Random outcomes of allergen-specific responses in atopic families.

BACKGROUND: Allergens are common non-infectious antigens to which people will mount T cell dependent humoral responses. Among genetically susceptible individuals, an antigen-specific response results involving the production of allergen-specific IgE (atopy). OBJECTIVE: Determine if this susceptibility is manifested as an inherited, allergen-specific trait or a random response to allergens among susceptible people. METHODS: We evaluated allergen-specific outcomes in 1099 members of families with positive atopic history (26 multi-generation and 112 nuclear families). Each was tested for sensitivity to 14 common allergens by standardized skin prick test (SPT), a marker of specific IgE production. Over 15,000 individual SPT's were evaluated. Among five randomly selected multi-generation families (N=163), semi-quantitative determinations of Amb a 1-specific IgA1,2 and IgG1-4 were determined in three groups: (A) Amb a SPT(+)/Amb a 1-IgE(+), (B) Amb a SPT(-)/Amb a 1-IgE(+), (C) Amb a SPT(-)/Amb a 1-IgE(-). RESULTS: By rank correlation statistics, there were no discernible 'patterns' of specific SPT outcomes among any of the multi-generation families, suggesting that environmental exposure rather than allergen-specific inheritance determined the responses. This was confirmed among the nuclear families since the conditional SPT outcomes among children were independent of the SPT responses of their parents. Among five randomly selected multi-generation families, the relative proportionate concentrations of the Amb a 1-specific IgA and IgG subclasses were comparable, regardless of atopic sensitization to the ragweed allergen Amb a. CONCLUSION: While the general propensity for atopy may be inherited, an individual's specific atopic outcome is a random variable independent of familial sensitization patterns.

Middle ear fluid cytokine and inflammatory cell kinetics in the chinchilla otitis media model.

Streptococcus pneumoniae is the most frequent microbe causing middle ear infection. The pathophysiology of pneumococcal otitis media has been characterized by measurement of local inflammatory mediators such as inflammatory cells, lysozyme, oxidative metabolic products, and inflammatory cytokines. The role of cytokines in bacterial infection has been elucidated with animal models, and interleukin (IL)-1beta, IL-6, and IL-8 and tumor necrosis factor alpha (TNF-alpha) are recognized as being important local mediators in acute inflammation. We characterized middle ear inflammatory responses in the chinchilla otitis media model after injecting a very small number of viable pneumococci into the middle ear, similar to the natural course of infection. Middle ear fluid (MEF) concentrations of IL-1beta, IL-6, IL-8, and TNF-alpha were measured by using anti-human cytokine enzyme-linked immunosorbent assay reagents. IL-1beta showed the earliest peak, at 6 h after inoculation, whereas IL-6, IL-8, and TNF-alpha concentrations were increasing 72 h after pneumococcal inoculation. IL-6, IL-8, and TNF-alpha but not IL-1beta concentrations correlated significantly with total inflammatory cell numbers in MEF, and all four cytokines correlated significantly with MEF neutrophil concentration. Several intercytokine correlations were significant. Cytokines, therefore, participate in the early middle ear inflammatory response to S. pneumoniae.

Low cord blood pneumococcal immunoglobulin G (IgG) antibodies predict early onset acute otitis media in infancy.

Low maternally derived serum immunoglobulin G (IgG) antibodies to Streptococcus pneumoniae capsular polysaccharides (PS) combined with the inability of infants to produce anti-PS antibody may explain onset of otitis media in the first 6 months of life. To explore this relation, cord blood samples were assayed for anti-PS IgG antibodies from 414 of 592 infants enrolled in a study of early onset otitis media between 1991 and 1994. Infants' ears were examined at health supervision and illness visits for the first 6 months of life in a large Minneapolis-St. Paul, Minnesota, health maintenance organization. Antibodies to seven common pneumococcal serotypes (3, 4, 6B, 14, 18C, 19F, and 23F) were measured by enzyme-linked immunoabsorbent assay (ELISA). Cox's regression analysis revealed that among infants with a sibling otitis media history, those with low concentrations of type 14 or 19F anti-PS cord blood antibody had earlier otitis media onset than those with higher cord blood antibody concentrations (relative risks (RR) (95% confidence intervals (CI)) = 1.77 (1.05-2.99) and 1.89 (1.11-3.23), respectively). Day care attendance also increased risk (RR = 1.56, 95% CI 0.96-2.52). Breastfeeding, parental smoking, and low anti-PS antibody to pneumococcal serotypes 3, 4, 6B, 18C, and 23F did not significantly affect the risk of early otitis media.

