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 allaround the world in 2014. Although antibiotics in treatment of TB havedecreased death rate, the possibility of drug resistance in these patients hasbeen increased due to plurality of prescribed drugsand long period of treatment. There are evidences of lack of vitamin D in TBpatients.

The prominent role of vitamin D in the activity of immune system iswell documented. Since vitamin D performs its role by a receptor on monocyte– macrophages nucleuses, so plasma concentrationof vitamin D on one hand and the role of their receptors on the other are thefactors that influence on the person’s ability to respond against TB by actingon host immune system. The studies have shown that using vitamin D supplementis a safe method that has had an important role in acceleration of theimprovement of the radiological outcomes and sputum smear/cultureconversion.  Taking prescribed vitamin Dsupplements in TB patients with lack of this vitamin could be critical. Key words:Culture, Drug resistance, Smear, Tuberculosis, VitaminD         IntroductionAbout one third of world population are infected with Mycobacteriumtuberculosis, but only one tenth of them. show clinical symptoms. It iscompared with HIV in mortality rate in the world(1). In spite of the fact that new drugs weredevelopment in the last sixty years; controling TB is still a big challenge.

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Usingmultiple antibiotics could potentially create problems such as drug resistance,expensive treatments and side effects(2) which encourage researchers to search foralternative remedies or use other auxiliary factors in acceleration oftreatment process to decrease drug resistance rates. In this field the role ofvitamin 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 theplurality of prescribed drugs (Rifampicin, Isoniazid, Pyrazinamide andEthambutol), 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 productionof antimicrobial peptide,cathelicidin, and helps the autophagyof macrophages which have been contaminated with M. tuberculosis(5). According to  in vitro evidences active form of thevitamin D inhibits the bacteria replication within macrophages throughstimulating the immune system (6). In addition to plasma concentration ofvitamin D, vitamin D receptor (VDR) gene polymorphisms have influence on thereceptor activity and other following targets.

Therefore awareness of hostgenetic factors, especially polymorphisms in VDR gene have great importance indetermining susceptibility or resistance of TB(7–9). The aim of this study is investigating andreviewing existing information on the effect of plasma vitamin D concentrationand its receptors on promoting immune system of TB patients and the role ofvitamin D in accelerating improvement of TB patients for limiting bacteriatransmission and clinical drug resistance. TuberculosisTB is one of the worst infectious disease in all aroundthe world.

According to a report from world health organization (WHO) 9.6million TB cases were diagnosed in 2014 resulting in1.5 million deaths(1) . This was mostly caused by mycobacteriumtuberculosis complex(10). TB mostly involves the lungs (pulmonary TB), however, other organs can be infected by this bacteria as well (extrapulmonary TB) (11) TB is latent in approximately one third ofthe world population having immune responses to bacteria antigen but only 10percent of patients show clinical symptoms. Not only the bacteria but alsoother 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 simplepulmonary infection, are not severe ,so delays in diagnosis and treatment causetransmission of bacteria at this stage thorough coughing and sneezing(20).

There are many  barriers to TB control and treatment such asdrug plurality against TB, patients’ mental tardiness because of long period ofdrug use and continuation of it, lack of effective vaccination, occurrence ofresistant species, lack of awareness in transmission and disease progression (4,21). Drug resistance in tuberculosisMismanagement of treatment such as inappropriatecombinatorial drugs prescription, single drug treatment, incomplete treatmentor in another word, not completing the course of prescribed drugs, and immunodeficiencyproblems 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 atleast two major and first line of drugs (isoniazid and rifampicin). In thissituation, the disease treatment is followed by prescription of second linedrugs which are less effective, more expensive (costs more), with severe sideeffects such as hepatoxicity and in need for a longer treatment (23). It is worth mentioning that according toWHO 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 noneof other fluoroquinolones and also at least one of second line drugs such askanamycin, capreomycin or amikacin which is called extensive drug resistanttuberculosis (XDR-TB)(24).This type of drug resistance, along withlong-term treatment durations, is one of the serious health system problems incountries involved with this issue.

