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1.
Nat Immunol ; 23(1): 40-49, 2022 01.
Article in English | MEDLINE | ID: mdl-34937928

ABSTRACT

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens.


Subject(s)
Antibodies, Viral/immunology , Coronavirus 229E, Human/immunology , Coronavirus OC43, Human/immunology , Cross Protection/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adaptive Immunity/immunology , Adult , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Child , Child, Preschool , Cross Reactions/immunology , Humans
2.
Br J Haematol ; 195(3): 433-446, 2021 11.
Article in English | MEDLINE | ID: mdl-34046897

ABSTRACT

Allogeneic immune responses underlie the graft-versus-leukaemia effect of stem cell transplantation, but disease relapse occurs in many patients. Minor histocompatibility antigen (mHAg) peptides mediate alloreactive T cell responses and induce graft-versus-leukaemia responses when expressed on patient haematopoietic tissue. We vaccinated nine HA-1-negative donors against HA-1 with a 'prime-boost' protocol of either two or three DNA 'priming' vaccinations prior to 'boost' with modified vaccinia Ankara (MVA). HA-1-specific CD8+ T cell responses were observed in seven donors with magnitude up to 1·5% of total CD8+ T cell repertoire. HA-1-specific responses peaked two weeks post-MVA challenge and were measurable in most donors after 12 months. HA-1-specific T cells demonstrated strong cytotoxic activity and lysed target cells with endogenous HA-1 protein expression. The pattern of T cell receptor (TCR) usage by HA-1-specific T cells revealed strong conservation of T cell receptor beta variable 7-9 (TRBV7-9) usage between donors. These findings describe one of the strongest primary peptide-specific CD8+ T cell responses yet recorded to a DNA-MVA prime-boost regimen and this may reflect the strong immunogenicity of mHAg peptides. Prime-boost vaccination in donors or patients may prove of substantial benefit in boosting graft-versus-leukaemia responses.


Subject(s)
Antigens, Neoplasm/immunology , Graft vs Leukemia Effect/immunology , Minor Histocompatibility Antigens/immunology , Oligopeptides/immunology , T-Lymphocytes, Cytotoxic/immunology , Vaccination , Vaccines, DNA/therapeutic use , Vaccinia virus/immunology , Viral Vaccines/therapeutic use , Adult , Aged , Allografts , Cytotoxicity, Immunologic , Epitopes/immunology , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , HLA-A2 Antigen/immunology , Hematopoietic Stem Cell Transplantation , Humans , Immunogenicity, Vaccine , Immunologic Memory , Male , Middle Aged , Peptides/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Vaccines, Attenuated , Vaccines, DNA/immunology , Viral Vaccines/immunology
4.
Nat Immunol ; 22(5): 620-626, 2021 05.
Article in English | MEDLINE | ID: mdl-33674800

ABSTRACT

The immune response to SARS-CoV-2 is critical in controlling disease, but there is concern that waning immunity may predispose to reinfection. We analyzed the magnitude and phenotype of the SARS-CoV-2-specific T cell response in 100 donors at 6 months following infection. T cell responses were present by ELISPOT and/or intracellular cytokine staining analysis in all donors and characterized by predominant CD4+ T cell responses with strong interleukin (IL)-2 cytokine expression. Median T cell responses were 50% higher in donors who had experienced a symptomatic infection, indicating that the severity of primary infection establishes a 'set point' for cellular immunity. T cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of nucleoprotein-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T cell responses are retained at 6 months following infection.


Subject(s)
Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity, Cellular , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral/blood , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/blood , COVID-19/virology , Female , Host-Pathogen Interactions , Humans , Interleukin-2/blood , Male , Middle Aged , Phenotype , SARS-CoV-2/pathogenicity , Time Factors , Young Adult
5.
PLoS Pathog ; 17(3): e1009349, 2021 03.
Article in English | MEDLINE | ID: mdl-33662046

