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In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T), a rare inherited disorder, usually affects the nervous and immune systems, and occasionally other organs. A-T is associated mainly with mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. We report here a novel ATM mutation (c.3244_3245insG; p.His1082fs) in an 11-year old female. This subject presented with typical features, with the addition of chest manifestations including mediastinal lymphadenopathy and diffuse bilateral micronodular infiltration of the lungs, along with a high EBV titer. The subject died as a result of rapid B-cell lymphoma progression before chemotherapy could be initiated. This case highlights the need for the rapid diagnosis of A-T mutations and the detection of associated life-threatening outcomes such as cancers. [ABSTRACT FROM AUTHOR]

Poly lactic-co-glycolic acid (PLGA), a biodegradable polymer, can effectively protect encapsulated peptides from enzymatic degradation. PLGA was approved by FDA as a safe drug delivery system suitable for inhalation administration. Vasoactive intestinal peptide (VIP), a 28-amino-acid peptide, displays anti-inflammatory and anti-spasmodic effects, which can be considered as a new therapeutic option to control and treat asthma. Because of in vivo enzymatic degradation of VIP including in the lung, there is a need for an applicable delivery system. In light of this, the purpose of this study was to prepare VIP-loaded PLGA microspheres as a drug delivery system, assuming that the newly-introduced model has the ability to persist for a longer time in respiratory tracts. The PLGA microsphere was produced, and loaded with VIP as an applicable nanodrug system. A series of physiochemical properties were determined, including the morphological characteristics, average size of nanoparticles, electric charge distribution, FTIR spectroscopy absorption, and loading and releasing percentage of the nanodrug. VIP-loaded PLGA exhibited an average size of approximately 550 ± 50 nm. Additionally, the produced microsphere showed 78 % VIP release after 10 h at the pH value corresponding to bronchioalveolar microenvironment (approximately 6.5). In the present study, PLGA was formulated and used as a delivery system for VIP. Taken together, the newly-introduced nanodrug seems to be helpful for the clinical treatment of allergic asthma. PLGA nanoparticles can be considered as a potential efficient delivery system for VIP in the respiratory system. [ABSTRACT FROM AUTHOR]

Zymosan, a polysaccharide derived from yeast cell wall, has been widely applied as a macrophage-activating factor. Application of immunomodulatory compounds as cancer therapeutics has emerged in recent years. The goal of this study was to assess the effect of zymosan in the modulation of pro-inflammatory cytokines in melanoma-bearing mice. C57BL/6 mice were divided into four groups of seven mice including zymosan (Z group), melanoma (M group), zymosan treated melanoma-bearing mice (ZM group), and control (C group). Mice were treated with zymosan (10 μg) for four continuous days. At the end of the last day (25 days after tumor induction), blood samples and peritoneal macrophages were collected and mice were euthanized. The levels of IL-1β and IL-6 were measured in sera by enzyme-linked immunosorbent assay (ELISA). The expression of messenger RNA (mRNA) levels was analyzed by real-time polymerase chain reaction (RT-PCR). The results showed that zymosan significantly increases both serum release and mRNA levels of IL-1β and IL-6 in mice-bearing melanoma. Phagocytic activity of macrophages increased significantly by zymosan. Thus, our data may suggest that zymosan has a potential activity in cancer regulation and might be used as an adjuvant role in conventional cancer treatment. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is considered a major worldwide health problem with 10 million new cases diagnosed each year. Our understanding of TB immunology has become greater and more refined since the identification of Mycobacterium tuberculosis (MTB) as an etiologic agent and the recognition of new signaling pathways modulating infection. Understanding the mechanisms through which the cells of the immune system recognize MTB can be an important step in designing novel therapeutic approaches, as well as improving the limited success of current vaccination strategies. A great challenge in chronic disease is to understand the complexities, mechanisms, and consequences of host interactions with pathogens. Innate immune responses along with the involvement of distinct inflammatory mediators and cells play an important role in the host defense against the MTB. Several classes of pattern recognition receptors (PRRs) are involved in the recognition of MTB including Toll-Like Receptors (TLRs), C-type lectin receptors (CLRs) and Nod-like receptors (NLRs) linked to inflammasome activation. Among the TLR family, TLR1, TLR2, TLR4, and TLR9 and their down-stream signaling proteins play critical roles in the initiation of the immune response in the pathogenesis of TB. The inflammasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of TB. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes. Abnormalities in PRR signaling pathways regulated by TB will affect disease pathogenesis and need to be elucidated. In this review we provide an update on PRR signaling during M. tuberculosis infection and indicate how greater knowledge of these pathways may lead to new therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Our knowledge of the role of innate immunity in protecting against cancers has expanded greatly in recent years. An early focus was on the adoptive transfer of natural killer (NK) cells and, although this approach has demonstrated promising results in many patients, a few limitations including immune escape of tumors from cytotoxic killing by NK cells have caused treatment failures. Downregulation of the expression of activating ligands on the surface of cancer cells and prevention of the activity of soluble factors are among the mechanisms employed by cancer cells to overcome NK-mediated immunity. It has become evident that a class of small membranous structures of endosomal origin known as exosomes play a key role in regulating the local tumor microenvironment. Here we hypothesize that exosome secretion by cancer cells, which is greater than that of normal cells, is an important escape mechanism employed by cancer cells. Interruption of exosome release by various inhibitory agents in combination with the adoptive transfer of NK cells may overcome, at least in part, the treatment failures that occur with adoptive NK cell transfer. In this regard, repositioning of approved drugs with previously shown effects on exosome release may be a good strategy to bypass the safety issues of newly identified agents and will also dramatically reduce the huge costs of drug approval process. [ABSTRACT FROM AUTHOR]

