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Home > Characterization of Immune Responses in Hiv/Tb Co-Infected Patients in Association With Hla Gene Profile

Characterization of Immune Responses in Hiv/Tb Co-Infected Patients in Association With Hla Gene Profile

Thesis Info

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Author

Naz Shaukat, Sobia

Program

PhD

Institute

University of Karachi

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2017

Thesis Completion Status

Completed

Subject

Microbiology

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12886/1/Sobia_Naz_Shaukat_Microbiology_HSR_2017_UoK_Karachi_01.10.2018.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676725688483

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Co-infection with Mycobacterium tuberculosis (M.tb), and Human immunodeficiency virus type (HIV) is a major global public health concern and a serious problem particularly in developing countries. According to the recent survey, undertaken in 2014, 1.5 million people were died due to TB, in which 0.4 million were HIV positive. Whereas, HIV’s death toll was estimated about 1.2 million. Furthermore, approximately, 9.6millionnew TB cases occurred in 2014 globally, of these12%were HIV-positive. The high rate of co-infection between M.tb and HIV makes the management of infections more challenging. The geographic and immune overlapping effects of M.tb and HIV enable themtospread and synergize the pathogenesis of both pathogens.Several studies reported that severe manifestation of TB in HIV may be due to alteration in specific cytokine production. Few lines of research have been carried out on immune pathology in context with TB and HIV infection in vivo models which investigated only small population of cytokines such as TNF α, IFN γ, IL-10, IL-6, IL-4, IL-1 , TGF β, IL-8. However, the comprehensive assessment of immune markers including cytokines, chemokines, chemokine receptors& transcription factors, etc, remain uncharacterized, particularly in thesynergic milieu of both pathogens. Therefore, the main focus of this study was to explore the early immune response developed by patients infected with M.tb, HIV alone and both (HIV/M.tb), in order to increase the understanding of the immune pathogenic mechanisms associated with both infections and to identify relevant biomarkers that contribute in modulating immune responses during HIV and M.tb infections. Additionally, the current study further sought to investigate the expression pattern of MHC class II genes (HLA-DRB1 & HLA-DQB1) in HIV/M.tb co-infected patients. For this purpose blood samples were collected from 116individuals. Out of the total, 44 were HIV mono-infected patients, 31 were M.tb mono-infected patients, 16 were co- infected HIV/M.tb patients and 25 were uninfected people without M.tb and HIV. PBMCs were isolated from each blood sample and further processed for mRNA extraction. These RNA samples were reverse transcribed into cDNA. Sequentially RT2 profiler PCR arrays, containing 70 inflammatory genes related to T-helper 1 & T-helper 2 immune subsets were performed on final set of 64 cDNA samples. According to our findings, in active Pulmonary Tuberculosis (PTB) patients who were untreated, we found significantly altered gene expression for 18 genes as compared to control.The only Interleukin (IL), that showed 3.5 folds (p<0.05) higher expression in active PTB patients was mRNA for IL-27, which is considered as a component of TH1 immune responses; however, it exhibits both; pro-inflammatory and anti-inflammatory properties. Other cytokine genes that were found to be significantly (p<0.05) downregulated include: mRNA for IL-24 (folds -2.8), mRNA for IL-7 (folds -1.5), mRNA for TGFβ(fold -1.8) & IL-2 receptor alpha (fold -1.8). Among various chemokines and chemokine receptors, the significant (p<0.05)mRNA expression pattern was obtained for CCL5 (fold -1.6) and CXCR3(folds - 7.6). The essential transcription factors for TH1/TH2 differentiation are T-bet and GATA 3 respectively.In our study, we found significant (p<0.05)downregulation of T-bet (folds- 1.7). This indicates immune dysregulation between TH1 and TH2 responses. Among other transcription mediators, the transcripts of STAT-1, which is the main inducer of IFNγ, were appeared to be significantly(p<0.05)up-regulated (folds 2.0), whereas STAT4, an essential component of the IL-12 signaling, showed diminished responses with folds -1.7 (p<0.05). In addition, mRNA for IRF1 (folds 1.3, p<0.05) and NFATC1(folds -1.4, p<0.05) were also expressed differentially in PTB patients. TH1 dysregulation is further highlighted by significant (p<0.05)down modulation of two more genes i.e. CD80 (folds -1.9) and CD28 (folds -2.5), which is involved in costimulation of T-cell activation and IL-2 secretion. These two markers (CD28 & IL-2) are also critical in maintaining T-regulatory cells and down modulation of these markers may also favor the suppression of TH1 immune responses