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Dive into the research topics where Ravishankar Sargur is active.

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Featured researches published by Ravishankar Sargur.


Proceedings of the National Academy of Sciences of the United States of America | 2009

Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen

Mohammad Alimohammadi; Noémie Dubois; Filip Sköldberg; Åsa Hallgren; Isabelle Tardivel; Håkan Hedstrand; Jan Haavik; Eystein S. Husebye; Jan Gustafsson; Fredrik Rorsman; Antonella Meloni; Christer Janson; Bernard Vialettes; Merja Kajosaari; William Egner; Ravishankar Sargur; Fredrik Pontén; Zahir Amoura; Alain Grimfeld; Filippo De Luca; Corrado Betterle; Jaakko Perheentupa; Olle Kämpe; Jean-Claude Carel

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.


Clinical and Experimental Immunology | 2014

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012

Jd Edgar; Matthew Buckland; D. Guzman; N. P. Conlon; V. Knerr; C. Bangs; V. Reiser; Z. Panahloo; S. Workman; Mary Slatter; Andrew R. Gennery; E. G. Davies; Zoe Allwood; P. D. Arkwright; Matthew Helbert; Hilary J. Longhurst; Sofia Grigoriadou; Lisa Devlin; Aarnoud Huissoon; Mamidipudi T. Krishna; S. Hackett; Dinakantha Kumararatne; Alison M. Condliffe; Helen Baxendale; K. Henderson; C. Bethune; C. Symons; P. Wood; K. Ford; S Patel

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty‐seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.


Annals of Clinical Biochemistry | 2010

Cryoglobulin evaluation: best practice?

Ravishankar Sargur; Peter White; William Egner

Cryoglobulins are serum immunoglobulins that precipitate at temperatures below 37°C and re-dissolve on warming. Cryoglobulinaemia leads to variable symptoms including characteristic purpura, ischaemia of extremities, renal failure, peripheral neuropathy, abdominal pain secondary to intestinal ischaemia and arthralgias. Cryoglobulin testing is underutilized in clinical practice. It has been neglected in clinical laboratories and by clinicians due to several factors, such as the length of time it takes for serum cryoglobulin analysis to be performed in the laboratory, the perceived difficulty in getting optimal sampling conditions and a failure to appreciate that even apparently low levels of cryoglobulin can be associated with severe symptoms in some patients. The most important variable confounding standardization of cryoglobulin testing is improper sample handling. A recent report critically appraising the current practice of cryoglobulin evaluation in 137 laboratories in Europe by United Kingdom National External Quality Assurance Scheme (UKNEQAS) illustrated the wide variability in practice. Although many clinical laboratories perform cryoglobulin evaluation, there are widespread differences in the methodology used and the care with which this is carried out and this leads to considerable intralaboratory and interlaboratory variability. The most common sources of error are false-negative results due to loss of cryoprecipitate during transport and storage. Better standardization is needed to avoid missed diagnoses and improve the comparability of results. Laboratories should ensure that sample temperature is maintained at 37°C until the serum is separated. In this article, we briefly review the classification and clinical features of cryoglobulins and suggest best practice guidelines for laboratory detection and identification of cryoglobulins.


Science Translational Medicine | 2013

BPIFB1 IS A LUNG-SPECIFIC AUTOANTIGEN ASSOCIATED WITH INTERSTITIAL LUNG DISEASE

Anthony K. Shum; Mohammad Alimohammadi; Catherine L. Tan; Mickie H. Cheng; Todd Metzger; Christopher S. Law; Wint Lwin; Jaakko Perheentupa; Hélène Bour-Jordan; Jean Claude Carel; Eystein S. Husebye; Filippo De Luca; Christer Janson; Ravishankar Sargur; Noémie Dubois; Merja Kajosaari; Paul J. Wolters; Harold A. Chapman; Olle Kämpe; Mark S. Anderson

