Ultradistal and cortical forearm bone density in the assessment of postmenopausal bone loss and nonaxial fracture risk.

Forearm bone mineral density (BMD) was measured by single-energy photon absorptiometry in 360 healthy females without known axial fractures, 202 of whom were postmenopausal. The three sites addressed included an ultradistal (U) region containing approximately 60% trabecular bone. The other sites, distal (D) and shaft (S), were progressively more cortical. Reproducibility was 1.7-1.9% CV. The earliest evidence of a significant correlation between BMD and years since menopause was seen in trabecular bone in subjects aged 45-55 years. Fractional decrease in BMD, relative to the premenopausal value, was significantly larger at U than at S for the decades 55-65 years and above. Fractional rates of bone loss at all sites were a maximum in the first postmenopausal decade, the rate at U being 0.035, approximately 1.5 times that at D or S. A total of 33 subjects reported 54 previous minimally traumatic nonaxial (MTNA) fractures. When BMD measurements of the entire study were divided into quintiles, the prevalence of MTNA fracture cases in the lowest quintile was eight times that of each of the upper three quintiles. Prevalence of fracture cases ranked by quintiles of BMD were not different for the three scan sites. Therefore, ultradistal measurements confer no advantages over distal or shaft BMD for discriminating past MTNA fracture cases but do show larger fractional rates of loss during the first postmenopausal decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional assessment of CD2, CD3 and CD28 on the surface of peripheral blood T-cells from infants at low versus high genetic risk for atopy.

Recent studies from several laboratories suggest that the rate of postnatal maturation of T-cell function(s) associated with in vitro activation may be slower in children at high genetic risk for atopy (HR), compared to their normal (low risk; LR) counterparts. The present study compared the in vitro activity of the function-associated surface molecules CD2, CD3 and CD28 in panels of 27 HR and 13 LR infants, with a reference panel of 10 adults, employing assay systems involving T-cell stimulation with MoAbs against these molecules. The response maxima induced by saturating levels of the MoAbs were equivalent in all 3 groups, but T-cells from the HR infants required 10-50 fold higher levels of anti-CD3 stimulation to attain their maximum response, relative to adults (p = 0.02); T-cells from LR infants were also less responsive to anti-CD3 than adults, but these differences were smaller and did not attain statistical significance. It is suggested that these differences are attributable to varying proportions of competent T-memory cells (which respond to low levels of anti-CD3) in PBL from these populations, the postnatal accumulation of which proceeds slowest in the HR group.

Low-level exposure to house dust mites stimulates T-cell responses during early childhood independent of atopy.

BACKGROUND: The immune responses which underlie the expression of allergic symptoms in childhood are believed to be initiated in infancy and early childhood. The kinetics of this response have hardly been researched. OBJECTIVE: To analyse, in an environment with low house dust mite (HDM) exposure levels, the relationship between house dust mite (HDM)-specific T-cell reactivity as expressed by in vitro proliferation of blood mononuclear cells. METHODS: The study comprised a prospective analysis of patterns of allergen-specific T-cell reactivity in a cohort of 19 children, from whom blood samples were obtained in the spring during their second and third years of life. Blood mononuclear cell cultures were established in 200 microL AIM-V serum free medium. Crude house dust mite (HDM) and purified Der p 1 and Der p 2 extracts were used at optimal concentrations, i.e. 100 micrograms/mL for HDM and 30 micrograms/mL for the purified allergens. Tetanus toxoid (0.5 microgram/mL) and ovalbumin (10 micrograms/mL) served as positive controls. A clinical diagnosis of allergy was verified with skin-prick tests. Dust samples were collected from a mattress and/or carpet or sofa in homes, day care centres and day care homes. Major mite allergen levels (Der p 1/Der f 1) in dust were analysed by an enzyme linked immunosorbent assay (ELISA). RESULTS: Specific T-cell responses were seen in the majority of the children against house dust mite (crude HDM extract, Der p 1 and Der p 2). The levels of the house dust mite allergens Der p 1 and Der f 1 were low, i.e. < 0.68 microgram/g fine dust in the homes of the children and the day care centres that they were attending. This indicates that doses of mite antigen well below the suggested sensitization threshold level of 2 micrograms/g dust can induce mite-specific T-cell responses in young children. None of them showed clinical reactivity to house dust mites as indicated by negative skin-prick tests. CONCLUSIONS: The findings suggest that active immunological recognition of environmental allergens and the ensuing initiation of allergen-specific T-cell responses, is a normal part of the 'education' of the immune system in early childhood and can occur even at very low exposure levels. Priming per se does not imply clinically significant sensitivity, however.

Genetic 'risk' for atopy is associated with delayed postnatal maturation of T-cell competence.

