Hasil untuk "Immunologic diseases. Allergy"

J. Marshall, R. Warrington, W. Watson et al.

Beyond structural and chemical barriers to pathogens, the immune system has two fundamental lines of defense: innate immunity and adaptive immunity. Innate immunity is the first immunological mechanism for fighting against an intruding pathogen. It is a rapid immune response, initiated within minutes or hours after aggression, that has no immunologic memory. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can provoke illness or disease, such as inappropriate inflammation, autoimmune diseases, immunodeficiency disorders and hypersensitivity reactions. This article provides a practical overview of innate and adaptive immunity, and describes how these host defense mechanisms are involved in both heath and illness.

Sanchita Bhattacharya, Sandra Andorf, Linda Gomes et al.

D. A. Hill, J. Spergel

M. Mcaleer, A. Irvine

Filaggrin is a major structural protein in the stratum corneum of the epidermis. Mutations in the filaggrin gene are the most significant known genetic risk factor for the development of atopic dermatitis. Mutations in the human filaggrin gene (FLG) also confer risk for the associated allergic diseases of food allergy, asthma, and allergic rhinitis. These discoveries have highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. In this review we discuss the mechanisms through which mutations in this protein contribute to the pathogenesis of atopic dermatitis and associated atopic conditions. We focus on recent human and murine discoveries characterizing the filaggrin-deficient epidermis with respect to biophysical, immunologic, and microbiome abnormalities.

Margaret A. Liu

Qingchao Wang, Dahai Yang, Linlin Zhang et al.

Rahul Tiwari, Awnish Kumar, Vishal Kumar Singh et al.

Understanding the development and maintenance of immunological memory is important for efforts to eliminate parasitic diseases like leishmaniasis. Leishmaniasis encompasses a range of pathologies, resulting from infection with protozoan parasites belonging to the subgenera Leishmania and Viannia of the genus Leishmania. A striking feature of these infections is that natural or drug-mediated cure of infection generally confers life-long protection against disease. The generation of protective T cell responses are necessary to control Leishmania infections. CD4+ T helper (Th) cells orchestrate immune responses in leishmaniasis and IFNγ+ Tbet+ CD4+ T (Th1) cells are required for the activation of phagocytes to kill captured or resident parasites, while other Th cell subset, including FoxP3+ natural regulatory T cells and Th2 cells can promote disease progression by suppressing the activities of Th1 cells. Upon resolution of a primary Leishmania infection, different subsets of CD4+ T cells, including tissue-resident memory T cells, effector memory T cells, central memory T cells, and short-lived effector T cells, help to confer resistance against reinfection. To maintain long-term protective Leishmania-specific CD4+ T cells responses, it is believed that persistent parasites or re-exposure to parasites at regular intervals is required (concomitant immunity). Despite the advances in our understanding about the immune responses during leishmaniasis, the generation of long-lasting protective immunity via vaccination has yet to be achieved. In this review, we summarize our current understanding about the formation and maintenance of immunological memory and control of leishmaniasis at the individual and population level. We will focus on Indian visceral leishmaniasis and discuss T cell responses that contribute to susceptibility to leishmaniasis, parasite persistence in populations and the environment, as well as describing advances in the development of leishmaniasis vaccines aimed at inducing protective CD4+ T cell responses.

R. Geha, L. Notarangelo, J. Casanova et al.

H. Wopereis, R. Oozeer, K. Knipping et al.

The development of the intestinal microbiota in the first years of life is a dynamic process significantly influenced by early‐life nutrition. Pioneer bacteria colonizing the infant intestinal tract and the gradual diversification to a stable climax ecosystem plays a crucial role in establishing host–microbe interactions essential for optimal symbiosis. This colonization process and establishment of symbiosis may profoundly influence health throughout life. Recent developments in microbiologic cultivation‐independent methods allow a detailed view of the key players and factors involved in this process and may further elucidate their roles in a healthy gut and immune maturation. Aberrant patterns may lead to identifying key microbial signatures involved in developing immunologic diseases into adulthood, such as asthma and atopic diseases. The central role of early‐life nutrition in the developmental human microbiota, immunity, and metabolism offers promising strategies for prevention and treatment of such diseases. This review provides an overview of the development of the intestinal microbiota, its bidirectional relationship with the immune system, and its role in impacting health and disease, with emphasis on allergy, in early life.

