Imperial College London

Dr Peter Kelleher

Faculty of MedicineDepartment of Infectious Disease

Reader in Immunology
 
 
 
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Contact

 

+44 (0)20 3315 8251p.kelleher

 
 
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Location

 

J.2.10Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

Publication Type
Year
to

149 results found

Shah A, Hull J, Moffatt M, Cookson W, Kelleher W, Cuthbertson Let al., 2022, Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness, EBioMedicine, Vol: 79, Pages: 1-16, ISSN: 2352-3964

BackgroundRespiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility.MethodsPeripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19).FindingsAthletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005).InterpretationAthletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis.FundingThis study was funded by the English Institute of Sport (UK).

Journal article

Spensley K, Gleeson S, Martin P, Thomson T, Clarke C, Pickard G, Thomas D, McAdoo S, Randell P, Kelleher P, Bedi R, Lightstone E, Prendecki M, Willicombe Met al., 2022, Comparison of vaccine effectiveness against the Omicron (B.1.1.529) variant in haemodialysis patients, Kidney International Reports, ISSN: 2468-0249

Journal article

Gerovasili V, Shah A, Singanayagam A, George PM, Njafuh R, Prendecki M, Carby M, Willicombe M, Kelleher P, Reed Aet al., 2022, Impaired Humoral and Cellular Responses to SARS-CoV-2 Vaccine in Heart and Lung Transplant Recipients., Am J Respir Crit Care Med

Journal article

Chanchlani N, Lin S, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad Tet al., 2022, Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients., Journal of Crohns & Colitis, Vol: 16, Pages: 389-397, ISSN: 1873-9946

BACKGROUND AND AIMS: Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-TNF level influences serological responses, remains unknown. METHODS: Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11422 (53.3% (6084) male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between 29 th January and 30 th September 2020. Data were linked to nationally-held SARS-CoV-2 PCR results to 4 th May 2021. RESULTS: Rates of PCR confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% (178/5893), adalimumab: 3.0% (152/5074), vedolizumab: 6.7% (25/375), p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index (COI) (1.94 - 9.96) vs 5.02 (2.18 - 18.70), p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI (4.39 - 68.10, p< 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels (<0.8 mg/L) were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were anti-TNF treated. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% (12/152) patients after a median time of 183.5 days (129.8 - 235.3), without differences between drugs. CONCLUSION: Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels supports a causal relationship, although confounding factors, such as combination therapy with immunomodulator, may have

Journal article

Pallett SJC, Wake R, Youngs J, Pope C, Tan NK, Taylor J, Hawkins L, Witney AA, Laing KG, Monahan IM, Akay M, Cox A, Groppelli E, Kelleher P, Miller P, Bicanic Tet al., 2021, Adjunctive viral cell culture supports treatment decision-making in patients with secondary humoral immunodeficiency and persistent SARS-CoV-2 infection, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 196, Pages: 1170-1174, ISSN: 0007-1048

Journal article

Turner SEG, Hull JH, Jackson A, Loosemore M, Ranson C, Kelleher P, Shah Aet al., 2021, Screening Identifies Suboptimal Vaccination Protection in Illness-Susceptible Elite Athletes, CLINICAL JOURNAL OF SPORT MEDICINE, Vol: 31, Pages: E470-E472, ISSN: 1050-642X

Journal article

Cuthbertson L, Turner SEG, Jackson A, Ranson C, Loosemore M, Kelleher P, Cookson WOC, Moffatt MF, Hull JH, Shah Aet al., 2021, ELITE ATHLETES SUSCEPTIBLE TO RESPIRATORY TRACT INFECTION ARE CHARACTERISED BY REDUCED CIRCULATING MEMORY T REGULATORY CELLS, UPPER AIRWAY MICROBIAL DYSBIOSIS AND DYSREGULATION OF SPHINGOLIPID METABOLISM, Publisher: BMJ PUBLISHING GROUP, Pages: A61-A62, ISSN: 0040-6376