Cerebrovascular lesions, a potent stimulus for endothelial cell activation, trigger cognitive and degenerative changes and contribute to pathology of Alzheimer's disease (AD). Circulating microparticles (MPs) are actively involved in the pathogenesis of AD and cerebrovascular diseases, which share common vascular risk factors. We examined the plasma changes of endothelial MPs (EMPs) and platelet MPs (PMPs) in AD patients with vascular risk factors. The plasma Annexin V CD 41a CD144 EMPs and Annexin V CD41a CD144 PMPs of 37 patients with AD, with or without vascular risk factors (hypertension, diabetes, dyslipidemia, stroke, coronary artery disease, and smoking), and 10 age-matched controls were quantified by flow cytometry. Pearson correlation analysis used to evaluate the linear relationship between variables. Significantly higher plasma levels of EMPs were observed in AD patients with vascular risk factors as compared to the patients without vascular risk factors [Mean Difference (MD): 2587.80, 95% confidence interval (CI) 770.30-4404.80], and control subjects (MD: 4990.60, 95% CI, 3054.40-6926.79). Significant correlations were found between circulating EMPs, total MPs, and PMPs. There were no significant correlations between plasma levels of EMPs/ PMPs, and cognitive decline indices. Circulating EMP levels are influenced by AD disease status, and plasma levels of MPs and PMPs are associated with vascular risk factors in patients with AD. EMP phenotyping, as cellular biomarkers of vascular injury/dysfunction, and their effects on cerebral perfusion, and cognitive decline should be further investigated. [ABSTRACT FROM AUTHOR]

The pathogenesis of coronavirus disease 2019 (COVID-19) is not fully elucidated. COVID-19 is due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes severe illness and death in some people by causing immune dysregulation and blood T cell depletion. Increased numbers of myeloid-derived suppressor cells (MDSCs) play a diverse role in the pathogenesis of many infections and cancers but their function in COVID-19 remains unclear. To evaluate the function of MDSCs in relation with the severity of COVID-19. 26 PCR-confirmed COVID-19 patients including 12 moderate and 14 severe patients along with 11 healthy age- and sex-matched controls were enrolled. 10 ml whole blood was harvested for cell isolation, immunophenotyping and stimulation. The immunophenotype of MDSCs by flow cytometry and T cells proliferation in the presence of MDSCs was evaluated. Serum TGF-β was assessed by ELISA. High percentages of M-MDSCs in males and of P-MDSCs in female patients were found in severe and moderate affected patients. Isolated MDSCs of COVID-19 patients suppressed the proliferation and intracellular levels of IFN-γ in T cells despite significant suppression of T regulatory cells but up-regulation of precursor regulatory T cells. Serum analysis shows increased levels of TGF-β in severe patients compared to moderate and control subjects (HC) (P = 0.003, P < 0.0001, respectively). The frequency of MDSCs in blood shows higher frequency among both moderate and severe patients and may be considered as a predictive factor for disease severity. MDSCs may suppress T cell proliferation by releasing TGF-β. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1–10% of humans worldwide with peripheral arterial disease. Cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs) have been used for the treatment of CLI. However, little information is available regarding the angiogenic potency of MSCs and mast cells (MC) in angiogenesis. The aim of this study was to evaluate the ability of MCs and MSCs to induce angiogenesis in a rat model of ischemic hind limb injury on a background of a tissue engineered hydrogel scaffold. Thirty rats were randomly divided into six control and experimental groups as follows: (a) Control healthy (b) Ischemic positive control with right femoral artery transection, (c) ischemia with hydrogel scaffold, (d) ischemia with hydrogel plus MSC, (e) ischemia with hydrogel plus MC and (f) ischemia with hydrogel plus MSC and MCs. 106 of each cell type, isolated from bone marrow stroma, was injected into the transected artery used to induce hind limb ischemia. The other hind limb served as a non-ischemic control. After 14 days, capillary density, vascular diameter, histomorphometry and immunohistochemistry at the transected location and in gastrocnemius muscles were evaluated. Capillary density and number of blood vessels in the region of the femoral artery transection in animals receiving MSCs and MCs was increased compared to control groups (P < 0.05). Generally the effect of MCs and MSCs was similar although the combined MC/MSC therapy resulted in a reduced, rather than enhanced, effect. In the gastrocnemius muscle, immunohistochemical and histomorphometric observation showed a great ratio of capillaries to muscle fibers in all the cell-receiving groups (P < 0.05). The data indicates that the combination of hydrogel and cell therapy generates a greater angiogenic potential at the ischemic site than cell therapy or hydrogels alone. [ABSTRACT FROM AUTHOR]

