Although several lines of evidence suggest that variation in human inflammation is genetically controlled, the genes which regulate these responses are largely unknown. TLRs (Toll-like receptors) ...mediate recognition of microbes, regulate activation of the innate immune response and influence the formation of adaptive immunity. Cellular and molecular studies over the past several years have identified a number of common TLR polymorphisms that modify the cellular immune response and production of cytokines in vitro. In addition, human genetic studies suggest that some of these polymorphisms are associated with susceptibility to a spectrum of diseases. In this review, we summarize studies of common TLR polymorphisms and how this work is beginning to illuminate the influence of human variation on inflammation and disease susceptibility.
Toll‐like receptors (TLR) are critical mediators of the immune response to pathogens and human polymorphisms in this gene family regulate inflammatory pathways and are associated with susceptibility ...to infection. Lipopeptides are present in a wide variety of microbes and stimulate immune responses through TLR1/2 or TLR2/6 heterodimers. It is not currently known whether polymorphisms in TLR1 regulate the innate immune response. We stimulated human whole blood with triacylated lipopeptide, a ligand for TLR1/2 heterodimers, and found substantial inter‐individual variation in the immune response. We sequenced the coding region of TLR1 and found a non‐synonymous polymorphism, I602S (base pair T1805G), that regulated signalling. In comparison to TLR1_602S, the 602I variant mediated substantially greater basal and lipopeptide‐induced NF‐κB signalling in transfected HEK293 cells. These signalling differences among TLR1 variants were also found with stimulation by extracts of Mycobacterium tuberculosis. Furthermore, individuals with the 602II genotype produced substantially more IL‐6 than those with the 602SS variant in a lipopeptide‐stimulated whole‐blood cytokine assay. Together, these observations demonstrate that variation in the inflammatory response to bacterial lipopeptides is regulated by a common TLR1 transmembrane domain polymorphism that could potentially impact the innate immune response and clinical susceptibility to a wide spectrum of pathogens.
See accompanying article: http://dx.doi.org/10.1002/eji.200737604
Abstract Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes, these findings ...have not been extensively validated. We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of seven polymorphisms, including a promoter region variant in TNF (G −308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR ( Fok I, Bsm I, and Taq I). We observed an association between TNF −308A and protection from leprosy with an odds ratio of 0.52 (95% confidence interval = 0.29–0.95, p = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (odds ratio = 0.33, 95% confidence interval = 0.12–0.85, p = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. These results confirm previous findings of an association of TNF −308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation.
The adipocyte is central to organismal metabolism and exhibits significant functional and morphological plasticity during its formation and lifespan. Remarkable transformations of this cell occur ...during obesity and lactation, and thus it is essential to gain a better understanding of adipocyte function in these two metabolic processes. Considering the critical importance of the cellular organelle endoplasmic reticulum (ER) in adapting to fluctuations in synthetic processes, we explored the role of XBP1, a central regulator of ER adaptive responses, in adipocyte formation and function. Unexpectedly, deletion of adipocyte-XBP1 in vivo in mice (XBP1ΔAd) had no effect on adipocyte formation or on systemic homeostatic metabolism in mice fed a a regular or high-fat diet. However, during lactation, XBP1ΔAd dams displayed increased adiposity, decreased milk production, and decreased litter growth as compared with control dams. Moreover, we demonstrate that XBP1 is regulated during lactation and responds to prolactin to alter lipogenic gene expression. These results demonstrate a role for adipocyte-XBP1 in the regulation of lactational metabolism.
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•Adipocyte-specific deletion of XBP1 does not affect metabolic homeostasis in mice•Adipocytes regulate lactational metabolism through XBP1•XBP1ΔAd mice have increased fat mass and decreased pup weight, and produce less milk•Prolactin stimulates adipocyte XBP1 and negatively regulates lipogenic gene expression
The adipocyte is poised to act at the intersection of energy supply and demand. Because of its extreme plasticity, it can expand in obesity or regress during starvation and lactation. How tissues crosstalk in the delicate balance of metabolism is an important question that remains unanswered. In this study, Hotamisligil and colleagues report that adipocytes can control the directional metabolism of lactation, introducing a new context in which to study the biology of these cells and how they regulate milk production.
Legionella pneumophila (Lp), the etiologic agent of Legionnaires' disease (LD), is an important cause of community-acquired and nosocomial pneumonia. However, the host immune and genetic determinants ...of human susceptibility to Lp are poorly understood. Here we show that both TLR6 and TLR1 cooperate with TLR2 to recognize Lp in transfected HEK293 cells. We also perform a human genetic association study of 14 candidate single-nucleotide polymorphisms in Toll-like receptors (TLRs) 1, 2 and 6 in 98 LD cases and 268 controls from the Netherlands. No polymorphisms in TLR1 or TLR2 were associated with LD. A TLR6 polymorphism, 359T>C (rs5743808), was associated with an elevated risk of LD in genotypic and dominant (odds ratio (OR) 5.83, P=7.9 × 10(-5)) models. The increased risk in persons with 359 TC or CC genotypes was further enhanced among smokers. In a multivariate model, 359T>C was associated with a higher risk of LD (OR 4.24, P=0.04), than any other variable, including age and smoking. Together, these data suggest that the human TLR6 variant, 359T>C, is an independent risk factor for LD.
Nontuberculous mycobacteria (NTM), predominately Mycobacterium avium complex (MAC), cause chronic pulmonary disease. Improvements in symptoms and health-related quality of life (HRQoL) are important ...treatment outcomes, but no validated patient-reported outcome (PRO) measure exists.
What are the validity and responsiveness of the Quality of Life-Bronchiectasis (QOL-B) questionnaire respiratory symptoms scale and key HRQoL measures during the first 6 months of MAC pulmonary disease (MAC-PD) treatment?
Comparison of Two- vs Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease (MAC2v3) is an ongoing randomized, multisite pragmatic clinical trial. Patients with MAC-PD were randomized to azithromycin-based two-drug or three-drug therapy; treatment groups were combined for this analysis. PROs were measured at baseline, 3 months, and 6 months. The QOL-B respiratory symptoms, vitality, physical functioning, health perceptions, and NTM symptom domain scores (on a scale of 0-100, with 100 being best) were analyzed separately. We performed psychometric and descriptive analyses in the population enrolled as of the time of analysis and calculated the minimal important difference (MID) using distribution-based methods. Finally, we evaluated responsiveness using paired t tests and latent growth curve analysis in the subset with longitudinal surveys completed by the time of analysis.
The baseline population included 228 patients, of whom 144 had completed longitudinal surveys. Patients predominately were female (82%) and had bronchiectasis (88%); 50% were 70 years of age or older. The respiratory symptoms domain showed good psychometric properties (no floor or ceiling effects; Cronbach’s α, 0.85) and an MID of 6.4 to 6.9. Vitality and health perceptions domain scores performed similarly. Respiratory symptoms domain scores improved by 7.8 points (P < .0001) and 7.5 points (P < .0001), and the physical functioning domain score improved by 4.6 points (P < .003) and 4.2 points (P = .01) at 3 and 6 months, respectively. Latent growth curve analysis confirmed a nonlinear, statistically significant improvement in respiratory symptoms and physical functioning domain scores by 3 months.
The QOL-B respiratory symptoms and physical functioning scales exhibited good psychometric properties in patients with MAC-PD. Respiratory symptoms scores improved beyond the MID by 3 months after treatment initiation.
ClinicalTrials.gov; No.: NCT03672630; URL: www.clinicaltrials.gov
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