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1. Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses

Author

Needham, EJ, Ren, AL, Digby, RJ, Norton, EJ, Ebrahimi, S, Outtrim, JG, Chatfield, DA, Manktelow, AE, Leibowitz, MM, Newcombe, VFJ, Doffinger, R, Barcenas-Morales, G, Fonseca, C, Taussig, MJ, Burnstein, RM, Samanta, RJ, Dunai, C, Sithole, N, Ashton, NJ, Zetterberg, H, Gisslén, M, Edén, A, Marklund, E, Openshaw, PJM, Dunning, J, Griffiths, MJ, Cavanagh, J, Breen, G, Irani, SR, Elmer, A, Kingston, N, Summers, C, Bradley, JR, Taams, LS, Michael, BD, Bullmore, ET, Smith, KGC, Lyons, PA, Coles, AJ, Menon, DK, Cambridge NeuroCOVID Group the CITIID-NIHR COVID-19 BioResource Collaboration and Cambridge NIHR Clinical Research Facility, Group, Cambridge NeuroCOVID, Collaboration, CITIID-NIHR COVID-19 BioResource, Facility, Cambridge NIHR Clinical Research, UKRI MRC COVID-19 Rapid Response Call, and Wellcome Trust

Subjects
Science & Technology, Neurology & Neurosurgery, Clinical Neurology, Neurosciences, Immunity, COVID-19, CITIID-NIHR COVID-19 BioResource Collaboration, Cambridge NIHR Clinical Research Facility, brain injury, 17 Psychology and Cognitive Sciences, neuroinflammation, Cambridge NeuroCOVID Group, Neurofilament Proteins, Brain Injuries, INFECTION, Influenza, Human, Humans, Neurosciences & Neurology, Neurology (clinical), Brain injury, Covid-19, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Biomarkers, Autoantibodies
Abstract

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Published
2022

2. Multiomic Analysis Identifies Metabolic Enhancement of Immune Memory by Increased Glutaminolysis in Cells, Mice and Humans

Author

Sowerby, John M., primary, Kotagiri, Prasanti, additional, Clare, Simon, additional, Griffiths, Daniel, additional, Knight, Oliver, additional, Cuthbertson, Iona, additional, Harcourt, Katherine, additional, Pereyra Gerber, Federico Pehuen, additional, Pshenichnaya, Irina, additional, Connor, Chris, additional, Denton, Alice E., additional, Stoll, Guido, additional, Matara, Cecilia, additional, Keel, Carol, additional, Manferrari, Giulia, additional, Birkle, Tim, additional, Naydenova, Plamena, additional, Peck, Heidi, additional, Lyons, Paul A., additional, Barr, Ian, additional, Modis, Yorgo, additional, Dougan, Gordon, additional, Matheson, Nicholas J., additional, Smith, KGC, additional, and McKinney, Eoin, additional

Published
2023
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3. The impact of hypoxia on B cells in COVID-19

Author

Kotagiri, P, Mescia, F, Hanson, AL, Turner, L, Bergamaschi, L, Penalver, A, Richoz, N, Moore, SD, Ortmann, BM, Dunmore, BJ, Morgan, MD, Tuong, ZK, Gottgens, B, Toshner, M, Hess, C, Maxwell, PH, Clatworthy, MR, Nathan, JA, Bradley, JR, Lyons, PA, Burrows, N, Smith, KGC, Kotagiri, P, Mescia, F, Hanson, AL, Turner, L, Bergamaschi, L, Penalver, A, Richoz, N, Moore, SD, Ortmann, BM, Dunmore, BJ, Morgan, MD, Tuong, ZK, Gottgens, B, Toshner, M, Hess, C, Maxwell, PH, Clatworthy, MR, Nathan, JA, Bradley, JR, Lyons, PA, Burrows, N, and Smith, KGC

Abstract

BACKGROUND: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. METHODS: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. FINDINGS: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. INTERPRETATION: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. FUNDING: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust.

Published
2022

4. B cell receptor repertoire kinetics after SARS-CoV-2 infection and vaccination

Author

Kotagiri, P, Mescia, F, Rae, WM, Bergamaschi, L, Tuong, ZK, Turner, L, Hunter, K, Gerber, PP, Hosmillo, M, Hess, C, Clatworthy, MR, Goodfellow, IG, Matheson, NJ, McKinney, EF, Wills, MR, Gupta, RK, Bradley, JR, Bashford-Rogers, RJM, Lyons, PA, Smith, KGC, Kotagiri, P, Mescia, F, Rae, WM, Bergamaschi, L, Tuong, ZK, Turner, L, Hunter, K, Gerber, PP, Hosmillo, M, Hess, C, Clatworthy, MR, Goodfellow, IG, Matheson, NJ, McKinney, EF, Wills, MR, Gupta, RK, Bradley, JR, Bashford-Rogers, RJM, Lyons, PA, and Smith, KGC

Abstract

B cells are important in immunity to both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and vaccination, but B cell receptor (BCR) repertoire development in these contexts has not been compared. We analyze serial samples from 171 SARS-CoV-2-infected individuals and 63 vaccine recipients and find the global BCR repertoire differs between them. Following infection, immunoglobulin (Ig)G1/3 and IgA1 BCRs increase, somatic hypermutation (SHM) decreases, and, in severe disease, IgM and IgA clones are expanded. In contrast, after vaccination, the proportion of IgD/M BCRs increase, SHM is unchanged, and expansion of IgG clones is prominent. VH1-24, which targets the N-terminal domain (NTD) and contributes to neutralization, is expanded post infection except in the most severe disease. Infection generates a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein, while a more focused response after vaccination mainly targets the spike's receptor-binding domain. Thus, the nature of SARS-CoV-2 exposure differentially affects BCR repertoire development, potentially informing vaccine strategies.

