Search

During SARS-CoV-2 infection, an effective immune response provides the first line of defense; however, excessive inflammatory innate immunity and impaired adaptive immunity may harm tissues. Soluble immune mediators are involved in the dynamic interaction of ligands with membrane-bound receptors to maintain and restore health after pathological events. In some cases, the dysregulation of their expression can lead to disease pathology. In this literature review, we described current knowledge of the basic features of soluble immune mediators and their dysregulation during SARS-CoV-2 infections and highlighted their contribution to disease severity and mortality. DXiAWb3TC5e1Uu4oQZrWWj Video Abstract [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has become the world's main life-threatening challenge in the third decade of the twenty-first century. Numerous studies have been conducted on SARS-CoV2 virus structure and pathogenesis to find reliable treatments and vaccines. The present study aimed to evaluate the immune-phenotype and IFN-I signaling pathways of COVID-19 patients with mild and severe conditions. Material and methods: A total of 100 COVID-19 patients (50 with mild and 50 with severe conditions) were enrolled in this study. The frequency of CD4 + T, CD8 + T, Th17, Treg, and B lymphocytes beside NK cells was evaluated using flow cytometry. IFN-I downstream signaling molecules, including JAK-1, TYK-2, STAT-1, and STAT-2, and Interferon regulatory factors (IRF) 3 and 7 expressions at RNA and protein status were investigated using real-time PCR and western blotting techniques, respectively. Immune levels of cytokines (e.g., IL-1β, IL-6, IL-17, TNF-α, IL-2R, IL-10, IFN-α, and IFN-β) and the existence of anti-IFN-α autoantibodies were evaluated via enzyme-linked immunosorbent assay (ELISA). Results: Immune-phenotyping results showed a significant decrease in the absolute count of NK cells, CD4 + T, CD8 + T, and B lymphocytes in COVID-19 patients. The frequency of Th17 and Treg cells showed a remarkable increase and decrease, respectively. All signaling molecules of the IFN-I downstream pathway and IRFs (i.e., JAK-1, TYK-2, STAT-1, STAT-2, IRF-3, and IRF-7) showed very reduced expression levels in COVID-19 patients with the severe condition compared to healthy individuals at both RNA and protein levels. Of 50 patients with severe conditions, 14 had anti-IFN-α autoantibodies in sera. Meanwhile, this result was 2 and 0 for patients with mild symptoms and healthy controls, respectively. Conclusion: Our results indicate a positive association of the existence of anti-IFN-α autoantibodies and immune cells dysregulation with the severity of illness in COVID-19 patients. However, comprehensive studies are necessary to find out more about this context. 5mo_nwLJpK7s-uZity9h4- Video abstract [ABSTRACT FROM AUTHOR]

To concentrate a potent anticancer drug (Arteether) in tumor microenvironment, we encapsulated it in biodegradable and pH sensitive polyurethane (PU) nanomicelles (NMs). The nanocomplex was characterized by Fourier transform infrared (FTIR), dynamic light scattering (DLS). The loading capacity and release profile in pH of 5.4 and 7.4 were considered. The cytotoxicity effect was evaluatedin vitroandin vivosettings. The level of IFN-γ and IL-4 cytokines of mice splenocytes were assessed by enzyme-linked immunosorbent assay (ELISA). The nanocomplex showed negative zeta charge of −26.2 mV, size of 42.30 nm and high loading capacity (92%). Release profile showed a faster rate of drug liberation at pH 5.4 as compared to that of pH 7.4. It indicated significant inhibitory effect on the growth of 4T1 cell line and increased IFN-γ level. [ABSTRACT FROM AUTHOR]

