transforming-growth-factor-beta and Meningitis--Bacterial

Project 6 of the NCCR 'Neural Plasticity and Repair' focuses on mechanisms of immunity and tissue damage in autoimmune and infectious diseases of the central nervous system (CNS). In one of the subprojects, the influence of transforming growth factor-beta (TGF-beta) on the immune reactivity of the CNS was investigated. In mice with Streptococcus pneumoniae-induced meningitis, a deletion of TGF-beta receptor II on leukocytes is found to enhance recruitment of neutrophils to the site of infection and to promote bacterial clearance. The improved host defense against S. pneumoniae was associated with an almost complete prevention of meningitis-induced vasculitis, a major intracranial complication leading to brain damage. The data show that endogenous TGF-beta suppresses host defense against bacterial infection in the CNS. This contrasts with findings from other body compartments that suggested that TGF-beta is a powerful chemotactic cytokine and increases microbial clearance.

Topics: Animals; Brain Injuries; Cytokines; Humans; Immunity, Innate; Meningitis, Bacterial; Monocytes; Neutrophils; Transforming Growth Factor beta

Cytokines are involved in the host response to bacterial infections. In bacterial meningitis, intrathecal synthesis of TNF-alpha and IL-1 is likely to contribute to CNS injury by recruitment and activation of inflammatory cells with subsequent release of toxic factors, such as reactive oxygen intermediates and excitatory amino acids (glutamate), leading to neuronal cell death with neurologic sequelae. In rats with experimental meningitis, pretreatment with TGF-beta inhibits cerebrovascular changes and brain edema formation in the early, TNF-alpha-independent phase. Provided its local production in bacterial infection, TGF-beta may comprise a host factor interfering with immune pathologic events altering the integrity of the endothelial barrier.

Topics: Animals; Cell Death; Child; Child, Preschool; Cytokines; Hematopoietic Cell Growth Factors; Humans; Infant; Interleukins; Meningitis, Bacterial; Mice; Nervous System Diseases; Neurons; Prospective Studies; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We investigated the levels of transforming growth factor beta 1 (TGF-beta 1) in cerebrospinal fluid (CSF) in children with meningitis, with a view to prognostic relevance. CSF TGF-beta 1 levels on admission were measured by a sandwich enzyme immunoassay in children with bacterial meningitis (n = 16), aseptic meningitis (n = 12), and control subjects without evidence of central nervous system (CNS) infection (n = 16). Patients were followed up for a mean duration of 13 months, and neurodevelopmental sequelae was determined for those with bacterial meningitis. On admission, CSF TGF-beta 1 levels were significantly higher in children with bacterial meningitis (mean, standard error, 32.92, 2.36 pg/ml) as opposed to those with aseptic meningitis (25.26, 1.72 pg/ml) (P = 0.0155), or control subjects (20.53, 1.05 pg/ml) (P < 0.0001). The CSF TGF-beta 1 levels in children with aseptic meningitis were higher than those in the control group, but without significance (P = 0.02). No apparent correlation existed between CSF TGF-beta 1 levels and CSF protein or cell counts in patients with bacterial meningitis. No significant difference in CSF TGF-beta 1 levels was found between patients with or without major sequelae following bacterial meningitis.

Topics: Acute Disease; Child; Child, Preschool; Female; Humans; Infant; Male; Meningitis, Aseptic; Meningitis, Bacterial; Prognosis; Transforming Growth Factor beta

