1,720,980 research outputs found
MAIT cells in autoimmunity, immune mediated diseases and airways disease
No full textMucosal associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T cell receptor and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans implies a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, to date little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as-yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools now available, including murine genetic models and human and murine specific tetramers
MR1 (in mouse and man)
No full textMR1 (major histocompatibility complex (MHC)-related protein 1) is a nonpolymorphic class Ib antigen presenting molecule recognized by the innate-like mucosal-associated invariant T cell subset. MR1 is highly conserved across all mammals, implying an essential role in host defense. It presents nonprotein antigens which include precursors and derivatives from highly conserved microbial biosynthetic pathways of riboflavin and folic acid metabolism. MR1 was identified in 1995 by degenerate PCR on human chromosome 1q25. MR1 is ubiquitously expressed across tissues, at relatively high abundance, but with virtually no detectable constitutive surface expression. MR1 has a standard MHC-I fold, with ?1 and ?2 helices forming an exposed antigen-binding cleft, held open by several bulky side chains, with a ?-sheet floor. MR1 ligands include formylpterins, naturally occurring photodegradation products of folic acid (vitamin B9), and ribityllumazines, precursors and derivatives of vitamin B2. MR1 predominantly exists in the late endoplasmic reticulum (ER), trafficking through the late endosomal and lysosomal compartments where it binds ligand, facilitated by chaperones from the MHC-II pathway: the invariant chain and HLA-DM. Diseases associated with MR1 deficiencies or polymorphisms are yet to be described, but are likely to produce predisposition to multisystem invasive infections, or chronic autoimmune inflammatory diseases
Mycobacterium tuberculosis-specific cellular immune profiles suggest bacillary persistence decades after spontaneous cure in untreated tuberculosis
No full textIndividuals with self-healed tuberculosis from the preantibiotic era offer a unique insight into the natural history of and protective immunity to tuberculosis. In 27 such persons whose tuberculosis self-healed >50 years earlier, circulating Mycobacterium tuberculosis antigen-specific interferon ? (IFN-?)- and interleukin 2 (IL-2)-secreting T cells were detected ex vivo in 16 and 19 individuals, respectively. The M. tuberculosis-specific T cell cytokine profile was dominated by effector memory T cells that secrete both IFN-? and IL-2 and included T cells that secrete only IFN-? or IL-2, suggesting persistence of antigen secreted by viable bacilli. Of 10 individuals with no M. tuberculosis antigen-specific IFN-?-secreting T cells detectable ex vivo, 7 had evidence of central memory T cells, consistent with clearance of infection
Changing minds: Understanding the use of oral steroids in acute asthma
No full textAsthma is a heterogenous disease with a substantial global burden. Asthma attacks are treated based on symptoms alone with oral steroids despite some attacks displaying little evidence of type-2 inflammation. Type-2 low inflammatory attacks may experience more dose-dependent harm from steroids than clinical benefits. A personalised medicine approach to treating asthma attacks using biomarkers may improve patient clinical outcomes and minimise side effects. FeNO and blood eosinophils are the two key biomarkers that measure type-2 inflammation. The goal of my DPhil was to provide supportive evidence for a biomarker-directed, placebo-controlled trial of oral steroid treatment for asthma attacks. A systematic review identified that trials of asthma attack treatment have been set almost entirely in urgent care, focussing on short-term, physiological outcome measures. A discrete choice experiment identified that patients and healthcare professionals will trade-off treatment benefits to avoid the side-effects associated with OCS. While symptom recovery was the most important clinical outcome to HCPs and patients, HCPs preferred avoiding further healthcare utilisation more than patients. Proteomic analysis of sputum and blood samples identified that prednisolone still had broad anti-inflammatory airway