18 results found
Szymula A, Palermo RD, Bayoumy A, et al., 2018, Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome., PLoS Pathog, Vol: 14
The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it has been reported to enhance gene activation by the EBV protein EBNA2 in vitro. We generated EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of internal repeat 1 (IR1). EBNA-LP-mutant EBVs established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but not from umbilical cord B cells, which died approximately two weeks after infection. Adult B cells only established EBNA-LP-null LCLs with a memory (CD27+) phenotype. Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes in the first 2 weeks. By 30 days post infection, LPKO transcription was the same as wild-type EBV. In contrast, EBNA2-regulated cellular genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that EBNA2 and the host transcription factors EBF1 and RBPJ were delayed in their recruitment to all viral latency promoters tested, whereas these same factors were recruited efficiently to several host genes, which exhibited increased EBNA2 recruitment. We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that EBNA-LP is essential for the survival of EBV-infected naïve B cells.
Grant CR, Holder BS, Liberal R, et al., 2017, Immunosuppressive drugs affect interferon (IFN)- and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 189, Pages: 71-82, ISSN: 0009-9104
Wilcox CR, Holder B, Jones CE, 2017, Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and implications for vaccination in Pregnancy, FRONTIERS IN IMMUNOLOGY, Vol: 8, ISSN: 1664-3224
Holder B, Jones T, Shimizu VS, et al., 2016, Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging, TRAFFIC, Vol: 17, Pages: 168-178, ISSN: 1398-9219
Donaldson B, Jain P, Holder BS, et al., 2015, What determines uptake of pertussis vaccine in pregnancy? A cross sectional survey in an ethnically diverse population of pregnant women in London, VACCINE, Vol: 33, Pages: 5822-5828, ISSN: 0264-410X
Liberal R, Grant CR, Holder BS, et al., 2015, In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression., Hepatology, Vol: 62, Pages: 863-875
UNLABELLED: Defective immune regulation plays a permissive role enabling effector cells to initiate and perpetuate tissue damage, eventually resulting in autoimmune disease. Numerical and functional regulatory T-cell (Treg) impairment has been previously reported in autoimmune liver disease (AILD; including autoimmune hepatitis and autoimmune sclerosing cholangitis ASC). However, in these early reports, Tregs were phenotypically defined as CD4(+) CD25(+) or CD4(+) CD25(high) cells. In the current study, we reexamined phenotypic and functional properties of Tregs by adopting a more refined definition of these cells that also includes negativity or low level of expression of CD127. We studied 43 AILD patients and 22 healthy subjects (HSs) and found that CD4(+) CD25(+) CD127(-) Tregs were decreased in the former. This decrease was more marked in patients with active disease than in those in remission. In AILD, Treg frequencies correlated inversely with parameters of disease activity and were not affected by immunosuppressive treatment. We also document, for the first time, that, in AILD, bona-fide Tregs produce less interleukin (IL)-10 and are impaired in their ability to suppress CD4(+) CD25(-) target cell proliferation, a feature that in HSs, but not in AILDs, is dependent, at least in part, on IL-10 secretion. Decreased IL-10 production by Tregs in AILD is linked to poor responsiveness to IL-2 and phospho signal transducer and activator of transcription 5 up-regulation. CONCLUSION: Tregs are numerically impaired in AILD, this impairment being more prominent during active disease. Notably, defective IL-10 production, resulting from low Treg responsiveness to IL-2, contributes to Treg functional impairment.
Grant CR, Liberal R, Holder BS, et al., 2014, Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis., Hepatology, Vol: 59, Pages: 1007-1015
UNLABELLED: Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T-cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39(pos) Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39(pos) Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4(pos) CD25(high) , CD4(pos) CD25(high) CD39(pos) , and CD4(pos) CD25(high) CD39(neg) subsets to suppress both proliferation of effector T cells and interleukin (IL)-17 production was evaluated. In AIH, CD39(pos) Tregs are decreased in frequency, exhibit limited adenosine triphosphate/adenosine diphosphate hydrolysis activity, and fail to suppress IL-17 production by effector CD4 T cells. Moreover, these CD39(pos) Tregs display a more proinflammatory profile in AIH, which is characterized by elevated CD127 positivity, and a greater propensity to produce interferon-gamma or IL-17 upon challenge with proinflammatory stimuli. CONCLUSIONS: In AIH, CD39(pos) Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL-17 production by effector CD4 T cells. CD39(pos) Tregs show plasticity and are unstable upon proinflammatory challenge, suggesting that defective immunoregulation in AIH might result not only from reduced Treg number and function, but also from increased conversion of Tregs into effector cells.
