Monocyte response receptors in BCG driven delayed type hypersensitivity to tuberculin.

Abstract

Tuberculosis (TB) still remains the leading cause of mortality due to bacterial pathogen. The only currently available vaccine against TB, Bacille Calmette-Guérin (BCG) is at best credited with a 50% overall protective efficacy. Skin testing with purified protein derivative (PPD) from Mycobacterium tuberculosis is the method of detecting BCG-induced cell mediated immunity, in vivo. In the previous study we found that approximately 60% young volunteers with no history of TB, who had been subjected to neonatal BCG vaccination and revaccination(s) at school age, developed delayed type hypersensitivity (DTH) to tuberculin. The remaining volunteers were persistently tuberculin negative. Moreover, we found a significant association between BCG driven development of DTH to PPD and the polymorphism within the CD14 C/T(-159) gene for macrophage receptor recognising mycobacterial compounds. It has suggested that the CD14 gene variants may play a role in the appearance and persistence of DTH to PPD in BCG vaccinated subjects. In order to extend our study on a possible role of CD14 in BCG driven DTH response to PPD, we measured the expression of mCD14 on macrophages, stimulated or not stimulated with mycobacterial antigens, and the serum levels of sCD14. Considering the importance of CD14 -TLR2/TLR4 interactions in macrophage signalling, we determined the polymorphism of TLR2 and TLR4 genes as well as macrophage expression of TLR2 for the volunteers with and without skin reactivity to PPD. We observed a subtle but significant decrease in CD14 density on adherent monocytes from tuberculin positive versus tuberculin negative volunteers. However, we found no difference in CD14 density on monocytes enriched in CD14+ cells using anti-CD14 mAb coupled to magnetic beads. A significant increase in CD14 density was observed on macrophages stimulated with PPD and LPS but not with live BCG bacilli. However, this increase as well as serum levels of soluble sCD14 were similar in the volunteers with and without skin reactions to PPD. Thus, our suggestion on the role of CD14 in the generation of DTH to tuberculin in BCG vaccinated subjects should be further explored. The most important CD14 co-receptors are Toll-like receptors (TLRs) which activate nuclear factors for the production of inflammatory cytokines. However, we could see no association between the polymorphisms of TLR4 (Asp299Gly and Thr399Ile) and TLR2 genes (Arg753Gln and Arg677Trp) and skin responses to PPD. Also, the TLR2 density was similar on monocytes from tuberculin negative and tuberculin positive volunteers.

Toll‐like receptors 2 and 4 gene polymorphisms in a southeastern Chinese population with tuberculosis

“…, 2004), Turkish (2.9% and 2.3%; Emingil et al. , 2007), Polish (8.3% and 8.5%; Strapagiel et al. , 2008) and Colombian (4.5% and 4.5%; Zafra et al.…”

CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin

“…Despite the fact that it has been more than 80 years since the first administration of BCG, the effectiveness of the vaccine is still the subject of disputes and discussions. BCG vaccination protects children from TB, especially from its most dangerous forms–miliary TB and TB meningitis but the effectiveness of the vaccine in adults does not exceed the average of 50%, ranging from 0% in India and Sub-Saharan Africa to 80% in the United Kingdom [ 2 , 3 , 4 ]. The WHO recommends that BCG should be given once, on the first day of life, to all children born in countries highly endemic for TB.…”

“…tb and the host immunity. The contribution of host genetic factors to the immune reactions underlying the development of DTH to tuberculin has also been widely suggested since a significant proportion of people display persistent lack of TST reactivity [ 4 , 13 – 18 ]. One of the human genes with a possible impact on TST reactivity is the CD14 gene encoding the CD14 receptor.…”

“…CD14 molecules belong to the group of pattern recognition receptors (PRRs) recognizing the structural components of bacteria (PAMPs; pathogen associated molecular patterns) at the first steps of infection. They are expressed on the surface of macrophages, neutrophils and interstitial dendritic cells, function to aid the delivery of various ligands to TLRs, including LPS, lipoteichoic acid, ceramide, lipoarabinomannan (LAM) or poly(I:C)/double-stranded RNA [ 4 , 19 – 23 ]. The CD14 receptors exist also in a soluble form in serum and body fluids, and appear either after the proteolytic cleavage of the membrane-anchored CD14 or are directly secreted from intracellular vesicles [ 24 ].…”

Πολυμορφισμοί Των TLR2 Και TLR4 Στη Χρόνια Αποφρακτική Πνευμονοπάθεια

“…Τα τελευταία ευρήµατα έρχονται σε συµφωνία και µε την in vitro παρατήρηση ότι η παρουσία ενός wt αλληλίου στο γονίδιο του TLR2 αρκεί για τη φυσιολογική παραγωγή κυτταροκινών µετά από διέγερση κυτ-τάρων µε λιποτειχοϊκό οξύ προερχόµενο απά S. aureus [263]. βολιαστεί µε BCG (Bacille Calmette-Guérin) δεν διαπιστώθηκε συσχέτιση της παρουσίας του πολυµορφισµού Arg753Gln µε την επαγόµενη ανάπτυξη υπερευαισθησίας επιβραδυνόµενου τύπου στη χορήγηση κεκαθαρµένης πρωτεΐνης του µυκοβακτηριδίου [266].…”