Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

BACKGROUND: Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators. Consequently, at least three genes in this interval have been implicated in the aetiology of obesity. METHODS: Here, we sequence a 2 Mb region encompassing the FTO, RPGRIP1L and IRXB cluster genes in 284 individuals from a well-characterised study group of Danish men containing extremely overweight young adults and controls. We further replicate our findings both in an expanded male cohort and an independent female study group. Finally, we compare our variant data with a previous study describing IRX3 and FTO interactions in this region. RESULTS: We obtain deep coverage across the entire region, allowing accurate and unequivocal determination of almost every single nucleotide polymorphism and short insertion/deletion. As well as confirming previous findings across the interval, we identify a further novel age-dependent association upstream of IRX5 that imposes a similar burden on BMI to the FTO locus. CONCLUSIONS: Our findings are consistent with the hypothesis that chromatin architectures play a role in regulating gene expression levels across topological domains while our targeted sequence approach represents a widely applicable methodology for high-resolution analysis of regional variation across candidate genomic loci. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-015-0250-3) contains supplementary material, which is available to authorized users

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth.

Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection

Additional file 7: Table S2. of Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

All associating haplotypes (P value <0.05) from the Haploview LD block definitions with MAF >0.05. (DOCX 24 kb

Boletín de Segovia: Número 143 - 1846 noviembre 15

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

Additional file 1: Table S1. of Complete re-sequencing of a 2Mb topological domain encompassing the FTO/IRXB genes identifies a novel obesity-associated region upstream of IRX5

Sample IDs, BMIs, ages and case/control classifications for the samples that were included in this study that passed quality control (n = 284). (DOCX 41 kb

Circulating immunological correlates of slow sputum culture conversion differ between PTB patients of African vs.

<p><b>Eurasian ancestry.</b> Upward arrows indicate parameters whose concentration was higher in patients with slow sputum culture conversion (defined as time to sputum culture conversion ≥37.25 days), and downward arrows indicate parameters whose concentration was lower in these patients. Only four of the 27 identified parameters have the same pattern of response in both ethnic groups.</p

Baseline characteristics of tuberculosis patients of African vs. Eurasian ancestry.

<p>Data are number (%) or mean (standard deviation) except where stated. IQR, inter-quartile range; BMI, body mass index; AFB, acid-fast bacilli. DBP, vitamin D binding protein; A, Baseline sputum smear result unavailable for 2 Eurasian participants; B, <i>M. tuberculosis</i> genotype unavailable for one Eurasian participant.</p

Inflammatory profiles of PTB patients of European/Middle Eastern and Central/South Asian ancestry are similar to each other, and different from those of patients of African ancestry.

<p>No statistically significant differences in neutrophil count (A), serum concentrations of CCL2 (B), CCL5 (C), CCL11 (D), CXCL8 (E), vitamin D binding protein (DBP) (F) or antigen-stimulated concentrations of CCL11 (G), IL1-RA (H) or IL-12 (I) were seen at baseline or at 8 weeks in PTB patients of European/Middle Eastern vs. Central/South Asian ancestry. However, when pooled data from patients of Eurasian ancestry were compared with those of patients of African ancestry, baseline differences attained statistical significance for all parameters except serum CXCL8 concentration (E) and antigen-stimulated CCL11 (G), and 8-week differences attained statistical significance for all parameters except antigen-stimulated IL1-RA (H) and IL-12 (I). P-values were derived from the t-test for general linear models, separately applied to baseline and 8-week samples, with adjustment for the following covariates: age, sex, months of symptoms pre-diagnosis, duration of antimicrobial therapy pre-sampling and either baseline vitamin D status (baseline samples) or isoniazid sensitivity and allocation to vitamin D vs. placebo (8-week samples). Parameters with a false discovery rate (q-value)>0.05, determined by the Benjamini Hochberg approach, were designated non-significant (ns). ***, p<0.001; **, p = 0.001 to <0.01. Lines at median. LOD, limit of detection. Afr, African ancestry; Eur, European/Middle Eastern ancestry; As, Central/South Asian ancestry.</p