Roles of autolysin and pneumolysin in middle ear inflammation caused by a type 3 Streptococcus pneumoniae strain in the chinchilla otitis media model.

Streptococcus pneumoniae cell wall and pneumolysin are important contributors to pneumococcal pathogenicity in some animal models. To further explore these factors in middle ear inflammation caused by pneumococci, penicillin-induced inflammatory acceleration was studied by using three closely related pneumococcal strains: a wild-type 3 strain (WT3), its pneumolysin-negative derivative (P-1), and into autolysin-negative derivative (A-1). Both middle ears of chinchillas were inoculated with one of the three pneumococcal strains. During the first 12 h, all three strains grew in vivo at the same rate, and all three strains induced similar inflammatory cell responses in middle ear fluid (MEF). Procaine penicillin G was given as 12 h to one-half of the animals in each group, and all treated chinchillas had sterile MEF at 24 h. Penicillin significantly accelerated MEF inflammatory cell influx into WT3-and P-1-infected ears at 18 and 24 h in comparison with the rate for penicillin-treated A-1-infected ears. Inflammatory cell influx was slightly, but not significantly, greater after treatment of WT3 infection than after treatment of P-1 infection. Interleukin (IL)-1beta and IL-6, but not IL-8, concentrations in MEF at 24 h reflected the penicillin effect on MEF inflammatory cells; however, differences between treatment groups were not significant. Results suggest that pneumococcal otitis media pathogenesis is triggered principally by the inflammatory effects of intact and lytic cell wall products in the middle ear, with at most a modes additional pneumolysin effect. Investigation strategies that limit the release of these products or neutralize them warrant further investigation.

Immunogenicity and efficacy of Streptococcus pneumoniae polysaccharide-protein conjugate vaccines against homologous and heterologous serotypes in the chinchilla otitis media model.

Cross-protection among pneumococcal serotypes within serogroups was measured in the chinchilla otitis media (OM) model because several serotypes that cause OM in children are closely related biochemically. Chinchillas were given tetravalent vaccine composed of pneumococcal capsular polysaccharides (PS; types 6B, 14, 19F, 23F) conjugated to an outer membrane protein complex, and 89% to 96% developed a > or = 2-fold serum IgG rise against vaccine PS. Vaccine efficacy was tested by inoculating middle ear hypotympanic bullae with Streptococcus pneumoniae types 6B, 6A, 19F, or 19A. OM severity in the vaccinated groups challenged with types 6B, 6A, and 19F but not 19A was significantly better than in the respective placebo groups. Culture-positive pneumococcal OM occurred in 38%, 62%, 0, and 78% of vaccinated chinchillas challenged with types 6B, 6A, 19F, and 19A, respectively, but in 88% of type 6B- and 100% of type 6A-, 19A-, and 19F-challenged placebo chinchillas.

Timing of penicillin treatment influences the course of Streptococcus pneumoniae-induced middle ear inflammation.

Penicillin treatment timing, using the chinchilla pneumococcal otitis media model, was investigated. Early treatment (when approximately 10(3) pneumococcal CFU/ml was present in middle ear fluid) significantly accelerated inflammatory-cell influx, whereas late treatment (with approximately 10(7) pneumococcal CFU/ml present in middle ear fluid) did not. Therefore, antiinflammatory interventions will be needed early in the course of inflammation.