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Pregnancy-induced immune modulation might lead to reactivation of latent tuberculosis infection (LTBI). This thesis explores aspects of immune-based LTBI diagnostics and how pregnancy affects the immune control of Mycobacterium tuberculosis (Mtb) infection. We studied a prospective cohort of women recruited during pregnancy in Ethiopia. LTBI testing was performed by quantification of interferon-γ (IFN-γ) in Mtb-antigen- stimulated whole blood supernatants using the QuantiFERON-TB Gold Plus (QFT) assay.In paper I, we found that 277/829 (33%) of pregnant women had LTBI using the conventional IFN-γ cut-off level (0.35 IU/ml). However, borderline results (0.20-0.70 IU/ml) were common, especially in HIV-positive women. In paper II, we characterized Mtb-antigen cytokine responses for LTBI classification in women with borderline IFN-γ results. A combination of MCP-2, IP-10 and IL-1ra classified 42% of women with borderline IFN-γ as having high likelihood of LTBI. In paper III, we studied longitudinal patterns of Mtb-triggered IFN-γ secretion during pregnancy and post-partum. We observed that Mtb-stimulated IFN-γ response was elevated during the 3rd trimester compared to early pregnancy and post-partum. In paper IV, we investigated longitudinal kinetics of Mtb-specific and -non-specific cytokine responses in women with LTBI. We found elevated expression of Mtb-specific IL-2 and IP-10, and reduced TGF-β1, secretion at the 3rd trimester. Non-specific levels of IL-2, IP-10 and MCP-2 were elevated post-partum in women with LTBI. In conclusion, these findings suggest that cytokines other than IFN-γ, could be used as biomarkers to assess LTBI status of pregnant women. The dynamic immune responses in women with LTBI indicate increased exposure to Mtb at later stages of pregnancy, which in turn suggests that LTBI is transiently reactivated during pregnancy.

Cardiovascular disease is the most common cause of death, which has the highest mortality rate worldwide. Although a diverse range of inflammatory diseases can affect the cardiovascular system, however, heart failure and stroke occur due to atherosclerosis. Atherosclerosis is a chronic autoinflammatory disease of small to large vessels in which different immune mediators are involved in lipid plaque formation and inflammatory vascular remodeling process. A better understanding of the pathophysiology of atherosclerosis may lead to uncovering immunomodulatory therapies. Despite present diagnostic and therapeutic methods, the lack of immunotherapy in the prevention and treatment of atherosclerosis is perceptible. In this review, we will discuss the promising immunological-based therapeutics and novel preventive approaches for atherosclerosis. This study could provide new insights into a better perception of targeted therapeutic pathways and biological therapies.

The microbiome influences the emotional and cognitive phenotype of its host, as well as the neurodevelopment and pathophysiology of various brain processes and disorders, via the well-established microbiome-gut-brain axis. Rapidly accumulating data link the microbiome to severe neuropsychiatric disorders in humans, including schizophrenia, Alzheimer's and Parkinson's. Moreover, preclinical work has shown that perturbation of the microbiome is closely associated with social, cognitive and behavioural deficits. The potential of the microbiome as a diagnostic and therapeutic tool is currently undercut by a lack of clear mechanistic understanding of the microbiome-gut-brain axis. This review establishes the hypothesis that the mechanism by which this influence is carried out is synaptic plasticity - long-term changes to the physical and functional neuronal structures that enable the brain to undertake learning, memory formation, emotional regulation and more. By examining the different constituents of the microbiome-gut-brain axis through the lens of synaptic plasticity, this review explores the diverse aspects by which the microbiome shapes the behaviour and mental wellbeing of the host. Key elements of this complex bi-directional relationship include neurotransmitters, neuronal electrophysiology, immune mediators that engage with both the central and enteric nervous systems and signalling cascades that trigger long-term potentiation of synapses. The importance of establishing mechanistic correlations along the microbiome-gut-brain axis cannot be overstated as they hold the potential for furthering current understanding regarding the vast fields of neuroscience and neuropsychiatry. This review strives to elucidate the promising theory of microbiome-driven synaptic plasticity in the hope of enlightening current researchers and inspiring future ones.

