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Bacterial Infections
exacerbations.
23,43,44
After streptomycin and isoniazid began to be 1,25(OH)2D3 analogues for immunosuppressive purposes in, for
widely used, some still recommended 600,000IU calciferol twice a instance, autoimmune diseases.
54,55
To the knowledge of the author,
week as supplementary treatment,
45
in particular in cases with there are no studies available regarding the effect of the host immune
streptomycin resistance.
43
response in TB patients treated with the dosage commonly used for VDD,
let alone the supraphysiological dosage of vitamin D that was common
less than 50 years ago.
Ever since lymphoid cells were
discovered to richly express the Specific Evidence from In Vitro Studies Linking
vitamin D receptor, there has been a
Tuberculosis and Vitamin D
There are, however, a number of laboratory studies that specifically link
growing understanding of the overall
vitamin D and host defence against MTB. 1,25(OH)2D3 has repeatedly
importance of vitamin D in various
been shown to enhance macrophage phagocytosis of live MTB.
56–63
The
mechanism is possibly a 1,25(OH)2D3-induced increased nitric oxide (NO)
aspects of the immune system.
synthesis, leading to suppression of MTB or Mycobacterium bovis in
macrophages.
62,64,65
A major part of the available 1,25(OH)2D3 seems to
Marcussen from the Finsen Institute reported that 83.5% of 280 lupus stem from local production: Cadranel has shown that lymphocytes
vulgaris patients treated with vitamin D
2
alone were clinically and isolated with bronchoalveolar lavage from 14 TB patients did in fact
histologically symptom-free during the course, but there were frequent produce 1,25(OH)2D3, while this was not seen in controls.
66
This may
relapses and only 33% remained symptom-free after five years of follow- be a result of increased 1α-hydroxylase activity. The enzyme can also be
up.
35
This observation led them to conclude that vitamin D acted on the host found in extrarenal tissue, such as skin and lymphnodes, and expression is
rather than on the tubercle bacillus. increased in granulomatous diseases
67,68
and upregulated by toll-like
receptor (TLR) stimulation.
63
Immunological Aspects
When the local environment is rich in 1,25(OH)2D3 there are other effects
More Than a Calcium-metabolism-regulating Hormone besides NO release. Rook et al. have shown that monocytes cultured in the
Ever since lymphoid cells were discovered to richly express the vitamin D presence of 1,25(OH)2D3 have an increased capacity of MTB-triggered
receptor (VDR),
46
there has been a growing understanding of the overall tumour necrosis factor (TNF)-α release,
69
and Stabel et al. showed that
importance of vitamin D in various aspects of the immune system.
47,48
1,25(OH)2D3 increased cytokine secretion in splenocytes from mice
Vitamin D modulates the proliferation, differentiation and immune infected with M. paratuberculosis.
70
function of lymphocytes and monocytes.
49
The VDR is found in significant
concentrations in the T lymphocyte and macrophage populations. Tuberculosis Immunopathology in Relation to
However, its highest concentration is in the immature immune cells of the Vitamin-D-mediated Immunology
thymus and the mature CD8 T lymphocytes.
50
CD4+ T cells express VDRs Recently, we have come closer to an understanding of the specific role
at a lower level,
48
but have been shown to increase five-fold following of vitamin D in immune reactions towards infection with MTB.
63
In a
activation.
51
Microarray technology has identified over 102 targets of series of elegant experiments published in Science in 2006, Liu et al.
1,25 di-hydroxy-cholecalciferol (1,25(OH)2D3) in CD4
+
T cells. Of these showed that TLR 1 and 2 stimulation of human macrophages results in:
102 genes, 57 were downregulated and 45 were upregulated by reduced viability of intracellular MTB in human monocytes and
1,25(OH)2D3 treatment of the CD4
+
T cells.
51
macrophages but not in dendritic cells; upregulation of the VDR gene
in monocytes; and hydroxylation of 25(OH)D3 into 1,25(OH)2D3. They
Intriguingly, it seems that 1,25(OH)2D3 is capable of stimulating immune further showed that adding 1,25(OH)2D3 to human monocytes led to
responses in certain circumstances and suppressing them in others.
49
Griffin upregulation of cathelicidin, an antimicrobial peptide, and a reduction
sums up the current evidence in the following statements:
52
of viable MTB in infected macrophages; in fact, simultaneous addition
of 25(OH)D3 and TLR 2/1-ligand also upregulated cathelicidin. The
• the current evidence implicates 1,25(OH)2D3 in the enhancement of
localised innate immune responses;
• the evidence points to a significant role for 1,25(OH)2D3 in the negative
regulation of Th1-type immunity; and
• administration of 1,25(OH)2D3 agonists is associated with the
There has been some hesitation to
promotion of Th2 or Treg-type T cells.
supplement tuberculosis patients with
Looking at vitamin-D-mediated immunological reactions with TB in mind,
vitamin D for fear of hypercalcaemia.
we may interpret this as beneficial in terms of strengthening the innate
response that is vital to host defence, and a limitation of unsuitably
strong Th1 reactions may also be desirable. However, it must be
emphasised that the immune response to mycobacterium tuberculosis authors called for clinical trials of the inexpensive vitamin D
(MTB) is complex and multifaceted and not completely understood,
53
and supplementation towards infectious diseases. A recent trial by
evaluating the impact of interventions on host immune defences can be Martineau et al.
71
did in fact test vitamin D for TB contacts, and found
difficult. Current research mainly focuses on treating VDD or using that vitamin D significantly enhanced the ability of whole blood to
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