Published
2022

5. Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

Author

Wang, J, Kotagiri, P, Lyons, PA, Al-Lamki, RS, Mescia, F, Bergamaschi, L, Turner, L, Morgan, MD, Calero-Nieto, FJ, Bach, K, Mende, N, Wilson, NK, Watts, ER, Maxwell, PH, Chinnery, PF, Kingston, N, Papadia, S, Stirrups, KE, Walker, N, Gupta, RK, Menon, DK, Allinson, K, Aitken, SJ, Toshner, M, Weekes, MP, Nathan, JA, Walmsley, SR, Ouwehand, WH, Kasanicki, M, Gottgens, B, Marioni, JC, Smith, KGC, Pober, JS, Bradley, JR, Wang, J, Kotagiri, P, Lyons, PA, Al-Lamki, RS, Mescia, F, Bergamaschi, L, Turner, L, Morgan, MD, Calero-Nieto, FJ, Bach, K, Mende, N, Wilson, NK, Watts, ER, Maxwell, PH, Chinnery, PF, Kingston, N, Papadia, S, Stirrups, KE, Walker, N, Gupta, RK, Menon, DK, Allinson, K, Aitken, SJ, Toshner, M, Weekes, MP, Nathan, JA, Walmsley, SR, Ouwehand, WH, Kasanicki, M, Gottgens, B, Marioni, JC, Smith, KGC, Pober, JS, and Bradley, JR

Abstract

Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

Published
2022

6. Shared Hypermutated Disease Specific B Cell Clones in Crohn's Disease

Author

Kotagiri, Prasanti, primary, Rae, William, additional, Bergamaschi, Laura, additional, Pombal, Diana, additional, Unger, Lukas, additional, Noor, Nurulamin, additional, Tolmeijer, Sofie, additional, Manferrari, Giulia, additional, Bashford-Rogers, Rachael, additional, Stift, Anton, additional, Lee, James, additional, Smith, KGC, additional, McKinney, Eoin, additional, and Lyons, Paul A., additional

Published
2022
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8. Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity

Author

Needham, EJ, Ren, AL, Digby, RJ, Outtrim, JG, Chatfield, DA, Manktelow, AE, Newcombe, VFJ, Doffinger, R, Barcenas-Morales, G, Fonseca, C, Taussig, MJ, Burnstein, RM, Dunai, C, Sithole, N, Ashton, NJ, Zetterberg, H, Gisslen, M, Edén, A, Marklund, E, Griffiths, MJ, Cavanagh, J, Breen, G, Irani, Elmer, A, Kingston, N, Bradley, Taams, LS, Michael, BD, Bullmore, ET, Smith, KGC, Lyons, PA, Coles, AJC, Menon, DK, Group, The Cambridge NeuroCOVID, BioResource, The NIHR COVID-19, Cambridge NIHR Clinical Research Facility, Needham, EJ [0000-0001-7042-7462], Outtrim, JG [0000-0001-8118-6430], Newcombe, VFJ [0000-0001-6044-9035], Sithole, N [0000-0002-8020-223X], Ashton, NJ [0000-0002-3579-8804], Gisslen, M [0000-0002-2357-1020], Irani, SR [0000-0002-7667-9748], and Apollo - University of Cambridge Repository

Subjects
the NIHR COVID-19 BioResource, Cambridge NIHR Clinical Research Facility, the Cambridge NeuroCOVID Group
Abstract

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly. We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray. During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens. Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.

Published
2021

9. Single-cell multi-omics analysis of the immune response in COVID-19

Author

Stephenson, E, Reynolds, G, Botting, RA, Calero-Nieto, FJ, Morgan, MD, Tuong, ZK, Bach, K, Sungnak, W, Worlock, KB, Yoshida, M, Kumasaka, N, Kania, K, Engelbert, J, Olabi, B, Spegarova, JS, Wilson, NK, Mende, N, Jardine, L, Gardner, LCS, Goh, I, Horsfall, D, McGrath, J, Webb, S, Mather, MW, Lindeboom, RGH, Dann, E, Huang, N, Polanski, K, Prigmore, E, Gothe, F, Scott, J, Payne, RP, Baker, KF, Hanrath, AT, van der Loeff, ICDS, Barr, AS, Sanchez-Gonzalez, A, Bergamaschi, L, Mescia, F, Barnes, JL, Kilich, E, de Wilton, A, Saigal, A, Saleh, A, Janes, SM, Smith, CM, Gopee, N, Wilson, C, Coupland, P, Coxhead, JM, Kiselev, VY, van Dongen, S, Bacardit, J, King, HW, Rostron, AJ, Simpson, AJ, Hambleton, S, Laurenti, E, Lyons, PA, Meyer, KB, Nikolic, MZ, Duncan, CJA, Smith, KGC, Teichmann, SA, Clatworthy, MR, Marioni, JC, Gottgens, B, Haniffa, M, Stephenson, E, Reynolds, G, Botting, RA, Calero-Nieto, FJ, Morgan, MD, Tuong, ZK, Bach, K, Sungnak, W, Worlock, KB, Yoshida, M, Kumasaka, N, Kania, K, Engelbert, J, Olabi, B, Spegarova, JS, Wilson, NK, Mende, N, Jardine, L, Gardner, LCS, Goh, I, Horsfall, D, McGrath, J, Webb, S, Mather, MW, Lindeboom, RGH, Dann, E, Huang, N, Polanski, K, Prigmore, E, Gothe, F, Scott, J, Payne, RP, Baker, KF, Hanrath, AT, van der Loeff, ICDS, Barr, AS, Sanchez-Gonzalez, A, Bergamaschi, L, Mescia, F, Barnes, JL, Kilich, E, de Wilton, A, Saigal, A, Saleh, A, Janes, SM, Smith, CM, Gopee, N, Wilson, C, Coupland, P, Coxhead, JM, Kiselev, VY, van Dongen, S, Bacardit, J, King, HW, Rostron, AJ, Simpson, AJ, Hambleton, S, Laurenti, E, Lyons, PA, Meyer, KB, Nikolic, MZ, Duncan, CJA, Smith, KGC, Teichmann, SA, Clatworthy, MR, Marioni, JC, Gottgens, B, and Haniffa, M