Muneto Izuhara, Muneto Izuhara, Kentaro Matsui et al.

IntroductionSleep enhances the antibody response to vaccination, but the relationship between sleep and mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not fully understood.MethodsIn this prospective observational study, we investigated the influence of sleep habits on immune acquisition induced by mRNA vaccines against SARS-CoV-2 in 48 healthy adults (BNT-162b2, n=34; mRNA-1273, n=14; female, n=30, 62.5%; male, n=18, 37.5%; median age, 39.5 years; interquartile range, 33.0–44.0 years) from June 2021 to January 2022. The study measured sleep duration using actigraphy and sleep diaries, which covered the periods of the initial and booster vaccinations.ResultsMultivariable linear regression analysis showed that actigraphy-measured objective sleep duration 3 and 7 days after the booster vaccination was independently and significantly correlated with higher antibody titers (B=0.003; 95% confidence interval, 0.000–0.005; Beta=0.337; p=0.02), even after controlling for covariates, including age, sex, the type of vaccine, and reactogenicity to the vaccination. Associations between acquired antibody titer and average objective sleep duration before vaccination, and any period of subjective sleep duration measured by sleep diary were negligible.DiscussionLonger objective, but not subjective, sleep duration after booster vaccination enhances antibody response. Hence, encouraging citizens to sleep longer after mRNA vaccination, especially after a booster dose, may increase protection against SARS-CoV-2.Study registrationThis study is registered at the University Hospital Medical Information Network Center (UMIN: https://www.umin.ac.jp) on July 30, 2021, #UMIN000045009.

Afsar U. Ahmed, Saleh Almasabi, Ron Firestein et al.

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and treatment options for advanced CRC, which has a low 5-year survival rate, remain limited. Integrin-linked kinase (ILK), a multifunctional, scaffolding, pseudo-kinase regulating many integrin-mediated cellular processes, is highly expressed in many cancers. However, the role of ILK in cancer progression is yet to be fully understood. We have previously uncovered a pro-inflammatory role for myeloid-specific ILK in dextran sodium sulfate (DSS)-induced colitis. To establish a correlation between chronic intestinal inflammation and colorectal cancer (CRC), we investigated the role of myeloid-ILK in mouse models of CRC. When myeloid-ILK deficient mice along with the WT control mice were subjected to colitis-associated and APCmin/+-driven CRC, tumour burden was reduced by myeloid-ILK deficiency in both models. The tumour-promoting phenotype of macrophages, M2 polarization, in vitro was impaired by the ILK deficiency and the number of M2-specific marker CD206-expressing tumour-associated macrophages (TAMs) in vivo were significantly diminished in myeloid-ILK deficient mice. Myeloid-ILK deficient mice showed enhanced tumour infiltration of CD8+ T cells and reduced tumour infiltration of FOXP3+ T cells in colitis-associated and APCmin/+-driven CRC, respectively, with an overall elevated CD8+/FOXP3+ ratio suggesting an anti-tumour immune phenotypes. In patient CRC tissue microarrays we observed elevated ILK+ myeloid (ILK+ CD11b+) cells in tumour sections compared to adjacent normal tissues, suggesting a conserved role for myeloid-ILK in CRC development in both human and animal models. This study identifies myeloid-specific ILK expression as novel driver of CRC, which could be targeted as a potential therapeutic option for advanced disease.