Autoimmunity targeting the lung-specific antigen BPIFB1 may be important to the pathogenesis of interstitial lung disease. Seeing the Forest by Examining the Trees Sometimes looking at something too closely obscures the big picture. However, when the big picture is too big, a reductionist approach may be best. Interstitial lung disease (ILD) is a complex and heterogeneous disorder, frequently associated with autoimmune syndromes. However, due in part to this heterogeneity, it remains unclear whether autoimmunity directly contributes to ILD. Now, Shum et al. attack this question by example—connecting one form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), with clinical ILD. The authors screened patients with APS1 and found autoantibodies to a lung-specific protein—BPIFB1—associated with the development of ILD in APS1 patients. They then extended these findings to non-APS1–associated ILD and found that 12 to 15% of patients also had these autoantibodies. The authors then examined a potential pathogenic mechanism of these autoantibodies in a mouse model of APS1, finding that similar autoantibodies and development of ILD resulted from a defect in thymic tolerance. Indeed, autoimmune targeting of BPIFB1 could cause ILD in mice without the autoimmune defect. These results suggest not only that ILD may be an autoimmune disorder in APS1 patients but also that autoimmunity may also contribute to pathology in a broader swath of ILD patients. Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease–associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire−/− mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.


Journal of Pediatric Gastroenterology and Nutrition | 2012

ESPGHAN guidance on coeliac disease 2012: multiples of ULN for decision making do not harmonise assay performance across centres.

William Egner; Anna Shrimpton; Ravishankar Sargur; Dina Patel; Kirsty Swallow

ABSTRACT The updated ESPGHAN guidance on coeliac disease recommends the use of common multiples of the upper limit of normal (ULN) for IgA tissue transglutaminase antibodies (TG2) when deciding which diagnostic pathway to follow. The current lack of standardisation between assays makes it difficult to harmonise results between centres as different performance characteristics are observed with each assay. This variability is shown in data from external quality assessment distributions. As a result, the updated guidance is too generalised for use with all the commercial TG2 kits and is therefore not translatable for use in all centres.


Clinical and Experimental Immunology | 2011

Raised tryptase without anaphylaxis or mastocytosis: heterophilic antibody interference in the serum tryptase assay

Ravishankar Sargur; D Cowley; Sai Murng; G Wild; K. Green; Anna Shrimpton; William Egner

Mast cell tryptase (MCT) is a key diagnostic test for mastocytosis and anaphylaxis. High serum tryptase levels are also one of the risk factors for adverse reaction in venom immunotherapy, yet occasional patients are seen with raised levels in the absence of either diagnosis. False positive results can be due to assay interference by heterophilic antibodies such as rheumatoid factor (RF) and human anti‐mouse antibodies (HAMA). We therefore investigated heterophilic antibody interference by rheumatoid factor activity and HAMA as a cause of raised MCT results in the Phadia tryptase assay. Serum samples from 83 patients were assayed for MCT and rheumatoid factor before and after the use of heterophilic antibody blocking tubes (HBT). Samples with more than 17% reduction in MCT with detectable RF were then assayed for HAMA. Fourteen (17%) of the 83 samples with positive RF showed a >17% decrease in mast cell tryptase after HBT blocking. Post‐HBT, eight of 14 (57%) reverted from elevated to normal range values with falls of up to 98%. RF levels were also decreased significantly (up to 75%). Only one of the 83 tested was apparently affected by HAMA in the absence of detectable IgM RF. In conclusion, any suspicious MCT result should be checked for heterophilic antibodies to evaluate possible interference. False positive MCT levels can be caused by rheumatoid factor. We suggest a strategy for identifying assay interference, and show that it is essential to incorporate this caveat into guidance for interpretation of MCT results.


Clinical and Experimental Immunology | 2013

Quality not quantity for transglutaminase antibody 2: the performance of an endomysial and tissue transglutaminase test in screening coeliac disease remains stable over time

K. Swallow; Graeme Wild; Ravishankar Sargur; David S. Sanders; I. Aziz; Andrew D. Hopper; William Egner

National Institute of Clinical Excellence (NICE) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidance for the diagnosis of coeliac disease has been published. However, there is some controversy regarding the advice on the use of stratifying levels of immunoglobulin (IgA) tissue transglutaminase antibody (TG2) test positivity in the absence of test standardization and the vagueness of the indication to test equivocal samples. Using repeat service audit, we demonstrate that a combination of TG2 followed by IgA endomysial antibodies (EMA) is the best strategy for all degrees of mucosal abnormality using our test combination. Reliance upon immunoassay titre is not as effective, and cannot be applied consistently across populations in the absence of assay standardization. Guidelines advocating the use of tests should involve experts in laboratory diagnostics and external quality assurance to ensure that errors of generalization do not occur and that test performance is achievable in routine diagnostic use.


