Imperial College London

Dr. Beth Holder

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Lecturer in Maternal and Fetal Health
 
 
 
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Contact

 

+44 (0)20 7594 1773b.holder Website

 
 
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Location

 

3 008Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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55 results found

Skirrow H, Holder B, Meinel A, Narh E, Donaldson B, Bosanquet A, Barnett S, Kampmann Bet al., 2021, Evaluation of a midwife-led, hospital based vaccination service for pregnant women, Human Vaccines and Immunotherapeutics, Vol: 17, Pages: 237-246, ISSN: 1554-8600

BACKGROUND: Vaccines against whooping cough (pertussis) and seasonal-influenza are recommended for pregnant women in England. Uptake however varies regionally and by ethnicity. Pregnant women are traditionally vaccinated in primary care, though some hospitals now offer vaccines through antenatal clinics. This mixed-methods evaluation describes the demographic characteristics of women seen in a hospital midwife-led antenatal vaccine clinic and explores vaccine decision making. METHODS: Descriptive statistics of women seen in a London hospital's midwife-led vaccine clinic were generated from electronic routine maternity records, including data on ethnicity, parity, age and deprivation indices. Reasons for vaccine decline given by women to midwives were categorized by themes. Qualitative interviews of women seen in the clinic were also undertaken. RESULTS: Between 1st April 2017 and 31st March 2018 the vaccine clinic saw 1501 pregnant women. Of these, 83% received pertussis vaccine and (during flu season) 51% received influenza vaccine, from the clinic. Fewer Black Afro-Caribbean women seen by the clinic were vaccinated, compared to other ethnicities with only 68% receiving pertussis and 34% flu vaccines respectively (p < .05). Among all women delivering at the hospital over the year, 42%, (1334/3147) were vaccinated by the clinic. Qualitative interviews found that reassurance from healthcare professionals, particularly midwives, was the most important factor influencing maternal vaccine decisions. CONCLUSIONS: Midwife-led hospital clinics can offer an effective alternative to primary care provision for vaccines in pregnancy. Consistent with previous work, vaccine uptake varied by ethnicity. Midwives play a key role in the provision of vaccine services and influence women's vaccine decisions.

Journal article

Clements T, Rice T, Vamvakas G, Barnett S, Barnes M, Donaldson B, Christine J, Kampmann B, Holder Eet al., 2020, Update on trans-placental transfer of IgG subclasses: impact of maternal and fetal factors, Frontiers in Immunology, Vol: 11, Pages: 1-17, ISSN: 1664-3224

Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccin

Journal article

Basu Roy R, Sambou B, Sissoko M, Holder B, Gomez MP, Egere U, Sillah AK, Koukounari A, Kampmann Bet al., 2020, Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure, EBioMedicine, Vol: 59, Pages: 1-10, ISSN: 2352-3964

BackgroundChildren are particularly susceptible to tuberculosis. However, most children exposed to Mycobacterium tuberculosis are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design.MethodsWe recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an in vitro functional auto-luminescent Bacillus Calmette–Guérin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses.Findings29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours.InterpretationHighly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status.FundingClinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).

Journal article

Rice T, Holder E, Kampmann B, 2020, Antibody glycosylation in pregnancy and in newborns: biological roles and implications, Current Opinion in Infectious Diseases, Vol: 33, Pages: 225-230, ISSN: 0951-7375

Purpose of review Glycosylation patterns have the potential to affect the function of antibody, antibody half-life and transplacental transfer from mother to foetus. Here, we review recent advances in our understanding of how glycosylation patterns of antibodies may be altered during pregnancy, vaccination and infection.Recent findings During pregnancy, there is preferential transplacental transfer of natural killer (NK) cell-activating antibodies that are galactosylated and sialylated, against both bacterial and viral antigens. Markers of NK cell function are also associated with a higher abundance of galactosylation and sialylation in respiratory syncytial virus-specific IgG, compared with total IgG, in infants up to 7 months of age which may suggest a role for NK-cell activating antibodies as important mediators of immunity during early infancy. Differential glycosylation patterns have been observed in some respiratory conditions, as increased nongalactosylated antibodies have been associated with the development of chronic inflammatory bronchopulmonary dysplasia (BPD) in preterm infants. Glycosylation patterns in children appear age-dependent, which could modulate the effector function of IgG. The clinical relevance of these findings needs to be established.Summary Glycosylation plays a key role in mediating antibody function. Glycosylation patterns associated with positive outcomes from infection in mothers and infants could inform the design of the next generation of vaccines for use in pregnancy and infancy.