Coronavirus disease 2019 (COVID-19) which is a respiratory system disease has created inevitable pandemic In the course of disease;the uncontrolled inflammatory response may cause tissue damage 80–90% of patients undergo mild-to-moderate disease symptoms, the rest of the patients proceeds to critical or severe disease Type I Interferons (IFN–I) are crucial immune mediators in order to host responses to viral infection likewise those are major components of the innate immune system moreover serve as critical antiviral molecules IFN-I are within the first cytokines secreted during a viral infection Until now, IFN-I response has been evaluated in patients with COVID-19 in a few publications and its contribution to the viral load control and inflammation is very little known In those studies, the researchers have found that IFN-I deficiency which characterized by no IFN- β and low IFN- α production and activity is a hallmark of severe and critical COVID-19 Until recently, measurement of circulating serum levels of IFN-α have been limited owing to the limits of conventional immunoassay technology Limit of detection problems of immunoassays has started to figure out thanks to SIMOA On the top of that, generally the platforms that use SIMOA technology is 10–100 fold more sensitive than most conventional immunoassays We should strive to do research that includes IFN-I with using platforms that include SIMOA technology, especially in severe COVID-19 (English) [ABSTRACT FROM AUTHOR] Oz: Bir solunum sistemi hastaligi olan Koronavirus hastaligi 2019 (COVID-19) onlenemez bir pandemi yaratti Hastalik seyrinde kontrolsuz inflamatuvar yanit doku hasarina neden olabilir Hastalarin% 80–90′i hafif-orta dereceli hastalik semptomlari gosterirken, geri kalan hastalar kritik veya siddetli hastalik gecirirler Tip I Interferonlar (IFN-I), viral enfeksiyonlara verilen cevapta cok onemli immun aracilardir Ayni sekilde bunlar, dogal immun sisteminin ana bilesenleridir, ayrica kritik antiviral molekuller olarak hizmet ederler IFN-I, viral enfeksiyon sirasinda salgilanan ilk sitokinler arasindadir Simdiye kadar, birkac yayinda COVID-19 hastalarinda IFN-I yaniti degerlendirildi ve bunun viral yuk kontrolu ve inflamasyona katkisi cok az bilinmektedir Bu calismalarda arastirmacilar dusuk IFN-α uretimi ve aktivitesi ile karakterize olan IFN-I eksikliginin siddetli ve kritik COVID-19′da ayirt edici ozelligi oldugunu bulmuslardir Yakin zamana kadar, IFN-a'nin dolasimdaki serum seviyelerinin olcumu, geleneksel immunoassay teknolojisinin sinirlari nedeniyle sinirliydi SIMOA sayesinde immunolojik testlerin tespit siniri problemleri cozulmeye basladi Ustelik SIMOA teknolojisini kullanan platformlar, geleneksel immunolojik testlerin cogundan 10–100 kat daha hassastir Ozellikle siddetli COVID-19′da SIMOA teknolojisini iceren platformlari kullanarak IFN-I iceren arastirmalar yapmaya calismaliyiz (Turkish) [ABSTRACT FROM AUTHOR] Copyright of Turkish Journal of Biochemistry / Turk Biyokimya Dergisi is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

Biologicals are a rapidly evolving group of drugs derived from biological agents which target specific immune mediators. The use of biologicals in dermatology is on the rise, especially for inflammatory and immunological conditions. As pregnancy and lactation are associated with exacerbation of various inflammatory conditions necessitating administration of biologicals in certain cases, their use in these physiologically altered states has to be evaluated. This article aims at reviewing the common biologicals used in dermatology and their feasibility in pregnancy and lactation. Tumor necrosis factor-alpha inhibitors are the most experienced group of biologicals in pregnancy and lactation, the newer biologicals have only animal studies and isolated case reports to back up their use. The commonly used biologicals are tabulated and discussed herewith. The guidelines and recommendations are derived from the data of use in other conditions such as inflammatory bowel disease and rheumatoid arthritis as there is no sufficient literature evidence for the use of biologicals in pregnancy for dermatological conditions. It was extrapolated that biologicals, being large molecular weight immunoglobulins or recombinant proteins, may be used with judicious care in the first two trimesters of pregnancy and after the 1stweek of lactation, if benefits to the mother outweigh the theoretical risk to the infant.

To determine the prevalence of Mycoplasmataceae species in pregnant women and evaluate their association with immune system mediators.Women were prospectively enrolled between 16-22 weeks' gestation. Vaginal swabs were self-collected and analyzed with PCR forOne-hundred-twenty women were enrolled and had complete lab data available. Colonization was 20.8, 2.5, 10.0, and 48.3% for MH, MG, UU, and UP, respectively. Women with any Mycoplasmataceae were more likely to be younger, of the Black race, and have public insurance. There were no significant differences in immune mediators between women with vaginal Mycoplasmataceae versus those without. After controlling for confounders, women with MH and/or MG had significantly elevated levels of IL-1β compared to women without MH or MG (estimate = 1.12; 95% CI = 0.33, 1.93). There were no other significant differences in immune mediators in women with MH and/or MG compared to those without.Colonization rates were highest for UP and lowest for MG. Higher IL-1β levels were seen in the presence of MH and/or MG, indicating that these less frequently encountered organisms may incite a stronger host response. There were no other significant differences in immune mediator levels.

