Publications
187 results found
Boyton RJ, Altmann D, 2016, Bronchiectasis: Current Concepts in Pathogenesis, Immunology, and Microbiology, Annual Review of Pathology-Mechanisms of Disease, Vol: 11, Pages: 523-554, ISSN: 1553-4014
Bronchiectasis is a disorder of persistent lung inflammation and recurrent infection, defined by a common pathological end point: irreversible bronchial dilatation arrived at through diverse etiologies. This suggests an interplay between immunogenetic susceptibility, immune dysregulation, bacterial infection, and lung damage. The damaged epithelium impairs mucus removal and facilitates bacterial infection with increased cough, sputum production, and airflow obstruction. Lung infection is caused by respiratory bacterial and fungal pathogens, including Pseudomonas aeruginosa, Haemophilus, Aspergillus fumigatus, and nontuberculous mycobacteria. Recent studies have highlighted the relationship between the lung microbiota and microbial-pathogen niches. Disease may result from environments favoring interleukin-17-driven neutrophilia. Bronchiectasis may present in autoimmune disease, as well as conditions of immune dysregulation, such as combined variable immune deficiency, transporter associated with antigen processing–deficiency syndrome, and hyperimmunoglobulin E syndrome. Differences in prevalence across geography and ethnicity implicate an etiological mix of genetics and environment underpinning susceptibility.
Ascough S, Ingram RJ, Chu KK, et al., 2016, CD4+ T Cells Targeting Dominant and Cryptic Epitopes from Bacillus anthracis Lethal Factor., Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X
Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called 'cryptic' or 'subdominant' epitopes. We analyzed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISpot assays we characterized epitopes that elicited a response following immunization with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, as a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 transgenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were influenced by the speci
Sim M, Stowell J, Seargent R, et al., 2015, KIR2DL3 and KIR2DL1 show similar impact on licensing ofhuman NK cells, European Journal of Immunology, Vol: 46, Pages: 185-191, ISSN: 1521-4141
Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated withdisease risk, implicating functional roles for NK cells (NKCs) or KIR+ T cells. KIR/HLA-I interactionscan act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsicresponsiveness. We compared licensing conferred by the weaker, HLA-C group 1/KIR2DL3, and thestronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The ‘rheostat model’ predicts weakerlicensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation inNKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensingimpact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to eachother. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3+ andKIR2DL1+ NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3+ and KIR2DL1+ NKC to asimilar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double positive NKCthan the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacityto license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands donot correlate with NKC licensing. Altogether, our results show that the basis for disease associationsof HLA-C and KIR2DL likely encompasses factors other than licensing.
Reynolds C, Goudet A, Jenjaroen K, et al., 2015, T cell immunity to the Alkyl Hydroperoxide Reductase of Burkholderia pseudomallei: A correlate of disease outcome in Acute Melioidosis., Journal of Immunology, Vol: 194, Pages: 4814-4824, ISSN: 0022-1767
There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of 'humanized' HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.
Reynolds CJ, Sim MJ, Quigley KJ, et al., 2015, Autoantigen cross-reactive environmental antigen can trigger multiple sclerosis-like disease., Journal of Neuroinflammation, Vol: 12, ISSN: 1742-2094
BACKGROUND: Multiple sclerosis is generally considered an autoimmune disease resulting from interaction between predisposing genes and environmental factors, together allowing immunological self-tolerance to be compromised. The precise nature of the environmental inputs has been elusive, infectious agents having received considerable attention. A recent study generated an algorithm predicting naturally occurring T cell receptor (TCR) ligands from the proteome database. Taking the example of a multiple sclerosis patient-derived anti-myelin TCR, the study identified a number of stimulatory, cross-reactive peptide sequences from environmental and human antigens. Having previously generated a spontaneous multiple sclerosis (MS) model through expression of this TCR, we asked whether any of these could indeed function in vivo to trigger CNS disease by cross-reactive activation. FINDINGS: A number of myelin epitope cross-reactive epitopes could stimulate T cell immunity in this MS anti-myelin TCR transgenic model. Two of the most stimulatory of these 'environmental' epitopes, from Dictyostyelium slime mold and from Emiliania huxleyi, were tested for the ability to induce MS-like disease in the transgenics. We found that immunization with cross-reactive peptide from Dictyostyelium slime mold (but not from E. huxleyi) induces severe disease. CONCLUSIONS: These specific environmental epitopes are unlikely to be common triggers of MS, but this study suggests that our search for the cross-reactivity triggers of autoimmune activation leading to MS should encompass epitopes not just from the 'infectome' but also from the full environmental 'exposome.'
