Publications
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Miguens Blanco J, Borghese F, McHugh N, et al., 2020, Longitudinal profiling of the gut microbiome in patients with psoriatic arthritis and ankylosing spondylitis: a multicentre, prospective, observational study, BMC Rheumatology, Vol: 4, Pages: 1-10, ISSN: 2520-1026
Background : Psoriasis is a chronic inflammatory disease of the skin affecting 2-3% ofUK population. 30% of people affected by psoriasis will develop a distinct form ofarthritis within 10 years of the skin condition onset. Although the pathogenesis ofpsoriatic arthritis is still unknown, there is a genetic predisposition triggered byenvironmental factors. Limited but convincing evidence link the gut microbiome topsoriatic arthritis. The Microbiome in Psoriatic ARThritis (Mi-PART) study propose is tocharacterise the microbiome-metabolic interface in patients affected by psoriaticarthritis to deepen our understanding of the pathogenesis of the disease.Methods : This is a multicentre, prospective, observational study. Psoriatic arthritis (n= 65) and ankylosing spondylitis (n = 30) patients will be recruited in addition to acontrol group of healthy volunteers (n = 30). Patients eligibility will be evaluated againstthe Criteria for Psoriatic Arthritis (CASPAR), the Bath Ankylosing Spondylitis ActivityIndex (BASDAI) and the healthy volunteers who fulfil study inclusion and exclusioncriteria.Information regarding their medical and medication history, demographics, diet andlifestyle will be collected. All the participants in the study will be asked to complete a 7-day food diary, to provide stool samples and to complete quality of life questionnaires.Routine clinical laboratory tests will be performed on blood and urine samples. Patientsand healthy volunteers with gastrointestinal symptoms, previous history of cancer,gastrointestinal surgery in the previous 6 months or alcohol abuse will be excludedfrom the study.Discussion : The aim of this trial is to characterise the microbiome of psoriatic arthritispatients and to compare it with microbiome of healthy volunteers and of patient withankylosing spondylitis in order to define if different rheumatologic conditions areassociated with characteristic microbiome profiles. Investigating the role of themicrobiome in the develop
Prendecki M, Clarke C, Gleeson S, et al., 2020, Detection of SARS-CoV-2 antibodies in kidney transplant recipients., Journal of the American Society of Nephrology, Vol: 31, Pages: 1-8, ISSN: 1046-6673
Kidney transplant recipients and other patient groups receiving immunosuppression have a poor prognosis following presentation with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.1 The immune response to SARS-CoV-2 in an immunocompromised population has not been systematically reported. Recognition that humoral immune responses against common viral infections are blunted in such patients has led to their exclusion from validation studies of serologic assays for SARS-CoV-2.2,3 In this study, we analyze the seroprevalence of SARS-CoV-2 antibodies in a transplant population. In order to ensure the accuracy of the seroprevalence rate, we also evaluate the performance of different serologic assays within this patient cohort.
Lou H, Wojciak-Stothard B, Ruseva MM, et al., 2020, Autoantibody-dependent amplification of inflammation in SLE, Cell Death and Disease, Vol: 11, ISSN: 2041-4889
Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.
Turner S, Hull J, Jackson A, et al., 2020, Evaluating salivary IgA levels as a biomarker for susceptibility to upper respiratory tract infection in elite athletes, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Clarke C, Prendecki M, Dhutia A, et al., 2020, High prevalence of asymptomatic COVID-19 infection in hemodialysis patients detected using serologic screening, Journal of the American Society of Nephrology, Vol: 31, Pages: 1969-1975, ISSN: 1046-6673
BACKGROUND: Strategies to minimize the risk of transmission and acquisition of COVID-19 infection in patients with ESKD receiving in-center hemodialysis have been rapidly implemented across the globe. Despite these interventions, confirmed COVID-19 infection rates have been high in the United Kingdom. Prevalence of asymptomatic disease in an adult hemodialysis population has not been reported. Also, to our knowledge, the development of humoral response to SARS-CoV-2 has not been previously reported in this population. Although serologic testing does not provide information on the infectivity of patients, seroprevalence studies may enable investigation of exposure within dialysis units and hence, assessment of current screening strategies. METHODS: To investigate the seroprevalence of SARS-CoV-2 antibodies in a hemodialysis population, we used the Abbott IgG assay with the Architect system to test serum samples from 356 patients receiving in-center hemodialysis for SARS-CoV-2 antibodies. RESULTS: Of 356 patients, 121 had been symptomatic when screened before a dialysis session and received an RT-PCR test; 79 (22.2% of the total study population) tested positive for COVID-19. Serologic testing of all 356 patients found 129 (36.2%) who tested positive for SARS-CoV-2 antibodies. Only two patients with PCR-confirmed infection did not seroconvert. Of the 129 patients with SARS-CoV-2 antibodies, 52 (40.3%) had asymptomatic disease or undetected disease by PCR testing alone. CONCLUSIONS: We found a high seroprevalence of SARS-CoV-2 antibodies in patients receiving in-center hemodialysis. Serologic evidence of previous infection in asymptomatic or PCR-negative patients suggests that current diagnostic screening strategies may be limited in their ability to detect acute infection.