Conference paper

Prendecki M, Thomson T, Clarke CL, Martin P, Gleeson S, De Aguiar RC, Edwards H, Mortimer P, McIntyre S, Mokreri D, Cox A, Pickard G, Lightstone L, Thomas D, McAdoo SP, Kelleher P, Willicombe Met al., 2021, responses to SARS-CoV-2 vaccines in kidney transplant recipients, LANCET, Vol: 398, Pages: 1482-1484, ISSN: 0140-6736

Journal article

Periselneris J, Schelenz S, Loebinger M, Macedo P, Adhya Z, Armstrong-James D, Kelleher WPet al., 2021, Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency, THORAX, Vol: 76, Pages: 1036-1039, ISSN: 0040-6376

Journal article

Prendecki M, Clarke C, Edwards H, McIntyre S, Mortimer P, Gleeson S, Martin P, Thomson T, Randell P, Shah A, Singanayagam A, Lightstone L, Cox A, Kelleher P, Willicombe M, McAdoo SPet al., 2021, Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression., Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

Journal article

Breathnach AS, Duncan CJA, El Bouzidi K, Hanrath AT, Payne BAI, Randell PA, Habibi MS, Riley PA, Planche TD, Busby JS, Sudhanva M, Pallett SJC, Kelleher WPet al., 2021, Prior COVID-19 protects against reinfection, even in the absence of detectable antibodies, JOURNAL OF INFECTION, Vol: 83, Pages: 239-241, ISSN: 0163-4453

Journal article

Kelleher P, 2021, The battle of testing in COVID-19: the secrets of victory against the virus, CARDIOVASCULAR RESEARCH, Vol: 117, Pages: E101-E103, ISSN: 0008-6363

Journal article

Froneman C, Kelleher P, Jose RJ, 2021, Pneumococcal Vaccination in Immunocompromised Hosts: An Update, VACCINES, Vol: 9

Journal article

Clarke CL, Prendecki M, Dhutia A, Gan J, Edwards C, Prout V, Lightstone L, Parker E, Marchesin F, Griffith M, Charif R, Pickard G, Cox A, McClure M, Tedder R, Randell P, Greathead L, Guckian M, McAdoo SP, Kelleher P, Willicombe Met al., 2021, Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection, Kidney International, Vol: 99, Pages: 1470-1477, ISSN: 0085-2538

Patients with end stage kidney disease receiving in-center hemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, patients receiving ICHD frequently develop circulating antibodies to SARS-CoV-2, even with asymptomatic infection. Here, we investigated the durability and functionality of the immune responses to SARS-CoV-2 infection in patients receiving ICHD. Three hundred and fifty-six such patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were regularly screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies, and those who became seronegative at six months were screened for SARS-CoV-2 specific T-cell responses. One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at time zero, of whom 127 also had detectable anti-RBD. Significantly, at six months, 71/111 (64.0%) and 99/116 (85.3%) remained anti-NP and anti-RBD seropositive, respectively. For patients who retained antibody, both anti-NP and anti-RBD levels were reduced significantly after six months. Eleven patients who were anti-NP seropositive at time zero, had no detectable antibody at six months; of whom eight were found to have SARS-CoV-2 antigen specific T cell responses. Independent of antibody status at six months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following six months. Thus, patients receiving ICHD mount durable immune responses six months post SARS-CoV-2 infection, with fewer than 3% of patients showing no evidence of humoral or cellular immunity.

Journal article

Turner-Stokes T, Jiang E, Johnson N, Khakhria K, Kong E, Cairns T, Clarke C, Greathead L, Griffith M, Guckian M, Kelleher P, McClure MO, Prendecki M, Rosadas C, Tedder R, Lightstone L, Willicombe M, McAdoo SP, ICHNT Renal COVID-19 Groupet al., 2021, Serological screening for COVID-19 in patients with glomerular disease, Kidney International Reports, Vol: 6, Pages: 1402-1406, ISSN: 2468-0249