and T- regulatory cells activity.Other mRNA that found to be significantly (p<0.05)altered, were PTGDR2, TLR-4, TYK2 and MAPK8 with folds -2.2, 1.6, -1.7&-1.3, respectively. In a nutshell, we observed active PTB patients was neither dominated by TH1, nor by TH2 signature immune responses, however, a new biomarker IL-27 was found to be a key player in TB pathogenesis and it may negatively regulate TH1 immune responses in M.tb infection. Similar analysis wasperformed on HIV patients.The differentially regulated mRNA found to be statistically significant (p<0.05)were: IL12B, STAT1, JAK2, IL-2RA, SOCS1, IL- 10, 1L-24, CTLA4, LAG3, TNFRSF9&TYK2. The transcriptional profiling among untreated HIV patients indicates two main findings, i.e. 1)TH1/TH2 antagonism:The 7.6folds higher expression of IL-12B (a potent subunit of IL-12 cytokine) along with upregulation of STAT1 (folds 2.1) and JAK2 (folds 1.4) genes, indicatesignificant inflammatory signals for TH1 immune responses. However, in contrast, higher expression of IL-10(folds 4.4), which is an anti-inflammatoryTH2 signature cytokine, and SOCS 1 (folds 2), a strong suppressive factor for TH1 immune responses, strongly counteract these pro-inflammatory responses. This suggests antagonism between TH1 and TH2 immune responses at some levels.2)T - cells dysfunction: Two folds higher expression of inhibitory receptors (CTLA4, LAG3) also indicate defects in T cell function & proliferation. Besides increased expression of inhibitory receptors, we also found abundant transcripts of TNFRSF9 (folds 2.6), which is a co-stimulatory receptor and acts contrary in order to expandT-cell clones and maintainsprotective immune responses. Therefore, combined stimulation of co-stimulatory TNFRSF9 and co-inhibitory receptorsCTLA4, LAG3, suggests dysfunctional CD4 T-cells activity. Furthermore, significant decrease in IL-2 RA(folds – 1.5, p<0.05), also reveals disrupted T-regulatory cell activity among HIV patients. Interestingly,this particular finding is common in HIV and M.tb mono-infected patients in our study. In case of HIV/M.tb co-infected patients we have noticed significant (p < 0.05) fold changes in the following genes. The up-regulated genes were LAG 3(folds 2.5), STAT1 (folds 1.7) & IRF 1(folds 1.5), whereas down-regulated genes were CCR2 (folds - 2.0), IL-4(folds -2.5), IL4R(folds -1.4), IL-24(folds -2.2), &CD40LG(folds -1.8). In the light of these observations we can interpret that co-infection of HIV and M.tbcan cause severe immune inhibition condition in same host. Up-regulation of LAG-3 (lymphocyte activation gene3), which is an immune inhibition receptor, while down regulation of CD40 LG, which playspotent role in T-cell activation and differentiation, suggest marked inhibition in immune functionality. Secondly, down regulation of CCR2, a potent chemokine receptor for several chemokines that specifically attract monocytes to the site of infection and contribute in granuloma formation, also indicates poor lymphocyte trafficking among HIV/M.tbco-infected patients. None of the cytokines was found to be significantly up-regulated. Although, the transcripts of STAT 1 & IRF 1, potent transcription factor for TH1 responses, were positively up regulated in co-infected individuals. Lastly, we investigated HLA-DRB1 & HLA-DQB1 genes expression in studied cohorts, in order to observe the genetic predispositions for HIV/M.tb co-infection. We observed no significant association of these genetic markers with co-infection, whereas, significantly higher expression of HLA-DRB1 gene (folds 3.3, p <0.05) was seen in active PTB patients only. Taking accumulated evidences together,wesuggestthatnew immune markers are playing key role in the negative modulation of host immune responses, instead of signature immune markers. Particularly, over expression of LAG-3 in HIV mono-infection and HIV/M.tb co-infections, andIL-27 in active PTB infection, were exclusive in our study. We did not find any significant contribution ofTH1/TH2 signature cytokines, mainly IFN γ,TNF α, IL-1, IL-13, IL-15,IL-3 & IL-5, whereas most fascinating outcome of this study was about IL-24(a component of IL-10 family of cytokines), the only cytokine that is found to be commonly under expressed (p<0.05) in all patient groups (TB, HIV monoinfection &their co-infection). In conclusion, this study represents potential biomarkers relevant to TB and HIV pathogenesis in Pakistani population. These biomarkers need to be further explored on different populations in order to evaluate their significance on global scale. Furthermore, the therapeutic implications of these biomarkers in HIV and M.tb infections and its associative role in other related diseases should be investigated and validated. More effective interventions and strategies would be developed against the two deadly infections only after confirmation of putative role of such molecular markers." xml:lang="en_US
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مولانا عبدالرحمن[امیر شریعت خامس]