In this regarding, investigating thetransmission process of drug resistant strains, especially in immigrants fromcountries with high TB burden(23) and researching on traditional treatments(25) along with standard treatments can help usto eradicate the epidemic TB in the world. Also using supplements which areable to shorten the period of treatment, or at least decrease the power oftransmission of this microorganism, and improve the outcome of treatments canbe effective.  Theimportance of Vitamin D in host immune systemVitamin D is a fat-soluble secosteroid whichis mainly synthesized in skin(26). The main part of this vitamin issynthesized by sunlight (UV-B) and some is provided through food (27,28). Based on its receptor on macrophagesnucleous, vitamin D is considered as a known human immune system modulator andso 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), anddownstream targets of VDR such as cathelicidin, through activation of Toll likereceptor I &II (5,7). 1-25-dihydroxyvitamin D (calcitriol) isable to promote innate immune system through inducing the production ofcathelicidin and ?-defensin2 as antimicrobial peptides.

Reduction in theproduction of these peptides increases the susceptibility to infectiousdiseases such as TB (31).LL-37 as only member of the family of human cathelicidin, recruit  monocytes, T cells andneutrophils to the site of infection and has a immunomodulatory role(32).In addition vitamin D can induce the differentiation of immature monocytes tomature ones(33). Binding of this vitamin to VDR on monocytesincreases  the phagolysosome  fusion and also activates nitrogen and oxygenmediators and antimicrobial peptides; this procedure can induce antimicrobialinnate immune responses(34). Calcitriol modulates adaptive responsesdirectly via suppressing the Th1 by reduction of INF-?, TNF-? and IL-6production and indirectly through reducing the expression of MHC II and IL-2 secretion by antigen presentingcells(35,36). Also, calcitriol, can play its role throughthe impact on the differentiation of T cells into regulatory T cells (Treg) orpro-inflammatory Th17 cells in adaptive immune system(37). This vitamin is even able to increase thematuration of Th2 cells and also reinforces the producing of anti-inflammatorycytokines such as TGF?1, IL-4,and IL-10(38).

The proliferation of activated B cells arerestricted by this vitamin and it results in reduction of producing theimmunoglobulins(39). So this vitamin has the power ofsuppressing the antigen stimulated pro-inflammatory responses which are able toincrease the mortality of patients with TB(40). Based on the study conducted by Selvaraj etal.(41) serum level of VDR protein significantlydecreased in patients with pulmonary tuberculosis in comparison with normalcases and it was probably due to decrease in VDR gene expression in response toan increase in the synthesis of 1,25-dihydroxy D(42).

Since cathelicidin is one of the directtargets of VDR, defects in VDR signaling can result in immune defects against M.tuberculosis  and inflammation due toincrease in inflammatory cytokines. Matrix metalloproteinases (MMPs), a familyof zinc and calcium dependent endopeptidases, regulate innate immune systemresponses by controlling the process of cytokines, chemokines, apoptosis andactivating the antimicrobial peptides(43). M.

tuberculosisis able to induceexpression of MMP-1, MMP-7 and MMP-10 genes in human macrophages and it canresult in increased tissue damages(38,44). It has been shown that circulatingconcentrations of MMP-9 are correlated with the severity of pulmonary TB(45). Tissue inhibitors of MMPs (TIMP) restrictthe activity of MMPs. TIMP-2 and TIMP-3 expression decreases in humanmacrophages and the expression of TIMP-1 is suppressed in pulmonary epithelialcells during infection by M.

tuberculosis(44).As it has beenwell documented, treatment of peripheral blood mononuclear cells by vitamin Dresults in attenuation in expression of M. tuberculosis -induced MMPssuch as MMP-7, MMP-9 and MMP-10 and on the other side increases the synthesisof TIMP-1 which has an important role in reducing the symptoms of disease andtissue damage caused by infection(38,46).Thus we can conclude that vitamin D leads tothe 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, patientswith low levels of 25-hydroxyvitamin D3 are more susceptible to tuberculosisand the risk of developing from infection phase to active disease is higher inthese patients(50,51). Therefore, vitamin D is able to preventconverting the latent TB to active form of disease and it can be used asprophylaxis in patients with latent TB(52,53).