effects on top of anti-IL5 monoclonal antibody therapy. However, these effects were heterogeneous and not present in some participants. A prospective observational study of adults on anti-IL5/5Rα therapy identified that FeNO-high attacks were associated with larger clinical improvements and airway anti-inflammatory effects after 7 days prednisolone treatment compared to FeNO-low attacks. In conclusion, after systemic blood eosinophil suppression there is heterogeneity in steroid-responsiveness amongst the asthma population, which can be discriminated by FeNO testing at attack. There is clinical equipoise in using oral steroids treatment for type-2 low asthma attacks. Given the willingness of patients and healthcare professionals to trade-off clinical benefits to avoid oral steroid risks, my thesis supports pursuing a biomarker-directed approach to treating asthma attacks
Improved diagnostic evaluation of suspected tuberculosis
No full textBackground: The role of new T-cell–based blood tests for tuberculosis in the diagnosis of active tuberculosis is unclear.Objective: To compare the performance of 2 interferon-? assays and tuberculin skin testing in adults with suspected tuberculosis.Design: Prospective study conducted in routine practice.Setting: 2 urban hospitals in the United Kingdom.Patients: 389 adults, predominantly of South Asian and black ethnicity, with moderate to high clinical suspicion of active tuberculosis.Intervention: Tuberculin skin testing, the enzyme-linked immunospot assay (ELISpot) incorporating early secretory antigenic target-6 and culture filtrate protein-10 (standard ELISpot), and ELISpot incorporating a novel antigen, Rv3879c (ELISpotPLUS) were performed during diagnostic assessment by independent persons who were blinded to results of the other test.Measurements: Sensitivity, specificity, predictive values, and likelihood ratios.Results: 194 patients had a final diagnosis of active tuberculosis, of which 79% were culture-confirmed. Sensitivity for culture confirmed and highly probable tuberculosis was 89% (95% CI, 84% to 93%) with ELISpotPLUS, 85% (CI, 79% to 90%) with standard ELISpot, 79% (CI, 72% to 85%) with 15-mm threshold tuberculin skin testing, and 83% (CI, 77% to 89%) with stratified thresholds of 15 and 10 mm in vaccinated and unvaccinated patients, respectively. The ELISpotPLUS assay was more sensitive than tuberculin skin testing with 15-mm cutoff points (P = 0.01) but not with stratified cutoff points (P = 0.10). The ELISpotPLUS assay had 4% higher diagnostic sensitivity than standard ELISpot (P = 0.02). Combined sensitivity of ELISpotPLUS and tuberculin skin testing was 99% (CI, 95% to 100%), conferring a negative likelihood ratio of 0.02 (CI, 0 to 0.06) when both test results were negative.Limitations: Local standards for tuberculin skin testing differed from others used internationally. The study sample included few immunosuppressed patients.Conclusion: The ELISpotPLUS assay is more sensitive than standard ELISpot and, when used in combination with tuberculin skin testing, enables rapid exclusion of active infection in patients with moderate to high pretest probability of tuberculosis
Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma
No full textAsthma arises from the complex interplay of inflammatory pathways in diverse cell types and tissues. We sought to undertake a comprehensive transcriptomic assessment of the epithelium and airway T cells that remain understudied in asthma, and investigate interactions between multiple cells and tissues. Epithelial brushings and flow-sorted CD3+ T cells from sputum and bronchoalveolar lavage were obtained from healthy subjects (N=19) and asthmatic patients (mild, moderate and severe asthma; N=46). Gene expression was assessed using Affymetrix HT HG-U133+ PM GeneChips and results were validated by real-time quantitative PCR. In the epithelium, IL-13 response genes (POSTN, SERPINB2, CLCA1), mast cell mediators (CPA3, TPSAB1), inducible nitric oxide synthase and cystatins (CST1, CST2, CST4) were upregulated in mild asthma but, except for cystatins, were suppressed by corticosteroids in moderate asthma. In severe asthma – with predominantly neutrophilic phenotype – several distinct processes were upregulated including neutrophilia (TCN1, MMP9), mucins and oxidative stress responses. The majority of the disease signature was evident in sputum T