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort (vol 583, pg 90, 2020), Nature, Vol: 584, Pages: E2-E2, ISSN: 0028-0836
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort, Nature, Vol: 583, Pages: 90-95, ISSN: 0028-0836
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
Turro E, Astle WJ, Megy K, et al., 2020, Whole-genome sequencing of patients with rare diseases in a national health system, Nature, Vol: 583, Pages: 96-102, ISSN: 0028-0836
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Williams A, Kelleher WP, Nicholson AG, et al., 2020, Diffuse granulomatous disease: looking inside and outside the lungs, Thorax, Vol: 75, Pages: 189-191, ISSN: 0040-6376
Shah NM, Imami N, Kelleher P, et al., 2019, Pregnancy-related immune suppression leads to altered influenza vaccine recall responses, Clinical Immunology, Vol: 208, ISSN: 1521-6616
Pregnancy is a risk factor for severe influenza infection. Despite achieving seroprotective antibody titres post immunisation fewer pregnant women experience a reduction in influenza-like illness compared to non-pregnant cohorts. This may be due to the effects that immune-modulation in pregnancy has on vaccine efficacy leading to a less favourable immunologic response.To understand this, we investigated the antigen-specific cellular responses and leukocyte phenotype in pregnant and non-pregnant women who achieved seroprotection post immunisation. We show that pregnancy is associated with better antigen-specific inflammatory (IFN-γ) responses and an expansion of central memory T cells (Tcm) post immunisation, but low-level pregnancy-related immune regulation (HLA-G, PIBF) and associated reduced B-cell antibody maintenance (TGF-β) suggest poor immunologic responses compared to the non-pregnant.Thus far, studies of influenza vaccine immunogenicity have focused on the induction of antibodies but understanding additional vaccine-related cellular responses is needed to fully appreciate how pregnancy impacts on vaccine effectiveness.
Garcia RH, Donovan J, Scadding G, et al., 2019, Is Pru p 3 a relevant test for lipid transfer protein allergy in a Northern European population?, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 142-142, ISSN: 0105-4538
Iskander D, Roberts I, Rees C, et al., 2019, Impaired cellular and humoral immunity is a feature of Diamond-Blackfan anaemia; experience of 107 unselected cases in the United Kingdom., British Journal of Haematology, Vol: 186, Pages: 321-326, ISSN: 1365-2141
Diamond-Blackfan anaemia (DBA) is a rare bone marrow failure syndrome characterised by anaemia, congenital anomalies and cancer predisposition. Although infections are the second leading cause of mortality in non-transplanted patients, immune function is largely unexplored. We identified quantitative deficits in serum immunoglobulins and/or circulating T, natural killer and B lymphocytes in 59 of 107 unselected patients (55·1%) attending our centre over a 7-year period. Immune abnormalities were independent of ribosomal protein genotype and arose in both steroid-treated and steroid-untreated patients. In summary, these data highlight the high prevalence and spectrum of infections and immune defects in DBA.
