., 1991).
Apoptosis has recently been shown as a mechanism of cell death in animal models of bacterial meningitis (BM) (Leib et al., 1996; Bogdan et al., 1997). Involvement of apoptosis has, in addition, been described in viral infections meningoencephalitis (VME), e.g., caused by experimental Venezuelan equine encephalitis virus infection (Jackson and Rossiter, 1997) or Theiler's murine encephalomyelitis virus (Tsunoda et al., 1997). In multiple sclerosis (MS), immunoreactivity to Fas or Fas ligand has been shown on microglia (D'Souza et al., 1996), oligodendrocytes (Bonetti and Raine, 1997), infiltrating and circulating lymphocytes (D'Souza et al., 1996; Ichikawa et al., 1996).
The aim of this study was to systemically analyze the intrathecal release of a soluble isoform of Fas, that is considered to reflect apoptotic events in vivo (Bansil et al., 1997; Inoue et al., 1997; Zipp et al., 1998), in infectious (BM, VME) and presumed autoimmune (MS) inflammatory CNS diseases. Since this serum concentrations of this molecule are up to 20-fold higher than levels in cerebrospinal fluid (CSF), we performed a correction for a possible passage through a disrupted blood-CSF barrier.
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Patients with acute BM (Table 1)
This disease was diagnosed based on the cultural evidence of a predominant microorganism from a CSF sample and/or pleocytosis of >1000 cells/mm3, >60% polymorphonuclear CSF leukocytes, marked protein elevation, and clinical signs and symptoms (fever, nuchal rigidity, headache, photophobia). The CSF was collected within the intervall of 72 h after onset of symptoms. The causative organisms were Streptococcus pneumoniae (n=5), Staphylococcus aureus (n=3), Neisseria meningitidis (n=3), Escherichia
Fas-concentrations in BM (Table 1)
Patients with bacterial meningitis revealed a significantly increased release of Fas in CSF. In addition, calculation of the corresponding indices revealed that considerable part of the Fas was actually intrathecally released and not only derived from peripheral blood by diffusion through a disrupted blood-CSF barrier.
Fas-concentrations in VME (Table 1)
Although concentrations of Fas in CSF but not in serum were significantly elevated, indices of Fas were not significantly increased in this disease (p=0.60). Therefore, most of
Discussion
This investigation of the expression and release of the pro-apoptotic receptor Fas in CSF and serum from patients with infectious and inflammatory CNS diseases demonstrated an increased intrathecal release of Fas exclusively in patients with BM but not in VME or MS.
BM is cytologically characterized by a rapid extravasation of a huge number of activated granulocytes into the subarachnoidal space. Interestingly, granulocytes have been demonstrated to be cleared in an ordered manner from the
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