Oryzatensin (ORZ) can reduce potentially IFN-γ secretion by natural killer (NK) cells. Therefore, current study was designed to evaluate the effects of ORZ treatment on peripheral blood mono-nuclear cells (PBMCs) cytokine secretion, proliferation and also to evaluate vascular endothelial growth factor (VEGF) and Matrix Metalloproteinase 9 (MMP-9) expression in HEP-G2 cell line after culture with ORZ-stimulated PBMCs. In this ex-vivo study, PBMCs from apparently healthy male volunteers (n=25) aged 20-30 were isolated by ficoll density gradient. Tetrazolium colorimetric test (MTT assay), ELISA test and real time PCR were performed to evaluate PBMCs proliferation, PBMCs cytokine secretion and the genes expression accordingly. The results of MTT assay showed that ORZ significantly stimulated proliferation of the isolated PBMCs. The results also indicated that ORZ treatment significantly decrease and increase IFN-γ and IL-4 secretion by isolated PBMCs, respectively. Also, VEGF and MMP-9 expression significantly increased in HEP-G2 cells after culture with ORZstimulated PBMCs. The previous studies have introduced ORZ-like peptide for pharmacological purpose and in this study we get to the conclusion that the administration of this peptide may change the immune system response and sensitize target populations to cancer. [ABSTRACT FROM AUTHOR]

Cytokines are considered important factors in the modulation of various immune responses. Among them, interleukin (IL)-21 is one of the major immune modulators, adjusting various immune responses by affecting various immune cells. It has been suggested that IL-21 may enhance autoimmunity through different mechanisms, such as development and activation of helper T (TH)-17 and follicular helper T (TFH) cells, activation of natural killer (NK) cells, enhancing B-cell differentiation and antibody secretion and suppression of regulatory T (Treg) cells. Moreover, IL-21 has also been suggested to be an inducer of autoimmunity when following treatment of MS patients with some therapeutics such as alemtuzumab. This review will seek to clarify the precise role of IL-21/IL-21R in the pathogenesis of MS and, in its animal model, experimental autoimmune encephalomyelitis (EAE). [ABSTRACT FROM PUBLISHER]

Tetanus is a highly fatal disease caused by tetanus neurotoxin (TeNT) and remains a major threat to human and animal health, despite preventive strategies. TeNT is composed of heavy and light chain linked by a disulfide bond. The antibody response to TeNT is polyclonal and directed to multiple epitopes within both the light and heavy chains, leading to toxin neutralization. This study was undertaken to localize and compare neutralizing epitopes recognized by human and mouse TeNT-specific antibodies at a clonal level. In the present study, 22 murine hybridoma clones and 50 human lymphoblastoid cell lines secreting monoclonal antibodies (mAb) were generated against TeNT. The specificity of these mAb was determined using different recombinant fragments of tetanus toxin. Moreover, this study investigated thein vitrotoxin neutralizing activity of these mAb by a ganglioside GT1b assay. The results showed that tetanus toxoid immunization in humans and BALB/c mice induced a vigorous humoral immune response against different fragments of TeNT, particularly the carboxyl-terminal fragment of the heavy chain (known as fragment C). The fragment C-specific human and mouse mAb could largely neutralize TeNT. However, while all fragment C-specific human mAb reacted with the carboxyl-terminal part of this fragment (HCC), the majority of the mouse mAb failed to recognize this region. These results suggested that fragment C is the major target for the TeNT neutralizing antibodies, although different epitopes seem to be targeted by human and mouse antibodies. [ABSTRACT FROM AUTHOR]

Leishmaniasis is one of the most common infectious diseases transmitted by an obligate intracellular genusLeishmania. As there is no efficient vaccination strategy for leishmaniasis, new immunostimulatory components may enhance protective immune responses against this parasite. Lipophosphoglycan 3 (LPG3) is an essential protein required for LPG assembling. In this study, the ability of recombinant LPG3 (rLPG) and its fragments to activate isolated healthy human T-cells and cytokine secretion was evaluatedin vitro. The results showed that rLPG3 and its N-terminal fragment (rNT-LPG3) enhanced expression of CD69 on the surface of T-cells and promoted differentiation of CD4+T-lymphocytes toward a T-helper 1 (TH1) phenotype, in part, through up-regulation of interferon (IFN)-γexpression in a TLR2-independent manner. These results indicated the protective effects of LPG3 (particularly NT-LPG3 fragment) as a potent immunostimulatory component ofleishmaniain vaccination against leishmaniasis. Further investigations inin vivoassays are clearly warranted. [ABSTRACT FROM AUTHOR]