Maurice JB, Garvey L, Tsochatzis EA, et al., 2019, Monocyte-macrophage activation is associated with nonalcoholic fatty liver disease and liver fibrosis in HIV monoinfection independently of the gut microbiome and bacterial translocation., AIDS, Vol: 33, Pages: 805-814, ISSN: 0269-9370
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common among people living with HIV. There are limited data available on the pathophysiology of NAFLD and the development of fibrosis in this population. OBJECTIVES: The aim of this study was to investigate the association of bacterial translocation, adipose tissue dysfunction, monocyte activation and gut dysbiosis in patients with HIV monoinfection and NAFLD. METHODS: Cases with biopsy-proven NAFLD and HIV monoinfection were age and sex-matched to HIV-positive and HIV-negative controls. Markers of bacterial translocation [lipopolysaccharide-binding protein (LBP), bacterial DNA and lipopolysaccharide (LPS)], adipose tissue dysfunction (leptin, adiponectin) and monocyte activation (sCD14 and sCD163) were measured by ELISA. Hepatic patterns of macrophage activation were explored with immunohistochemistry. 16 s rRNA sequencing was performed with stool. RESULTS: Thirty-three cases were included (≥F2 fibrosis n = 16), matched to HIV-positive (n = 29) and HIV-negative (n = 17) controls. Cases with NAFLD were more obese (BMI 31.0 ± 4.4 vs. 24.1 ± 2.8 kg/m, P < 0.001) and had significantly increased levels of sCD14, sCD163 and higher leptin to adiponectin ratio vs. HIV-positive controls. Cases with ≥F2 verses < F2 fibrosis had increased sCD14 (1.4 ± 0.4 vs. 1.1 ± 0.3 μg/ml, P = 0.023) and sCD163 (1.0 ± 0.3 vs. 0.8 ± 0.3 μg/ml, P = 0.060), which correlated with waist circumference (sCD14 P = 0.022, sCD163 P = 0.011). Immunohistochemistry showed increased hepatic portal macrophage clusters in patients with fibrosis. No markers of bacterial translocation or changes to the microbiome were associated with NAFLD or fibrosis. CONCLUSION: NAFLD fibrosis stage in HIV monoinfected patients is associated with monocyte activation in the context of obesity, which may be independent of bacterial translocation and gut microbiome.
Cocker ATH, Greathead L, Herasimtschuk AA, et al., 2019, Therapeutic immunisation benefits mucosal-associated invariant T-cell recovery in contrast to IL-2, GM-CSF, and rhGH addition in HIV-1+ treated patients: individual case reports from phase I trial, AIDS Research and Human Retroviruses, Vol: 35, ISSN: 0889-2229
Mucosal-associated invariant T (MAIT) cell populations are reduced in frequency in HIV-1+ patients, and this disruption is associated with systemic immune activation. Reconstitution of MAIT frequency may benefit HIV-1-infected individuals; however, only recently has in vivo work been endeavored. Treatment with interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and recombinant human growth hormone (rhGH) immunotherapy combined with an HIV-1 vaccine in the context of antiretroviral therapy (ART) has shown to reconstitute CD4 T cell population numbers and function. In this study cryopreserved peripheral blood mononuclear cells (PBMCs) from 12 HIV-1+ patients who were undergoing a combination of HIV-1 vaccine and/or IL-2, GM-CSF and rhGH immunotherapy in conjunction with ART were analyzed to assess the potential of this treatment to promote MAIT cell proliferation. PBMCs were thawed from study baseline, weeks 2 and 48 time points, fluorescently stained for MAIT cell markers, and assessed by flow cytometric analysis. Matched pairs and intergroup results were statistically compared using appropriate methods. MAIT cell frequency was increased from baseline at 48 weeks in participants who received vaccine only, whereas individuals receiving IL-2, GM-CSF, and rhGH immunotherapy with or without vaccine did not show additional benefit. Although IL-2, GM-CSF, and rhGH treatment promotes CD4 T cell reconstitution and HIV-1-specific T cell function, it does not support MAIT cell recovery in patients on suppressive ART. Therapeutic immunization however has a positive effect, highlighting the importance of aiming for balanced promotion of T cell population reconstitution to impact on HIV-1 transmission and pathogenesis.
Schuetz K, Alecsandru D, Grimbacher B, et al., 2019, Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group (vol 39, pg 45, 2019), JOURNAL OF CLINICAL IMMUNOLOGY, Vol: 39, Pages: 225-227, ISSN: 0271-9142
Gossez M, Martin GE, Pace M, et al., 2019, Virological remission after antiretroviral therapy interruption in female African HIV seroconverters, AIDS, Vol: 33, Pages: 185-197, ISSN: 0269-9370
INTRODUCTION: There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) in primary HIV infection (PHI). METHODS: We studied participants (n = 82) from South Africa and Uganda in Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion, the first trial of treatment interruption in African individuals with PHI randomized to deferred ART or 48 weeks of immediate ART. All were female and infected with non-B HIV subtypes, mainly C. We measured HIV DNA in CD4 T cells, CD4 cell count, plasma viral load (pVL), cell-associated HIV RNA and T-cell activation and exhaustion. We explored associations with clinical progression and time to pVL rebound after treatment interruption (n = 22). Data were compared with non-African Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion participants. RESULTS: Pretherapy pVL and integrated HIV DNA were lower in Africans compared with non-Africans (median 4.16 vs. 4.72 log10 copies/ml and 3.07 vs. 3.61 log10 copies/million CD4 T cells, respectively; P < 0.001). Pre-ART HIV DNA in Africans was associated with clinical progression (P = 0.001, HR per log10 copies/million CD4 T cells increase (95% CI) 5.38 (1.95-14.79)) and time to pVL rebound (P = 0.034, HR per log10 copies/ml increase 4.33 (1.12-16.84)). After treatment interruption, Africans experienced longer duration of viral remission than non-Africans (P < 0.001; HR 3.90 (1.75-8.71). Five of 22 African participants (22.7%) maintained VL less than 400 copies/ml over a median of 188 weeks following treatment interruption. CONCLUSION: We find evidence of greater probability of virological remission following treatment interruption among African participants, although we are unable to differentiate between sex, ethnicity and viral subtype. The finding warrants further investigation.