Holder B, Jones T, Okala S, et al., 2014, UPTAKE OF MACROPHAGE EXOSOMES BY THE HUMAN PLACENTA., International-Federation-of-Placenta-Associations (IFPA)/EPG Meeting, Publisher: W B SAUNDERS CO LTD, Pages: A59-A59, ISSN: 0143-4004
Holder BS, Grant CR, Liberal R, et al., 2014, Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2, JOURNAL OF AUTOIMMUNITY, Vol: 53, Pages: 26-32, ISSN: 0896-8411
Burl S, Holder BS, Lo BKM, et al., 2013, Optimisation of a functional mycobacterial growth-inhibition assay to improve its suitability for infant TB vaccine studies, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 394, Pages: 121-124, ISSN: 0022-1759
Holder BS, Tower CL, Forbes K, et al., 2012, Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1, IMMUNOLOGY, Vol: 136, Pages: 184-191, ISSN: 0019-2805
Holder BS, Tower CL, Jones CJP, et al., 2012, Heightened Pro-Inflammatory Effect of Preeclamptic Placental Microvesicles on Peripheral Blood Immune Cells in Humans, BIOLOGY OF REPRODUCTION, Vol: 86, ISSN: 0006-3363
Liberal R, Grant CR, Holder BS, et al., 2012, The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway., Hepatology, Vol: 56, Pages: 677-686
UNLABELLED: In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4(pos) CD25(pos) regulatory T cells (T-regs). Galectin-9 (Gal9), a β-galactosidase-binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9(pos) CD4(pos) CD25(pos) and Tim-3(pos) CD4(pos) CD25(neg) T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4(pos) CD25(neg) T cells amenable to T-reg control, purified CD4(pos) CD25(neg) Tim-3(pos) (Tim-3(pos)) and CD4(pos) CD25(neg) Tim-3(neg) (Tim-3(neg)) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3(pos) cells within CD4(pos) CD25(neg) cells and their T-bet(pos) and RORC(pos) subsets were fewer and contained higher numbers of interferon-γ (IFNγ)(pos) and interleukin (IL)-17(pos) cells than healthy subjects (HS). In AIH and HS, Tim-3(pos) cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3(neg) cells. In AIH, Gal9(pos) T-regs were fewer and contained less FOXP3(pos), IL-10(pos), and transforming growth factor β(pos) and more IFNγ(pos) and IL-17(pos) cells than HS. siRNA treatment of Gal-9(pos) T-regs drastically reduced T-reg ability to suppress CD4(pos) CD25(neg) and Tim-3(pos) cell proliferation in AIH and HS. Tim-3(pos) cell percentage correlated inversely with aminotransferase and CD25(neg) T-bet(pos) cell values. CONCLUSION: Reduced levels of Tim-3 on CD4(pos) CD25(neg) effector cells and of Gal9 i
Longhi MS, Liberal R, Holder B, et al., 2012, Inhibition of interleukin-17 promotes differentiation of CD25⁻ cells into stable T regulatory cells in patients with autoimmune hepatitis., Gastroenterology, Vol: 142, Pages: 1526-35.e6
BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) have reduced numbers and function of CD4+CD25(high)FOXP3+ T regulatory cells (Tregs). Tregs can be generated from CD25⁻ (ngTreg) cells, which suppress the immune response less efficiently than Tregs. We investigated whether their differentiation into T-helper (Th)17 cells, an effector subset that has the same CD4+ progenitors as Tregs, accounts for the reduced suppressive functions of ngTregs. We investigated whether blocking interleukin (IL)-17 increased the immunosuppressive activity of Tregs. METHODS: ngTregs were generated from 36 patients with AIH and 23 healthy subjects (controls). During Treg differentiation, expression of IL-17 was inhibited by physical removal of IL-17-secreting cells, exposure to recombinant transforming growth factor β or neutralizing antibodies against IL-6 and IL-1β (to promote differentiation of ngTregs vs Th17 cells), small inhibitory RNAs specific for the Th17 transcription factor RORC, or a combination of all these approaches. RESULTS: ngTregs from patients with AIH contained greater proportions of IL-17+ and RORC+ cells than Tregs from controls. All approaches to inhibit IL-17 increased expression of FOXP3 by ngTregs and their suppressive functions. Inhibition of IL-17 led to development of ngTregs that were phenotypically stable and did not acquire proinflammatory properties after exposure to IL-6 and IL-1β. CONCLUSIONS: Blocking Th17 allows ngTregs to differentiate into functionally stable immune inhibitory cells; this approach might be developed for therapy of patients with AIH.
Holder B, Miles DJC, Kaye S, et al., 2010, Epstein-Barr Virus but Not Cytomegalovirus Is Associated with Reduced Vaccine Antibody Responses in Gambian Infants, PLOS ONE, Vol: 5, ISSN: 1932-6203
Miles DJC, Sanneh M, Holder B, et al., 2008, Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants, IMMUNOLOGY, Vol: 124, Pages: 388-400, ISSN: 0019-2805
Le Doare K, Holder B, Bassett A, et al., Mother’s milk: A purposeful contribution to the development of the infant microbiota and immunity, Frontiers in Immunology, ISSN: 1664-3224
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