Patients with autoimmune rheumatic diseases including rheumatoid arthritis and systemic lupus erythematosus have an increased prevalence of hypertension. There is now a large body of evidence showing that the immune system is a key mediator in both human primary hypertension and experimental models. Many of the proposed immunological mechanisms leading to primary hypertension are paralleled in autoimmune rheumatic disorders. Therefore, examining the link between autoimmunity and hypertension can be informative for understanding primary hypertension. This review examines the prevalent hypertension, the immune mediators that contribute to the prevalent hypertension and their impact on renal function and how the risk of hypertension is potentially influenced by common hormonal changes that are associated with autoimmune rheumatic diseases. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Background Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. Objectives Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. Methods We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. Results Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. Conclusions The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.

Aggregation and accumulation of amyloid-β (Aβ) is a defining feature of Alzheimer’s disease (AD) pathology. To study microglial responses to Aβ, we applied exogenous Aβ peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system level transcriptional changes and then compared these to transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change to in response to Aβ. Transcriptomic responses to oligomeric or fibrillar Aβ in primary microglia, though partially overlapping, are distinct and are not recapitulated in vivo where Aβ progressively accumulates. Furthermore, though classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar Aβ can be distinguished.

Primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) are characterized by neurological deficits caused by a permanent neuronal damage, clinically quantified by the expanded disability status scale (EDSS). Neuronal tissue damage is also mediated by immune infiltrates producing soluble factors, such as cytokines and chemokines, which are released in the cerebrospinal fluid (CSF). The mechanisms regulating the production of a soluble factor are not completely defined. Using multiplex bead-based assays, we simultaneously measured 27 immune soluble factors in the CSF collected from 38 patients, 26 with PP-MS and 12 with SP-MS. Then, we performed a correlation matrix of all soluble factors expressed in the CSF. The CSF from patients with PP-MS and SP-MS had similar levels of cytokines and chemokines; however, the stratification of patients according to active or inactive magnetic resonance imaging (MRI) unveils some differences. Correlative studies between soluble factors in the CSF of patients with PP-MS and SP-MS revealed two clusters of immune mediators with pro-inflammatory functions, namely IFN-γ, MCP-1, MIP-1α, MIP-1β, IL-8, IP-10, and TNF-α (group 1), and anti-inflammatory functions, namely IL-9, IL-15, VEGF, and IL-1ra (group 2). However, most of the significant correlations between cytokines of group 1 and of group 2 were lost in patients with more severe disability (EDSS ≥ 4) compared to patients with mild to moderate disability (EDSS < 4). These results suggest a common regulation of cytokines and chemokines belonging to the same group and indicate that, in patients with more severe disability, the production of those factors is less coordinated, possibly due to advanced neurodegenerative mechanisms that interfere with the immune response.

