Influenza-induced production of interferon-alpha is defective in geriatric individuals.

BACKGROUND: The majority of deaths (90%) attributed to influenza are in person's age 65 or older. Little is known about whether defects in innate immune responses in geriatric individuals contribute to their susceptibility to influenza. OBJECTIVE: Our aim was to analyze interferon-alpha (IFN-alpha) production in peripheral blood mononuclear cells (PBMCs) isolated from young and geriatric adult donors, stimulated with influenza A or Toll-like receptor (TLR) ligands. IFN-alpha is a signature anti-viral cytokine that also shapes humoral and cell-mediated immune responses. RESULTS: Geriatric PBMCs produced significantly less IFN-alpha in response to live or inactivated influenza (a TLR7 ligand) but responded normally to CpG ODN (TLR9 ligand) and Guardiquimod (TLR7 ligand). All three ligands activate plasmacytoid dendritic cells (pDCs). While there was a modest decline in pDC frequency in older individuals, there was no defect in uptake of influenza by geriatric pDCs. DISCUSSION AND CONCLUSION: Influenza-induced production of IFN-alpha was defective in geriatric PBMCs by a mechanism that was independent of reduced pDC frequency or viability, defects in uptake of influenza, inability to secrete IFN-alpha, or defects in TLR7 signaling.

Rapid MHC-II antigen presentation of HIV type 1 by human dendritic cells.

HIV-1 is taken up by dendritic cells (DC) and degradation is detectable within a few hours. Little is known about how rapidly HIV-peptide-loaded MHC-II complexes appear on the surface of DC, however. A key impediment to the detailed understanding of MHC-II antigen presentation of HIV-1 has been the lack of good tools to quantitatively measure antigen presentation. We have developed HIV-1-gag p24 and reverse transcriptase (RT)-specific CD4(+) T cell hybridomas that demonstrate high sensitivity and specificity to detect HIV-1 antigens presented by MHC-II on human DC. We demonstrate that ex vivo primary blood myeloid DC (mDC) and monocyte-derived DC (MDDC) presented HIV-1 peptides on MHC-II molecules within 2 h of exposure to virions. HIV-1 was degraded in a compartment requiring acidification for processing and then was loaded onto newly synthesized MHC-II molecules for presentation.

The differential interaction of p38 MAP kinase and tumor necrosis factor-alpha in human alveolar macrophages and monocytes induced by Mycobacterium tuberculois.

Cellular signaling by TNF-alpha is mediated through activation of mitogen activated protein (MAP) kinases. In particular, p38 MAP kinase is activated in mononuclear phagocytes and may be important in sustaining TNF-alpha activity. Here, we compared the activation and mutual regulation of p38 MAP kinase and TNF-alpha by MTB in human alveolar macrophages (AM) and blood monocytes (MN). AM and autologous MN were prepared, and stimulated by MTB at 1:1 (bacteria/cell). MAP kinase activation was assessed by immunoprecipitation and kinase activity. TNF-alpha mRNA was assessed by real-time RT-PCR, and TNF-alpha immunoreactivity was assessed by ELISA. MTB-induced p38MAP kinase rapidly in AM as compared to MN, and inhibition of p38 MAP kinase by SB203580 reduced both TNF-alpha mRNA and protein. Activation of ERK (1/2) by MTB followed similar kinetics in both AM and MN. TNF-alpha produced by MTB sustained p38 MAP kinase activation in MN only. These data suggest that interaction of resident pulmonary macrophages and the more immature MN with MTB differ with regard to both p38 MAP kinase activation and TNF-alpha expression.