Abstract

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

Published
2021

10. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Author

Bergamaschi, L, Mescia, F, Turner, L, Hanson, AL, Kotagiri, P, Dunmore, BJ, Ruffieux, H, De Sa, A, Huhn, O, Morgan, MD, Gerber, PP, Wills, MR, Baker, S, Calero-Nieto, FJ, Doffinger, R, Dougan, G, Elmer, A, Goodfellow, IG, Gupta, RK, Hosmillo, M, Hunter, K, Kingston, N, Lehner, PJ, Matheson, NJ, Nicholson, JK, Petrunkina, AM, Richardson, S, Saunders, C, Thaventhiran, JED, Toonen, EJM, Weekes, MP, Gottgens, B, Toshner, M, Hess, C, Bradley, JR, Lyons, PA, Smith, KGC, Bergamaschi, L, Mescia, F, Turner, L, Hanson, AL, Kotagiri, P, Dunmore, BJ, Ruffieux, H, De Sa, A, Huhn, O, Morgan, MD, Gerber, PP, Wills, MR, Baker, S, Calero-Nieto, FJ, Doffinger, R, Dougan, G, Elmer, A, Goodfellow, IG, Gupta, RK, Hosmillo, M, Hunter, K, Kingston, N, Lehner, PJ, Matheson, NJ, Nicholson, JK, Petrunkina, AM, Richardson, S, Saunders, C, Thaventhiran, JED, Toonen, EJM, Weekes, MP, Gottgens, B, Toshner, M, Hess, C, Bradley, JR, Lyons, PA, and Smith, KGC

Abstract

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Published
2021

11. A CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis

Author

McKinney, EF, Cuthbertson, I, Harris, KM, Smilek, DE, Connor, C, Manferrari, G, Carr, EJ, Zamvil, SS, Smith, KGC, McKinney, EF, Cuthbertson, I, Harris, KM, Smilek, DE, Connor, C, Manferrari, G, Carr, EJ, Zamvil, SS, and Smith, KGC

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution. Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy. Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome. NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression. We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS.

Published
2021

12. Retrospective Diagnosis of SARS-CoV-2 Infection in Patients with Long COVID by Measuring Specific T Cell Mediated IL-2 Release

Author

Krishna, Benjamin A., primary, Lim, Eleanor Y., additional, Mactavous, Lenette, additional, Team, NIHR BioResource, additional, Lyons, Paul A., additional, Doffinger, Rainer, additional, Bradley, John, additional, Smith, KGC, additional, Sinclair, John, additional, Matheson, Nicholas J., additional, Lehner, Paul, additional, Wills, Mark R., additional, and Sithole, Nyarie, additional

Published
2021
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14. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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15. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Author

French, CE, Delon, I, Dolling, H, Sanchis-Juan, A, Shamardina, O, Mégy, K, Abbs, S, Austin, T, Bowdin, S, Branco, RG, Firth, H, Tuna, S, Aitman, TJ, Ashford, S, Astle, WJ, Bennet, DL, Bleda, M, Carss, KJ, Chinnery, PF, Deevi, SVV, Fletcher, D, Gale, DP, Gräf, SF, Hu, F, James, R, Kasanicki, MA, Kingston, N, Koziell, AB, Allen, HL, Maher, ER, Markus, HS, Meacham, S, Morrell, NW, Penkett, CJ, Roberts, I, Smith, KGC, Stark, H, Stirrups, KE, Turro, E, Watkins, H, Williamson, C, Young, T, Bradley, JR, Ouwehand, WH, Raymond, FL, Agrawal, S, Armstrong, R, Beardsall, K, Belteki, G, Bohatschek, M, Broster, S, Campbell, R, Chaudhary, R, Costa, C, D’Amore, A, Fitzsimmons, A, Hague, J, Harley, J, Hoodbhoy, S, Kayani, R, Kelsall, W, Mehta, SG, O’Donnell, R, O’Hare, S, Ogilvy-Stuart, A, Papakostas, S, Park, SM, Parker, A, Pathan, N, Prapa, M, Sammut, A, Sandford, R, Schon, K, Singh, Y, Spike, K, Tavares, ALT, Wari-Pepple, D, Wong, HS, Woods, CG, Rowitch, DH, Raymond, F Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
Male, NICU, medicine.medical_specialty, Palliative care, Adolescent, PICU, Original, Critical Illness, Critically ill children, Genomics, Critical Care and Intensive Care Medicine, Intensive Care Units, Pediatric, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Anesthesiology, Intensive care, Intensive Care Units, Neonatal, Genetics, Medicine, Humans, Prospective Studies, Medical diagnosis, Intensive care medicine, Prospective cohort study, Child, Whole genome sequencing, Whole Genome Sequencing, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Infant, 030208 emergency & critical care medicine, 030228 respiratory system, England, FOS: Biological sciences, Child, Preschool, Female, business, Genetic Background, Cohort study
Abstract

Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.

Published
2019

16. B cell Fcγ receptor IIb modulates atherosclerosis in male and female mice by controlling adaptive germinal center and innate B1-cell responses

Author

Bagchi-Chakraborty, J, Francis, A, Bray, T, Masters, L, Tsiantoulas, D, Nus, M, Harrison, J, Broekhuizen, M, Leggat, J, Clatworthy, MR, Espeli, M, Smith, KGC, Binder, CJ, Mallat, Z, Sage, AP, Nus Chimeno, Meritxell [0000-0002-6378-8910], Harrison, James [0000-0003-4960-5062], Clatworthy, Menna [0000-0002-3340-9828], Smith, Kenneth [0000-0003-3829-4326], Mallat, Ziad [0000-0003-0443-7878], Sage, Andrew [0000-0001-7255-3497], and Apollo - University of Cambridge Repository

Subjects
Male, B-Lymphocytes, Tumor Necrosis Factor-alpha, Receptors, IgG, Atherosclerosis, Germinal Center, plasma cells, Immunity, Innate, cardiovascular diseases, Mice, Inbred C57BL, Mice, Apolipoproteins E, Immunoglobulin M, inflammation, Animals, Female
Abstract

