370 research outputs found
Plasmacytoid Dendritic Cells Are Proportionally Expanded at Diagnosis of Type 1 Diabetes and Enhance Islet Autoantigen Presentation to T-Cells Through Immune Complex Capture
OBJECTIVEāImmune-mediated destruction of Ī²-cells resulting in type 1 diabetes involves activation of proinflammatory, islet autoreactive T-cells, a process under the control of dendritic cells of the innate immune system. We tested the hypothesis that type 1 diabetes development is associated with disturbance of blood dendritic cell subsets that could enhance islet-specific autoimmunity
Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes.
The appearance of circulating islet-specific autoantibodies before disease diagnosis is a hallmark of human type 1 diabetes (T1D), and suggests a role for B cells in the pathogenesis of the disease. Alterations in the peripheral B cell compartment have been reported in T1D patients; however, to date, such studies have produced conflicting results and have been limited by sample size. In this study, we have performed a detailed characterization of the B cell compartment in T1D patients (nā=ā45) and healthy controls (nā=ā46), and assessed the secretion of the anti-inflammatory cytokine interleukin (IL)-10 in purified B cells from the same donors. Overall, we found no evidence for a profound alteration of the B cell compartment or in the production of IL-10 in peripheral blood of T1D patients. We also investigated age-related changes in peripheral B cell subsets and confirmed the sharp decrease with age of transitional CD19(+) CD27(-) CD24(hi) CD38(hi) B cells, a subset that has recently been ascribed a putative regulatory function. Genetic analysis of the B cell compartment revealed evidence for association of the IL2-IL21ā
T1D locus with IL-10 production by both memory B cells (Pā=ā6Ā·4āĆā10(-4) ) and islet-specific CD4(+) T cells (Pā=ā2Ā·9āĆā10(-3) ). In contrast to previous reports, we found no evidence for an alteration of the B cell compartment in healthy individuals homozygous for the non-synonymous PTPN22ā
Trp(620) T1D risk allele (rs2476601; Arg(620) Trp). The IL2-IL21 association we have identified, if confirmed, suggests a novel role for B cells in T1D pathogenesis through the production of IL-10, and reinforces the importance of IL-10 production by autoreactive CD4(+) T cells
The Sexual Use of a Social Networking Site: The Case of Pup Twitter
This article examines how Twitter has been adopted and used by a sexual subculture in distinct ways. Drawing on interviews with 26 gay and bisexual men based in the UK who identify as āpupsā, it demonstrates how a kinky sexual subculture exists on a social networking site in new and innovative ways, adapting various elements of Twitter to form a unique subculture that I call āPup Twitterā. Engaging with debates about social trends related to sexuality, as well as contemporary understandings of social networking sites, the study documents how this subcultural sexual community, while predating Twitter, has adopted online methods to enhance communication, engagement, and even visibility. The intersection of sexuality and social networking sites is an area ripe for further study, and this article develops empirical and conceptual ways to examine this issue in the future
Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort.
OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged ā„5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7ākg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results
Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and reāemerging phenotype is associated with graft function
Islet transplantation is an effective therapy for lifeāthreatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized isletāspecific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fiftyāeight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with isletāspecific T cell responses was not significantly different over time (preāTx: 59%; 1ā6 m posttransplant: 38%; 7ā12 m: 44%; 13ā24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFNāĪ³ādominated response in the pretransplant group replaced by ILā10ādominated response in the 1ā6 m posttransplant group, reverting to predominantly IFNāĪ³āoriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFNāĪ³ and ILā10 phenotypes, respectively. ILā10āoriented posttransplant response was associated with relatively low graft function. Recipients within the ILā10+ cluster had a significant decline in Cāpeptide levels in the period preceding the ILā10 response, but stable graft function following the response. In contrast, an IFNāĪ³ response was associated with subsequently decreased Cāpeptide. Islet transplantation favoring ATZ induction is associated with an initial altered isletāspecific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function
Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014;63:3835ā3845
The article to which this is the erratum is available in ORE at: http://hdl.handle.net/10871/17968In the article, there are two errors in the research design and methods section.
In the section with the heading āStudies on Islet-Infiltrating Leukocytes,ā the antibody listed as #M0701 should be attributed to Dako and not to Abcam and the Abcam rabbit anti-CD8 catalogue number should read #ab4055 and not #GR404-4.
The online version reflects these changes
Validity and Reproducibility of Measurement of Islet Autoreactivity by T-Cell Assays in Subjects With Early Type 1 Diabetes
Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches
PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research
Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support
from the Oxford NIHR Biomedical Research Centre and from the Oxford
British Heart Foundation Centre of Research Excellence. SP and PL are
funded by a BHF Senior Clinical Research fellowship. RC is supported by a
BHF Research Chair and acknowledges the support of the Oxford BHF Centre
for Research Excellence and the MRC and Wellcome Trust. PMM gratefully
acknowledges training fellowships supporting his laboratory from the
Wellcome Trust, GlaxoSmithKline and the Medical Research Council
Ī²-cell specific T-lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults.
AIM: To examine the hypothesis that the quality, magnitude and breadth of helper T-lymphocyte responses to Ī² cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood. METHODS: We studied helper T-lymphocyte reactivity against Ī²-cell autoantigens by measuring production of the pro-inflammatory cytokine interferon-Ī³ and the anti-inflammatory cytokine interleukin-10, using enzyme-linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401), of whom 33 were children/adolescents, and a further 91 were unaffected siblings. RESULTS: Interferon-Ī³ responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children (P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon-Ī³ response was also greater, with 70% of children having an interferon-Ī³ response to three or more peptides compared with 14% of adults (P < 0.0001). Islet Ī²-cell antigen-specific interleukin-10 responses were similar in children and adults in terms of frequency, breadth and magnitude, with the exception of responses to glutamic acid decarboxylase 65, which were significantly less frequent in adults. CONCLUSIONS: At diagnosis of Type 1 diabetes, pro-inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age-related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune-based therapies.We would like to acknowledge the support of the National Institute for Health Research Clinical Research Network.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/dme.1315
Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity
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