Human Toll-like receptors (TLRs) are a family of transmembrane receptors, which play a key role in both innate and adaptive immune responses. Beside of recognizing specific molecular patterns that associated with different types of pathogens, TLRs may also detect a number of self-proteins and endogenous nucleic acids. Activating TLRs lead to the heightened expression of various inflammatory genes, which have a protective role against infection. Data rising predominantly from human patients and animal models of autoimmune disease indicate that, inappropriate triggering of TLR pathways by exogenous or endogenous ligands may cause the initiation and/or perpetuation of autoimmune reactions and tissue damage. Given their important role in infectious and non-infectious disease process, TLRs and its signaling pathways emerge as appealing targets for therapeutics. In this review, we demonstrate how TLRs pathways could be involved in autoimmune disorders and their therapeutic application. [ABSTRACT FROM AUTHOR]

Background: Natural killer (NK) cells play an important role in early stages of innate immune responses against viral and tumoral attacks. Activation of NK cells by leishmaniasis results in secretion of cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, which enhances the phagocytosis and clearance of parasite. Lipophosphoglycan 3 (LPG3), the Leishmania homologous with GRP94 (glucose regulated protein 94), a member of HSP90 family, contributes to LPG assembly as the most abundant macromolecule on the surface of Leishmania promastigotes. Methods: We purified NK cells from healthy individuals (n=10) using magneticactivated cell sorting (MACS) technology. Purified NK cells were co-incubated with different concentrations of recombinant LPG3 (rLPG3), and its N-terminal (NT) and C-terminal (CT) fragments. Finally, the production of IFN-γ and TNF- α by NK cells were measured by ELISA. Results: Recombinant LPG3 but not its fragments (CT and NT), can significantly enhance the production of TNF-α by NK cells (P<0.05). Moreover, rLPG3, CT, and NT fragments were markedly stimulated the secretion of IFN-γ by NK cells (P<0.001). Conclusion: The Leishmania LPG3 antigen can effectively activate NK cells, in vitro. Leishmania LPG3 participates in the innate immunity against leishmaniasis and thereby improves the effective parasite destruction. However, its efficiency should be tested in vivo. [ABSTRACT FROM AUTHOR]

Little is known regarding the immunobiology of regulatory T (Treg) cells in hematopoietic malignancies, particularly in chronic lymphocytic leukemia (CLL). In the present study, we showed that the frequencies of CD8+ and CD4+ Treg cells were significantly increased in progressive as compared with indolent CLL patients and normal subjects. Enriched CD4+ Treg cells induced a similar level of inhibition in polyclonally activated B cells and effector T cells from CLL patients and normal subjects. Our results suggest that the increase in circulating Treg cells may result in downregulation of tumor-specific immune response, leading to tumor expansion and disease progression. [ABSTRACT FROM AUTHOR]

The concept of reduced maternal immune responsiveness in pregnancy emerged when some studies demonstrated that the immune response to particular antigens is decreased throughout pregnancy. Manifold substances are stated to be immunomodulatory or immunosuppressive, such as the components of the seminal fluid as well as several regulatory and inhibitory molecules. Slight changes take place in the maternal immune competence in pregnancy, which makes sense since a generalized immunosuppression would probably result in the loss of fetus. Supposedly, enhancement of the immune system and the following immunomodulation in mother are the operative mechanism throughout pregnancy. Conceivably, the overall response of the immune system during pregnancy could be the net result of interactions which operate for ensuring the survival of the antigenically alien fetus and simultaneously prevent an excessive immunosuppression state. Therefore, such dynamic homeostatic mechanisms seem to be significant for a successful pregnancy. [ABSTRACT FROM AUTHOR]

Different mature immune cells are being produced during infection by hematopoietic stem cells in order to compensate the required cells battling against pathogens. A wide variety of pro-inflammatory cytokines like G-CSF, TNFα, IFNα, IL-1, IL-6, etc. affect HSCs and provoke different responses including maintenance, survival, activation, proliferation, differentiation, and immune responses. The exact mechanisms of translating pathogen sensing into cytokine signals for regulating HSCs are not fully understood yet. Moreover, the interaction between these cytokines modulating different responses have to be well established in order to understand HSC responses during inflammatory complications, since several different effects have been attributed to cytokines in various conditions. IFN γ demonstrates pleiotropic influences on various cell types such as HSCs and HSPCs. It can induce HSC proliferation, quiescence, reconstitution, mobilization and differentiation. Similar to other inflammatory cytokines including IL-6, IL-3, IL-2, and GM-CSF, G-CSF is a significant mobilizing factor. It contributes to increase phenotypic HSCs in bone marrow (BM), induction of HSC cycling and quiescence, and declined long-term repopulating activity of HSCs. Growth inhibition and apoptosis induction have been understood to be elicited by TNFα, similar to IFN γ. IL-1 is a significant component for inflammatory responses, which can synergize with TNFα enhancing neutrophil production in bone marrow. It has been demonstrated that HSPC-derived cytokines, especially IL-6, is important in the functional context for promoting myelopoiesis in vitro and in vivo. Therefore, understanding their effects on HSCs in normal and stressed situation can be helpful in managing different inflammatory complications. [ABSTRACT FROM AUTHOR]