Journal article

Rice T, Diavatopoulos D, Smits G, van Gageldonk P, Berbers G, van der Klis F, Vamvakas G, Donaldson B, Bouqueau M, Holder B, Kampmann Bet al., 2019, Antibody responses to Bordetella pertussis and other childhood vaccines in infants born to mothers who received pertussis vaccine in pregnancy- a prospective, observational cohort study from the UK, Clinical and Experimental Immunology, Vol: 197, Pages: 1-10, ISSN: 1365-2249

The maternal Tdap (tetanus, diphtheria and acellular pertussis) vaccination program in the UK has successfully reduced cases of pertussis in young infants. In addition to prevention of pertussis cases, it is also important to investigate persistence of maternal antibody during infancy and possible interference of maternal antibodies with infant responses to vaccines. We recruited mother‐infant pairs from vaccinated and unvaccinated pregnancies and measured concentrations of IgG against pertussis toxin (PTx), filamentous hemagglutinin (FHA), pertactin (Prn), diphtheria toxin (DTx), tetanus toxoid (TTx) Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in mothers and infants at birth, and in infants at 7 weeks and at 5 months. 31 mother‐infant pairs were tested. Tdap‐vaccinated women had significantly higher antibody against Tdap antigens, compared to unvaccinated women (DTx p=0.01; PTx, FHA, Prn and TTx p<0.001). All antibodies were actively transferred to the infants (transfer ratio >1) with higher transfer of DTx (P=0.04) and TTx (P=0.02) antibody in Tdap‐vaccinated pregnancies compared to unvaccinated. Infants from Tdap‐vaccinated pregnancies had significantly elevated antibodies to all antigens at birth (p<0.001) and at 7 weeks (FHA, Prn, TTx p<0.001; DTx p=0.01; PTx p=0.004) compared to infants from unvaccinated pregnancies. Infants from Tdap‐vaccinated and unvaccinated pregnancies had comparable antibody concentrations following primary pertussis immunization (PTx p=0.77; FHA p=0.58; Prn p=0.60; DTx p=0.09; TTx p=0.88). These results support maternal immunisation as a method of protecting vulnerable infants during their first weeks of life.

Journal article

Szymula A, Palermo RD, Bayoumy A, Groves IJ, Abdullah MB, Holder B, White REet al., 2019, Correction: Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, PLoS Pathogens, Vol: 15, ISSN: 1553-7366

In the original submission, the negative control in ChIP experiments was misidentified as detecting the myoglobin promoter: it in fact detects the myogenin promoter. As a result, there are textual errors in the captions for Fig 8, “Binding of EBNA2 to viral and host loci is influenced by EBNA-LP,” and Fig 9, “EBNA-LP enhances binding of host transcription factors RBPJ and EBF1 to viral but not host promoters.” There is also an ambiguity in the second table in the S3 Table file that has been clarified.

Journal article

Zhong Z, Haltalli M, Holder B, Rice T, Donaldson B, O'Driscoll M, Le-Doare K, Kampmann B, Tregoning JSet al., 2019, The impact of timing of maternal influenza immunisation on infant antibody levels at birth., Clinical and Experimental Immunology, Vol: 195, Pages: 139-152, ISSN: 1365-2249

Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunisation is a potent tool to protect both of these at-risk groups. Whilst the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunised in the second trimester of pregnancy had the highest antibody titres compared to children immunised in the third trimester. The aim of the current study was to investigate how timing of maternal influenza immunisation impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both IgG-binding ELISA and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunisation was performed less than four weeks before birth. These studies confirm that immunisation during pregnancy increases the antibody titre in infants. Importantly antibody levels in cord blood were significantly higher when mother was vaccinated in either trimester two or three, though titres were significantly lower if the mother was immunised less than 4 weeks before birth. Based on this data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.