M. A. Shevchenko, D. G. Garbuz, A. I. Davletshin et al.

Heat shock proteins 70 kDa (HSP70) protect intracellular proteins from the damaging effects of stress factors of various natures. Moreover, HSP70 play an important role in the vital activity of cells under normal physiological conditions, performing chaperone functions. These functions are realized in the intracellular space; however, in some cases, these proteins are also found on the cell surface and in the extracellular environment. The causes and mechanisms of HSP70 translocation to the cell surface and secretion into the extracellular space have not yet been well understood, but such an unusual localization of HSP70 activates the immune system. The surface HSP70 and their extracellular pool stimulate the cytotoxic activity of NK cells. However, direct experimental evidence for the internalization of HSP70 molecules by NK cells has not yet been demonstrated. This paper presents the results of the interaction of the extracellular HSP70 pool with NK cells from the peripheral blood. The results demonstrated the confirmation of the internalization of exogenous HSP70 molecules by NK cells. To this end, fluorescently labeled recombinant stress-inducible human HSP70 were obtained. The electrophoretic data indicated the absence of protein degradation during the labeling process, the purity and stability of the modified protein. To assess the interaction of HSP70 with NK cells, the fluorescently labeled HSP70 was added to an in vitro culture of NK cells isolated by magnetic separation from the peripheral blood mononuclear fraction and analyzed by confocal microscopy. This analysis indicated that living NK cells internalize extracellular HSP70 with localization both in lysosomes and in phagosomes. Our experiments illustrated for the first time the process of penetration of the extracellular form of HSP70 into these cells. The results suggest that the activation of NK cells under the action of exogenous HSP70 could be associated with the internalization of these protein molecules.

Ying Dong, Ying Dong, Ying Dong et al.

BackgroundAnoikis is a programmed cell death process that was proven to be associated with cancer. Uroepithelial carcinoma of the bladder (BLCA) is a malignant disease of the urinary tract and has a strong metastatic potential. To determine whether anoikis-associated genes can predict the prognosis of BLCA accurately, we evaluated the prognostic value of anoikis-associated genes in BLCA and constructed the best model to predict prognosis.MethodThe BLCA transcriptome data were downloaded from TCGA and GEO databases, and genes with differential expression were selected and then clustered using non-negative matrix factorization (NMF). The genes with the most correlation with anoikis were screened and identified using univariate Cox regression, lasso regression, and multivariate Cox regression. The GEO dataset was used for external validation. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with receiver operating characteristic (ROC) curves. The immunotherapeutic significance of this risk score was assessed using the immune phenomenon score (IPS). IC50 values of predictive chemotherapeutic agents were calculated. Finally, we used RT-qPCR to determine the mRNA expression of four genes, CALR, FASN, CASP6, and RAD9A.ResultWe screened 406 tumor samples and 19 normal tissue samples from the TCGA database. Based on anoikis-associated genes, we classified patients into two subtypes (C1 and C2) using NMF method. Subsequently, nine core genes were screened by multiple methods after analysis, which were used to construct risk profiles. The design of nomograms based on risk profiles and clinical variables, ROC, and calibration curves confirmed that the model could well have the ability to predict the survival of BLCA patients at 1, 3, and 5 years. By predicting the IC50 values of chemotherapeutic drugs, it was learned that the high-risk group (HRG) was more susceptible to paclitaxel, gemcitabine, and cisplatin, and the low-risk group (LRG) was more susceptible to veriparib and afatinib.ConclusionIn summary, the risk score of anoikis-associated genes can be applied as a predictor to predict the prognosis of BLCA in clinical practice.

Clemence J. Belle, James M. Lonie, Sandra Brosda et al.

The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemoradiotherapy treatment could lead to higher immune infiltrations and higher expression of immune checkpoints, such as PD-1/PDL-1, CTLA4 or emerging new targets: LAG-3, TIM-3, TIGIT or ICOS. Multiple trials support the addition of immune checkpoint inhibitors to the current standard of care. However, results vary, supporting the need for better response biomarkers based on TME composition. This review explores what is known about OAC TME, the clinical significance of the various cell populations infiltrating it and the emerging therapeutical combination with a focus on immune checkpoints inhibitors.