• Recurrent pregnancy loss, also known as RPL, happens to 2–5% of women of reproductive age. • Immune system between the mother and the fetus plays an important role in the acceptance of the fetus and maintaining the pregnancy. • Modulation of the immune system by lymphocyte immunotherapy (LIT) is a reasonable way to prevent embryo rejection. • Pro-Inflammatory cytokines decline following subcutaneous LIT of women with RPL. In order to prevent miscarriage in RPL patients, the goal of this study was to determine how well lymphocyte immunotherapy (LIT) works in modifying immunological responses produced by cells, cytokines, transcription factors, and microRNAs. 200 RPL patients and 200 healthy controls were included in the study. Using flow cytometry, it was possible to compare the frequency of cells before and after lymphocyte treatment. Real-time PCR was used to assess the gene expression levels of transcription factors, cytokines, and microRNAs. ELISA method was used to evaluate the level of secretion of cytokines in the serum. Primary evaluation of the immune profile between healthy controls and RPL cases showed a higher frequency of Th17, NK, B cells and a lower frequency of Treg cells in RPL cases. Also, pro-inflammatory cytokines showed increased expression at mRNA and protein levels in the RPL group in comparison with the control group. Whereas, anti-inflammatory cytokines showed decreased expression in RPL patients. Decreased and increased frequency of Th17 and Treg lymphocytes observed in RPL cases following LIT, respectively. The same results obtained for RORγt and FoxP3 mRNA expression as transcription factor of Th17 and Treg cells, respectively. NK cell cytotoxicity decreased after LIT in RPL patients. miR-326a and miR-155 expression after LIT reduced, but miR-146a and miR-10a expression increased in RPL instances. LIT in RPL cases causes to elevation and modulation of anti-inflammatory and pro-inflammatory cytokines. Our data showed that lymphocyte therapy can be proposed as an effective therapeutic agent in RPL patients with immunological background by a modulating inflammatory condition. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic and organ-specific autoimmune disease in which immune cells act against the myelin sheath, resulting in central nervous system (CNS) damage. It has been revealed that miRNAs can play significant role in the pathogenesis of MS. These regulatory molecules lead to the activation of different signaling pathways, regulation of several transcriptional factors, influencing the differentiation of Th17 cells, development of Tregs and alteration from Th2 to Th1 response in MS. New studies have discovered that dysregulation of miRNAs may trigger abnormal immune responses leading consequently in the emergence of autoimmunity. In this review, we have discussed the altered expression patterns of miRNAs discovered in MS patients. These types of dysregulated miRNAs have been associated with MS pathogenesis. Current outcomes propose that such dysregulated miRNAs are potential to serve as useful biomarkers to diagnose MS, and to recognize new healing targets for its treatment. [ABSTRACT FROM AUTHOR]