Previous studies have demonstrated that activation/expansion by certain cytokines as well as recruitment by specific chemokines is involved in enrichment of regulatory T (Treg) cells in local tissues or organs under pathological conditions. Recent evidence indicates that human Treg cells are a heterogeneous population that comprises three distinct subpopulations: CD25⁺CD45RA⁺ resting Treg (rTreg) cells, CD25(hi)CD45RA⁻ activated Treg (aTreg) cells, which are both suppressive, and CD25⁺CD45RA⁻ cytokine-secreting T cells with proinflammatory capacity. Moreover, rTreg cells can proliferate and convert to aTreg cells. Here, we found an increase in aTreg-cell frequency in the cerebrospinal fluid (CSF) of patients with postneurosurgery bacterial meningitis. We revealed that such an increased aTreg-cell frequency in the CSF was not due to enhanced chemotaxis. Instead of a classic conversion pathway from rTreg to aTreg cells, we identified an alternative route of Treg-cell conversion from cytokine-secreting cells to aTreg cells induced by myeloid-specific chemokine CXC chemokine receptor (CXCR) ligand 5 via CXCR1 and CXCR2 receptors, or by CSF myeloid cells in a cell-cell contact manner. Our results reveal a different view of how the immune system controls overwhelming local immune responses during infection, and provide evidence of how innate immunity negatively regulates adaptive immunity.

Topics: Adult; Cerebrospinal Fluid; Chemotaxis; Female; Granulocytes; Humans; Male; Meningitis, Bacterial; Myeloid Cells; Receptors, Chemokine; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Although the roles played by systemic tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta), and their upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, in the pathogenesis of human cerebral malaria (CM) are well established, the role of local cytokine release, in the brain, remains unclear. Immunohistochemistry was therefore used to compare the expression of ICAM-1, VCAM-1, E-selectin, IL-1beta, TNF and transforming growth factor beta (TGF-beta) at light-microscope level, in cryostat sections of cerebral, cerebellar and brainstem tissues collected, post-mortem, from Ghanaian children. Among the 21 children investigated were 10 cases of CM, five of severe malarial anemia (SMA), one of purulent bacterial meningitis (PBM), two of non-central-nervous-system infection (NCNSI) and three children who had no infection (NI) when they died. Parasitised erythrocytes were detected in all of the sections from the cases of fatal malaria (CM and SMA), and sequestered leucocytes were present in most of the sections from the CM cases (but none of the sections from the SMA cases). Significantly elevated vascular expression of all three adhesion molecules investigated was detected in the brains of the 15 cases of fatal malaria and one of the cases of NCNSI (a child with Salmonella septicaemia), and in the malaria cases this showed highly significant co-localization with the areas of erythrocyte sequestration. In terms of the levels of expression of ICAM-1, VCAM-1 and E-selectin, there were, however, negligible differences between the CM and SMA cases. Although TGF-beta showed intravascular and perivascular distribution in all the subjects, its expression was most intense in the PBM case and the CM group. Only in the sections from the PBM and CM cases did TNF and IL-1beta show prominent brain parenchymal staining, in addition to the intravascular and perivascular staining seen in all subjects. The highest observed expression of each of the six antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation in the brain therefore appears to be a feature of fatal malaria and Salmonella sepsis, and in cases of fatal malaria is closely associated with leucocyte sequestration. In the present study, IL-1beta and TNF were only up-regulated in the brains of children with neurodegenerative lesions, whereas TGF-beta was present in all cases.

Topics: Anemia; Cell Adhesion Molecules; Child; Child, Preschool; Cytokines; E-Selectin; Erythrocytes; Female; Humans; Immunohistochemistry; Infant; Intercellular Adhesion Molecule-1; Interleukin-1; Leukocytes, Mononuclear; Malaria, Cerebral; Male; Meningitis, Bacterial; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P=.0003) more TGF-beta1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P=.0081) more TGF-beta2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Dürck's granulomas, and significantly (P=.0022) more TGF-beta3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-beta1, -beta2, and -beta3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.

Topics: Alzheimer Disease; Brain; Humans; Malaria, Cerebral; Meningitis, Bacterial; Multiple Sclerosis; Protein Isoforms; Transforming Growth Factor beta

Topics: Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Interleukin-10; Interleukin-6; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Listeria; Meningitis, Pneumococcal; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha