Clinical & Experimental Immunology最新文献

{"title":"Conventional and unconventional T cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients","authors":"Ross J Burton, Loïc Raffray, Linda M Moet, Simone M Cuff, Daniel A White, Sarah E Baker, Bernhard Moser, Valerie B O’Donnell, Peter Ghazal, Matt P Morgan, Andreas Artemiou, Matthias Eberl","doi":"10.1093/cei/uxae019","DOIUrl":"https://doi.org/10.1093/cei/uxae019","url":null,"abstract":"Sepsis is characterised by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients. By using a modelling pipeline employing multiple feature selection algorithms, we demonstrate the feasibility to identify integrative patterns from clinical parameters, plasma biomarkers and extensive phenotyping of blood immune cells. Whilst no single variable had sufficient predictive power, models that combined five and more features showed a macro area under the curve (AUC) of 0.85 to predict 90 day mortality after sepsis diagnosis, and a macro AUC of 0.86 to discriminate between Gram-positive and Gram-negative bacterial infections. Parameters associated with the cellular immune response contributed the most to models predictive of 90 day mortality, most notably, the proportion of T cells among PBMCs, together with expression of CXCR3 by CD4+ T cells and CD25 by mucosal-associated invariant T (MAIT) cells. Frequencies of Vδ2+ γδ T cells had the most profound impact on the prediction of Gram-negative infections, alongside other T cell-related variables and total neutrophil count. Overall, our findings highlight the added value of measuring the proportion and activation patterns of conventional and unconventional T cells in the blood of sepsis patients in combination with other immunological, biochemical and clinical parameters.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140020093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organoids as a tool to study the impact of heterogeneity in gastrointestinal epithelium on host-pathogen interactions","authors":"Mindaugas Paužuolis, Pilar Samperio Ventayol, Mastura Neyazi, Sina Bartfeld","doi":"10.1093/cei/uxae002","DOIUrl":"https://doi.org/10.1093/cei/uxae002","url":null,"abstract":"Summary The epithelium of the gastrointestinal tract has been extensively characterized using advanced histological and RNA sequencing techniques, which has revealed great cellular diversity. Pathogens, such as viruses and bacteria, are highly adapted to their host and often exhibit not only species-specificity, but also a preference or tropism for specific gastrointestinal segments or even cell types – some of these preferences are so specific, that these pathogens still cannot be cultured in the lab. Organoid technology now provides a tool to generate human cell types, which enables the study of host cell tropism. Focusing on the gastrointestinal tract, we provide an overview about cellular differentiation in vivo and in organoids and how differentiation in organoids and their derived models is used to advance our understanding of viral, bacterial, and parasitic infection. We emphasize that it is central to understand the composition of the model, as the alteration of culture conditions yields different cell types which affects infection. We examine future directions for wider application of cellular heterogeneity and potential advanced model systems for gastrointestinal tract infection studies.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139508143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplantation tolerance: the big picture. Where do we stand, where should we go?","authors":"H. Waldmann","doi":"10.1111/cei.12933","DOIUrl":"https://doi.org/10.1111/cei.12933","url":null,"abstract":"A major goal in organ transplantation has been to safely exploit the natural processes of immune tolerance in order to minimize the dose and duration of drug immunosuppression. In this commentary, I argue that we can learn from how tumours avoid rejection, to evolve a three‐stage tolerance‐inducing strategy for transplanted tissues.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73307715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplantation tolerance: don't forget about the B cells","authors":"A. Chong, S. Khiew","doi":"10.1111/cei.12927","DOIUrl":"https://doi.org/10.1111/cei.12927","url":null,"abstract":"Establishing a state of transplantation tolerance that leads to indefinite graft survival without the need for lifelong immunosuppression has been achieved successfully in limited numbers of transplant recipients in the clinic. These successes led to studies aimed at identifying potential biomarkers that diagnose allograft tolerance and identify the patients most amenable to drug minimization, and implicated an enriched B cell signature of tolerance. The emergence of a specialized subset of regulatory B cell (Bregs), that possess immune‐modulatory function in inflammation and autoimmune disease, raised the possibility that Bregs play critical roles in the promotion of transplantation tolerance and that Bregs are the underlying explanation for the B cell signature of tolerance. However, B cells are best known to play a key role in humoral immunity, and excessive production of donor specific antibodies has clear deleterious effects in transplantation. Thus, for tolerance to be persistent, alloantibody responses must also be curtailed, either through the suppression of T cell help or the induction of B cell‐intrinsic dysfunction. Recent findings indicate a unique subset of follicular regulatory T cells (Tfr) that can suppress B cell function and induce epigenetic modifications that result in sustained defects in B cell differentiation and function. In this review, we summarize studies in animals and humans that suggest roles for Bregs and dysfunctional B cells in transplantation tolerance, and discuss how these insights may provide a roadmap for new approaches to diagnose, and new therapies to induce allograft tolerance.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78540095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic norovirus infection and common variable immunodeficiency","authors":"J. Woodward, E. Gkrania-Klotsas, D. Kumararatne","doi":"10.1111/cei.12884","DOIUrl":"https://doi.org/10.1111/cei.12884","url":null,"abstract":"Chronic infection with norovirus is emerging as a significant risk for patients with immunodeficiency – either primary or secondary to therapeutic immunosuppression. Patients with primary immunodeficiency present a range of pathological responses to norovirus infection. Asymptomatic infections occur and differentiating viral carriage or prolonged viral shedding after self‐limiting infection from infection causing protracted diarrhoea can be challenging, due to relatively mild pathological changes that may mimic other causes of diarrhoea in such patients (for instance pathogenic bacteria or parasites or graft‐versus‐host disease). However, a subset of patients with common variable immunodeficiency (CVID) experience a severe norovirus‐associated enteropathy leading to intestinal villous atrophy and malabsorption. Symptomatic infection of up to 8 years has been demonstrated with clinical and histological recovery on viral clearance. Although oral immunoglobulins and nitazoxanide have been used to treat noroviral infections associated with immunosuppression, ribavirin is the only agent to date that has been linked to viral clearance in the Noroviral enteropathy associated with CVID.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82537495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of peripheral NK cell counts with Helios+IFN‐γ– Tregs in patients with good long‐term renal allograft function","authors":"Karina Trojan, Li Zhu, M. Aly, R. Weimer, N. Bulut, C. Morath, G. Opelz, Volker Daniel","doi":"10.1111/cei.12945","DOIUrl":"https://doi.org/10.1111/cei.12945","url":null,"abstract":"Little is known about a possible interaction of natural killer (NK) cells with regulatory T cells (Treg) in long‐term stable kidney transplant recipients. Absolute counts of lymphocyte and Treg subsets were studied in whole blood samples of 136 long‐term stable renal transplant recipients and 52 healthy controls using eight‐colour fluorescence flow cytometry. Patients were 1946 ± 2201 days (153–10 268 days) post‐transplant and showed a serum creatinine of 1·7 ± 0·7 mg/dl. Renal transplant recipients investigated > 1·5 years post‐transplant showed higher total NK cell counts than recipients studied < 1·5 years after transplantation (P = 0·006). High NK cells were associated with high glomerular filtration rate (P = 0·002) and low serum creatinine (P = 0·005). Interestingly, high NK cells were associated with high CD4+CD25+CD127–forkhead box protein 3 (FoxP3+) Treg that co‐express the phenotype Helios+interferon (IFN)‐γ– and appear to have stable FoxP3 expression and originate from the thymus. Furthermore, high total NK cells were associated with Treg that co‐express the phenotypes interleukin (IL)−10–transforming growth factor (TGF)‐β+ (P = 0·013), CD183+CD62L– (P = 0·003), CD183+CD62+(P = 0·001), CD183–CD62L+ (P = 0·002), CD252–CD152+ (P < 0·001), CD28+human leucocyte antigen D‐related (HLA‐DR–) (P = 0·002), CD28+HLA‐DR+ (P < 0·001), CD95+CD178– (P < 0·001) and CD279–CD152+ (P < 0·001), suggesting that these activated Treg home in peripheral tissues and suppress effector cells via TGF‐β and cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4). The higher numbers of NK and Treg cell counts in patients with long‐term good allograft function and the statistical association of these two lymphocyte subsets with each other suggest a direct or indirect (via DC) interaction of these cell subpopulations that contributes to good long‐term allograft acceptance. Moreover, we speculate that regulatory NK cells are formed late post‐transplant that are able to inhibit graft‐reactive effector cells.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85580471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sarcoidosis extent relates to molecular variability","authors":"C. S. Monast, K. Li, M. Judson, R. Baughman, E. Wadman, R. Watt, P. Silkoff, E. Barnathan, C. Brodmerkel","doi":"10.1111/cei.12942","DOIUrl":"https://doi.org/10.1111/cei.12942","url":null,"abstract":"The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti‐tumour necrosis factor (TNF)‐α] and ustekinumab [anti‐interleukin (IL)−12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78971371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach","authors":"Stephen Jolles, Helen Chapel, Jiří Litzman","doi":"10.1111/cei.12915","DOIUrl":"https://doi.org/10.1111/cei.12915","url":null,"abstract":"Primary antibody deficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) and immunoglobulin replacement forms the mainstay of therapy for many patients in this category. Secondary antibody deficiencies (SAD) represent a larger and expanding number of patients resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal or gastrointestinal immunoglobulin losses. While there are clear similarities between primary and secondary antibody deficiencies, there are also significant differences. This review describes a practical approach to the clinical, laboratory and radiological assessment of patients with antibody deficiency, focusing on the factors that determine whether or not immunoglobulin replacement should be used. The decision to treat is more straightforward when defined diagnostic criteria for some of the major PADs, such as common variable immunodeficiency disorders (CVID) or X‐linked agammaglobulinaemia (XLA), are fulfilled or, indeed, when there is a very low level of immunoglobulin production in association with an increased frequency of severe or recurrent infections in SAD. However, the presentation of many patients is less clear‐cut and represents a considerable challenge in terms of the decision whether or not to treat and the best way in which to assess the outcome of therapy. This decision is important, not least to improve individual quality of life and reduce the morbidity and mortality associated with recurrent infections but also to avoid inappropriate exposure to blood products and to ensure that immunoglobulin, a costly and limited resource, is used to maximal benefit.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76642123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential responses of human dendritic cells to metabolites from the oral/airway microbiome","authors":"K. Whiteson, S. Agrawal, A. Agrawal","doi":"10.1111/cei.12943","DOIUrl":"https://doi.org/10.1111/cei.12943","url":null,"abstract":"Small molecule metabolites that are produced or altered by host‐associated microbial communities are emerging as significant immune response modifiers. However, there is a key gap in our knowledge of how oral microbial metabolites affect the immune response. Here, we examined the effects of metabolites from five bacterial strains found commonly in the oral/airway microbial communities of humans. The five strains, each isolated from cystic fibrosis patient sputum, were Pseudomonas aeruginosa FLR01 non‐mucoid (P1) and FLR02 mucoid (P2) forms, Streptococcus pneumoniae (Sp), S. salivarius (Ss) and Rothia mucilaginosa (Rm). The effect of bacterial metabolites on dendritic cell (DC) activation, T cell priming and cytokine secretion was determined by exposing DCs to bacterial supernatants and individual metabolites of interest. Supernatants from P1 and P2 induced high levels of tumour necrosis factor (TNF)‐α, interleukin (IL)−12 and IL‐6 from DCs and primed T cells to secrete interferon (IFN)‐γ, IL‐22 compared to supernatants from Sp, Ss and Rm. Investigations into the composition of supernatants using gas chromatography–mass spectroscopy (GC‐MS) revealed signature metabolites for each of the strains. Supernatants from P1 and P2 contained high levels of putrescine and glucose, while Sp and Ss contained high levels of 2,3‐butanediol. The individual metabolites replicated the results of whole supernatants, although the magnitudes of their effects were reduced significantly. Altogether, our data demonstrate for the first time that the signature metabolites produced by different bacteria have different effects on DC functions. The identification of signature metabolites and their effects on the host immune system can provide mechanistic insights into diseases and may also be developed as biomarkers.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78486940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutational spectrum of the SERPING1 gene in Swiss patients with hereditary angioedema","authors":"U. Steiner, M. Keller, Pirmin Schmid, S. Cichon, W. Wuillemin","doi":"10.1111/cei.12941","DOIUrl":"https://doi.org/10.1111/cei.12941","url":null,"abstract":"Hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) is a rare autosomal dominant disease caused by mutations in the C1 inhibitor gene SERPING1. Phenotype and clinical features of the disease are extremely heterogeneous, varying even within the same family. Compared to HAE cohorts in other countries, the genetic background of the Swiss HAE patients has not yet been elucidated. In the present study we investigated the mutational spectrum of the SERPING1 gene in 19 patients of nine unrelated Swiss families. The families comprise a total of 111 HAE‐affected subjects which corresponds to approximately 70% of all HAE‐affected patients living in Switzerland. Three of the identified mutations are newly described. Members of family A with a nucleotide duplication as genetic background seem to have a more intense disease manifestation with a higher attack frequency compared to the other families. Newly designed genetic screening tests allow a fast and cost‐efficient testing for HAE in other family members.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78637457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}