Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes.

BACKGROUND: Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. OBJECTIVE: To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). RESULTS: Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. CONCLUSION: In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

Respiratory symptoms among crab processing workers in Alaska: epidemiological and environmental assessment.

BACKGROUND: Crab processing workers may develop respiratory symptoms and specific IgE responses, but the risk factors have not been fully described. METHODS: In 1998, 107 workers at a crab processing facility completed a survey both at the beginning and end of the processing season. The surveys included standardized symptom questionnaires, spirometry, and serological testing, as well as measurement of workplace airborne crab allergens and microscopic analysis of aerosolized materials. RESULTS: Over the crab processing season, asthma-like symptoms developed in 26% of study participants and bronchitic symptoms in 19%. Only 9% of those with new asthma-like symptoms were IgE-sensitized to crab at the end of the season. Among the crab processing jobs, butchering and degilling workers had the highest incidence of respiratory symptoms. CONCLUSIONS: Both personal and process-related factors appear to affect the development of respiratory symptoms in crab processing workers. In this study, crab specific IgE was not detected in most of the workers with new symptoms. Published 2001 Wiley-Liss, Inc.

Lymphocyte proliferative response and tissue distribution of methylmercury sulfide and chloride in exposed rats.

The immunotoxic effects and tissue distribution of different forms of methylmercury compounds were studied in rats. Methylmercury sulfide or methylmercury chloride was fed to rats at concentrations of 5 or 500 microg/L in drinking water for 8 wk. T-cell lymphocyte proliferative response to phytohemagglutinin (PHA) and determination of tissue distribution of mercury by gas chromatography using electron capture were assayed. Four different forms of mercury compounds were employed: MeHgS-, (MeHg)2S, (MeHg)3S+, and MeHgCl. Results indicated that exposure to methylmercury significantly enhanced lymphocyte responsiveness in most of the exposed groups at the low concentration of 5 microg/L, with the highest proliferative response (fourfold increase) in the MeHgCl group. At 500 microg/L, a significant decrease in the lymphocyte proliferative response was observed in the (MeHg)3S+ and MeHgCl groups; conversely, the MeHgS(-)- and (MeHg)2S-exposed animals had a modest increase of the lymphocyte proliferative response. The largest concentrations of all four mercury forms were detected in the kidney and spleen. The levels of mercury found in kidney, spleen, liver, brain, and testis were lower in the MeHgCl group than in those exposed to (MeHg)2S and (MeHg)3S+. These data indicate that the organ distribution of mercury and immune alteration may vary according to the chemical structure of the compound. This observation may have important implications in humans potentially exposed to low levels of methylmercury present in the environment, since the immune system plays an important regulatory role in the host-defense mechanisms.

Neuroimmunological effects of exposure to methylmercury forms in the Sprague-Dawley rats. Activation of the hypothalamic-pituitary-adrenal axis and lymphocyte responsiveness.

The effects of different methylmercury (MeHg) forms on the immune system and the hypothalamic pituitary adrenal (HPA) axis were assessed. The lymphocyte response to Concanavalin A (Con A) stimulation, blood levels of interleukin-6 (IL-6), adrenocorticotrophin hormone (ACTH), and corticosterone in the presence of different MeHg compounds was measured. Rats were exposed to methylmercury sulfide [(MeHg)2S] and methylmercury chloride (MeHgCl) at concentrations of 5 and 500 micrograms per liter in the drinking water for 8 or 16 weeks. Short-term exposure (8 weeks) at both, low- and high-doses of (MeHg)2S significantly enhanced lymphocyte responsiveness. MeHgCl only induced increased lymphocyte responsiveness at the low-dose exposure. Circulating levels of IL-6 after short-term exposure were increased in the MeHgCl-exposed group. The HPA axis activation was demonstrated by increased levels of ACTH and corticosterone levels. This response was predominant in low-dose exposed animals. Long-term (16 weeks) exposure resulted in a reduction in lymphocyte prolife ration after both low- and high-dose MeHgCl exposures. The (MeHg)2S exposure resulted in a 3-fold increase in the proliferative response. Levels of ACTH were elevated 3-fold in the (MeHg)2S-exposed group and no increase of corticosterone was observed in the high-dose exposed group at 8 weeks, no effect of (MeHg)2S was observed at 16 weeks. The MeHgCl exposed group showed an increase in ACTH and corticosterone levels at 8 weeks; this response was not observed at 16 weeks. These data indicate that exposure to MeHg compounds enhances T-cell proliferation in most of the cases, in a dose- and time-dependent fashion. Release of IL-6 also depends on the length of exposure. Early increases in circulating ACTH at 8 weeks also suggest activation of the HPA axis. This may contribute to the production of IL-6 and surveillance of regulatory homeostatic responses against environmental agents that mimic stress-like responses.

Immune system alteration in the rat after indirect exposure to methyl mercury chloride or methyl mercury sulfide.

Methyl mercury is a well-recognized health hazard. It is an environmental contaminant that accumulates in the food chain. The primary source of mercury exposure for humans is through the consumption of contaminated fish. We studied the effects of indirect methyl mercury exposure on the immune system of Sprague-Dawley rats. The effects of different forms of methyl mercury on immune system development were studied in Sprague-Dawley rats at 6 and 12 weeks of age. Rats were indirectly exposed to mercury during gestation and during nursing by exposing pregnant rats to either 5 or 500 micrograms/liter of methyl mercury chloride (CH3HgCl) or 5 micrograms/liter of methyl mercury sulfide [(CH3Hg)2S] in their drinking water. Total body, splenic, and thymic weights were measured, and NK cell cytolytic activity and lymphoproliferative response to T and B cell mitogens were evaluated in the offspring. At 6 weeks of age, total body and splenic weights were significantly increased in both high- and low-dose methyl mercury chloride-exposed groups. Rats exposed to methyl mercury sulfide had a significant increase in thymic weight at 6 weeks of age. At 12 weeks, the total body and organ weights were not different from controls. The lymphocyte proliferative response of splenocytes to PWM was enhanced at 6 weeks in both CH3HgCl exposed groups and not affected in the (CH3Hg)2S exposed group. NK cell activity was not affected in either group at 6 weeks of age. At age 12 weeks, NK cell activity was statistically significantly decreased by 56.6% in both CH3HgCl-exposed groups and not affected in the (CH3Hg)2S-exposed rats. The lymphocyte proliferative response of splenocytes to the B cell mitogen pokeweed remained increased in the CH3HgCl groups. Indirect exposure of rats (during gestation and nursing) to different forms of methyl mercury reveals that chloride forms have prolonged predominantly enhancing effects on lymphoproliferative response of splenocytes, followed by significant depression of NK cell activity.