ABSTRACT

PD-1 is expressed on exhausted T cells in cancer patients but its physiological role remains uncertain. We determined the phenotype, function and transcriptional correlates of PD-1 expression on cytomegalovirus-specific CD4+ T cells during latent infection. PD-1 expression ranged from 10-85% and remained stable over time within individual donors. This 'setpoint' was correlated with viral load at primary infection. PD-1+ CD4+ T cells display strong cytotoxic function but generate low levels of Th1 cytokines which is only partially reversed by PD-1 blockade. TCR clonotypes showed variable sharing between PD-1+ and PD-1- CMV-specific cells indicating that PD-1 status is defined either during T cell priming or subsequent clonal expansion. Physiological PD-1+ CD4+ T cells therefore display a unique 'high cytotoxicity-low cytokine' phenotype and may act to suppress viral reactivation whilst minimizing tissue inflammation. Improved understanding of the physiological role of PD-1 will help to delineate the mechanisms, and potential reversal, of PD-1+ CD4+ T cell exhaustion in patients with malignant disease.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Cytomegalovirus Infections/virology , Cytomegalovirus/pathogenicity , Programmed Cell Death 1 Receptor/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytokines/immunology , Cytomegalovirus/metabolism , Cytomegalovirus Infections/immunology , Gene Expression/immunology , Humans , Programmed Cell Death 1 Receptor/immunology , Viral Load/immunology
6.
Front Immunol ; 10: 2832, 2019.
Article in English | MEDLINE | ID: mdl-31921116

ABSTRACT

Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8+ T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; p = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of "inflated" virus-specific CD8+ T cells. These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent.


Subject(s)
CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Aged , Biomarkers , CD8-Positive T-Lymphocytes/pathology , Cytomegalovirus/immunology , Duration of Therapy , Female , Herpesvirus 4, Human/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/etiology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Peptides/immunology , Piperidines , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Treatment Outcome
7.
J Immunol ; 203(5): 1160-1171, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31358657

ABSTRACT

Immune senescence is a significant contributor to health problems in the developed world and may be accelerated by chronic viral infections. To date, there have been few studies of immune function in healthy older people in sub-Saharan Africa. We assessed T cell and B cell phenotypes and immune responses to CMV, EBV, and influenza virus in Malawians aged 20-69 y. Notably, the proportion of naive (CCR7+CD45RA+) CD4 and CD8 T cells was only 14% of the lymphoid repertoire even in donors aged under 30 y but did not decrease further with age. A small increase in the late differentiated (CD27-CD28-) CD8 T cell subpopulation was observed in older donors but the CD4/CD8 T cell ratio remained stable in all age groups. Interestingly, the regulatory (CD25hiFOXP3hi) T cell subpopulation was small in all age groups, and we observed no age-associated accumulation of cells expressing the senescence- and exhaustion-associated markers CD57 and PD-1. We assessed functional T cell responses to mitogenic and viral antigenic stimulation by the expression of CD154, IFN-γ, TNF-α, IL-2, and IL-17 and proliferation. All responses were robust across the life course, although we observed an age-associated shift from IFN-γ to TNF-α in the response to EBV. In summary, we found the naive T cell subpopulation of young adult Malawians was smaller than in their contemporaries in high-income settings but remains stable thereafter and that lymphocyte function is retained across the life course. These observations indicate that studies of the genetic and environmental factors influencing immune function in different environments may provide insights into minimizing immune ageing.


Subject(s)
T-Lymphocyte Subsets/immunology , Adult , Age Factors , Aged , Cell Differentiation , Cytomegalovirus/immunology , Female , Herpesvirus 4, Human/immunology , Humans , Immunologic Memory , Influenza, Human/immunology , Lymphocyte Activation , Male , Middle Aged , T-Lymphocyte Subsets/cytology
8.
Eur J Immunol ; 48(2): 316-329, 2018 02.
Article in English | MEDLINE | ID: mdl-28944953

ABSTRACT

Natural killer (NK) cells rapidly reconstitute following allogeneic stem cell transplantation (allo-SCT), at the time when alloreactive T cell immunity is being established. We investigated very early NK cell reconstitution in 82 patients following T cell-depleted allo-SCT. NK cell number rapidly increased, exceeding T cell reconstitution such that the NK:T cell ratio was over 40 by day 14. NK cells at day 14 (NK-14) were donor-derived, intensely proliferating and expressed chemokine receptors targeted to lymphoid and peripheral tissue. Spontaneous production of the immunoregulatory cytokine IL-10 was observed in over 70% of cells and transcription of cytokines and growth factors was augmented. NK-14 cell number was inversely correlated with the incidence of grade II-IV acute graft versus host disease (GVHD). These findings reveal that robust reconstitution of immunoregulatory NK cells by day 14 after allo-SCT is an important determinant of the clinical outcome, suggesting that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10.


