106 results found
Pinato DJ, Gramenitskaya D, Altmann DM, et al., 2019, Antibiotic therapy and outcome from immune-checkpoint inhibitors, Journal for ImmunoTherapy of Cancer, Vol: 7, ISSN: 2051-1426
Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.
Boyton RJ, Altmann DM, 2019, Muco-Obstructive Lung Diseases, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 381, Pages: E20-+, ISSN: 0028-4793
Lu Y, Qiu Y, Chen P, et al., 2019, The ER-localised Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4- induced inflammation during bacterial infection, Nature Microbiology, Vol: 4, Pages: 2331-2346, ISSN: 2058-5276
The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-κB activation to produce proinflammatory cytokines for bacteria clearance, effectors with special organelle localisation have not been identified. Here, we screened over 280 E3 ubiquitin ligases and discovered that the endoplasmic reticulum-located Hrd1 regulated TLR4-induced inflammation during bacterial infection. Hrd1 directly interacted with the deubiquitinating enzyme (DUB) Usp15. Unlike the classical function of Hrd1 in ER-associated degradation, Usp15 was not degraded but lost its DUB activity for IκBα deubiquitination, resulting in excessive NF-κB activation. Importantly, Hrd1 deficiency in macrophages protected mice against LPS-induced septic shock, and knock-down of Usp15 in Hrd1 KO macrophages restored the reduced IL-6 production. This study has proposed the crosstalk between Hrd1 and TLR4 linking the ER-plasma membrane function during bacterial infection.
Chambers E, Byrne C, Morrison D, et al., 2019, Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial, Gut, Vol: 68, Pages: 1430-1438, ISSN: 0017-5749
Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses.Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.
Sim MJW, Rajagopalan S, Altmann DM, et al., 2019, Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C., Proc Natl Acad Sci U S A, Vol: 116, Pages: 12964-12973
Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01-restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.
Boyton R, Reynolds C, Chong D, et al., 2019, Bioluminescent reporting of in vivo interferon gamma immune responses during infection and autoimmunity, Journal of Immunology, Vol: 202, Pages: 2502-2510, ISSN: 1550-6606
IFN-γ is a key cytokine of innate and adaptive immunity. It is important to understand temporal changes in IFN-γ production and how these changes relate to the role of IFN-γ in diverse models of infectious and autoimmune disease, making the ability to monitor and track IFN-γ production in vivo of a substantial benefit. IFN-γ ELISPOTs have been a central methodology to measure T cell immunity for many years. In this study, we add the capacity to analyze IFN-γ responses with high sensitivity and specificity, longitudinally, in vitro and in vivo. This allows the refinement of experimental protocols because immunity can be tracked in real-time through a longitudinal approach. We have generated a novel murine IFN-γ reporter transgenic model that allows IFN-γ production to be visualized and quantified in vitro and in vivo as bioluminescence using an imaging system. At baseline, in the absence of an inflammatory stimulus, IFN-γ signal from lymphoid tissue is detectable in vivo. Reporter transgenics are used in this study to track the IFN-γ response to Pseudomonas aeruginosa infection in the lung over time in vivo. The longitudinal development of the adaptive T cell immunity following immunization with Ag is identified from day 7 in vivo. Finally, we show that we are able to use this reporter transgenic to follow the onset of autoimmune T cell activation after regulatory T cell depletion in an established model of systemic autoimmunity. This IFN-γ reporter transgenic, termed “Gammaglow,” offers a valuable new modality for tracking IFN-γ immunity, noninvasively and longitudinally over time.
Reynolds CJ, Quigley K, Cheng X, et al., 2018, Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 557-571, ISSN: 1044-1549
RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function.
Altmann DM, Reynolds CJ, Boyton RJ, 2018, Immunology of the microbiome: Implications for rheumatoid arthritis and other autoimmune diseases, The Microbiome in Rheumatic Diseases and Infection, Pages: 55-62, ISBN: 9783319790251
Nithichanon A, Rinchai D, Buddhisa S, et al., 2018, Immune control of Burkholderia pseudomallei––common, high-frequency T-cell responses to a broad repertoire of immunoprevalent epitopes, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Burkholderia pseudomallei (Bp) is an environmental bacterial pathogen that causes potentially lethal sepsis in susceptible individuals and is considered a Category B, Tier-1 biothreat agent. As such, it is crucial to gain an improved understanding of protective immunity and potential vaccine candidates. The nature of immune correlates dictating why most exposed individuals in endemic regions undergo asymptomatic seroconversion while others succumb to life-threatening sepsis is largely uncharted. Bp seroreactive, immunogenic proteins have previously been identified by antigen microarray. We here set out to conduct an analysis of T-cell recognition of the Bp immunome using serodominant antigens represented in the original antigen microarray, examining immune correlates of disease in healthy seropositive individuals and those with acute disease or in convalescence. By screening a library of 739 overlapping peptides representing the sequences of 20 different Bp antigens, we aimed to define immune correlates of protection at the level of immunoprevalent T-cell epitopes. Responses to a large number of epitopes were common in healthy seropositive individuals: we found remarkably broad responsiveness to Bp epitopes, with 235 of 739 peptides recognized by ≥80% of all tested donors. The cumulative response to Bp epitopes in healthy, seropositive, donors from this endemic region were of the order of thousands of spot forming cells per million cells, making Bp recognition a significant component of the T-cell repertoire. Noteworthy among our findings, analysis revealed 10 highly immunoprevalent T-cell epitopes, able to induce Bp-specific IFNγ responses that were high in responding T-cell frequency within the repertoire, and also common across individuals with different human leukocyte antigen types. Acute melioidosis patients showed poor T-cell responses to the immunoprevalent epitopes, but acquired responsiveness following recovery from infection. Our findings suggest
Reynolds CJ, Suleyman OM, Ortega-Prieto AM, et al., 2018, T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses, Scientific Reports, Vol: 8, ISSN: 2045-2322
Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1–4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1–4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.
Dunachie SJ, Jenjaroen K, Reynolds CJ, et al., 2017, Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.
Lima Keesen TS, de Almeida RP, Gois BM, et al., 2017, Guillain-Barre syndrome and arboviral infection in Brazil, Lancet Infectious Diseases, Vol: 17, Pages: 693-694, ISSN: 1473-3099
Sim MJW, Malaker SA, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Immunology Meeting, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
SIM M, Malaker S, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Background.Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL 3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.Results.The impact of HLA-C bound peptide on inhibit ory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL 2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL 2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding.Conclusions.KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cros
Boelen LP, O'Neill PK, Quigley KJ, et al., 2016, BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data, PLOS Computational Biology, Vol: 12, ISSN: 1553-734X
Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.
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
Musson JA, Reynolds CJ, Rinchai D, et al., 2014, CD4(+) T Cell Epitopes of FliC Conserved between Strains of Burkholderia: Implications for Vaccines against Melioidosis and Cepacia Complex in Cystic Fibrosis, JOURNAL OF IMMUNOLOGY, Vol: 193, Pages: 6041-6049, ISSN: 0022-1767
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(+) T Cell Immunity, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
Rinchai D, Nithichanon A, Buddhisa S, et al., 2013, Large scale human T cell epitope mapping of Burkholderia pseudomallei, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 133-133, ISSN: 0019-2805
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