Recent in vitro studies suggest that IgE production in adults is co-ordinately regulated by negative signals from gamma IFN-producing CD4+ T-helper-1 (TH-1) and positive signals from IL-4 producing (TH-2) T-cells. Additionally, seroepidemiological evidence has pinpointed infancy as the period of maximum lifetime risk for T-cell sensitization to ubiquitous environmental antigens. The present study sought to elucidate the relationship between these observations, by examination of CD4+ T-cell function in normal children and those genetically at 'high risk' for atopy, spanning the age range (up to 4 years) in which IgE responses to environmental allergens is typically manifest. Immunocompetent T-cell precursor frequencies (determined by cloning at limiting dilution) were markedly reduced in 'high risk' children relative to normals (0.53 +/- 0.29 vs 0.26 +/- 0.19; P = 0.0025). Consistent with reports from other laboratories employing bulk T-cell culture techniques, the gamma IFN producing capacity of CD4+ T-cell clones from both groups of children were markedly reduced relative to adults, and was lowest in the high risk group (P < 0.02). IL-4 production by CD4+ T-cell clones from the normal children was within the adult range, but again was significantly lower in the high risk group (P < 0.00005). This indicates that initial immune responses to environmental allergens in early childhood occur against a background of maturational 'deficiency' in CD4+ T-cell function, and suggests the possibility that variations in the rate of postnatal maturation of T-cell competence may be a contributing factor in the development of differing patterns of immunological responsiveness to environmental allergens.

A clonal analysis of lung T cells derived by bronchoalveolar lavage of healthy individuals.

The characteristics of the T-cell population in the healthy human lung have been investigated by analysing the properties of T-cell clones derived from bronchoalveolar lavage (BAL) samples and comparing them with T cells cloned from the blood of the same individuals. The proportions of CD4+ and CD8+ T cells in the starting populations from BAL and blood were similar although only 14% of BAL T cells were CD45RA+ compared to 70% of blood T cells. The precursor frequency of T-cell clones derived from BAL was less than from blood. The cytokine profiles [after phytohaemagglutinin (PHA) stimulation] of the clones derived from both sources were markedly different and these differences lay in the CD4+ population. BAL-derived CD4+ clones produced interferon-gamma (IFN-gamma) more frequently than did those from blood while blood-derived clones were more likely to produce interleukin-2 (IL-2) than those from BAL. IL-4 was produced by the majority of BAL- or blood-derived clones (93% and 88% respectively) either along with IFN-gamma (BAL) or IL-2 (blood). The cytokine profiles of BAL-derived T-cell clones are consistent with those derived from lung interstitium and suggest that the BAL T-cell populations reflect those in the lung wall. Whether the unique properties of lung T cells are acquired after leaving the blood or whether there is selective entry of T-cell subpopulations into the lung remains to be determined.

T-cell "priming" against environmental allergens in human neonates: sequential deletion of food antigen reactivity during infancy with concomitant expansion of responses to ubiquitous inhalant allergens.

The study below comprises prospective analysis of patterns of allergen-specific T-cell reactivity in a cohort of 23 children bled at regular intervals from 6-10 weeks to 2 years of age, together with cross sectional studies on panels of cord and adult blood samples. The results indicate reciprocal patterns of responses to dietary and inhalant allergens, the former being frequent in infancy but rare in adults, whereas the latter are preserved and expand between infancy and adulthood. These findings are consistent with a recently proposed model for the development of immunity to environmental allergens which involves allergen-driven T-cell "selection" during early life leading to deletion of food allergen-specific T-cells via the induction of specific anergy, with concomitant selection and ultimately expansion of mutually exclusive TH-1-like or TH-2-like reactivity to inhalant allergens via Immune Deviation mechanisms.

Inhalant allergen-specific T-cell reactivity is detectable in close to 100% of atopic and normal individuals: covert responses are unmasked by serum-free medium.

BACKGROUND: It is widely held that in vitro T cell responses to allergens are more prominent in atopic than in normal individuals, though this conclusion is based upon culture techniques which fail to detect proliferative responses in a significant minority of atopics and many normals. OBJECTIVES: Study allergen-specific proliferative responses of T cells cultured in serum-free medium (SFM). Examine associations between atopic status, age and T cell reactivity. METHODS: Initially, peripheral blood mononuclear cells were stimulated with allergens or antigens in SFM, and compared with cells cultured in RPMI + 10% fetal calf serum or human AB serum. Subsequently, T cell reactivity was studied in 34 adults (20-49 years), 27 children (2-13 years), and 19 infants (< or = 10 weeks) using SFM alone. RESULTS: Compared with serum-supplemented medium, SFM enhanced net T cell proliferation, both in bulk culture and when cloning at limiting dilution. In many subjects, SFM unmasked T cell reactivity to allergens which was not otherwise evident, and lowered the threshold allergen levels required for in vitro T cell triggering. For most allergens, T cell proliferative responses did not differ between adults who had specific IgE, and those who did not. The most vigorous responses observed were to ubiquitous inhalant allergens, which stimulated T cells from close to 100% of adults and children, and over 60% of infants. In contrast, responses to the 'vaccine' antigen tetanus toxoid were completely absent in the latter age group, but present in the majority of adults and children. CONCLUSIONS: These findings suggest that the extent of active T cell recognition of environmental allergens has been hitherto underestimated, and further that these responses may frequently be initiated in very early life. Additionally, these findings reinforce the notion that qualitative (as opposed to quantitative) variations in specific T cell reactivity ultimately determine allergen responder phenotype.