Tese de doutoramento em Ciências da Saúde, O envelhecimento é um processo complexo que envolve acumulação progressiva de danos celulares em diversos sistemas de órgãos, influenciando a sua função. Este processo decorre de forma variável, como se pode constatar pelo efeito da idade na detioração da função cognitiva de diferentes indivíduos. Compreender as diversas trajetórias de envelhecimento e as variáveis associadas torna-se crucial para se poder projetar estratégias que permitam melhorar a qualidade de vida ao longo do envelhecimento. Sabendo que o cérebro requer constante vigilância imunitária, e que o envelhecimento também está associado a alterações no sistema imunitário, propusemos dissecar a relação entre as alterações no sistema imunitário associadas à idade e a cognição. Para tal avaliámos, transversalmente, uma coorte de indivíduos seniores saudáveis e fizemos uma análise longitudinal em murganhos. Analisando os mesmos animas desde os 3 aos 18 meses de idade, caracterizámos a progressão da frequência relativa das principais células do sangue, tanto do sistema imunitário adaptativo como do inato. Verificámos que o envelhecimento é acompanhado por um aumento da frequência de células do sistema imunitário inato e diminuição das do adquirido, num efeito que é moderado pelo sexo. Também explorámos o papel das alterações do sistema imunitário associadas à idade na heterogeneidade cognitiva. Através de uma caracterização comportamental multi-paramétrica, dividimos os animais velhos em 2 grupos, referentes a bom e mau desempenho cognitivo. Observámos que machos com desempenhos cognitivos distintos apresentam diferenças moderadas na progressão de algumas células imunitárias ao longo do envelhecimento. Adicionalmente, observámos que a percentagem de células T CD4+ e CD8+ e as células NK Ly6C aos 18 meses também está associada ao desempenho cognitivo de murganhos, mesmo controlando para o sexo. Dada a ligação já conhecida entre os componentes solúveis do sangue e o envelhecimento cognitivo, quantificámos 30 moléculas relacionadas com o sistema imunitário em indivíduos seniores saudáveis. Não só confirmámos associações entre moléculas imunitárias periféricas e heterogeneidade cognitiva já previamente descritas, como a IL-6; como fortalecemos outras associações, como a IL-1b, IL-8, IP-10 (CXCL10) e o TNF; e revelámos novos mediadores, como a IL-13. Em suma, os presentes estudos enriquecem o conhecimento sobre as alterações do sistema imunitário periférico durante o envelhecimento e a sua associação com a cognição. Os resultados apresentados corroboram uma interação próxima entre o sistema imunitário e a cognição que merece uma investigação mais detalhada., Aging is a complex phenomenon that encompasses a progressive accumulation of cellular damage impacting in multiple systems and affecting individuals differently. For instance, the cognitive function, which commonly deteriorates with age, presents inter-individual variability. Understanding such diverse trajectories in aging, and the associated variables, is crucial to design strategies to overcome the natural effect of aging and improve quality of life. Knowing that throughout aging the brain requires constant immune surveillance to maintain its normal functioning and that aging is also associated with alterations in the immune system, we proposed to further dissect the relation between age-associated alterations in the immune system and cognition. For that purpose, we took advantage of a cohort of healthy senior individuals using a cross-sectional approach, and launch a longitudinal evaluation of mice. By following the same mice from 3 to 18 months of age we characterized the progression of the relative frequency of the main blood immune cells, both from adaptive and innate immune system. We observed that aging promotes an imbalance towards the innate immune system and that sex moderates the relation between the frequency of cells and age. We also explored the role of age associated alterations of the immune system as a potential contributor for cognitive heterogeneity. By performing a multiparametric behavioral characterization we segregated old mice as good and poor cognitive performers. We found that males with distinct cognitive performances at old age present moderate differences on specific immune cells progression over time. The percentage of CD4+ and CD8+ T cells among T cells and of NK Ly6C- cells, is also associated with mice cognitive performance, even controlling for sex at 18 months. Given the known link between the soluble components of the blood and cognitive aging, 30 immune-related molecules were quantified in healthy senior individuals. We not only confirmed already well described associations between peripheral immune molecules and cognitive heterogeneity, such as IL-6, but also strengthen others, like IL-1b, IL-8, IP-10 (CXCL10) and TNF, and revealed new players, such as IL-13. Altogether, the present studies enrich the knowledge on the peripheral immune system changes with aging and their association with cognition. These findings are supportive of a close interplay that deserve to be further investigated., Financial support was provided by grants from the European Commission (FP7) “SwitchBox—Maintaining health in old age through homeostasis” (Seventh Framework Programme; Contract HEALTH-F2-2010-259772); by Fundação Calouste Gulbenkian (Portugal) with the project “Better mental health during ageing based on temporal prediction of individual brain ageing trajectories” (TEMPO Contract P-139977); by Portuguese Foundation of Science and Technology - Doctoral Fellowship to C. Serre-Miranda (SFRH/BD/112494/2015); by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020, UIDP/50026/2020 and POCI-01-0145-FEDER-016428; and by the projects NORTE-01-0145- FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).