Journal article

Thery C, Witwer KW, Aikawa E, Jose Alcaraz M, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach J-M, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Zavec AB, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman MLD, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas E, Byrd JB, Camussi G, Carter DRF, Caruso S, Chamley LW, Chang Y-T, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FAW, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Chaudhuri AD, de Candia P, De Santana Junior EF, De Wever O, del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TAP, Duarte F, Duncan HM, Eichenberger RM, Ekstrom K, Andaloussi SEL, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gaertner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Goergens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG-E, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano S-I, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanovic MM, Kovacs AF, Kraemer-Albers E-Met al., 2018, Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines, Journal of Extracellular Vesicles, Vol: 7, ISSN: 2001-3078

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Journal article

Rice T, Donaldson B, Bouqueau M, Kampmann B, Holder Bet al., 2018, Macrophage- but not monocyte-derived extracellular vesicles induce placental pro-inflammatory responses, Placenta, Vol: 69, Pages: 92-95, ISSN: 0143-4004

The placenta sheds extracellular vesicles (EVs), including exosomes, into the maternal circulation. We recently demonstrated that this trafficking of EVs is bi‐directional; with uptake of macrophage exosomes by the placenta inducing cytokine release. The specificity of this response is currently unknown. THP-1 cells were cultured as monocytes or differentiated to macrophages, and EVs isolated by ultra-centrifugation. The effect of EVs on human placental explants was measured by cytokine ELISA/luminex. Macrophage, but not monocyte, EVs induce the release of pro-inflammatory cytokines by the placenta. Thus, placental responses to immune cell EVs, including exosomes, reflects the phenotype of the source cell.

Journal article

Le Doare K, Holder B, Bassett A, Pannaraj Pet al., 2018, Mother’s milk: A purposeful contribution to the development of the infant microbiota and immunity, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

Breast milk is the perfect nutrition for infants, a result of millions of years of evolution. In addition to providing a source of nutrition, breast milk contains a diverse array of microbiota and myriad biologically active components that are thought to guide the infant’s developing mucosal immune system. It is believed that bacteria from the mother’s intestine may translocate to breast milk and dynamically transfer to the infant. Such interplay between mother and her infant is a key to establishing a healthy infant intestinal microbiome. These intestinal bacteria protect against many respiratory and diarrheal illnesses, but are subject to environmental stresses such as antibiotic use. Orchestrating the development of the microbiota are the human milk oligosaccharides (HMOs), the synthesis of which are partially determined by the maternal genotype. HMOs are thought to play a role in preventing pathogenic bacterial adhesion though multiple mechanisms, while also providing nutrition for the microbiome. Extracellular vesicles (EVs), including exosomes, carry a diverse cargo, including mRNA, miRNA, and cytosolic and membrane-bound proteins, and are readily detectable in human breast milk. Strongly implicated in cell–cell signaling, EVs could therefore may play a further role in the development of the infant microbiome. This review considers the emerging role of breast milk microbiota, bioactive HMOs, and EVs in the establishment of the neonatal microbiome and the consequent potential for modulation of neonatal immune system development.

Journal article

Szymula A, Palermo RD, Bayoumy A, Groves IJ, Abdulla MB, Holder B, White REet al., 2018, Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, PLoS Pathogens, Vol: 14, Pages: 1-34, ISSN: 1553-7366

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.

Journal article

Wilcox CR, Holder E, 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

At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. Transcytosis of IgG occurs via binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest. This review highlights factors of relevance to maternal vaccination that may modulate placental transfer—IgG subclass, glycosylation of antibody, total maternal IgG concentration, maternal disease, infant gestational age, and birthweight—and outlines the conflicting evidence and questions that remain regarding the complexities of these relationships. Furthermore, the intricacies of the Ab–FcRn interaction remain poorly understood and models that may help address future research questions are described.