Subject(s)
Graft vs Host Disease/immunology , Killer Cells, Natural/immunology , Stem Cell Transplantation , Acute Disease , Adolescent , Adult , Aged , Cell Self Renewal , Cells, Cultured , Disease Progression , Female , Humans , Interleukin-10/metabolism , Lymphocyte Depletion , Male , Middle Aged , T-Lymphocytes/pathology , Transplantation, Homologous , Young Adult
9.
J Virol ; 91(21)2017 11 01.
Article in English | MEDLINE | ID: mdl-28835490

ABSTRACT

Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR- natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8+ T cells, but overall CD8+ T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control.IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection.


Subject(s)
Asymptomatic Infections/epidemiology , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Epstein-Barr Virus Infections/virology , Killer Cells, Natural/immunology , Adult , Antibodies, Viral/blood , DNA, Viral/genetics , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/immunology , Female , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/isolation & purification , Humans , Male , Prognosis , Prospective Studies , United Kingdom/epidemiology , Viral Load , Young Adult
10.
PLoS Pathog ; 12(9): e1005832, 2016 09.
Article in English | MEDLINE | ID: mdl-27606804

ABSTRACT

Cytomegalovirus (CMV) infection elicits a very strong and sustained intravascular T cell immune response which may contribute towards development of accelerated immune senescence and vascular disease in older people. Virus-specific CD8+ T cell responses have been investigated extensively through the use of HLA-peptide tetramers but much less is known regarding CMV-specific CD4+ T cells. We used a range of HLA class II-peptide tetramers to investigate the phenotypic and transcriptional profile of CMV-specific CD4+ T cells within healthy donors. We show that such cells comprise an average of 0.45% of the CD4+ T cell pool and can reach up to 24% in some individuals (range 0.01-24%). CMV-specific CD4+ T cells display a highly differentiated effector memory phenotype and express a range of cytokines, dominated by dual TNF-α and IFN-γ expression, although substantial populations which express IL-4 were seen in some donors. Microarray analysis and phenotypic expression revealed a profile of unique features. These include the expression of CX3CR1, which would direct cells towards fractalkine on activated endothelium, and the ß2-adrenergic receptor, which could permit rapid response to stress. CMV-specific CD4+ T cells display an intense cytotoxic profile with high level expression of granzyme B and perforin, a pattern which increases further during aging. In addition CMV-specific CD4+ T cells demonstrate strong cytotoxic activity against antigen-loaded target cells when isolated directly ex vivo. PD-1 expression is present on 47% of cells but both the intensity and distribution of the inhibitory receptor is reduced in older people. These findings reveal the marked accumulation and unique phenotype of CMV-specific CD4+ T cells and indicate how such T cells may contribute to the vascular complications associated with CMV in older people.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Endothelium, Vascular/immunology , Immunity, Cellular , Adult , Aged , Aged, 80 and over , Cytomegalovirus Infections/pathology , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Female , Humans , Interferon-gamma/immunology , Interleukin-4/immunology , Male , Middle Aged , Programmed Cell Death 1 Receptor/immunology , Tumor Necrosis Factor-alpha/immunology
11.
Am J Hematol ; 91(8): 776-81, 2016 08.
Article in English | MEDLINE | ID: mdl-27124884

ABSTRACT

Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus-specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/complications , Adult , Aged , Aged, 80 and over , Cohort Studies , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/mortality , Female , Humans , Immunity , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Prospective Studies , Survival Rate , Time-to-Treatment , Treatment Outcome , Young Adult
12.
J Immunol ; 195(8): 3803-15, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26363059

