Skewed Invariant Natural Killer T (iNKT) Cells, Impaired iNKT:B Cell Help and Decreased SAP Expression in Blood Lymphocytes from Patients with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a syndrome with predominantly defective B cell function. However, abnormalities in the number and function of other lymphocyte subpopulations in peripheral blood (PB) have been described in most patients. We have analysed the distribution of iNKT cell subpopulations in the PB of CVID patients and the ability of these cells to provide in vitro cognate B cell help. The total of iNKT cells was reduced in the PB of CVID patients, especially CD4+, CD4-/CD8- and CCR5+/CXCR3+. These findings were associated with an enrichment of memory-like and a tendency towards a reduction in TNF-α-expressing effector iNKT cells in the peripheral blood mononuclear cells (PBMC) of CVID patients. Moreover, an accumulation of follicular helper iNKT cells in the PB of CVID patients was demonstrated. CVID αGalCer-pulsed iNKT cells are not able to induce autologous B cell proliferation although they do induce proliferation to healthy donor B cells. Interestingly, autologous and heterologous co-cultures did not differ in the amount of immunoglobulin secreted by B cells in vitro. Finally, reduced intracellular SAP expression in iNKT cells and other lymphocytes in the blood from CVID patients was observed. These results provide further insights into the immunological mechanisms underlying the iNKT cell defects and the potential targets to improve B cell help in CVID.

Quantitative defects in invariant NKT cells and TLR responses in patients with hyper-IgE syndrome.

BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency mainly caused by mutations in STAT3, a signalling molecule implicated in the development of appropriate immune responses. We aimed to characterise the innate immune response in AD-HIES. METHODS: The frequency of innate immune cells in peripheral blood (PB) from seven AD-HIES patients and healthy controls were determined. CD80/CD86 surface expression and cytokine levels in supernatants from PBMC after stimulation with TLR-2, -4 and -9 agonists were also measured by flow cytometry. In addition, several SNPs within these TLR genes in genomic DNA samples from patients and controls were examined. RESULTS: A significantly reduced number of PB iNKT cells was observed in the AD-HIES group. CpG-stimulated pDC and mDC from patients exhibited a lower increase in the expression of the costimulatory molecule CD80. We also observed an increase in the secretion of IL-12p70, TNF-alpha and IL-10 in PBMC from HIES patients after LTA or LPS stimuli. No association was found between the different SNPs detected and the HIES phenotype. CONCLUSIONS: These findings demonstrate that important mediators of the innate immunity responses are affected in AD-HIES. More studies are necessary to investigate how the STAT3 function interferes with development of iNKT cells and TLR-mediated responses.

Vaccinations with T-helper type 1 directing adjuvants have different suppressive effects on the development of allergen-induced T-helper type 2 responses.

BACKGROUND: Allergen-induced T-helper type 2 (Th2) responses can be inhibited with Th1 directing vaccines. However, studies comparing the efficacy of the different adjuvants have not been performed in detail. OBJECTIVE: For this reason we compare the effects of live Bacillus-Calmette-Guerin(BCG), heat-killed (hk)-BCG, CpG-ODN (oligodeoxynucleotide) or PPD on the development of allergen-induced Th2 responses in mice. METHODS: Ovalbumin (OVA)-specific allergic responses were induced in C57BL/6 mice by two intraperitoneally (i.p.) applications of OVA/alum followed by the intranasal challenge with OVA. The different Th1-inducing adjuvants were applied to the mice together with OVA/alum i.p. during the OVA-sensitization period and, subsequently, different parameters of allergic immune responses were evaluated. RESULTS: All the adjuvants were effective in inhibiting the development of allergen-induced airway eosinophilia, mucous production and, with the exception of PPD, also airway hyper-reactivity, when they were applied together with OVA/alum. However, allergen-specific IgG1 and IgE serum levels were only reduced in live BCG- and PPD-treated mice. Suppression of airway eosinophilia was not observed in IFN-gamma- or IL-12-deficient mice (hk-BCG, CpG-ODN and PPD). Interestingly, live BCG was still able to suppress allergen-induced Th2 responses in the absence of either IFN-gamma or IL-12. When mice vaccinated with the different adjuvants together with OVA/alum were subjected to a second period of OVA/alum immunization, only live and hk-BCG were able to efficiently suppress the development of airway inflammation. This effect could be adoptively transferred by splenic CD4(+) T cells. CONCLUSIONS: Taken together our data suggest that live BCG>hk-BCG>CpG-ODN >PPD are effective in suppressing allergen-induced Th2 responses. The degree of suppression and the component of the Th2 response affected (airway inflammation vs. the production of allergen-specific IgE and IgG1) were dependent upon the adjuvant used and how it was applied. Our results contribute to the design of novel vaccines protecting humans from developing allergic disorders.