Dalia D. Hadi, Mohammed Dheyaa Marsool Marsool, Ali Dheyaa Marsool Marsool et al.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms. Aims We aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF. Materials and Methods We conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science. Results The two Food and Drug Administration‐approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials. Conclusions The advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.

Jing Yang, Pengfei Li, Pengfei Li et al.

ObjectiveExtranodal natural killer/T cell lymphoma (NKTCL) is an aggressive EBV-related lymphoma, originating from NK cells or T cells. Previous study demonstrated that CD56 negative NKTCL should be recognized as a distinct subtype. In this study, the value of CD56 in NKTCL is validated in the era of asparaginase, and genomic analysis was done to dissect the differences between CD56-negative and positive NKTCL.Methods443 patients with newly diagnosed NKTCL were enrolled in this retrospective study, and correlation between CD56 positivity and survival outcomes was analyzed. The gene sequencing data was downloaded (http://www.biosino.org/node/project/detail/OEP000498), and bioinformatics analysis was done to delineate the tumor microenvironment and differentially expressed genes.ResultsCD56 was expressed in 337 patients (76.1%). Within a median follow-up time of 51 months, the 5-year overall survival (OS) and progression free survival (PFS) rates were 63.8% and 51.9%, respectively. For the whole cohort, patients who were CD56-positive had superior OS (5-year OS, 86.2% vs. 51.9%, p=0.019) and PFS (5-year PFS, 55.9% vs. 40.1%, p=0.016). For patients in early stage disease, CD56 positivity was associated with superior OS and PFS (p=0.008 and 0.005, respectively). In patients who received non-asparaginase-based chemotherapy, CD56-negative was associated with shorter OS and PFS (p<0.001), and in patients who received asparaginase-based chemotherapy, CD56-negative was not related to inferior OS and PFS (p=0.093 and p=0.829, respectively). The genomic analysis demonstrated that CD56 positive NKTCL probably originated from NK cells and CD56 negative NKTCL originated from T cells. CD56 positive NKTCL had significantly higher proportion of resting NK cells, activated NK cells, and activated CD8+ and CD4+ T cells in the tumor microenvironment.ConclusionsCD56 negative NKTCL differs from CD56 positive NKTCL in both the tumor microenvironment and survival outcomes, and asparaginase-based treatment may overcome the poor prognosis brought by CD56 negativity.

Jinhua Chen, Zhenhua Yin, Wenping Song et al.

Accumulating evidence has showed that sushi-repeat-containing protein X-linked 2 (SRPX2) is an abnormal expression in a variety of cancers and involved in cancer carcinogenesis, chemosensitivity, and prognosis, which mainly promote cancer cell metastasis, invasion, and migration by regulating the uPAR/integrins/FAK signaling pathway, epithelial-mesenchymal transition (EMT), angiogenesis, and glycosylation. Inflammation has been regarded as a key role in regulating cancer initiation, progression, EMT, and therapeutics. Furthermore, SRPX2 exhibited excellent antifibrosis effect via the TGFβR1/SMAD3/SRPX2/AP1/SMAD7 signaling pathway. Therefore, this review provides compelling evidence that SRPX2 might be a therapeutic target for inflammation and cancer-related inflammation for future cancer therapeutics.

Katherine A Rhodes, Man Cheong Ma, María A Rendón et al.