ABSTRACT

CMV infection is a significant cause of morbidity and mortality in immunocompromised individuals, and the development of a vaccine is of high priority. Glycoprotein B (gB) is a leading vaccine candidate but the glycoprotein H (gH) pentameric complex is now recognized as the major target for neutralizing Abs. However, little is known about the T cell immune response against gH and glycoprotein L (gL) and this is likely to be an important attribute for vaccine immunogenicity. In this study, we examine and contrast the magnitude and phenotype of the T cell immune response against gB, gH, and gL within healthy donors. gB-specific CD4(+) T cells were found in 95% of donors, and 29 epitopes were defined with gB-specific response sizes ranging from 0.02 to 2.88% of the CD4(+) T cell pool. In contrast, only 20% of donors exhibited a T cell response against gH or gL. Additionally, gB-specific CD4(+) T cells exhibited a more cytotoxic phenotype, with high levels of granzyme B expression. Glycoproteins were effectively presented following delivery to APCs but only gB-derived epitopes were presented following endogenous synthesis. gB expression was observed exclusively within vesicular structures colocalizing with HLA-DM whereas gH was distributed evenly throughout the cytoplasm. Grafting of the C-terminal domain from gB onto gH could not transfer this pattern of presentation. These results reveal that gB is a uniquely immunogenic CMV glycoprotein and this is likely to reflect its unique pattern of endogenous Ag presentation. Consideration may be required toward mechanisms that boost cellular immunity to gH and gL within future subunit vaccines.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Epitopes, T-Lymphocyte/immunology , Immunity, Cellular , Viral Envelope Proteins/immunology , Adult , CD4-Positive T-Lymphocytes/pathology , Cytomegalovirus/genetics , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/pathology , Cytomegalovirus Vaccines/genetics , Cytomegalovirus Vaccines/immunology , Epitopes, T-Lymphocyte/genetics , Female , Granzymes , Humans , Male , Middle Aged , Viral Envelope Proteins/genetics
14.
PLoS One ; 10(4): e0125287, 2015.
Article in English | MEDLINE | ID: mdl-25923913

ABSTRACT

Cytomegalovirus (CMV) infects the majority of the global population and leads to the development of a strong virus-specific immune response. The CMV-specific CD4+ and CD8+ T cell immune response can comprise between 10 and 50% of the T cell pool within peripheral blood and there is concern that this may impair immunity to other pathogens. Elderly individuals with the highest magnitude of CMV-specific immune response have been demonstrated to be at increased risk of mortality and there is increasing interest in interventions that may serve to moderate this. Acyclovir is an anti-viral drug with activity against a range of herpes viruses and is used as long term treatment to suppress reactivation of herpes simplex virus. We studied the immune response to CMV in patients who were taking acyclovir to assess if therapy could be used to suppress the CMV-specific immune response. The T cell reactivity against the immunodominant late viral protein pp65 was reduced by 53% in people who were taking acyclovir. This effect was seen within one year of therapy and was observed primarily within the CD4+ response. Acyclovir treatment only modestly influenced the immune response to the IE-1 target protein. These data show that low dose acyclovir treatment has the potential to modulate components of the T cell response to CMV antigen proteins and indicate that anti-viral drugs should be further investigated as a means to reduce the magnitude of CMV-specific immune response and potentially improve overall immune function.


Subject(s)
Acyclovir/administration & dosage , CD4-Positive T-Lymphocytes/immunology , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , Phosphoproteins/immunology , Viral Matrix Proteins/immunology , Adult , Aged , Cytomegalovirus/genetics , Cytomegalovirus Infections/genetics , Female , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/genetics , Male , Middle Aged , Phosphoproteins/genetics , Viral Matrix Proteins/genetics
15.
Mult Scler ; 20(6): 751-3, 2014 May.
Article in English | MEDLINE | ID: mdl-24192216

ABSTRACT

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.