Objective. Investigate the impact of modulating B cell FcγRIIb (Fcγ receptor IIb) expression on atherosclerosis. Approach and Results. Western diet–induced atherosclerosis was assessed in Ldlr−/− or Apoe−/− mice with B cell–specific overexpression of FcγRIIb or with an FcγRIIb promoter mutation that alters FcγRIIb expression in germinal center (GC) B cells. In males, overexpression of FcγRIIb on B cells severely reduced activated, class switched B cell responses, as indicated by reductions in GC B cells, plasma cells, and serum IgG but not IgM antibodies. Male mice overexpressing FcγRIIb developed less atherosclerosis, suggesting a pathogenic role for GC B cell IgG responses. In support of this hypothesis, male mice with a promoter polymorphism-driven reduction in FcγRIIb on GC B cells but not plasma cells have a converse phenotype of enhanced GC responses and IgG2c antibodies and enhanced atherosclerosis. IgG2c significantly enhanced TNF (tumor necrosis factor) secretion by CD11b+ CD11c+ cells expressing the high-affinity receptor FcγRIV. In females, overexpression of FcγRIIb on B cells not only reduced GC B cell responses but also substantially reduced B-1 cells and IgM antibodies, which translated into acceleration of atherosclerosis. Promoter-driven reduction in FcγRIIb did not alter GC B cell responses in females and, therefore, had no impact on atherosclerosis. Conclusions. B cell FcγRIIb differentially alters proatherogenic adaptive GC B cell and atheroprotective innate B-1 responses in male and female mice fed a western diet. Our results highlight the importance of a better understanding and ability to selectively target B cell responses in future immunotherapeutic approaches against human cardiovascular disease.

Published
2019
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17. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, P, Peters, J, Alberici, F, Liley, J, Coulson, R, Astle, W, Baldini, C, Bonatti, F, Cid, M, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, D, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, M, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramierez, G, Rewerska, B, Schett, G, Sinico, R, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, A, Bruce, I, Clarkson, M, Conlon, N, Dasgupta, B, Doulton, T, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, A, Marguerie, C, Maritati, F, Marvisi, C, Mchugh, N, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, R, Vaglio, A, Holle, J, Wallace, C, Smith, K, Lyons, PA, Peters, JE, Cid, MC, Little, MA, Ramierez, GA, Butterworth, AS, DasGupta, B, Doulton, TWR, Manfredi, AA, McHugh, NJ, Watts, RA, Holle, JU, Smith, KGC, Lyons, P, Peters, J, Alberici, F, Liley, J, Coulson, R, Astle, W, Baldini, C, Bonatti, F, Cid, M, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, D, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, M, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramierez, G, Rewerska, B, Schett, G, Sinico, R, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, A, Bruce, I, Clarkson, M, Conlon, N, Dasgupta, B, Doulton, T, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, A, Marguerie, C, Maritati, F, Marvisi, C, Mchugh, N, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, R, Vaglio, A, Holle, J, Wallace, C, Smith, K, Lyons, PA, Peters, JE, Cid, MC, Little, MA, Ramierez, GA, Butterworth, AS, DasGupta, B, Doulton, TWR, Manfredi, AA, McHugh, NJ, Watts, RA, Holle, JU, and Smith, KGC

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Published
2019

18. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, PA, Peters, JE, Alberici, F, Liley, J, Coulson, RMR, Astle, W, Baldini, C, Bonatti, F, Cid, MC, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, DRW, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, MA, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramirez, GA, Rewerska, B, Schett, G, Sinico, RA, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, AS, Bruce, I, Clarkson, M, Conlon, N, DasGupta, B, Doulton, TWR, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, AA, Marguerie, C, Maritati, F, Marvisi, C, McHugh, NJ, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, RA, Vaglio, A, Holle, JU, Wallace, C, Smith, KGC, Lyons, PA, Peters, JE, Alberici, F, Liley, J, Coulson, RMR, Astle, W, Baldini, C, Bonatti, F, Cid, MC, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, DRW, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, MA, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramirez, GA, Rewerska, B, Schett, G, Sinico, RA, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, AS, Bruce, I, Clarkson, M, Conlon, N, DasGupta, B, Doulton, TWR, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, AA, Marguerie, C, Maritati, F, Marvisi, C, McHugh, NJ, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, RA, Vaglio, A, Holle, JU, Wallace, C, and Smith, KGC

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Published
2019

19. Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author

Karyn Megy, William Rae, Thaventhiran Jed., A Herwadkar, Paul Tuijnenburg, S Grigoriadou, Oliver S. Burren, Christopher J. Penkett, Zinan Zhang, Daniel Greene, Sinisa Savic, Willem H. Ouwehand, Matthew E. Hurles, Deevi Svv., Edgar Jdm., Crina Samarghitean, A Worth, Nicholas Gleadall, David Ellinghaus, Taco W. Kuijpers, Tom H. Karlsen, H Lango Allen, Catharina Schuetz, Pavels Gordins, Antony J. Cutler, Jesmeen Maimaris, Smith Kgc., David M. Sansom, Steven Hanson, Jonathan Stephens, Paul A. Lyons, Paula Rayner-Matthews, Kathleen Stirrups, Alba Sanchis-Juan, Adrian J. Thrasher, Anita Chandra, Andy G. Lynch, E Rivers, Siobhan O. Burns, Matthew A. Brown, Rachel Linger, Ilenia Simeoni, Eva Ellinghaus, Kimberly Gilmour, Ravishankar Sargur, Farmery Jhr., Matthew Buckland, Aarnoud Huissoon, Sarah Goddard, Dinakantha S. Kumararatne, Emily Staples, Ernest Turro, Helen Baxendale, Moira Thomas, Silje F. Jørgensen, Stephen Jolles, Suranjith L. Seneviratne, F Boschann, and Neill S. Cooper

Subjects
Whole genome sequencing, Multidisciplinary, business.industry, Cohort, MEDLINE, Primary immunodeficiency, Medicine, Genomics, Computational biology, business, medicine.disease
Published
2020

20. Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

Author

Whitworth, J, Smith, PS, Martin, J-E, West, H, Luchetti, A, Rodger, F, Clark, G, Carss, K, Stephens, J, Stirrups, K, Penkett, C, Mapeta, R, Ashford, S, Megy, K, Shakeel, H, Ahmed, M, Adlard, J, Barwell, J, Brewer, C, Casey, RT, Armstrong, R, Cole, T, Evans, DG, Fostira, F, Greenhalgh, L, Hanson, H, Henderson, A, Hoffman, J, Izatt, L, Kumar, A, Kwong, A, Lalloo, F, Ong, KR, Paterson, J, Park, S-M, Chen-Shtoyerman, R, Searle, C, Side, L, Skytte, A-B, Snape, K, Woodward, ER, Tischkowitz, MD, Maher, ER, Aitman, T, Alachkar, H, Ali, S, Allen, L, Allsup, D, Ambegaonkar, G, Anderson, J, Antrobus, R, Arno, G, Arumugakani, G, Astle, W, Attwood, A, Austin, S, Bacchelli, C, Bakchoul, T, Bariana, TK, Baxendale, H, Bennett, D, Bethune, C, Bibi, S, Bitner-Glindzicz, M, Bleda, M, Boggard, H, Bolton-Maggs, P, Booth, C, Bradley, JR, Brady, A, Brown, M, Browning, M, Bryson, C, Burns, S, Calleja, P, Canham, N, Carmichael, J, Caulfield, M, Chalmers, E, Chandra, A, Chinnery, P, Chitre, M, Church, C, Clement, E, Clements-Brod, N, Clowes, V, Coghlan, G, Collins, P, Cookson, V, Cooper, N, Corris, P, Creaser-Myers, A, Dacosta, R, Daugherty, L, Davies, S, Davis, J, De Vries, M, Deegan, P, Deevi, SVV, Deshpande, C, Devlin, L, Dewhurst, E, Dixon, P, Doffinger, R, Dormand, N, Drewe, E, Edgar, D, Egner, W, Erber, WN, Erwood, M, Everington, T, Favier, R, Firth, H, Fletcher, D, Flinter, F, Frary, A, Freson, K, Furie, B, Furnell, A, Gale, D, Gardham, A, Gattens, M, Ghali, N, Ghataorhe, PK, Ghurye, R, Gibbs, S, Gilmour, K, Gissen, P, Goddard, S, Gomez, K, Gordins, P, Graf, S, Gräf, S, Greene, D, Greenhalgh, A, Greinacher, A, Grigoriadou, S, Grozeva, D, Hackett, S, Hadinnapola, C, Hague, R, Haimel, M, Halmagyi, C, Hammerton, T, Hart, D, Hayman, G, Heemskerk, JWM, Henderson, R, Hensiek, A, Henskens, Y, Herwadkar, A, Holden, S, Holder, M, Holder, S, Hu, F, Veld, A, Huissoon, A, Humbert, M, Hurst, J, James, R, Jolles, S, Josifova, D, Kazmi, R, Keeling, D, Kelleher, P, Kelly, AM, Kennedy, F, Kiely, D, Kingston, N, Koziell, A, Krishnakumar, D, Kuijpers, TW, Kuijpers, T, Kumararatne, D, Kurian, M, Laffan, MA, Lambert, MP, Allen, HL, Lango-Allen, H, Lawrie, A, Lear, S, Lees, M, Lentaigne, C, Liesner, R, Linger, R, Longhurst, H, Lorenzo, L, Louka, E, Machado, R, Ross, RM, Maclaren, R, Maher, E, Maimaris, J, Mangles, S, Manson, A, Markus, HS, Martin, J, Masati, L, Mathias, M, Matser, V, Maw, A, McDermott, E, McJannet, C, Meacham, S, Meehan, S, Mehta, S, Michaelides, M, Millar, CM, Moledina, S, Moore, A, Morrell, N, Mumford, A, Murng, S, Murphy, E, Nejentsev, S, Noorani, S, Nurden, P, Oksenhendler, E, Othman, S, Ouwehand, WH, Papadia, S, Parker, A, Pasi, J, Patch, C, Payne, J, Peacock, A, Peerlinck, K, Penkett, CJ, Pepke-Zaba, J, Perry, D, Perry, DJ, Pollock, V, Polwarth, G, Ponsford, M, Qasim, W, Quinti, I, Rankin, S, Rankin, J, Raymond, FL, Rayner-Matthews, P, Rehnstrom, K, Reid, E, Rhodes, CJ, Richards, M, Richardson, S, Richter, A, Roberts, I, Rondina, M, Rosser, E, Roughley, C, Roy, N, Rue-Albrecht, K, Samarghitean, C, Sanchis-Juan, A, Sandford, R, Santra, S, Sargur, R, Savic, S, Schotte, G, Schulman, S, Schulze, H, Scott, R, Scully, M, Seneviratne, S, Sewell, C, Shamardina, O, Shipley, D, Simeoni, I, Sivapalaratnam, S, Smith, KGC, Sohal, A, Southgate, L, Staines, S, Staples, E, Stark, H, Stauss, H, Stein, P, Stock, S, Suntharalingam, J, Talks, K, Tan, Y, Thachil, J, Thaventhiran, J, Thomas, E, Thomas, M, Thompson, D, Thrasher, A, Tischkowitz, M, Titterton, C, Toh, C-H, Toshner, M, Treacy, C, Trembath, R, Tuna, S, Turek, W, Turro, E, Van Geet, C, Veltman, M, Vogt, J, Von Ziegenweldt, J, Noordegraaf, AV, Wakeling, E, Wanjiku, I, Warner, TQ, Wassmer, E, Watkins, H, Watt, C, Webster, N, Welch, S, Westbury, S, Wharton, J, Whitehorn, D, Wilkins, M, Willcocks, L, Williamson, C, Woods, G, Wort, J, Yeatman, N, Yong, P, Young, T, and Yu, P