Background Th17 cells and Treg cells have been proposed as new risk factors for recurrent miscarriage (RM). In this study, we investigated the effect of Intravenous immunoglobulin G (IVIG) on the levels and function of Th17 and Treg cells and pregnancy outcome in women with RM. Materials and methods 94 pregnant women with RM were enrolled in this study. Blood was drawn at the time of positive pregnancy. On the same day, IVIG 400 mg/kg was administered intravenously for 44 patients. 50 other RM patients were included as no IVIG interfering control group. Following the first administration, IVIG was given every 4 weeks through 32 weeks of gestation. Peripheral blood was drawn after the last administration (32 weeks after pregnancy). Results IVIG down-regulated Th17 cells population and function and up-regulated Treg cells population and function were significant in the treated group. Pregnancy outcome in IVIG treated subjects was successful in 38 out of 44 RM women (86.3%). However, pregnancy outcome was successful in 21 out of 50 untreated RM women (42%). Conclusion Administration of IVIG in RM women with cellular immune cells abnormalities during pregnancy influences Th17/Treg ratio in peripheral blood and enhances Treg and decreases Th17 responses. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is known as a chronic inflammatory disease (CID) that affects the central nervous system and leads to nerve demyelination. However, the exact cause of MS is unknown, but immune system regulation and inhibiting the function of inflammatory pathways may have a beneficial effect on controlling and improving the disease. Studies show that probiotics can alter the gut microbiome, thereby improving and affecting the immune system and inflammatory responses in patients with MS. The results show that probiotics have a good effect on the recovery of patients with MS in humans and animals. The present study investigated the effect of probiotics and possible therapeutic mechanisms of probiotics on immune cells and inflammatory cytokines. This review article showed that probiotics could improve immune cells and inflammatory cytokines in patients with MS and can play an effective role in disease management and control. [Display omitted] • Probiotics alter the gut microbiome, thereby improving and affecting the immune system and inflammatory responses in patients with MS. • Probiotics have a promising effect on the recovery of patients with MS in humans and animals. • Oral administration of probiotics is the most effective route. • Gut microbiological balance can be maintained in MS patients through probiotic strains by reducing inflammatory responses. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, which is accompanying with demyelination, neurodegeneration and sensibility to oxidative stress. In MS, auto-reactive lymphocytes cross the blood–brain barrier (BBB) and reside in the perivenous demyelinating lesions which create various distinct inflammatory demyelinated plaques situated predominantly in the white matter. The current MS-related therapeutic approaches can be classified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs suppress circulating immune cells, inhibit passing the BBB and decrease the inflammatory responses. Recent advances have remarkably delayed disease development and improved the quality of life for numerous patients. In spite of major improvements in therapeutic options, there are some limitations regarding the routes of administration and the necessity for repeated and long-term dosing in which cause to systemic disadvantageous consequences and patient non-compliance. Nanotechnology presents promising approaches to improve autoimmune disease treatment with the capability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we emphasis on nanomedicine-based drug delivery approaches of biological immunomodulatory mediators for the treatment of multiple sclerosis. This comprehensive review details the most successful drugs in MS therapy and also focuses on conceptions and clinical potential of novel nanomedicine attitudes for inducing immunosuppression and immunological tolerance in MS to modulate abnormal and pathologic immune responses. [ABSTRACT FROM AUTHOR]

• Excessive innate immune response leading to high amounts of inflammatory cytokines and inflammatory disorder. • Neutralizing antibodies can be detectable in patients at day 10–15 after the disease initiated. • Virus mutations may raise the possibility of re-infection with the SARS-CoV-2. • Reinfection may occur in persons with underlying immunological disorders. • Insufficiencies serum levels of the anti-SARS-CoV-2 antibodies may render patients susceptible to disease relapse. The possibility of human reinfection with SARS-CoV-2, the coronavirus responsible for COVID-19, has not previously been thoroughly investigated. Although it is generally believed that virus-specific antibodies protect against COVID-19 pathogenesis, their duration of function and temporal activity remain unknown. Contrary to media reports that people retain protective antibody responses for a few months, science does not exclude reinfection and disease relapse shortly after initiating all immune responses during the primary onset of COVID-19. Despite production of antiviral antibodies, activated CD4+/CD8+ lymphocytes, and long-lived memory B cells, susceptibility to reinfection in humans for extended periods cannot be precluded due to repeated exposures to coronavirus or potential reactivation of the virus due to incomplete virus clearance. However, the mechanism of reinfection remains unknown. The biological characteristics of SARS-CoV-2, such as emergence of multiple mutations in the virus RNA molecules, transmissibility, rates of infection, reactivation and reinfection, can all affect the trajectory of the virus spread. Innate and adaptive immune response variables, differences in underlying diseases, and comorbidities, particularly in high risk individuals, can influence the dynamics of the virus infection. In this article, immune parameters and viral mutations pertaining to reinfection and disease relapse are reviewed and scientific gaps are discussed. [ABSTRACT FROM AUTHOR]