Background Predictive markers represent a solution for the proactive management of severe dengue. Despite the low mortality rate resulting from severe cases, dengue requires constant examination and round-the-clock nursing care due to the unpredictable progression of complications, posing a burden on clinical triage and material resources. Accordingly, identifying markers that allow for predicting disease prognosis from the initial diagnosis is needed. Given the improved pathogenesis understanding, myriad candidates have been proposed to be associated with severe dengue progression. Thus, we aim to review the relationship between the available biomarkers and severe dengue. Methodology We performed a systematic review and meta-analysis to compare the differences in host data collected within 72 hours of fever onset amongst the different disease severity levels. We searched nine bibliographic databases without restrictive criteria of language and publication date. We assessed risk of bias and graded robustness of evidence using NHLBI quality assessments and GRADE, respectively. This study protocol is registered in PROSPERO (CRD42018104495). Principal findings Of 4000 records found, 40 studies for qualitative synthesis, 19 for meta-analysis. We identified 108 host and viral markers collected within 72 hours of fever onset from 6160 laboratory-confirmed dengue cases, including hematopoietic parameters, biochemical substances, clinical symptoms, immune mediators, viral particles, and host genes. Overall, inconsistent case classifications explained substantial heterogeneity, and meta-analyses lacked statistical power. Still, moderate-certainty evidence indicated significantly lower platelet counts (SMD -0.65, 95% CI -0.97 to -0.32) and higher AST levels (SMD 0.87, 95% CI 0.36 to 1.38) in severe cases when compared to non-severe dengue during this time window. Conclusion The findings suggest that alterations of platelet count and AST level—in the first 72 hours of fever onset—are independent markers predicting the development of severe dengue., Author summary The major concern in dengue fever is the abrupt occurrence of severe complications, for which only close monitoring of patients is the treatment scheme. Thus, the markers managing to predict the subsequent progression of complications—in the early stage of disease course—could alleviate the clinical management burden. Ideally, the predictors foretell the outcomes before the severe complications occur—usually on days 4–7 following fever onset. In this study, therefore, we reviewed the available markers collected during the first 3 days of fever onset. We found robust evidence of significantly lower platelet counts and higher AST levels in those who subsequently developed severe dengue than those who did not. In this regard, platelet count could serve as an independent warning sign rather than combining with hematocrit—as seen in the current classification—which remains unaltered during this time window. Also, abdominal pain and vomiting could predict the outcomes, but using these signs is arduous when their manifestations vary as per the patient without cutoffs. Hepatomegaly rate is substantially higher in severe dengue, but likely yields a high false-negative prediction rate. There is a need for larger studies to confirm the relatedness of hyaluronan in severe dengue.

The ‘era of corticosteroids’ brought about a revolutionary change in the course of asthma treatment in the mid-twentieth century. A few decades later, a lack of response to corticosteroids was recognised in some asthma patients, thereby revealing a distinct endotype of the disease called ‘steroid-resistant asthma’. This finding set in motion a plethora of research to elucidate its inducers and unravel the underlying mechanisms driving this variant. Surprisingly, apart from possible genetic factors and infection, lifestyle-related conditions like stress and obesity were found to invoke this disease. Alteration in the pathways mediating anti-inflammatory effect of glucocorticoids, defective autophagy, certain immune mediators and micro RNAs has been found to slacken the steroid response in asthma. This chapter focuses on the fundamental cell types and key mechanistic pathways involved in steroid-resistant asthma and also discusses the treatment strategies that have been adopted to combat the disease in the recent past.

The prevalence of allergic diseases has in the past century increased among children in affluent societies. Underlying causes are incompletely disentangled, but decreased diversity in environmental ...

Mast cells (MCs) play an essential role in host defense, primarily because of their location, their ability to pathogen destruction via several mechanisms, and the pattern recognition receptors they express. Even though most data is available regarding MC activation by various bacteria- or virus-derived molecules, those cells’ activity in response to constituents associated with fungi is not recognized enough. Our research aimed to address whether Saccharomyces cerevisiae-derived zymosan, i.e., β-(1,3)-glucan containing mannan particles, impacts MC activity aspects. Overall, the obtained results indicate that zymosan has the potential to elicit a pro-inflammatory response of rat peritoneal MCs. For the first time ever, we provided evidence that zymosan induces fully mature MC migration, even in the absence of extracellular matrix (ECM) proteins. Moreover, the zymosan-induced migratory response of MCs is almost entirely a result of directional migration, i.e., chemotaxis. We found that zymosan stimulates MCs to degranulate and generate lipid mediators (cysLTs), cytokines (IFN-α, IFN-β, IFN-γ, GM-CSF, TNF), and chemokine (CCL2). Zymosan also upregulated mRNA transcripts for several cytokines/chemokines with pro-inflammatory/immunoregulatory activity. Moreover, we documented that zymosan activates MCs to produce reactive oxygen species (ROS). Lastly, we established that the zymosan-induced MC response is mediated through activation of the Dectin-1 receptor. In general, our results strongly support the notion that MCs contribute to innate antifungal immunity and bring us closer to elucidate their role in host-pathogenic fungi interactions. Besides, provided findings on IgE-sensitized MCs appear to indicate that exposure to fungal zymosan could affect the severity of IgE-dependent disorders, including allergic ones.