Nicholas RS, Kostadima V, Hanspal M, et al., 2015, MS in South Asians in England: early disease onset and novel pattern of myelin autoimmunity., BMC Neurology, Vol: 15, ISSN: 1471-2377
BACKGROUND: Epidemiological studies describe a latitude gradient for increased MS prevalence and a preponderance of disease in Caucasian individuals. However, individuals from other ethnic backgrounds and low-risk regions can acquire a raised risk through migration. Nearly a fifth of the London population is of Asian/Asian-British origin and a significant proportion of referrals are from this group. METHODS: We investigated whether there were differences in timing, presentation, severity, and immunology of disease (with respect to CD4 myelin epitope recognition) between individuals in London with MS who were either of S. Asian or Caucasian origin. Individuals of S. Asian origin with MS were compared with healthy S. Asian controls, individuals with MS and of Caucasian origin and Caucasian controls. RESULTS: Age at MS onset is significantly lower in the S. Asian group, attributable to earlier onset specifically in UK-born individuals, though clinical presentation is similar. Analysis of CD4 autoimmunity to myelin antigens shows disease in S. Asian individuals to encompass recognition of novel epitopes; immunity to MBP116-130 in S. Asian individuals was highly disease-specific. CONCLUSIONS: These findings emphasize the need to define disease profiles across ethnicities and identify environmental triggers conferring acquired risk. Such findings must inform choices for immunotherapeutic interventions suitable for all, across ethnicities.
Ingram RJ, Ascough S, Reynolds CJ, et al., 2015, Natural cutaneous anthrax infection, but not vaccination, induces a CD4(+) T cell response involving diverse cytokines., Cell and Bioscience, Vol: 5, ISSN: 2045-3701
BACKGROUND: Whilst there have been a number of insights into the subsets of CD4(+) T cells induced by pathogenic Bacillus anthracis infections in animal models, how these findings relate to responses generated in naturally infected and vaccinated humans has yet to be fully established. We describe the cytokine profile produced in response to T cell stimulation with a previously defined immunodominant antigen of anthrax, lethal factor (LF), domain IV, in cohorts of individuals with a history of cutaneous anthrax, compared with vaccinees receiving the U.K. licenced Anthrax Vaccine Precipitated (AVP) vaccine. FINDINGS: We found that immunity following natural cutaneous infection was significantly different from that seen after vaccination. AVP vaccination was found to result in a polarized IFNγ CD4+ T cell response, while the individuals exposed to B. anthracis by natural infection mounted a broader cytokine response encompassing IFNγ, IL-5, -9, -10, -13, -17, and -22. CONCLUSIONS: Vaccines seeking to incorporate the robust, long-lasting, CD4 T cell immune responses observed in naturally acquired cutaneous anthrax cases may need to elicit a similarly broad spectrum cellular immune response.
Quigley KJ, Reynolds CJ, Goudet A, et al., 2015, Chronic infection by Mucoid Pseudomonas aeruginosa associated with dysregulation in T cell immunity to OprF., American Journal of Respiratory and Critical Care Medicine, Vol: 191, ISSN: 1073-449X
RATIONALE: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting on morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease. OBJECTIVES: We characterized T cell immunity to the PA antigen, outer membrane porin F (OprF), analyzing immunodominant epitopes in relation to infection status. METHODS: Non-CF bronchiectasis patients were stratified by frequency of PA isolation. T cell IFNγ immunity to OprF and its immunodominant epitopes was characterized. Patterns of HLA-restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response and T cell activation transcripts. MEASUREMENTS AND MAIN RESULTS: Patients were stratified according to whether PA was never, sometimes (<50%) or frequently (>or=50%) isolated from sputum. Patients with frequent PA sputum-positive isolates were more likely to be infected by mucoid PA, and showed a narrow T cell epitope response and a relative reduction in Th1 polarizing transcription factors, but enhanced immunity with respect to antibody production, innate cytokines and chemokines. CONCLUSIONS: We have defined the immunodominant, HLA-restricted, T cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.