Incidence of hypertension and educational attainment: the NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey.

Previous research has demonstrated the association between cardiovascular disease and education. However, few studies have described the incidence of hypertension, a risk factor for cardiovascular disease, by education or other socioeconomic status indicators. To examine the association between hypertension incidence and education, the authors analyzed data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Followup Study (NHEFS) (1971-1984). The relative risk of hypertension incidence (blood pressure > or =160/95 and/or using antihypertensive medication) by education was calculated for non-Hispanic Whites (aged 25-64 years) and non-Hispanic Blacks (aged 25-44 years) normotensive at baseline using Cox proportional hazards models. The age-adjusted relative risk of hypertension incidence among persons with less than 12 years of education compared with those with more than 12 years was significant among non-Hispanic Whites aged 25-44 years (men: relative risk (RR) = 2.14, 95% confidence interval (CI): 1.29, 3.54; women: RR = 2.06, 95% CI: 1.39, 3.05) but not among non-Hispanic Blacks (RR = 1.16, 95% CI: 0.63, 2.14). Relative risks for non-Hispanic White men remained stable after adjusting for age, systolic blood pressure, body mass index, and region of residence; relative risks for non-Hispanic White women were reduced but remained significant. Non-Hispanic White men and women aged 45-64 years with less than 12 years of education were not at higher risk of developing hypertension compared with their more educated counterparts. These results demonstrate a significant interaction between age and education with an independent association between education and hypertension incidence among younger but not older non-Hispanic White men and women.

Sociodemographic correlates of tooth pain among adults: United states, 1989.

This study presents the sociodemographic distribution of tooth pain and the dental care utilization of affected individuals. Data for adults 20 years of age and over were derived from the 1989 National Health Interview Survey's supplements on dental health, orofacial pain, and health insurance (n=33073). Prevalence of tooth pain by socioeconomic status (SES) and adjusted odds ratios of reporting tooth pain in the past 6 months and of having no dental visits in the past year among persons reporting pain in the previous 6 months were computed taking into account the survey's complex sample design. Tooth pain in the past 6 months was reported by 14.5% (95% CI 14.0, 15.0) of adults aged 20-64 years and by 7.0% (95% CI 6.1, 7.9) of those 65 years and over. In the younger age group, tooth pain was more likely to be reported by those with low SES than it was by those with high SES; in the older age group, tooth pain was more likely reported by non-Hispanic blacks than it was by non-Hispanic whites or Hispanics. Of those reporting pain, younger and older non-Hispanic blacks and persons with lower educational attainment were more likely not to have a dental visit in the previous 12 months. Persons with low SES characteristics were more likely to report tooth pain and to endure their pain without the benefit of dental care while the pain was present.

Geographic variation in stroke risk in the United States. Region, urbanization, and hypertension in the Third National Health and Nutrition Examination Survey.

BACKGROUND: In the United States, stroke mortality is higher in the south than in other regions. Hypertension is the main risk factor for stroke among older adults; however, few studies have examined group-specific regional and urbanization differences in hypertension prevalence. METHODS: Data from the Third National Health and Nutritional Examination Survey (NHANES III), 1988 to 1994, were analyzed to calculate the prevalence of hypertension (systolic >140 mm Hg and/or diastolic >90 mm Hg and/or taking antihypertensive medication) by region and urbanization for age (40 to 59 and 60 to 79 years), sex, and ethnic subgroups. Logistic regression models were fitted to estimate the association of hypertension with region and urbanization. RESULTS: With age and urbanization kept constant, southern residence was associated with hypertension among middle-aged non-Hispanic white men (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.12 to 1.90; P<0.006), non-Hispanic black men (OR, 1.36; 95% CI, 1.05 to 1.66; P=0.019), and non-Hispanic black women (OR, 1.23; 95% CI, 1.01 to 1.45; P=0.034). Among older non-Hispanic white men, a significant interaction was noted between region and urbanization (P=0.01), with a higher prevalence in the south only for nonmetropolitan residents (OR, 1.32; 95% CI, 1.06 to 1.56; P<0.013). A similar but not statistically significant trend was also confirmed among non-Hispanic black men in logistic regression analysis (OR, 1.38; 95% CI, 0.97 to 1.68; P=0.061). No statistically significant association was observed for urbanization or region in the other subgroups. CONCLUSIONS: Southern residence was associated with increased hypertension prevalence among middle-aged non-Hispanic white men, non-Hispanic black men and women, and older non-Hispanic white men.