The new coronavirus (COVID‐19) was first reported in Wuhan in China, on 31 December 2019. COVID‐19 is a new virus from the family of coronaviruses that can cause symptoms ranging from a simple cold to pneumonia. The virus is thought to bind to the angiotensin‐converting enzyme 2, as a well‐known mechanism to enter the cell. It then transfers its DNA to the host in which the virus replicates the DNA. The viral infection leads to severe lack of oxygen, lung oxidative stress because of reactive oxygen species generation, and overactivation of the immune system by activating immune mediators. The purpose of this review is to elaborate on the more precise mechanism(s) to manage the treatment of the disease. Regarding the mechanisms of the virus action, the suggested pharmacological and nutritional regimens have been described.

Introductory ParagraphThe COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding half a million patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity.1 Clear mechanistic understanding of how these comorbidities converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts the lipidome and this disruption may be a unifying feature of severe COVID-19.1-7 Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.8

Item does not contain fulltext Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis.

Chemical allergy can manifest into allergic contact dermatitis and asthma and the importance of skin sensitization in both of these diseases is increasingly being recognized. Given the unique characteristics of chemical allergy, coupled with the distinct immunological microenvironment of the skin research is still unraveling the mechanisms through which sensitization and elicitation occur. This review first describes the features of chemical sensitization and the known steps that must occur to develop a chemical allergy. Next, the unique immunological properties of the skin - which may influence chemical sensitization - are highlighted. Additionally, mediators involved with the development of allergy are reviewed, starting with early ones - including the properties of haptens, skin integrity, the microbiome, the inflammasome, and toll-like receptors (TLR). Novel cellular mediators of chemical sensitization are highlighted, including innate lymphoid cells, mast cells, T-helper (TH) cell subsets, and skin intrinsic populations including γδ T-cells and resident memory T-cells. Finally, this review discusses two epigenetic mechanisms that can influence chemical sensitization, microRNAs and DNA methylation. Overall, this review highlights recent research investigating novel mediators of chemical allergy that are present in the skin. It also emphasizes the need to further explore these mediators to gain a better understanding of what makes a chemical an allergen, and how best to prevent the development of chemical-induced allergic diseases.

Microorganisms establish a symbiotic relationship at all stages of growth in man, beginning from birth to adulthood. They are found in every part of the body, and they participate in the immune system against pathogen-mediated immune responses. Their actions are elicited by secreting microorganism associated-molecular proteins (MAMPs) which they use as signalling molecules to activate a cascade of immunological responses within the host cell. They maintain the barrier function of the intestinal wall as well as prevent colonisation of the intestine by pathogens. Using their MAMPs, they bind to specific pattern recognition receptors (PRR) activating immune mediators in response to pro-inflammation by pathogens. These immune mediators are either induced or suppressed (in the case of overproduced immune response). Some of these symbionts elicit their action by anaerobic fermentation of dietary fibres into byproducts of short-chain fatty acids (SCFAs). These bacterial metabolites functions by binding to G-protein coupled reactions (GPCRs) on colonic macrophages and Dendritic cells (DCs) and contributed to the increased production of interleukin 10 (IL 10) in response to pathogen-mediated immune response. These unique immunological actions of intestinal microbiota, have shown that microorganisms are beneficial to the host as against the widespread belief that they are disease-causing agents.

Although allergies exert a devastating global impact and often lack effective treatment strategies, our knowledge on the mechanisms that initiate and propagate type-2 immune responses remain enigmatic. Recent advances have highlighted additional roles for epithelial cells (e.g. tuft cells) and sensory neurons as initiators and amplifiers of type-2 immune responses. In response to protease activity of allergens, Toll-like receptor stimulation or cellular damage, these type-2 sentinels can release cytokines, alarmins or neuropeptides capable of (i) activating and expanding innate immune cells, (ii) polarizing T helper type-2 cells and (iii) promoting allergic inflammation. Overexpression of these type-2 immune mediators has been associated with allergic disorders and together with their disease promoting role in experimental model systems have paved the way for the generation of new biologics. The aim of this review is to provide a concise view on recent developments in the field and to discuss these findings in the context of allergic inflammation.

Purpose: The purpose of this article is to analyze possible associations between systemic and ocular cytokine levels and specific clinical ophthalmologic signs from patients with a reactiva...