Abstract

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Published
2018

21. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

22. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Author

Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository

Subjects
Adult, DNA-Binding Proteins, Homeodomain Proteins, Immunologic Deficiency Syndromes, Prevalence, Humans, Nuclear Proteins
Published
2018
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23. Metabolic exhaustion in infection, cancer and autoimmunity

Author

McKinney, EF, Smith, KGC, McKinney, Eoin [0000-0003-3516-3072], and Apollo - University of Cambridge Repository

Subjects
Neoplasms, Animals, Humans, Autoimmunity, Cell Differentiation, CD8-Positive T-Lymphocytes, Infections, Lymphocyte Activation
Abstract

It has become increasingly clear that changes in metabolism are not just consequences of T cell activation but instead are also essential drivers of that process that shape the extent and nature of differentiation and function. The process of T cell exhaustion has been linked to the outcome of chronic immune responses in multiple contexts, including chronic infection, cancer and autoimmunity. Factors that regulate the development and maintenance of exhaustion are of increasing interest as targets of therapeutic modulation. Studies have shown T cell immunometabolism to be integral to the control and development of T cell exhaustion. Early metabolic changes are responsible for the later emergence of exhaustion, do not simply reflect changes secondary to chronic activation and are modifiable. Increased understanding of this metabolic control promises to improve the ability to modulate T cell immunity to chronic antigen stimulation in multiple contexts.

Published
2018
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24. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease

Author

Lee, JC, Biasci, D, Roberts, R, Gearry, RB, Mansfield, JC, Ahmad, T, Prescott, NJ, Satsangi, J, Wilson, DC, Jostins, L, Anderson, CA, UK IBD Genetics Consortium, Traherne, JA, Lyons, PA, Parkes, M, Smith, KGC, Lee, James [0000-0001-5711-9385], Biasci, Daniele [0000-0003-3148-8152], Traherne, James [0000-0002-6003-8559], Lyons, Paul [0000-0001-7035-8997], Parkes, Miles [0000-0002-6467-0631], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Genotype, Genome-wide association study, Disease, Biology, Bioinformatics, Inflammatory bowel disease, Polymorphism, Single Nucleotide, Article, outcomes research, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Polymorphism (computer science), inflammatory bowel disease, Genetic variation, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Crohn's disease, Genome, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, genome-wide association studies, 030211 gastroenterology & hepatology, Female, Colitis, Ulcerative, Disease Susceptibility, Outcomes research, Genome-Wide Association Study
Abstract

For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis)1,2,3. Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis4,5,6, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants7,8,9,10,11,12,13. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.

Published
2017
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25. Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity

Author

Thomas, DC, Clare, S, Sowerby, JM, Pardo, M, Juss, JK, Goulding, DA, van der Weyden, L, Storisteanu, D, Prakash, A, Espeli, M, Flint, S, Lee, JC, Hoenderdos, K, Kane, L, Harcourt, K, Mukhopadhyay, S, Umrania, Y, Antrobus, R, Nathan, JA, Adams, DJ, Bateman, A, Choudhary, JS, Lyons, PA, Condliffe, AM, Chilvers, ER, Dougan, G, Smith, KGC, Thomas, DC, Clare, S, Sowerby, JM, Pardo, M, Juss, JK, Goulding, DA, van der Weyden, L, Storisteanu, D, Prakash, A, Espeli, M, Flint, S, Lee, JC, Hoenderdos, K, Kane, L, Harcourt, K, Mukhopadhyay, S, Umrania, Y, Antrobus, R, Nathan, JA, Adams, DJ, Bateman, A, Choudhary, JS, Lyons, PA, Condliffe, AM, Chilvers, ER, Dougan, G, and Smith, KGC

Abstract

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense.

Published
2017

26. CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection

Author

Linterman, MA, Denton, AE, Divekar, DP, Zvetkova, I, Kane, L, Ferreira, C, Veldhoen, M, Clare, S, Dougan, G, Espeli, M, Smith, KGC, Linterman, MA, Denton, AE, Divekar, DP, Zvetkova, I, Kane, L, Ferreira, C, Veldhoen, M, Clare, S, Dougan, G, Espeli, M, and Smith, KGC

Abstract

The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4(+) T cells after priming. We show that continued CD28 expression is important for effector CD4(+) T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.

Published
2014

27. Foxp3+ follicular regulatory T cells control the germinal center response

Author

Linterman, MA, Pierson, W, Lee, SK, Kallies, A, Kawamoto, S, Rayner, TF, Srivastava, M, Divekar, DP, Beaton, L, Hogan, JJ, Fagarasan, S, Liston, A, Smith, KGC, Vinuesa, CG, Linterman, MA, Pierson, W, Lee, SK, Kallies, A, Kawamoto, S, Rayner, TF, Srivastava, M, Divekar, DP, Beaton, L, Hogan, JJ, Fagarasan, S, Liston, A, Smith, KGC, and Vinuesa, CG

Abstract

Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.

Published
2011

28. Copy number, linkage disequilibrium and disease association in the FCGR locus

Author

Niederer, HA, Willcocks, LC, Rayner, TF, Yang, W, Lau, YL, Williams, TN, Scott, JAG, Urban, BC, Peshu, N, Dunstan, SJ, Hien, TT, Phu, NH, Padyukov, L, Gunnarsson, I, Svenungsson, E, Savage, CO, Watts, RA, Lyons, PA, Clayton, DG, Smith, KGC, Niederer, HA, Willcocks, LC, Rayner, TF, Yang, W, Lau, YL, Williams, TN, Scott, JAG, Urban, BC, Peshu, N, Dunstan, SJ, Hien, TT, Phu, NH, Padyukov, L, Gunnarsson, I, Svenungsson, E, Savage, CO, Watts, RA, Lyons, PA, Clayton, DG, and Smith, KGC

Abstract

The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.

