Tuberculosis only one tenth of them. show clinical symptoms.

Tuberculosis (TB) is a global health problem.
According to WHO report 9.6 million people suffered from this disease all
around the world in 2014. Although antibiotics in treatment of TB have
decreased death rate, the possibility of drug resistance in these patients has
been increased due to plurality of prescribed drugs
and long period of treatment. There are evidences of lack of vitamin D in TB
patients. The prominent role of vitamin D in the activity of immune system is
well documented. Since vitamin D performs its role by a receptor on monocyte– macrophages nucleuses, so plasma concentration
of vitamin D on one hand and the role of their receptors on the other are the
factors that influence on the person’s ability to respond against TB by acting
on host immune system. The studies have shown that using vitamin D supplement
is a safe method that has had an important role in acceleration of the
improvement of the radiological outcomes and sputum smear/culture
conversion.  Taking prescribed vitamin D
supplements in TB patients with lack of this vitamin could be critical.

Key words:Culture, Drug resistance, Smear, Tuberculosis, Vitamin
D

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Introduction

About one third of world population are infected with Mycobacterium
tuberculosis, but only one tenth of them. show clinical symptoms. It is
compared with HIV in mortality rate in 
the world(1). In spite of the fact that new drugs were
development in the last sixty years; controling TB is still a big challenge. Using
multiple antibiotics could potentially create problems such as drug resistance,
expensive treatments and side effects(2) which encourage researchers to search for
alternative remedies or use other auxiliary factors in acceleration of
treatment process to decrease drug resistance rates. In this field the role of
vitamin D is one of the most important factors in promoting host immune system(3) which has drawn the researchers’ attention.
The possibility of drug resistance in TB patients is very high because of the
plurality of prescribed drugs (Rifampicin, Isoniazid, Pyrazinamide and
Ethambutol), long treatment period (at least six months) or stopping treatment(4).

The active form of vitamin D (1, 25(OH) 2 vitamin D3)
inhibits the intracellular growth of the bacteria, through inducing production
of antimicrobial peptide,cathelicidin, and helps the autophagy
of macrophages which have been contaminated with M. tuberculosis(5). According to  in vitro evidences active form of the
vitamin D inhibits the bacteria replication within macrophages through
stimulating the immune system (6). In addition to plasma concentration of
vitamin D, vitamin D receptor (VDR) gene polymorphisms have influence on the
receptor activity and other following targets. Therefore awareness of host
genetic factors, especially polymorphisms in VDR gene have great importance in
determining susceptibility or resistance of TB(7–9). The aim of this study is investigating and
reviewing existing information on the effect of plasma vitamin D concentration
and its receptors on promoting immune system of TB patients and the role of
vitamin D in accelerating improvement of TB patients for limiting bacteria
transmission and clinical drug resistance.

 

Tuberculosis

TB is one of the worst infectious disease in all around
the world. According to a report from world health organization (WHO) 9.6
million TB cases were diagnosed in 2014 resulting in1.5 million deaths(1) . This was mostly caused by mycobacterium
tuberculosis complex(10). TB mostly involves the lungs (pulmonary TB)
, however, other organs can be infected by this bacteria as well (extra
pulmonary TB) (11) TB is latent in approximately one third of
the world population having immune responses to bacteria antigen but only 10
percent of patients show clinical symptoms. Not only the bacteria but also
other factors can cause this disease such as genetic factors (12–14), immune system (15,16), nutrition(17,18), stress and life style of the host(19). At early stages of TB, symptoms like simple
pulmonary infection, are not severe ,so delays in diagnosis and treatment cause
transmission of bacteria at this stage thorough coughing and sneezing(20). There are many  barriers to TB control and treatment such as
drug plurality against TB, patients’ mental tardiness because of long period of
drug use and continuation of it, lack of effective vaccination, occurrence of
resistant species, lack of awareness in transmission and disease progression (4,21).

 

Drug resistance in tuberculosis

Mismanagement of treatment such as inappropriate
combinatorial drugs prescription, single drug treatment, incomplete treatment
or in another word, not completing the course of prescribed drugs, and immunodeficiency
problems are the main causes of drug resistance(22). Multi drug resistant tuberculosis (MDR-TB)
is a type of TB which is caused by resistance of M. tuberculosis to at
least two major and first line of drugs (isoniazid and rifampicin). In this
situation, the disease treatment is followed by prescription of second line
drugs which are less effective, more expensive (costs more), with severe side
effects such as hepatoxicity and in need for a longer treatment (23). It is worth mentioning that according to
WHO reports, unfortunately, 480000 people have been affected by MDR-TB(1). The more critical situation happens when M.
tuberculosis doesn’t respond to isoniazid (INH), rifampicin (RNP) or none
of other fluoroquinolones and also at least one of second line drugs such as
kanamycin, capreomycin or amikacin which is called extensive drug resistant
tuberculosis (XDR-TB)(24).This type of drug resistance, along with
long-term treatment durations, is one of the serious health system problems in
countries involved with this issue. In this regarding, investigating the
transmission process of drug resistant strains, especially in immigrants from
countries with high TB burden(23) and researching on traditional treatments(25) along with standard treatments can help us
to eradicate the epidemic TB in the world. Also using supplements which are
able to shorten the period of treatment, or at least decrease the power of
transmission of this microorganism, and improve the outcome of treatments can
be effective.

