MTB ranks as the first worldwide pathogen latently infecting one third of the population and the second leading cause of death from a single infectious agent, after the human immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune response upon infection with M.tuberculosis in humans and experimental animals conflict with failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it may exit. From a clinical standpoint, our views on MTB infection may take advantage from updating the overall perspective, that has quite changed over the last decade, following remarkable advances in our understanding of the manipulation of the immune system by M.tuberculosis and of the role of innate components of the immune response, including macrophages, neutrophils, dendritic cells and NK cells in the initial spread of MTB and in its exit from latency. Scope of this review is to highlight the the major mechanisms of MTB escape from immune control and to provide a supplementary translational perspective for the interpretation of innate immune mechanisms with particular impact on clinical aspects.

/pdf/immunology-of-tuberculosis-55xecqgi4x.pdf

Immunology of Tuberculosis

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61889-2.pdf

High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.

Vitamin D sufficiency is required for optimal health. The conditions with strong evidence for a protective effect of vitamin D include several bone diseases, muscle weakness, more than a dozen types of internal cancers, multiple sclerosis, and type 1 diabetes mellitus. There is also weaker evidence for several other diseases and conditions. There are good reasons that vitamin D sufficiency be maintained during all stages of life, from fetal development to old age. Adequate calcium intake is also recommended. The current vitamin D requirements in the United States are based on protection against bone diseases. These guidelines are being revised upward in light of new findings, especially for soft-tissue health. The consensus of scientific understanding appears to be that vitamin D deficiency is reached for serum 25-hydroxyvitamin D (25(OH)D) levels less than 20 ng/mL (50 nmol/L), insufficiency in the range from 20-32 ng/mL, and sufficiency in the range from 33-80 ng/mL, with normal in sunny countries 54-90 ng/mL, and excess greater than 100 ng/mL. Solar ultraviolet-B (UVB) irradiation is the primary source of vitamin D for most people. In general, the health benefits accruing from moderate UV irradiation, without erythema or excess tanning, greatly outweigh the health risks, with skin pigmentation (melanin) providing much of the protection. In the absence of adequate solar UVB irradiation due to season, latitude, or lifestyle, vitamin D can be obtained from fortified food, oily fish, vitamin D supplements, and artificial sources of UVB radiation. (Altern Med Rev 2005;10(2):94-111)

http://agdnutrition.com/pdfs/press/Benefits-and-Requirements%20.pdf

Benefits and requirements of vitamin D for optimal health: a review.

Vitamin D receptor polymorphisms and diseases.

Aim To review the literature for genetic risk factors associated with periodontitis. Methods Computerized search of the literature in English using key words: Periodontitis; Genes; Mutation; Polymorphism; Risk. Results and conclusions Mutations in the cathepsin C gene (CTSC) have been identified as causal for the Papillon-Lefevre syndrome (PLS), which includes prepubertal periodontitis (PP). Some CTSC mutations are causal for PP without PLS. No relationship has been demonstrated between CTSC mutations and other forms of periodontitis. Genetic polymorphisms in a candidate gene approach have been explored as risk factors for periodontitis. There is limited evidence that some polymorphisms in the genes encoding interleukins (IL)-1, Fc gamma receptors (Fc gammaR), IL-10 and the vitamin D receptor, may be associated with periodontitis in certain ethnic groups. However relatively large variations in carriage rates of the Rare (R)-alleles among studies on any polymorphism were observed. The available studies appear under-powered and do not adequately take into account other pertinent risk factors for periodontitis. Future studies should include larger cohorts, should clearly define phenotypes and should adequately control for other risk factors. In addition to the candidate gene approach, alternative strategies need to be considered to elucidate the gene variations, which confer risk for periodontitis.

Identification of genetic risk factors for periodontitis and possible mechanisms of action.

The regulatory role of vitamin D receptor (VDR) gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on vitamin D(3)-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D(3) at a concentration of 1 x 10(-7) M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D(3) at 10(-9), 10(-8), and 10(-7) M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D(3) had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D(3) and modulate the immune functions to M. tuberculosis in NHS.

Regulatory Role of Vitamin D Receptor Gene Variants of Bsm I, Apa I, Taq I, and Fok I Polymorphisms on Macrophage Phagocytosis and Lymphoproliferative Response to Mycobacterium tuberculosis Antigen in Pulmonary Tuberculosis

Spinal tuberculosis [an extrapulmonary form of
tuberculosis (TB)] is a degenerative disease of the
spine caused by Mycobacterium tuberculosis,
known as Pott’s disease. Infection is usually due
to lymphematogenous spread from a primary
focal area, such as the lung. It may also result
from direct invasion of a paravertebral focus by
lymphatic spread from paravertebral lymph
nodes or the pleural space

Vitamin D receptor gene variants of BsmI, ApaI, TaqI, and FokI polymorphisms in spinal tuberculosis.