cells in severe asthma, where 267 genes were differentially regulated compared to health, highlighting compartmentalisation of inflammation. This signature included IL-17-inducible chemokines (CXCL1, CXCL2, CXCL3, IL8, CSF3) and chemoattractants for neutrophils (IL8, CCL3, LGALS3), T cells and monocytes. A protein interaction network in severe asthma highlighted signatures of responses to bacterial infections across tissues (CEACAM5, CD14, TLR2) including toll-like receptor signalling. In conclusion, the82 activation of innate immune pathways in the airways suggests that activated T cells may be driving neutrophilic inflammation and steroid-insensitive IL-17 response in severe asthma
High background rates of positive tuberculosis-specific interferon-? release assays in a low prevalence region of UK: a surveillance study
No full textBackground: Background rates of latent tuberculosis infection in low prevalence regions of Britain are unknown. These would be valuable data for interpreting positive IGRA results, and guiding cost-benefit analyses. The management of a large outbreak of tuberculosis occurring in a rural district hospital provided an opportunity to determine the background rates and epidemiology of IGRA-positivity amongst unselected hospital patients in a low-prevalence region of U.K.Methods: As part of a public health surveillance project we identified 445 individuals exposed to the index cases for clinical assessment and testing by a TB-specific interferon-? release assay (IGRA): T-Spot.TB. Uniquely, an additional comparator group of 191 age-matched individuals without specific recent exposure, but with a similar age distribution and demographic, were recruited from the same wards where exposure had previously occurred, to undergo assessment by questionnaire and IGRA. Results: Rates of IGRA positivity were 8.7% (95%CI, 4.2-13, n=149) amongst unexposed patients, 9.5%(3.0-22, n=21) amongst unexposed staff, 22%(14–29, n=130) amongst exposed patients, 11%(6.1-16, n=142) amongst exposed staff. Amongst the individuals without history of recent exposure to the outbreak, IGRA-positivity was associated with prior TB treatment (OR11, P.04) and corticosteroid use (OR5.9, P.02). Background age-specific prevalences of IGRA-positivity amongst unexposed individuals were: age <40 0%(N/A), age 40–59 15%(12–29), age 60–79 7.0%(1.1-13), age?80 10%(5.9-19).Conclusions: Background rates of IGRA-positivity remain high amongst unselected white-Caucasian hospital inpatients in U.K. These data will aid interpretation of future outbreak studies. As rates peak in the 5th and 6th decade, given an ageing population and increasing iatrogenic immunosuppression, reactivation of LTBI may be a persistent hazard in this population for several decades to come
Dynamic relationship between IFN-gamma and IL-2 profile of Mycobacterium tuberculosis-specific T cells and antigen load
No full textDistinct IFN-gamma and IL-2 profiles of Ag-specific CD4(+) T cells have recently been associated with different clinical disease states and Ag loads in viral infections. We assessed the kinetics and functional profile of Mycobacterium tuberculosis Ag-specific T cells secreting IFN-gamma and IL-2 in 23 patients with untreated active tuberculosis when bacterial and Ag loads are high and after curative treatment, when Ag load is reduced. The frequencies of M. tuberculosis Ag-specific IFN-gamma-secreting T cells declined during 28 mo of follow-up with an average percentage decline of 5.8% per year (p = 0.005), while the frequencies of Ag-specific IL-2-secreting T cells increased during treatment (p = 0.02). These contrasting dynamics for the two cytokines led to a progressive convergence of the frequencies of IFN-gamma- and IL-2-secreting cells over 28 mo. Simultaneous measurement of IFN-gamma and IL-2 secretion at the single-cell level revealed a codominance of IFN-gamma-only secreting and IFN-gamma/IL-2 dual secreting CD4(+) T cells in active disease that shifted to dominance of IFN-gamma/IL-2-secreting CD4(+) T cells and newly detectable IL-2-only secreting CD4(+) T cells during and after treatment. These distinct T cell functional signatures before and after treatment suggest a novel immunological marker of mycobacterial load and clinical status in tuberculosis that now requires validation in larger prospective studies
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