Clinical and Experimental Immunology | 2010

NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders

Kerri Packwood; E. Drewe; E. Staples; David Webster; Torsten Witte; Jiří Litzman; William Egner; Ravishankar Sargur; W. Sewell; Eduardo López-Granados; Suranjith L. Seneviratne; Richard J. Powell; Berne Ferry; Helen Chapel

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohns disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence‐specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild‐type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.


Clinical and Experimental Immunology | 2013

Defining the impact of individual sample variability on routine immunoassay of serum free light chains (sFLC) in multiple myeloma

S. H. K. Murng; L. Follows; P. Whitfield; John A. Snowden; K. Swallow; K. Green; Ravishankar Sargur; William Egner

Serum free light chain (sFLC) measurement has gained widespread acceptance and is incorporated into various diagnostic and response criteria. Non‐linearity and antigen excess are the main causes of ‘variability’ in the measurement of sFLC using immunoassay, but the impact of these on measurement has been unclear. We performed a retrospective evaluation using a dilutional strategy to detect these phenomena. A total of 464 samples in 2009 and 373 samples in 2010 were analysed for sFLC. Non‐linearity was detected in both high and apparently normal sFLC. Major non‐linearity of more than twofold is common in high kappa (20·2%) and lambda (14·1%). It is less common in samples with apparently normal levels – kappa (6·4%) and lambda (9·5%). 9·4% of kappa and 15·5% of lambda showed antigen excess at screening dilutions. 34·4% of the samples had either non‐linearity or antigen excess. We conclude that significant measurement variability is common in the measurement of sFLC. There is currently no reliable technique to detect non‐linearity phenomena unless a serial dilution strategy is applied to every analysis. We recommend that laboratories routinely reporting sFLC results for clinical services need appropriate strategies for addressing these issues. Clinicians should be aware of these limitations in interpretation of sFLC assay for individual patients. Future guidelines should adopt action thresholds which are grounded firmly in test performance parameters.


Clinical and Experimental Immunology | 2017

Chlorhexidine allergy in four specialist allergy centres in the United Kingdom, 2009–13: clinical features and diagnostic tests

William Egner; Matthew Helbert; Ravishankar Sargur; Kirsty Swallow; Nigel Harper; Tomaz Garcez; Sinisa Savic; Louise Savic; E. Eren

We describe an observational survey of diagnostic pathways in 104 patients attending four specialist allergy clinics in the United Kingdom following perioperative hypersensitivity reactions to chlorhexidine reactions. The majority were life‐threatening. Men undergoing urological or cardiothoracic surgery predominated. Skin prick testing and specific immunoglobulin (sIg)E testing were the most common tests used for diagnosis. Fifty‐three per cent of diagnoses were made on the basis of a single positive test. Where multiple tests were performed the sensitivity of intradermal, basophil activation and skin prick testing was 68% (50–86%), 50% (10–90%) and 35% (17–55%), respectively. Seven per cent were negative on screening tests initially, and 12 cases were only positive for a single test despite multiple testing. Intradermal tests appeared most sensitive in this context. Additional sensitization to other substances used perioperatively, particularly neuromuscular blocking agents (NMBA), was found in 28 patients, emphasizing the need to test for possible allergy to all drugs to which the patient was exposed even where chlorhexidine is positive.

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William Egner

Northern General Hospital

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Aarnoud Huissoon

Heart of England NHS Foundation Trust

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Anna Shrimpton

Northern General Hospital

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Matthew Helbert

Central Manchester University Hospitals NHS Foundation Trust

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Sinisa Savic

National Institute for Health Research

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