The mechanisms used by human adapted commensal Neisseria to shape and maintain a niche in their host are poorly defined. These organisms are common members of the mucosal microbiota and share many putative host interaction factors with Neisseria meningitidis and Neisseria gonorrhoeae. Evaluating the role of these shared factors during host carriage may provide insight into bacterial mechanisms driving both commensalism and asymptomatic infection across the genus. We identified host interaction factors required for niche development and maintenance through in vivo screening of a transposon mutant library of Neisseria musculi, a commensal of wild-caught mice which persistently and asymptomatically colonizes the oral cavity and gut of CAST/EiJ and A/J mice. Approximately 500 candidate genes involved in long-term host interaction were identified. These included homologs of putative N. meningitidis and N. gonorrhoeae virulence factors which have been shown to modulate host interactions in vitro. Importantly, many candidate genes have no assigned function, illustrating how much remains to be learned about Neisseria persistence. Many genes of unknown function are conserved in human adapted Neisseria species; they are likely to provide a gateway for understanding the mechanisms allowing pathogenic and commensal Neisseria to establish and maintain a niche in their natural hosts. Validation of a subset of candidate genes confirmed a role for a polysaccharide capsule in N. musculi persistence but not colonization. Our findings highlight the potential utility of the Neisseria musculi-mouse model as a tool for studying the pathogenic Neisseria; our work represents a first step towards the identification of novel host interaction factors conserved across the genus.

Joy Onyinyechi Chionuma, Helen Onyeaka, Osmond C. Ekwebelem et al.

During pregnancy, women are at an increased risk of getting sick from respiratory viruses and when compared to non-pregnant women, pregnant women are more susceptible to severe illness from COVID-19. Owing to this fact and the emergence of a more infectious COVID-19 variants, pregnant women are currently classified as a vulnerable population, along with pediatric patients and older adults. While scientists are still learning more about the new variants, it is becoming clear that COVID-19 infected pregnant women are also at a real increased risk of poor pregnancy outcomes, as premature birth and babies born with lifelong health issues are possible if people become infected during pregnancy. Added to these facts, recommendation for COVID-19 has largely varied globally. The conspiracy-laden information on social media has led to pregnant women being hesitant about getting COVID-19 vaccine. Furthermore, as the transmissibility of COVID-19 is higher with this variant and the health system for maternal care in many countries regarded as “very bad” there is need to clearly highlight the impacts of the variants and for countries to speed up vaccination programme to reach all members of society.

Lisa Göschl, Daniel Mrak, Katharina Grabmeier-Pfistershammer et al.

BackgroundPatients with inborn errors of immunity (IEI) are at increased risk for severe courses of SARS-CoV-2 infection. COVID-19 vaccination provides effective protection in healthy individuals. However, it remains unclear whether vaccination is efficient and safe in patients with constitutional dysfunctions of the immune system. Thus, we analyzed the humoral response, adverse reactions and assessed the disease activity of the underlying disease after COVID-19 vaccination in a cohort of patients suffering from IEIs or mannan-binding lectin deficiency (MBLdef).MethodsVaccination response was assessed after basic immunization using the Elecsys anti-SARS-CoV-2 S immunoassay and via Vero E6 cell based assay to detect neutralization capabilities. Phenotyping of lymphocytes was performed by flow cytometry. Patient charts were reviewed for disease activity, autoimmune phenomena as well as immunization status and reactogenicity of the vaccination. Activity of the underlying disease was assessed using a patient global numeric rating scale (NRS).ResultsOur cohort included 11 individuals with common variable immunodeficiency (CVID), one patient with warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) syndrome, two patients with X-linked agammaglobulinemia (XLA), one patient with Muckle Wells syndrome, two patients with cryopyrin-associated periodic syndrome, one patient with Interferon-gamma (IFN-gamma) receptor defect, one patient with selective deficiency in pneumococcal antibody response combined with a low MBL level and seven patients with severe MBL deficiency. COVID-19 vaccination was generally well tolerated with little to no triggering of autoimmune phenomena. 20 out of 26 patients developed an adequate humoral vaccine response. 9 out of 11 patients developed a T cell response comparable to healthy control subjects. Tested immunoglobulin replacement therapy (IgRT) preparations contained Anti-SARS-CoV-2 S antibodies implicating additional protection through IgRT.SummaryIn summary the data support the efficacy and safety of a COVID-19 vaccination in patients with IEIs/MBLdef. We recommend evaluation of the humoral immune response and testing for virus neutralization after vaccination in this cohort.