Patients with complete IFN-gamma R deficiency are unable to respond to IFN-gamma and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-alpha... Show morePatients with complete IFN-gamma R deficiency are unable to respond to IFN-gamma and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-alpha and IFN-gamma share signalling pathways, treatment with IFN-alpha has been proposed in complete IFN-gamma R deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-gamma R1 with IFN-alpha and IFN-gamma, to establish whether IFN-alpha would substitute for IFN-gamma effects. IFN-alpha induced STAT1 phosphorylation in monocytes of the IFN-gamma R1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-alpha inhibited the priming effect of IFN-gamma on LPS-induced pro-inflammatory cytokine release. Finally, IFN-gamma but not IFN-alpha induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-alpha in IFN-gamma R-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-alpha may even adversely affect host defence against Mycobacteria. (C) 2010 Elsevier Inc. All rights reserved. Show less
Wetering, D. van de; Wengen, A. van; Savage, N.D.L.; Vosse, E. van de; Dissel, J.T. van 2011
Patients with complete IFN-γR deficiency are unable to respond to IFN-γ and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-α and IFN-γ... Show morePatients with complete IFN-γR deficiency are unable to respond to IFN-γ and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-α and IFN-γ share signalling pathways, treatment with IFN-α has been proposed in complete IFN-γR deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-γR1 with IFN-α and IFN-γ, to establish whether IFN-α would substitute for IFN-γ effects. IFN-α induced STAT1 phosphorylation in monocytes of the IFN-γR1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-α inhibited the priming effect of IFN-γ on LPS-induced pro-inflammatory cytokine release. Finally, IFN-γ but not IFN-α induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-α in IFN-γR-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-α may even adversely affect host defence against Mycobacteria. Show less
Background: C-reactive protein (CRP) is elevated in patients with acute myocardial infarction (AMI). When CRP binds to membrane phospholipids or Fc receptors, it activates the complement system.... Show moreBackground: C-reactive protein (CRP) is elevated in patients with acute myocardial infarction (AMI). When CRP binds to membrane phospholipids or Fc receptors, it activates the complement system. Recent studies show that CRP can be exposed on cell-derived microparticles (MP) and is associated complement activation. Objectives. We studied complement activation on circulating MP in AMI patients and healthy controls. Methods. MP were isolated from plasma of AMI patients (n=21) and sex- and age-matched healthy individuals (n=10), and analyzed by flow cytometry for bound complement components (C1q, C4, C3) and complement inhibitor and activator molecules (C4bp, CRP, serum amyloid P component, immunoglobulins IgM and IgG). Concurrently, the levels of fluid phase complement activation products and inhibitor and activator molecules were determined Results: Fluid phase CRP, MP with bound CRP (CRP + MP), and C3 activation products were elevated in AMI patients compared to controls (P=0.032, P=0.031 and P=0.023, respectively), and fluid phase CRP correlated with CRP+ MP (r=0.84, P<0.001). Although CRP+ MP were elevated, they were not associated with C1q+ MP (r=0.32, P=0.174). In contrast, IgG+ MP were associated with C1q+ MP (r=0.73, P<0.001), C4+ MP and C3+ MP (r=0.78 and r=0.87, respectively, both P<0 001), and C4bp (r=0.63, P=0.004). In healthy individuals, CRP+ MP were strongly associated with C1q+ MP (r=0 82, P=0.007), which in turn were associated with C4+ MP and C3+ MP (r=0.68, P=0.032 and r=0.68, P=0.031, respectively). Conclusions: Despite CRP-associated complement activation on the surface of MP in healthy individuals and a strong correlation between MP-bound CRP and fluid phase CRP in AMI patients, the MP-associated complement activation is IgG- but not CRP-dependent in AMP patients (C) 2010 Elsevier Inc. All rights reserved. Show less