 

The
importance of Vitamin D in host immune system

Vitamin D is a fat-soluble secosteroid which
is mainly synthesized in skin(26). The main part of this vitamin is
synthesized by sunlight (UV-B) and some is provided through food (27,28). Based on its receptor on macrophages
nucleous, vitamin D is considered as a known human immune system modulator and
so it can enhance cellular immune system(14,29,30). Interactions between macrophages and M.
tuberculosis antigens can cause the expression of 1- ?-hydroxilase (CYP27B1), vitamin D receptors (VDR), and
downstream targets of VDR such as cathelicidin, through activation of Toll like
receptor I &II (5,7). 1-25-dihydroxyvitamin D (calcitriol) is
able to promote innate immune system through inducing the production of
cathelicidin and ?-defensin2 as antimicrobial peptides. Reduction in the
production of these peptides increases the susceptibility to infectious
diseases such as TB (31).
LL-37 as only member of the family of human cathelicidin, recruit  monocytes, T cells and
neutrophils to the site of infection and has a immunomodulatory role(32).
In addition vitamin D can induce the differentiation of immature monocytes to
mature ones(33). Binding of this vitamin to VDR on monocytes
increases  the phagolysosome  fusion and also activates nitrogen and oxygen
mediators and antimicrobial peptides; this procedure can induce antimicrobial
innate immune responses(34). Calcitriol modulates adaptive responses
directly via suppressing the Th1 by reduction of INF-?, TNF-? and IL-6
production and indirectly through reducing the expression of MHC II and IL-2 secretion by antigen presenting
cells(35,36). Also, calcitriol, can play its role through
the impact on the differentiation of T cells into regulatory T cells (Treg) or
pro-inflammatory Th17 cells in adaptive immune system(37). This vitamin is even able to increase the
maturation of Th2 cells and also reinforces the producing of anti-inflammatory
cytokines such as TGF?1, IL-4,and IL-10(38).The proliferation of activated B cells are
restricted by this vitamin and it results in reduction of producing the
immunoglobulins(39). So this vitamin has the power of
suppressing the antigen stimulated pro-inflammatory responses which are able to
increase the mortality of patients with TB(40). Based on the study conducted by Selvaraj et
al.(41) serum level of VDR protein significantly
decreased in patients with pulmonary tuberculosis in comparison with normal
cases and it was probably due to decrease in VDR gene expression in response to
an increase in the synthesis of 1,25-dihydroxy D(42). Since cathelicidin is one of the direct
targets of VDR, defects in VDR signaling can result in immune defects against M.
tuberculosis  and inflammation due to
increase in inflammatory cytokines. Matrix metalloproteinases (MMPs), a family
of zinc and calcium dependent endopeptidases, regulate innate immune system
responses by controlling the process of cytokines, chemokines, apoptosis and
activating the antimicrobial peptides(43). M. tuberculosisis able to induce
expression of MMP-1, MMP-7 and MMP-10 genes in human macrophages and it can
result in increased tissue damages(38,44). It has been shown that circulating
concentrations of MMP-9 are correlated with the severity of pulmonary TB(45). Tissue inhibitors of MMPs (TIMP) restrict
the activity of MMPs. TIMP-2 and TIMP-3 expression decreases in human
macrophages and the expression of TIMP-1 is suppressed in pulmonary epithelial
cells during infection by M. tuberculosis(44).
As it has been
well documented, treatment of peripheral blood mononuclear cells by vitamin D
results in attenuation in expression of M. tuberculosis -induced MMPs
such as MMP-7, MMP-9 and MMP-10 and on the other side increases the synthesis
of TIMP-1 which has an important role in reducing the symptoms of disease and
tissue damage caused by infection(38,46).Thus we can conclude that vitamin D leads to
the activation of effective microbicidal mechanisms and on the other side,
reduces the expression of inflammatory mediators with pathogenic effects(47–49). Based on clinical observations, patients
with low levels of 25-hydroxyvitamin D3 are more susceptible to tuberculosis
and the risk of developing from infection phase to active disease is higher in
these patients(50,51). Therefore, vitamin D is able to prevent
converting the latent TB to active form of disease and it can be used as
prophylaxis in patients with latent TB(52,53).