Morbidity and mortality associated with the restrictive spirometric pattern: a longitudinal study.

BACKGROUND: Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively. METHODS: Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio >or=70% and FVC >or=80% predicted), restrictive (FEV(1)/FVC >or=70% and FVC <80% predicted) and obstructive (FEV(1)/FVC <70%) patterns were assessed at the enrollment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed at January 2005. RESULTS: Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern >or=50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2)). CONCLUSIONS: The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.

Phenotypic and functional properties of Helios+ regulatory T cells.

Helios, an Ikaros family transcription factor, is preferentially expressed at the mRNA and protein level in regulatory T cells. Helios expression previously appeared to be restricted to thymic-derived Treg. Consistent with recent data, we show here that Helios expression is inducible in vitro under certain conditions. To understand phenotypic and functional differences between Helios(+) and Helios(-) Treg, we profiled cell-surface markers of FoxP3(+) Treg using unmanipulated splenocytes. We found that CD103 and GITR are expressed at high levels on a subset of Helios(+) Treg and that a Helios(+) Treg population could be significantly enriched by FACS sorting using these two markers. Quantitative real-time PCR (qPCR) analysis revealed increased TGF-ß message in Helios(+) Treg, consistent with the possibility that this population possesses enhanced regulatory potential. In tumor-bearing mice, we found that Helios(+) Treg were relatively over-represented in the tumor-mass, and BrdU studies showed that, in vivo, Helios(+) Treg proliferated more than Helios(-) Treg. We hypothesized that Helios-enriched Treg might exert increased suppressive effects. Using in vitro suppression assays, we show that Treg function correlates with the absolute number of Helios(+) cells in culture. Taken together, these data show that Helios(+) Treg represent a functional subset with associated CD103 and GITR expression.

HIV type 1-mediated downregulation of HLA-B*57/B*5801 proteins on elite suppressor CD4+ T cells.

Elite controllers or suppressors (ES) are HIV-1-infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. While HLA-B*57 and B*5801 alleles are overrepresented in ES, many HLA-B*57/B*5801 patients become chronic progressors (CP). We show here that HIV-1 infection results in similar levels of downregulation of HLA-B*57 and HLA-B*5801 molecules on primary CD4(+) T cells from ES and CP. Thus, differences in HIV-1-mediated downregulation of HLA-B*57/B*5801 molecules do not distinguish ES from CP.

HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia.

We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia. Thus, the development of escape mutations alone does not determine virologic outcome in recently infected HLA-B*57 patients.