امیر شریعت خامس کی رحلت
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حضرت امیر شریعت کی علالت کا سلسلہ کئی ماہ سے چل رہا تھا، افاقہ نہ ہونے کی بنا پر مدرسہ حمیدیہ گودنا (چھپرہ) سے پھلواری شریف لائے گئے اور سجاد میموریل اسپتال کے علاج سے کسی قدر حالت بہتر ہوئی مگر پھر مرض نے شدت اختیار کرلی تو حی کلینک پٹنہ میں داخل کئے گئے مگر وقتِ موعود آگیا اور یہیں ۲۹؍ ستمبر ۹۸؁ء کو رشد و ہدایت کا یہ چراغ ہمیشہ کے لیے بجھ گیا۔
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صفات الجنة في سورة الرحمن: دراسة موضوعية

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Phytic Acid in Relation to Minerals Availability at Different Extraction Rates of Wheat Flour

Minerals are one of the nutrient groups vital to the human health and the deficiencies of minerals remain a momentous public health problem in many parts of the world, predominantly in developing and under developing countries where imperfection to vitamin A, iron, iodine and other micronutrients leads to adverse health disorders. The phytic acid has serious health concerns as it decreases the bioavailability of many essential minerals by interacting with multivalent cations and proteins to form complexes that may be insoluble or otherwise unavailable under physiologic conditions. This project is designed to increase the availability of minerals in flour with high and low extraction rates. In the present study three wheat varieties namely AARI-11, Faisalabad-08 and Lasani-08 at different extraction rates were characterized with special reference to physico-chemical analysis. The grains of each wheat variety was tempered and then milled through Quadrumate Senior Mill and whole wheat flour was formed through Udy Cyclon Mill. The results showed that significant variations were found in physico- chemical analysis and mineral profile of different wheat varieties. The test weight and thousand kernel weight ranged from 73.79 to 76.97 kg/hL and 40.71 to 43.85 grams, respectively, among different wheat varieties. The chemical parameters including moisture, ash, protein, fat and fiber contents were affected significantly by the wheat varieties and the extraction rates. The results exhibited variations among different extraction rates flour. It was revealed that 70% extraction rates flour possessed the highest moisture (12.36%), wet and dry gluten contents (27.56% and 10.58%, respectively) where as the whole wheat flour exhibited the highest ash (1.66%), fat (2.48%), protein (12.84%) and fiber (1.54%) contents. Rheological characteristics i.e. Farinographic and Mixographic studies of the flour were significantly affected by the different extraction rates and wheat varieties. The whole wheat flour exhibited the highest mineral contents as compared to the flour with low extraction rates. Hydrochloric acid extractability of minerals was increased significantly with the increase in extraction rates and significantly affected by the extraction rates and wheat varieties. Low phytate flour was prepared through autoclaving, fermentation and enzymatic degradation of phytic acid. The phytic acid content was significantly affected by the different processing treatments. The highest phytic acid content was found in whole wheat flour. Sensory parameters of chapattis and naan demonstrated non significant (P>0.05) effect among the wheat varieties where as significant effect was observed among the extraction rates. The efficacy study was conceded and degraded phytic acid samples were fed to rats for the analysis of serum biochemical profile. Two year study i.e. 2011 and 2012 was carried out to check the efficiency of the product and then results of both years were compared. It was concluded that fermented flour has higher value in the bioavailability of the minerals