Background Immune system abnormalities have been repeatedly observed in several psychiatric disorders, including severe depression and anxiety. However, whether specific immune mediators play an early role in the etiopathogenesis of these disorders remains unknown. Methods In a longitudinal design, component-wise gradient boosting was used to build models of depression, assessed by the Mood-Feelings Questionnaire-Child (MFQC), and anxiety, assessed by the Screen for Child Anxiety Related Emotional Disorders (SCARED) in 254 adolescents from a large set of candidate predictors, including sex, race, 39 inflammatory proteins, and the interactions between those proteins and time. Each model was reduced via backward elimination to maximize parsimony and generalizability. Results Component-wise gradient boosting and model reduction found that female sex, growth- regulated oncogene (GRO), and transforming growth factor alpha (TGF-alpha) predicted depression, while female sex predicted anxiety. Limitations Differential onset of puberty as well as a lack of control for menstrual cycle may also have been responsible for differences between males and females in the present study. In addition, investigation of all possible nonlinear relationships between the predictors and the outcomes was beyond the computational capacity and scope of the present research. Conclusions This study highlights the need for novel statistical modeling to identify reliable biological predictors of aberrant psychological behavior.

Background The field of new biological agents is increasing exponentially over the past years, thus making prevention and management of associated infectious complications a challenge for nonspecialized clinicians. Aims The present consensus document is an initiative of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) aimed at analysing, from an infectious diseases perspective, the safety of targeted and biological therapies. Sources Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. Content The document is structured in sections according to the targeted site of action of each drug class: proinflammatory cytokines; interleukins, immunoglobulins and other soluble immune mediators; cell surface receptors and associated signaling pathways; intracellular signaling pathways; lymphoma and leukaemia cells surface antigens; and other targeted therapies. A common outline is followed for each agent: summary of mechanism of action, approved indications and common off-label uses; expected impact on the host's susceptibility to infection; available clinical evidence (i.e. pivotal clinical trials, postmarketing studies, case series and case reports); and suggested prevention and risk minimization strategies. The methodologic and practical difficulties of assessing the specific risk posed by a given agent are also discussed. Implications This ESGICH consensus document constitutes not only a comprehensive overview of the molecular rationale and clinical experience on the risk of infection associated with approved targeted therapies but also an attempt to propose a series of recommendations with the purpose of guiding physicians from different disciplines into this emerging framework.

In the recent years, many studies have shown that MSCs must be stimulated by pro-inflammatory cytokines or other immune mediators before they can modulate immune cells in inflamed and damaged tissues. MSCs appear to be involved in inducing several regulatory immune cells, such as Tregs, Bregs, and regulatory NK cells. This new immune milieu created by MSCs may establish a tolerogenic environment that leads to an optimal condition for the treatment of immune diseases. The mechanisms of MSC action to treat immune disorders need to be further investigated in more detail. Since there have been some contradictory outcomes of clinical trials, it is necessary to perform large-scale and randomized clinical studies, such as a phase 3 placebo-controlled double-blind study of a third party MSCs to optimize MSC administration and to prove safety and efficacy of MSC treatment. MSCs offer great therapeutic promise, especially for the treatment of difficult-to-treat immune diseases.

Ongoing research has strongly suggested the role the immune system plays in the pathogenesis of neuropathic pain. T cells appear to be one of the main regulators of the immune system with many mediators appearing to promote or suppress pain resolution. Limited effective therapies are available for treatment of neuropathic pain. Treatments available appear to modulate specific T cell with altered ratios present 3 months post treatment and parallels clinical improvement. This further supports the neuro-immune basis for neuropathic pain chronicity. Identification of novel immune mediators involved in pain development may suggest new target areas in treatment., Highlights • Neuroimmunity plays a significant role in neuropathic pain pathogenesis neuropathic pain. • Immune mediators contribute to promotion, suppression or resolution of neuropathic pain. • Clinical studies in humans are lacking, most research available is pre-clinical or animal-based. • Evidence-based therapies for treatment of neuropathic pain demonstrate alteration in T cell phenotype and behavior post therapy.

Incipiently named extracellular vesicles, exosomes are forming now a separate class of cellular mediators with important functions in physiological and pathological states. Their ability to transfer information between cells through encapsulation of proteins, nucleic acids and lipids for the preservation of the homeostatic equilibrium is translated also in pathological conditions. The recipient cells react to the reception of foreign molecules adjusting their molecular state according to the enclosed message. Cancer cells, in order to influence the microenvironment and facilitate the malignant expanding, exploit this intercellular trafficking. Immune cells are also producing exosomes that ensure the transportation of immune mediators and signaling molecules between cells. Current experimental attempts are concentrated on the adjustment of exosomes level for therapeutic purposes, enrolment of these vesicles as diagnosis or prognosis tools and also exosomes' use as drug delivery vehicles or immune stimulatory agents.