Patients with tuberculous pleural effusion (TPE) or malignant pleural effusions (MPE) frequently have similar pleural fluid profiles. New biomarkers for the differential diagnosis of TPE are required. We determined whether cytokine profiles in the PE of patients could aid the differential diagnosis of TPE. 30 patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP) and 14 patients with parapneumonic effusion (PPE) were enrolled between Dec 2018 and 2019. The levels of interleukin (IL)-6, IL-18, IL-27, CXCL8, CCL-1 and IP-10 were determined in PE by ELISA along with measurements of adenosine deaminase (ADA). The best predictors of TPE were combined ADA.IL-27 [optimal cut-off value = 42.68 (103 U ng/l2), sensitivity 100%, specificity 98.28%], ADA [cut off value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] and IL-27 [cut-off value = 2363 (pg/ml), sensitivity 96.7%, specificity 98.3%, p ≤ 0.0001]. A high level of IL-6 [cut-off value = 3260 (pg/ml), sensitivity 100%, specificity 67.2%], CXCL8 [cut-off value = 144.5 (pg/ml), sensitivity 93.3%, specificity 58.6%], CCL1 [cut-off value = 54 (pg/ml), sensitivity 100%, specificity 70.7%] and IP-10 [cut-off value = 891.9 (pg/ml), sensitivity 83.3%, specificity 48.3%] were also predictive of TPE. High ADA.IL-27, ADA and IL-27 levels differentiate between TPE and non-TPE with improved specificity and diagnostic accuracy and may be useful clinically. [ABSTRACT FROM AUTHOR]

Background: Despite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance. Objectives: a) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions. Methods: L363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies. Results: Myeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions. Conclusion: Our observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are multipotent stem cells found in many adult tissues, especially bone marrow (BM) and are capable of differentiation into various lineage cells such as osteoblasts, adipocytes, chondrocytes and myocytes. Moreover, MSCs can be mobilized from connective tissue into circulation and from there to damaged sites to contribute to regeneration processes. MSCs commitment and differentiation are controlled by complex activities involving signal transduction through cytokines and catecholamines. There has been an increasing interest in recent years in the neural system, functioning in the support of stem cells like MSCs. Recent efforts have indicated that the catecholamine released from neural and not neural cells could be affected characteristics of MSCs. However, there have not been review studies of most aspects involved in catecholamines-mediated functions of MSCs. Thus, in this review paper, we will try to describe the current state of catecholamines in MSCs destination and discuss strategies being used for catecholamines for migration of these cells to damaged tissues. Then, the role of the nervous system in the induction of osteogenesis, adipogenesis, chondrogenesis and myogenesis from MSCs is discussed. Recent progress in studies of signaling transduction of catecholamines in determination of the final fate of MSCs is highlighted. Hence, the knowledge of interaction between MSCs with the neural system could be applied towards the development of new diagnostic and treatment alternatives for human diseases. [ABSTRACT FROM AUTHOR]