Serum IL-1ra is elevated in lepromatous leprosy patients.

Patterns of production of specific cytokines are accepted as standards for T-lymphocyte subsets in diseases caused by intracellular parasites. These lymphocyte subsets (Th1 and Th2) have been associated with the different poles of the leprosy spectrum. Lepromatous leprosy (LL) onset correlates with cytokines produced by Th2 cells on the grounds of the patient's poor cellular immune response, i.e., interleukin 2 (IL-2) and gamma interferon (IFN-gamma) deficiency. On the other hand, tuberculoid leprosy (TL) has been associated with a Th1 response. Moreover, pro-inflammatory cytokines like IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) play a major role in chronic inflammatory pathologies being IL-1ra and TNF-alpha soluble receptors, natural counterbalancing inhibitors. In light of this background, we decided to measure serum levels of IL-1 beta, IL-1ra, TNF-alpha and IL-6 in LL and TL patients, and we also studied the production in vitro of Th1 (IFN-gamma, IL-2), Th2 (IL-4, IL-10) and TNF-alpha cytokines. Our data showed that IL-1ra is highly elevated in sera from LL patients; there were no differences in Th2 cytokine levels and there were diminished levels in Th1 cytokines.

Addiction of anti-CD28 antibodies restores PBMC proliferation and IFN-gamma production in lepromatous leprosy patients.

During antigen recognition, T lymphocytes are primed by a physical interaction with antigen-presenting cells (APC). At least two signals are needed to activate T cells. One is provided by T cell receptor (TCR)/CD3 in the context of the mayor histocompatibility complex (MHC), and another signal is mediated by antigen-independent molecules, that is T cell membrane-bound CD28 and its specific ligand B7-1 (CD80) present in APC. Both signals trigger a series of metabolic events initiating right at the cell membrane and ending with activation and proliferation of T cells as well as specific cytokines synthesis. Our main goal was to determine whether deficiency in interferon-gamma (IFN-gamma) production shown by peripheral blood mononuclear cells (PBMC) from lepromatous leprosy (LL) patients, could be overcome by reconstituting in vitro the appropriate signals (by means of addition of anti-CD28 and anti-CD80 monoclonal antibodies). We also determined the stimulation index (SI) in the same PBMC. Our results demonstrated no significant differences in CD80 expression monocytes and B lymphocytes from LL patients when compared with healthy subjects. Nonetheless, CD28 expression significantly decreased in lymphocytes from LL patients (p < 0.01). Regarding IFN-gamma levels and SI, LL-PBMC failure before mitogenic stimuli could be reversed by further incubation with anti-CD28 antibody, but stimulation by specific antigen of Mycobacterium leprae was not changed. Addition of anti-CD80 antibody significantly increased IFN-gamma levels in phytohemagglutinin (PHA)-stimulated PBMC, although proliferation deficiency persisted. Cells stimulated with specific antigen did not modify either their proliferation or IFN-gamma levels.

Dental expenditures and source of payment by race/ethnicity and other sociodemographic characteristics.

OBJECTIVE: This study presents race/ethnic-specific distributions of dental expenditures and their sources of payment by socioeconomic characteristics among US working-age adults. METHODS: Data for persons aged 19-64 years from the 1987 National Medical Expenditure Survey (NMES) (n = 18,696) were used to calculate mean dental expenditures and their 95 percent confidence intervals. RESULTS: Dental expenditures were reported by 44.5 percent of participants. Non-Hispanic whites and persons with higher income were more likely to report dental expenditures than their counterparts. Among persons reporting expenditures, those with lower income had lower expenditures than higher-income persons. No differences in the amount of expenditures by race/ethnicity, sex, or employment status were observed. In all race/ethnic groups almost half the expenditures were paid out-of-pocket and one-third by dental insurance. CONCLUSION: While sociodemographic characteristics determined who had dental expenditures, they did not determine the amount or source of those expenditures.