Altmann D, Boyton R, 2015, Replace 'pathogens' with 'perceptogens', NATURE, Vol: 518, Pages: 35-35, ISSN: 0028-0836
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Musson JA, Reynolds CJ, Rinchai D, et al., 2014, CD4<SUP>+</SUP> T Cell Epitopes of FliC Conserved between Strains of <i>Burkholderia</i>: Implications for Vaccines against Melioidosis and Cepacia Complex in Cystic Fibrosis, JOURNAL OF IMMUNOLOGY, Vol: 193, Pages: 6041-6049, ISSN: 0022-1767
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- Citations: 18
Boelen L, O'Neill PK, Boyton R, et al., 2014, Mapping MHC-II epitopes from Elispot data, the Bayesian way, IMMUNOLOGY, Vol: 143, Pages: 185-186, ISSN: 0019-2805
Reynolds CJ, Jones C, Blohmke CJ, et al., 2014, The serodominant secreted effector protein of Salmonella, SseB, is a strong CD4 antigen containing an immunodominant epitope presented by diverse HLA class II alleles, Immunology, Vol: 143, Pages: 438-446, ISSN: 0019-2805
Reynolds C, Chong D, Raynsford E, et al., 2014, Elongated TCR alpha chain CDR3 favors an altered CD4 cytokine profile., BMC Biology, Vol: 12, ISSN: 1741-7007
Ascough S, Ingram RJ, Chu KK, et al., 2014, Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4<SUP>+</SUP> T Cell Immunity, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 15
Rinchai D, Nithichanon A, Buddhisa S, et al., 2013, Large scale human T cell epitope mapping of <i>Burkholderia pseudomallei</i>, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 133-133, ISSN: 0019-2805
Till SJ, Raynsford EJ, Reynolds CJ, et al., 2013, Peptide-induced immune regulation by a promiscuous and immunodominant CD4T-cell epitope of Timothy grass pollen: a role of Cbl-b and Itch in regulation, Thorax, Vol: 69, Pages: 335-345, ISSN: 0040-6376
Ascough S, Ingram R, Abarra A, et al., 2013, Injectional anthrax infection due to heroin use induces strong immunological memory, J Infect
Lowther DE, Chong DL, Ascough S, et al., 2013, Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response, ACTA NEUROPATHOLOGICA, Vol: 126, Pages: 501-515, ISSN: 0001-6322
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- Citations: 32
Boyton RJ, Reynolds CJ, Quigley KJ, et al., 2013, Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis., Clin Exp Immunol., Vol: 171(2), Pages: 117-123
Boyton RJ, Reynolds CJ, Quigley KJ, et al., 2013, Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 171, Pages: 117-123, ISSN: 0009-9104
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- Citations: 45
Boyton RJ, 2012, The lung road to recovery, Public Service Review: UK Science and Technology, Vol: 07
Boyton RJ, 2012, New tools for the challenges of lung immunology research., Public Service Review: UK Science and Technology, Vol: 07
Parham P, Norman P, Abi-Rached L, et al., 2012, Human-specific evolution of killer immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Thorsby E, 2012, The polynesian gene pool: an early contribution by Amerindians to Easter Island, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Fernandez Vina M, Hollenbach J, Lyke K, et al., 2012, Tracking human migrations by analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Sanchez-Mazas A, Lemaitre J-F, Currat M, 2012, Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Hill A, 2012, Evolution, revolution and heresy in the genetics of infectious disease susceptibility, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Gagneux S, 2012, Host-pathogen coevolution in human tuberculosis, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
Achtman M, 2012, Insights from genomic comparisons of genetically monomorphic bacterial pathogens, Philosophical Transactions of the Royal Society of London: Biological Sciences, Vol: 367 (1590)
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