Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology.

Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

3-week inhalation exposure to cigarette smoke and/or lipopolysaccharide in AKR/J mice.

AKR/J mice were exposed to cigarette smoke (CS) and/or lipopolysaccharide (LPS) via inhalation for 3 wk and pulmonary responses were evaluated. The objective was to explore the feasibility of coexposing LPS with cigarette smoke under a subacute exposure, as a surrogate for viral or bacterial insults, that would mimic the pathogenesis of infection-related chronic obstructive pulmonary disease (COPD) exacerbations. The study was the first step in an effort to develop a rodent COPD model in which morphologic lesions of COPD develop in a shorter period of exposure and more closely simulate human COPD. Mice were exposed 6 h/day, 5 days/wk for 3 wk to one of the following: (1) sham control: filtered air; (2) CS: 250 microg/L wet total particulate matter (WTPM) for 5 h/day followed by 1 h/day air; (3) LPS: 0.5 microg/L LPS (055:B5 Escherichia coli; 3,000,000 EU/mg) for the last 1 h/day 2 day/wk (following 5 h/day of filtered air); and (4) CS/LPS: CS 5 h/day followed by air or LPS (2 days/wk) for 1 h/day. After the last exposure, animals were necropsied and subjected to bronchoalveolar lavage (BAL) or histopathology. The BAL neutrophil counts were highest in the LPS group, while macrophage counts were higher in the CS/LPS group than other exposed groups. The LPS group displayed the greatest increases in BAL cytokines, while KC (keratinocyte-derived chemokine) and TARC (thymus and activation-regulated chemokine) were highest in the CS group. The CS/LPS group had generally lower cytokine levels relative to the LPS or CS groups, except for the levels of RANTES and G-CSF (granulocyte-colony stimulating factor) comparable to the LPS group. At microscopic examination of lung sections, cellular inflammatory infiltrates were most notable in the CS/LPS group, which had a diffuse, predominantly macrophage infiltrate with fewer neutrophils. The LPS group had predominantly neutrophils in the pulmonary infiltrate and the CS group had a predominantly macrophage infiltrate in alveolar ducts and adjacent alveoli. Apoptotic labeling of lung cells was highest with the CS/LPS group. In summary, the CS/LPS group displayed greater cellular infiltration and apoptotic responses in the lung with an indication of immunosuppressive effects (lower BAL cytokines) than the CS or LPS group, suggesting that the CS/LPS model shows promise to be further explored as an animal model for studying pathogenesis of COPD exacerbations. A longer term study with interim assessments is needed to confirm that the subacute responses observed in the CS/LPS group will result in greater severity of COPD-related pulmonary lesions following prolonged exposures.

Analysis of human serum immunoglobulin G against O-acetyl-positive and O-acetyl-negative serogroup W135 meningococcal capsular polysaccharide.

The capsular polysaccharide of Neisseria meningitidis serogroup W135 is expressed in both O-acetyl-positive (OA+) and O-acetyl-negative (OA-) forms. This study investigates the impact of OA status (OA+ versus OA-) on serological measurements of anti-W135 immunoglobulin G (IgG) antibodies in immunized adults. W135-specific serum antibody assignments were made for 28 postimmunization sera from adults by enzyme-linked immunosorbent assay using the meningococcal standard reference serum CDC1992. The established IgG concentration in micrograms per milliliter ([IgG]microg/ml) for CDC1992 against OA+ antigen (16.2 microg/ml) was used as a reference to assign a concentration of 10.13 microg/ml IgG against OA- antigen by cross-standardization. Overall, the IgG assignments for these sera were higher against OA+ antigen (geometric mean concentration [GMC] = 7.16 microg/ml) than against OA- antigen (GMC = 2.84 microg/ml). However, seven sera showed higher specific [IgG]microg/ml values against the OA+ antigen than against the OA- antigen. These sera were also distinguished by the inability of fluid-phase OA- antigen to compete for antibody binding to OA+ solid-phase antigen. Although there was no overall difference in functional activity measured by complement-mediated serum bactericidal assay (SBA) against OA+ and OA- target bacteria (geometric mean titers of 9,642 and 9,045, respectively), three serum specimens showed a large difference in SBA antibody titers against OA+ versus OA- W135 target bacteria, which may reflect different epitope specificities for these sera. Our data indicate that, for some sera, the agreement in anti-OA+ versus anti-OA- W135 IgG assignments is serum specific and does not reflect the functional (killing) activity in vitro.