Published
2010

29. Distinct cell-specific control of autoimmunity and infection by Fc gamma RIIb

Author

Brownlie, RJ, Lawlor, KE, Niederer, HA, Cutler, AJ, Xiang, Z, Clatworthy, MR, Floto, RA, Greaves, DR, Lyons, PA, Smith, KGC, Brownlie, RJ, Lawlor, KE, Niederer, HA, Cutler, AJ, Xiang, Z, Clatworthy, MR, Floto, RA, Greaves, DR, Lyons, PA, and Smith, KGC

Abstract

FcgammaRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcgammaRIIb can modulate these processes, we created transgenic mice overexpressing FcgammaRIIb on B cells or macrophages. Overexpression of FcgammaRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcgammaRIIb in immune responses, demonstrate the contrasting roles played by FcgammaRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcgammaRIIb expression on B cells in inflammatory and autoimmune disease.

Published
2008

31. Microarray analysis of human leucocyte subsets: the advantages of positive selection and rapid purification.

Author

Lyons, PA, Koukoulaki, M, Hatton, A, Doggett, K, Woffendin, HB, Chaudhry, AN, Smith, KGC, Lyons, PA, Koukoulaki, M, Hatton, A, Doggett, K, Woffendin, HB, Chaudhry, AN, and Smith, KGC

Abstract

BACKGROUND: For expression profiling to have a practical impact in the management of immune-related disease it is essential that it can be applied to peripheral blood cells. Early studies have used total peripheral blood mononuclear cells, and as a consequence the majority of the disease-related signatures identified have simply reflected differences in the relative abundance of individual cell types between patients and controls. To identify cell-specific changes in transcription it would be necessary to profile purified leucocyte subsets. RESULTS: We have used sequential rounds of positive selection to isolate CD4 and CD8 T cells, CD19 B cells, CD14 monocytes and CD16 neutrophils for microarray analysis from a single blood sample. We compared gene expression in cells isolated in parallel using either positive or negative selection and demonstrate that there are no significant consistent changes due to positive selection, and that the far inferior results obtained by negative selection are largely due to reduced purity. Finally, we demonstrate that storing cells prior to separation leads to profound changes in expression, predominantly in cells of the myeloid lineage. CONCLUSION: Leukocyte subsets should be prepared for microarray analysis by rapid positive selection.

Published
2007

32. European consensus statement on the terminology used in the management of lupus glomerulonephritis

Author

Gordon, C, primary, Jayne, D, additional, Pusey, C, additional, Adu, D, additional, Amoura, Z, additional, Aringer, M, additional, Ballerin, J, additional, Cervera, R, additional, Calvo-Alén, J, additional, Chizzolini, C, additional, Dayer, JM, additional, Doria, A, additional, Ferrario, F, additional, Floege, J, additional, Guillevin, L, additional, Haubitz, M, additional, Hiepe, F, additional, Houssiau, F, additional, Lesavre, P, additional, Lightstone, L, additional, Meroni, PL, additional, Meyer, O, additional, Moulin, B, additional, O’Reilly, K, additional, Praga, M, additional, Schulze-Koops, H, additional, Sinico, RA, additional, Smith, KGC, additional, Tincani, A, additional, Vasconcelos, C, additional, and Hughes, G, additional

Published
2009
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33. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells

Author

Smith, KGC, Light, A, O'Reilly, LA, Ang, SM, Strasser, A, Tarlinton, D, Smith, KGC, Light, A, O'Reilly, LA, Ang, SM, Strasser, A, and Tarlinton, D

Abstract

Immunization with T cell-dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2-transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.

Published
2000

36. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment.

Author

Smith KGC, Jones RB, Burns SM, and Jayne DRW

Abstract

OBJECTIVE: Current treatments for systemic lupus erythematosus (SLE) and vasculitis contribute to mortality and incapacity and are only partially effective; thus, newer therapies are clearly needed. Depletion of B cells has led to disease control in patients with autoimmune disorders. We sought to assess the long-term efficacy and safety of a B cell-depleting therapy in patients with SLE and patients with vasculitis. METHODS: In a prospective study with a median followup of 24 months, 11 patients with active or refractory SLE and 11 patients with active or refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) received a course of therapy with rituximab (an anti-CD20 monoclonal antibody) along with a single dose of intravenous cyclophosphamide. RESULTS: Remission followed rapid B cell depletion, with response rates of 100% among the 11 patients with SLE (6 patients had a complete response, and 5 patients had a partial response) and 91% among the 11 patients with AAV (9 patients had a complete response, and 1 patient had partial remission). A renal response occurred in all 6 patients with lupus nephritis. Clinical improvement was accompanied by significant reductions in the daily dose of prednisolone. Relapse occurred in 64% of the patients with SLE and in 60% of those with AAV. B cell return preceded relapse in the majority of patients, and further treatment with rituximab proved effective. IgG and IgM levels were maintained in the normal range. The incidence of infective complications was low; however, infusion reactions were common, and human antichimeric antibodies developed in 5 of 14 patients. CONCLUSION: B cell depletion offers the prospect of sustained disease remission and improved disease control combined with low toxicity in patients with active or refractory SLE or AAV. Relapse following treatment is common, but re-treatment is rapidly effective. [ABSTRACT FROM AUTHOR]

Published
2006
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37. Suppression of the humoral immune response by mycophenolate mofetil.

Author

Smith, KGC, Isbel, NM, Catton, MG, Leydon, JA, Becker, GJ, and Walker, RG

Abstract

Background: No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. [ABSTRACT FROM PUBLISHER]

Published
1998
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38. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease

Author

Lee, JC, Biasci, D, Roberts, R, Gearry, RB, Mansfield, JC, Ahmad, T, Prescott, NJ, Satsangi, J, Wilson, DC, Jostins, L, Anderson, CA, UK IBD Genetics Consortium, Traherne, JA, Lyons, PA, Parkes, M, and Smith, KGC

Subjects
outcomes research, inflammatory bowel disease, genome-wide association studies, 3. Good health
Abstract

For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.