Journal article

Samri A, Chalouni M, Blanco J, Behrens G, Kelleher P, Massanella M, Ahmad F, Clotet B, Plettenberg A, Katlama C, Richert L, Raffi F, Thiebaut R, Autran Bet al., 2021, Influence of the Antiretroviral Regimen on the Early Changes in Plasma HIV RNA and Immune Activation at Initiation of Antiretroviral Therapy in Naive HIV-1-Infected Patients, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 86, Pages: e146-e149, ISSN: 1525-4135

Journal article

Prendecki M, Clarke C, Brown J, Cox A, Gleeson S, Guckian M, Randell P, Pria AD, Lightstone L, Xu X-N, Barclay W, McAdoo SP, Kelleher P, Willicombe Met al., 2021, Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine, The Lancet, Vol: 397, Pages: 1178-1181, ISSN: 0140-6736

Journal article

Turner SEG, Loosemore M, Shah A, Kelleher P, Hull JHet al., 2021, Salivary IgA as a potential biomarker in the evaluation of respiratory tract infection risk in athletes, Journal of Allergy and Clinical Immunology: In Practice, Vol: 9, Pages: 151-159, ISSN: 2213-2198

In recent years, there has been attention focused on the value of salivary IgA (sIgA) as a potential biomarker for the identification of athletes who may be at increased risk of developing respiratory tract infection (RTI). The utility of sIgA, in this context, is based on biological plausibility and several observational studies revealing an apparent association between sIgA and RTI susceptibility. The overall published evidence evaluating the value of sIgA in this context is however conflicting, and there is currently a lack of clear guidance as to whether this marker has a place in the health surveillance and care of athletes. In this review, we critically appraise the literature assessing the potential for sIgA to be used in this context, evaluating it against 4 key biomarker characteristics, including its (1) practicality, (2) reproducibility, (3) specificity/sensitivity, and (4) potential clinical impact and relevance. This process reveals that although there is an apparent association between respiratory illness and sIgA in many studies, with some promising results, overall there remains a paucity of evidence supporting its overall value in this context. Key deficiencies in the metrics employed to endorse a valid biomarker are apparent, including a lack of reproducibility and low specificity and sensitivity in the detection of RTI susceptibility. The review outlines these issues and makes future recommendations.

Journal article

Miguens Blanco J, Borghese F, McHugh N, Kelleher P, Sengupta R, Marchesi J, Abraham Set 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

Journal article

Prendecki M, Clarke C, Gleeson S, Greathead L, Santos E, McLean A, Randell P, Moore LSP, Mughal N, Guckian M, Kelleher P, Mcadoo SP, Willicombe Met 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.

Journal article

Lou H, Wojciak-Stothard B, Ruseva MM, Cook HT, Kelleher P, Pickering MC, Mongkolsapaya J, Screaton GR, Xu X-Net 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.

Journal article

Turner S, Hull J, Jackson A, Ranson C, Kelleher P, Loosemore M, Shah Aet 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

Conference paper

Clarke C, Prendecki M, Dhutia A, Ali MA, Sajjad H, Shivakumar O, Lightstone L, Kelleher P, Pickering MC, Thomas D, Charif R, Griffith M, McAdoo SP, Willicombe Met 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.

Journal article

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann Fet 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

Journal article

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F, Primary Immunodeficiency Consortium for the NIHR Bioresource, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, Smith KGCet 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.

Journal article

Turro E, Astle WJ, Megy K, Graef S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, Ouwehand WHet 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.

Journal article

Williams A, Kelleher WP, Nicholson AG, Devaraj A, Pavesio C, Chua Fet al., 2020, Diffuse granulomatous disease: looking inside and outside the lungs, Thorax, Vol: 75, Pages: 189-191, ISSN: 0040-6376

Journal article

Shah NM, Imami N, Kelleher P, Barclay WS, Johnson MRet 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.

Journal article

Garcia RH, Donovan J, Scadding G, Durham SR, Kelleher WP, Skypala IJet 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

Conference paper

Iskander D, Roberts I, Rees C, Szydlo R, Alikian M, Neale M, Harrington Y, Kelleher P, Karadimitris A, de la Fuente Jet 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.

Journal article

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