Hill AT, Sullivan AL, Chalmers JD, et al., 2019, British Thoracic Society Guideline for bronchiectasis in adults, THORAX, Vol: 74, Pages: 1-54, ISSN: 0040-6376
Schütz K, Alecsandru D, Grimbacher B, et al., 2019, Imaging of bronchial pathology in antibody deficiency: data from the European Chest CT Group, Journal of Clinical Immunology, Vol: 39, Pages: 45-54, ISSN: 0271-9142
Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.
Hill AT, Sullivan AL, Chalmers JD, et al., 2018, British Thoracic Society guideline for bronchiectasis in adults, BMJ Open Respiratory Research, Vol: 5, ISSN: 2052-4439
The full British Thoracic Society Guideline for Bronchiectasis in Adults is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline. The appendices are available in the full guideline.
Evans D, Papadimitriou KI, Vasilakis N, et al., 2018, A novel microfluidic point-of-care biosensor system on printed circuit board for cytokine detection, Sensors, Vol: 18, ISSN: 1424-2818
Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H2O2 depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes.
Santiago V, Rezvani K, Sekine T, et al., 2018, Human NK cells develop an exhaustion phenotype during polar degranulation at the aspergillus fumigatus hyphal synapse, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.
Shillitoe B, Bangs C, Guzman D, et al., 2018, The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017, Clinical and Experimental Immunology, Vol: 192, Pages: 284-291, ISSN: 1365-2249
This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well‐established registry.
Eades CP, Armstrong-James DPH, Periselneris J, et al., 2018, Improvement in Exophiala dermatitidis airway persistence and respiratory decline in response to interferon-gamma therapy in a patient with cystic fibrosis, Journal of Cystic Fibrosis, Vol: 17, Pages: e32-e34, ISSN: 1569-1993
Kelleher P, Xu X-N, 2018, Hard-to-kill macrophages lead to chronic inflammation in HIV., Nat Immunol, Vol: 19, Pages: 433-434
Maurice J, Tsochatzis E, Nelson M, et al., 2018, Diagnostic accuracy of non-invasive markers of fibrosis in HIV mono-infected patients with histologically confirmed NAFLD, 4th Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH), Publisher: WILEY, Pages: S75-S76, ISSN: 1464-2662
Maurice J, Kelleher P, Nelson M, et al., 2018, NAFLD in HIV mono-infection is a consequence of insulin resistance but not bacterial translocation, International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S358-S358, ISSN: 0168-8278
Cowman SA, Jacob J, Hansell DM, et al., 2018, Whole blood gene expression in pulmonary non-tuberculous mycobacterial infection, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 510-518, ISSN: 1044-1549
RATIONALE: The factors predisposing towards the development of pulmonary non-tuberculous mycobacterial disease (pNTM) and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM but data are limited and inconsistent. OBJECTIVES: To use gene expression profiling to examine the host response to pNTM. METHODS: Microarray analysis of whole blood gene expression was performed on 25 subjects with pNTM and 27 uninfected controls with respiratory disease. Gene expression results were compared to phenotypic variables and survival data. MEASUREMENTS AND MAIN RESULTS: Compared with uninfected controls, pNTM was associated with down-regulation of 213 transcripts enriched for terms related to T cell signalling including IFNG. Reduced IFNG expression was associated with more severe CT changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. CONCLUSIONS: These findings suggest that pNTM is associated with an aberrant immune response which may reflect an underlying propensity to infection, or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM.
Wijesinghe H, Galappatthy P, de Silva R, et al., 2017, Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial, BMC MUSCULOSKELETAL DISORDERS, Vol: 18, ISSN: 1471-2474
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Afzali B, Gronholm J, Vandrovcova J, et al., 2017, BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency, Nature Immunology, Vol: 18, Pages: 813-+, ISSN: 1529-2908
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.
Hurst JR, Verma N, Lowe D, et al., 2017, Blf/ukpin Consensus Statement On The Definition, Diagnosis And Management Of Granulomatous-Lymphocytic Interstitial Lung Disease (glild) In Common Variable Immunodeficiency Disorders (cvid), International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
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