40. Analysis of the B cell receptor repertoire in six immune-mediated diseases

Author

Bashford-Rogers, RJM, Bergamaschi, L, McKinney, EF, Pombal, DC, Mescia, F, Lee, JC, Thomas, DC, Flint, SM, Kellam, P, Jayne, DRW, Lyons, PA, and Smith, KGC

Subjects
Adult, Immunoglobulin Isotypes, Young Adult, Immune System Diseases, Immunoglobulin G, Humans, Receptors, Antigen, B-Cell, Middle Aged, Immunoglobulin Class Switching, 3. Good health, Aged, Clone Cells, Immunoglobulin A
Abstract

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

41. Blood Coagulation

Author

Preissner, Klaus T, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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42. Western Blot Analysis

Author

Brunner, Georg, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank AM, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub FJ FJ, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney EW, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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43. Bone Marrow and Hematopoiesis

Author

Henschler, Reinhard, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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44. Birth Defects, Immune Protection Against

Author

Holladay, Steven, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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45. B Cell Maturation and Immunological Memory

Author

Berek, Claudia, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

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2005
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46. Blotting Membrane

Author

Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

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2005
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47. Bioaerosols

Author

Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

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2005
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48. B Lymphocytes

Author

Kaminski, Norbert E, Sulentic, Courtney E W, Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

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2005
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49. Buffy Coat

Author

Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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50. Buehler Test

Author

Assenmacher, Mario, Avraham, Hava Karsenty, Avraham, Shalom, Bala, Shukal, Barnett, John, Basketter, David, Ben-David, Yaacov, Berek, Claudia, Blümel, Jörg, Bolliger, Anne Provencher, Bolon, Brad, Bradley, S Gaylen, Brundage, Kathleen M, Brunner, Georg, Bugelski, Peter J, Burchiel, Scott W, Burns-Naas, Leigh Ann, Bussiere, Jeanine L., Cameron, Scott B, Carey, Michelle, Cederbrant, Karin, Chow, Anthony W, Cohen, Mitchell D., Colagiovanni, Dorothy, Contreras, Marcela, Cornacoff, Joel B, Corsini, Emanuela, Crevel, René, Cuff, Christopher, Czuprynski, Charles J, Damoiseaux, Jan GMC, Daniels, Geoff, Dayan, Anthony D, Dearman, Rebecca J, Dodson, Sarah V. M., Ebringer, Alan, Engel, Andrea, Esser, Charlotte, Fairley, Kimberly J, Fernandez-Botran, Rafael, Flaherty, Dennis K, Frings, Werner, Gad, Shayne Cox, Gardner, Donald E, Gardner, Susan C, Garssen, Johan, Gashev, Anatoliy A, Geffner, Jorge, Geginat, Gernot, Gemsa, Diethard, Gerberick, Frank, Germolec, Dori, Gilbert, Kathleen M., Giles-Komar, Jill, Gore, Elizabeth R, Griem, Peter, Hagelschuer, Ina, Haggerty, Helen G., Hall, Andrew, Hanneken, S., Hastings, Kenneth L, Havelaar, Arie H, Heisler, Eckhart, Helm, Ricki M, Henschler, Reinhard, Herrmann, Thomas, Herzyk, Danuta J, Higgins, Rachel R., Hitzfeld, Bettina, Holladay, Steven, Holsapple, Michael, House, Robert V, Hughes, Lucy, Jeong, Tae Cheon, Johnson, Victor J, de Jong, Wim H, de Jonge, Rob, Kamath, Arati, Kaminski, Norbert E, Kaminsky, Ronald, Karol, Meryl, Kashon, Michael L, Kerkvliet, Nancy I, Kimber, Ian, Knight, David M, Knulst, AC, Koren, Eugen, Kraal, Georg, Kretz-Rommel, Anke, Kuper, C Frieke, Ladics, Gregory, Laiosa, Michael, Landreth, Kenneth S., Lawrence, B Paige, Lawrence, David A, Lee, Byeong-Chel, Lee, William, Leino, Lasse, Lemke, Hilmar, Lewis, JG, Liebau, Jutta, Lollini, Pier-Luigi, van Loveren, Henk, Luebke, Bob, Luster, Michael I, Mage, Rose G, Maier, Curtis C., Martin, Michael U., Maurer, Thomas, McKarns, Susan C, Meade, B Jean, Moser, Bernhard, Nagata, Shigekazu, Nain, Marianne, Neumann, Norbert J., Novicki, Deborah L, Olsen, John L, Pauluhn, Jürgen, Pichler, Werner, Pieters, Raymond, Pollard, K Michael, Preissner, Klaus T, Pruett, Stephen B, Pumford, Neil R., Rashid, Taha, Ratajczak, Helen V, Redegeld, Frank A M, Regal, Jean F, Resch, Klaus, Rodgers, Kathleen, Roman, Danielle, Rose, Noel R, Rosenthal, Gary J., Sali, Tina, Samsom, Janneke N, Savelkoul, Huub F J, Schafer, Rosana, Schatz, Mark, Schild, Hansjoerg, Shepherd, David, Shiohara, Tetsuo, Silverstone, Allen, Simeonova, Petia P, Smialowicz, Ralph J, Smith, KGC, Soos, Jeanne M, Stittelaar, Koert J, Straube, Frank, Sulentic, Courtney E W, Swart, B, Takumi, Katsuhisa, Tarkowski, Maciej, Tervaert, Jan Willem Cohen, Thomas, Peter T, Tinkle, Sally S, Treacy, George, Trouba, Kevin, Tryphonas, Helen, Uguccioni, Mariagrazia, Ulrich, Peter, van der Heijden, Maurice W, Van Loveren, H, Vandebriel, Rob J, Vleminckx, Kris, Vohr, Hans-Werner, Weinbauer, Gerhard F, Weinstein, I Bernard, Weltzien, Hans Ulrich, Weston, Ainsley, White, Kimber L., Wilson, Clyde, Wing, Mark, Wolf, Anna Maria, Yaqoob, Parveenn, Yucesoy, Berran, Zawieja, David C, Zelikoff, Judith T, Zola, H, and van Zwieten, PA

Published
2005
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