Sociodemographic distribution of pediatric dental caries: NHANES III, 1988-1994.

This article examines the extent to which caries prevalence and untreated caries vary in children by ethnicity and household income level. Data from the Third National Health and Nutrition Examination Survey, 1988-1994, for 10,332 children 2 to 18 years of age indicate that lower-income children and Mexican-American and African-American children are more likely to have a higher prevalence of caries and more unmet treatment needs than their higher-income and non-Hispanic white counterparts.

Association of serum albumin concentration, serum ionized calcium concentration, and blood pressure in the Third National Health and Nutrition Examination Survey.

A few small studies of white persons have found a positive association between serum albumin and blood pressure. However, this association might be due to ionized calcium. No data on albumin or ionized calcium have appeared for African Americans or Hispanics, and few for women. To explore the association of serum albumin (g/L) and ionized calcium (mmol/L) with both systolic and diastolic blood pressure, data from the Third National Health and Nutrition Examination Survey, 1988-94, were analyzed. Results from multiple regressions, controlling for age, overweight, alcohol intake, hematocrit, pulse, antihypertensive medication, and smoking indicate that serum albumin is positively correlated (P < 0.01) to systolic and diastolic blood pressure among non-Hispanic white men 25-59 and 60-89 years old. Ionized calcium was associated negatively with diastolic blood pressure among younger Mexican-American men. In this national sample, serum albumin was consistently associated with systolic and diastolic blood pressure only among non-Hispanic white men.

Validity of self-reported hypertension in the National Health and Nutrition Examination Survey III, 1988-1991.

BACKGROUND: The National Health and Nutrition Examination Survey (NHANES) is the main data source for hypertension surveillance. However, because of a gap of almost 10 years between each NHANES, self-reported data from annual surveys need to be examined as an alternative data source. This study analyzes the validity of self-reported hypertension in a national sample of non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. METHODS: Sensitivity, specificity, and predictive values positive (PVP) and negative (PVN) of self-reported hypertension were calculated against two definitions of hypertension: the definition recommended by the Third Joint National Committee on Hypertension, JNC III (blood pressure > or = 140/90 and/or taking antihypertension medication) and a broader definition including control with lifestyle modifications. Data used come from the NHANES III, 1988-1991. RESULTS: Overall test characteristics using the JNC III definition are sensitivity 71%, specificity 90%, PVP 72%, and PVN 89%. Test characteristics were consistently higher for the broad than for the JNC III definition. Validity of self-reported hypertension is higher among women than among men and among persons with a medical visit during the past year than among those with no visits: validity was lowest among Mexican-American men. Due to the similarity between sensitivity and PVP, the prevalence of self-reported hypertension is nearly equal to the prevalence of JNC III-defined hypertension. CONCLUSIONS: Self-reported hypertension may be used for surveillance of hypertension trends, in the absence of measured blood pressure, among non-Hispanic whites and non-Hispanic black women and persons with a medical visit in the past year. Validation should be repeated with each NHANES.

Recognition of Mycobacterium leprae antigens with antibodies present in sera from patients with lepromatous leprosy.

A great diversity of antigens from Mycobacterium leprae have been described. One practical approach should be to utilize them as markers to indicate when a household contact is at risk of becoming infected and then moving to an active form of leprosy. For this purpose, sonic extracts of M. leprae were fractionated in 10% SDS-PAGE under reducing conditions. The fractionated proteins were then transferred to nitrocellulose sheets and incubated with sera from lepromatous leprosy cases, their contacts, and normal subjects in order to reveal the frequency of antigen recognition of each set of sera. The results showed that sera from lepromatous leprosy patients frequently recognized two proteins, one of approximately 28 kDa and the other of approximately 65 kDa, when compared with the sera from normal subjects. The contacts frequently recognized an approximately 16-kDa antigenic band, while sera from normal subjects recognized one protein of approximately 18 kDa. According to the results, the four recognized proteins from M. leprae can be considered markers of the above conditions (approximately 65 kDa, approximately 28 kDa for lepromatous leprosy, approximately 16 kDa for contacts, and approximately 19 kDa for normal subjects). From these, an easy serological test, such as an ELISA, can be developed to predict if a contact is moving toward lepromatous leprosy before detection of the actual clinical signs or symptoms.