Subject(s)
Avitaminosis/immunology , Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/virology , Vitamin D/metabolism , Adult , Antibodies, Viral/analysis , Cohort Studies , Epstein-Barr Virus Nuclear Antigens/metabolism , Humans , Risk Factors , Seasons , United Kingdom , Young Adult
16.
Arthritis Rheum ; 63(7): 2127-37, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21437878

ABSTRACT

OBJECTIVE: Expanded populations of CD4+CD28- T cells with a cytotoxic phenotype have been repeatedly reported in patients with granulomatosis with polyangiitis (Wegener's) (GPA). In healthy individuals expansion of this T cell population follows cytomegalovirus (CMV) infection. We undertook this study to investigate whether CMV infection may be responsible for driving the expansion of CD4+CD28- T cells in GPA patients and how this might relate to clinical features. METHODS: Forty-eight GPA patients and 38 age-matched healthy donors were included in the study. CMV-specific IgG in serum was detected by enzyme-linked immunosorbent assay. Flow cytometric analysis was used to study T cell populations and phenotype. The presence of CMV in renal biopsy tissue from GPA patients was investigated by immunohistochemistry and polymerase chain reaction (PCR). Clinical information was obtained from patient records. RESULTS: Populations of CD4+CD28- T cells were only expanded in CMV-seropositive GPA patients and controls. In CMV-seropositive GPA patients we observed negative correlations between the percentages of CD4+CD28- T cells and both the percentage of naive T cells and the glomerular filtration rate at presentation. There was a significant association between the percentage of CD4+CD28- T cells and risk of infection and mortality. CMV could not be detected in renal tissue by PCR or immunohistochemistry. CMV seropositivity itself was not a risk factor for infection in a cohort of 182 patients with antineutrophil cytoplasmic antibody-associated vasculitis who had been recruited into clinical trials performed by the European Vasculitis Study Group. CONCLUSION: The expansion of CD4+CD28- T cells in GPA patients is associated with CMV infection and leads to a reduction in the number of naive T cells in peripheral blood. Patients with expanded CD4+CD28- T cells have significantly increased mortality and risk of infection.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cytomegalovirus Infections/immunology , Granulomatosis with Polyangiitis/immunology , Adult , Aged , CD28 Antigens/metabolism , CD4-Positive T-Lymphocytes/virology , Cytomegalovirus/immunology , Female , Granulomatosis with Polyangiitis/mortality , Granulomatosis with Polyangiitis/virology , Humans , Male , Middle Aged
17.
Eur J Gastroenterol Hepatol ; 21(7): 794-804, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19404207

ABSTRACT

BACKGROUND: Sixty percent of people with coeliac disease (CD) are iron deficient. Many, however, remain iron replete despite the disease. AIMS: (i) To characterize the changes in duodenal iron transport proteins in CD with and without iron deficiency. (ii) To examine if iron-activated gut lymphocytes can inhibit iron export in an enterocyte cell model. METHODS: Endoscopic duodenal biopsies were collected from patients with normal duodenum with and without iron deficiency anaemia and untreated CD sufferers with iron deficiency (n=10 each group). mRNA expression of iron transport proteins was determined by quantitative real time PCR. Protein localization and expression was determined from histology sections in patients with normal duodenum (n=20), and patients with untreated CD with and without iron deficiency (n=20). In addition, CaCo2 cells were cocultured with iron-activated lymphocytes 55Fe was used to determine the effect on CaCo2 cell iron transport. RESULTS: The expression of divalent metal transporter 1 and ferroportin was increased in CD with or without iron deficiency. Ferritin expression was increased in CD but only in those with associated iron deficiency. TNF-alpha produced by activated lymphocytes inhibited iron export from CaCo2 cells. CONCLUSION: Increased enterocyte ferritin expression may promote iron deficiency in CD and this effect seems to be dependent upon TNF-alpha expression in gut lymphocytes.


Subject(s)
Anemia, Iron-Deficiency/metabolism , Celiac Disease/metabolism , Enterocytes/metabolism , Ferritins/metabolism , Anemia, Iron-Deficiency/genetics , Cation Transport Proteins/metabolism , Celiac Disease/genetics , Female , Ferritins/genetics , Humans , Immunohistochemistry , Intestinal Absorption/genetics , Male , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction
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