NRAMP1 gene polymorphisms such as 823 C/T (exon
8), deletion of TGTG in the 3'-UTR (3¢ untranslated
region) and D543N G/A (exon 15) were studied to
find out whether the gene polymorphic variants are
associated with the susceptibility or resistance to
tuberculosis (TB). The study was carried out in pulmonary
(n = 100) and spinal TB patients (n = 57) and
control subjects (n = 112). No difference was observed
in the variant genotype frequencies of
NRAMP1 – 823 C/T, TGTG+/del and D543N G/A
polymorphisms. However, a trend towards an increased
frequency of the variant genotype 823 C/T
(heterozygotes) was observed in pulmonary TB patients
than control and spinal TB patients (odds ratio
(OR) : 1.6; confidence interval (CI): 0.74–3.4). A
trend towards an increased frequency of the variant
genotype TGTG del/del of 3'-UTR was observed in
control subjects than pulmonary and spinal TB patients
(OR : 0.48; CI: 0.10–1.78; OR: 0.42; CI: 0.04–
2.12, respectively). The above trends were not significant.
The study suggests that NRAMP1 gene may
not be associated with the susceptibility to pulmonary
and spinal TB in the Indian population. Major
Histocompatibility Complex (MHC) and other non-
MHC gene polymorphic variants may be associated.

NRAMP1 gene polymorphism inpulmonary and spinal tuberculosis

NRAMP1 gene polymorphisms such as 823 C/T (exon 8), deletion of TGTG in the 3' -UTR (3' untranslated region) and D543N G/A (exon 15) were studied to find out whether the gene polymorphic variants are associated with the susceptibility or resistance to tuberculosis (TB). The study was carried out in pulmonary ( n = 100), spinal TB patients ( n = 57) and control subjects ( n = 112). No difference was observed in the variant genotype frequencies of NRAMP1 - 823 C/T, TGTG+/del and D543N G/A polymorphisms. However, a trend towards an increased frequency of the variant genotype 823 C/T (heterozygotes) was observed in pulmonary TB patients than control and spinal TB patients (odds ratio (OR) : 1.6; confidence Interval (CI) 0.74-3.4). A trend towards an increased frequency of the variant genotype TGTG del/del of 3'-UTR was observed in control subjects than pulmonary and spinal TB patients (OR : 0.48; CI: 0.10-1.78; OR: 0.42; CI : 0.04-2.12, respectively). The above trends were not significant. The study suggests that NRAMP1 gene may not be associated with the susceptibility to pulmonary and spinal TB in the Indian population. Major Histocompatibility Complex (MHC) and other non-MHC gene polymorphic variants may be associated.

NRAMP1 gene polymorphism in pulmonary and spinal tuberculosis

Interleukin-8 (IL-8) is a chemokine which functions as
a potent chemo attractant for the recruitment of leucocytes
to the inflammatory sites. A polymorphism in
position –251 in the promoter region of the IL-8 gene
has been shown to be associated with altered IL-8 production.
IL-8-251A promoter polymorphism was studied
in 127 pulmonary tuberculosis (PTB) patients and
124 normal healthy subjects (NHS). IL-8 gene variants
were correlated with IL-8 levels from peripheral blood
mononuclear cells stimulated with phytohaemagglutinin,
culture filtrate antigen (CFA) of Mycobacterium
tuberculosis and live M. tuberculosis. No difference
was observed in the variant genotype frequencies of
IL-8 gene and IL-8 levels between NHS and PTB patients.
NHS positive for TT genotype showed a higher spontaneous
IL-8 production than AA genotype (P = 0.05).
Similarly, PTB patients with TT genotype showed significantly
higher IL-8 production to CFA (P = 0.009)
and live M. tuberculosis (P = 0.022), compared to patients
with AA genotype. The study suggests that the
variant genotypes of –251 promoter polymorphism of
the IL-8 gene are not associated with susceptibility to
PTB. Probably, TT genotype may be associated with
higher IL-8 production and increased leucocyte accumulation
and inflammation at the site of M. tuberculosis
infection.

Promoter polymorphism of IL-8 gene and IL-8 production in pulmonary tuberculosis

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