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of this review is to summarize the main factors involved in the pathogenesis of vitiligo, the latest findings regarding the cytokines involved and to evaluate the treatments based on the use of biological drugs in order to stop disease progression and achieve repigmentation. According to the results, the most recurrent studies dealt with inhibitors of IFN-gamma and TNF-alpha. It is possible that, given the great deal of cytokines involved in the lesion formation process of vitiligo, other biologics could be developed in the future to be used as adjuvants and/or to entirely replace the treatments that have proven to be unsatisfactory so far.

The discovery of biomarkers for periodontal disease requires an in-depth understanding of the molecular basis of the initiation and progression of the disease. The gingival crevicular fluid is a biological medium suitable for identifying and measuring such biomarkers because it can be easily and noninvasively sampled from the immediate vicinity of the affected tissues. An ever-expanding pool of gingival crevicular fluid proteins associated with periodontal health or disease has been catalogued over the years, particularly with the recent implementation of proteomic technologies. 'Proteomics' refers to the large-scale study of entire arrays of proteins expressed by a genome and present in a cell, tissue, biological fluid or organism. Hence, such technologies provide a broad qualitative and quantitative insight of the proteins present in gingival crevicular fluid. Pertinent studies have amassed on the information gathered to date on protein signatures in periodontal health and disease, and have confirmed the nature of the immunological host response. This review discusses the application of proteomic technologies in characterizing the molecular networks present in gingival crevicular fluid, their potential for discovery of biomarkers that are meaningful for clinical practice, and the associated technical challenges.

Cellular senescence has recently become causally implicated in pathological ageing. Hence, a great deal of research is currently dedicated towards developing senolytic agents to selectively kill senescent cells. However, senescence also plays important roles in a range of physiological processes including during organismal development, providing a barrier to tumorigenesis and in limiting fibrosis. Recent evidence also suggests a role for senescence in coordinating tissue remodelling and in the regeneration of complex structures. Through its non-cell-autonomous effects, a transient induction of senescence may create a permissive environment for remodelling or regeneration through promoting local proliferation, cell plasticity, tissue patterning, balancing growth, or indirectly through finely tuned interactions with infiltrating immune mediators. A careful analysis of the beneficial roles of cellular senescence may provide insights into important physiological processes as well as informing strategies to counteract its detrimental consequences in ageing and disease.

Purinergic receptors are inflammatory mediators activated by extracellular nucleotides released by dying or injured cells. Several studies have described an important role for these receptors in HIV-1 entry, particularly regarding their activity on HIV-1 viral membrane fusion. Several reports identify purinergic receptor antagonists that inhibit HIV-1 membrane fusion; these drugs are suspected to act through antagonizing Env-chemokine receptor interactions. They also appear to abrogate activity of downstream mediators that potentiate activation of the NLRP3 inflammasome pathway. Here we review the literature on purinergic receptors, the drugs that inhibit their function, and the evidence implicating these receptors in HIV-1 entry.

OBJECTIVES: Depot medroxyprogesterone acetate (Depo-Provera) is the most commonly used injectable hormone contraceptive in Sub-Sahara Africa where HIV incidence is high. We determined the impact of Depo-Provera on cervical immune cells and mediators in healthy women. METHODS: In this longitudinal study, vaginal, endocervical, and rectal swabs were collected at baseline (visit 1), one month (visit 2), and three months (visit 3) after Depo-Provera injection. Cervical cells were collected by cytobrush and immune markers on cervical CD4(+) T cells were analyzed by multicolor flow cytometry at 3 different visits. The levels of immune mediators in cytobrush supernatants as well as vaginal, cervical, and rectal secretions from swabs were analyzed by multiplex assays and ELISA. RESULTS: Compared to baseline levels we found a significant increase in the frequency of cervical CCR5(+)CD4(+) T cells and a significant decrease in the frequency of cervical central memory CD4(+) T cells. Depo-Provera treatment had little effect on expression of immune mediators in rectal mucosa but significantly suppressed numerous immune mediators at cervicovaginal mucosa. Levels of MCP-1, G-CSF, IL-6, IL-10, GM-CSF, and IP-10 were significantly decreased in both vaginal and cervical secretions after Depo-Provera injection. In cervical samples collected by cytobrush, we found reduced levels of 22 of 25 immune mediators after Depo-Provera injection. Changes in immune mediators differed between vaginal and cervical mucosa, demonstrating compartment-specific responses. CONCLUSION: Depo-Provera altered immune profiles of cervical CD4(+) T cells and suppressed host immune response at cervicovaginal mucosa, suggesting its likely effect on transmission of sexually transmitted infections including HIV.