Journal article

Rice T, Kampmann B, Holder B, 2017, One size fits all? Antibody avidity measurement against multiple antigens in maternal vaccination studies, Virulence, Vol: 8, Pages: 1066-1068, ISSN: 2150-5608

Journal article

Grant CR, Holder BS, Liberal R, Heneghan MA, Ma Y, Mieli-Vergani G, Vergani D, Longhi MSet al., 2017, Immunosuppressive drugs affect interferon (IFN)-γ 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: 1365-2249

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4(+) CD25(-) cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4(+) CD25(-) cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .

Journal article

Holder BS, Jones T, Sancho Shimizu V, Rice TF, Donaldson B, Bouqueau M, Forbes K, Kampmann Bet al., 2016, Macrophage exosomes induce placental inflammatory cytokines: a novel mode of maternal-placental messaging, Traffic, Vol: 17, Pages: 168-178, ISSN: 1600-0854

During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle-mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus. We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus.

Journal article

Liberal R, Grant CR, Holder BS, Ma Y, Heneghan MA, Mieli-Vergani G, Vergani D, Longhi MSet al., 2015, In autoimmune liver disease defective regulatory T cell responsiveness to IL-2 results in low IL-10 production and impaired suppression, 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 364A-364A, ISSN: 0270-9139

Conference paper

Donaldson B, Jain P, Holder BS, Lindsay B, Regan L, Kampmann Bet 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: 1873-2518

Journal article

Liberal R, Grant CR, Holder BS, Cardone J, Martinez-Llordella M, Ma Y, Heneghan MA, Mieli-Vergani G, Vergani D, Longhi MSet 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, ISSN: 0270-9139

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+CD25high 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. (Hepatology 2015;62:863–875)

Journal article

Grant CR, Liberal R, Holder BS, Mieli-Vergani G, Vergani D, Longhi Set al., 2015, EFFECT OF IMMUNOSUPPRESSIVE DRUGS ON THE KINETICS OF CO-INHIBITORY MOLECULE EXPRESSION AND PRO-INFLAMMATORY CYTOKINE PRODUCTION BY EFFECTOR T CELLS IN AUTOIMMUNE HEPATITIS, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S807-S808, ISSN: 0168-8278

Conference paper

Grant CR, Liberal R, Holder BS, Mieli-Vergani G, Vergani D, Longhi MSet al., 2014, Effect of immunosuppressive drugs on the kinetics of co-inhibitory molecule expression and pro-inflammatory cytokine production by effector T cells in autoimmunity, Publisher: WILEY-BLACKWELL, Pages: 125-125, ISSN: 0019-2805

Conference paper

Holder BS, Grant CR, Liberal R, Ma Y, Heneghan MA, Mieli-Vergani G, Vergani D, Longhi MSet 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

Journal article

Holder B, Jones T, Okala S, Forbes K, Kampmann Bet 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

Conference paper

Grant CR, Liberal R, Holder BS, Cardone J, Ma Y, Robson SC, Mieli-Vergani G, Vergani D, Longhi MSet 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, ISSN: 0270-9139

Journal article

Grant CR, Liberal R, Holder BS, Cardone J, Ma Y, Robson SC, Mieli-Vergani G, Vergani D, Longhi MSet al., 2013, In autoimmune hepatitis low expression of CD39 by regulatory T-cells is associated with decreased ATP hydrolysis and impaired control over Th17 cells, 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 566A-566A, ISSN: 0270-9139

Conference paper

Burl S, Holder BS, Lo BKM, Kampmann Bet 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

Journal article

Grant CR, Liberal R, Holder BS, Ma Y, Robson SC, Mieli-Vergani G, Vergani D, Longhi MSet al., 2013, DEFECTIVE CD39 EXPRESSION BY Tregs IN AUTOIMMUNE HEPATITIS PREVENTS SUPPRESSION OF IL17 PRODUCTION AND IS ASSOCIATED WITH IMPAIRED ATP-HYDROLYSIS, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S385-S385, ISSN: 0168-8278

Conference paper

Liberal R, Grant CR, Holder BS, Heneghan MA, Mieli-Vergani G, Vergani D, Longhi MSet al., 2013, PHENOTYPIC CHARACTERISATION OF CD4 EFFECTOR IMMUNE RESPONSES IN CHILDHOOD AUTOIMMUNE LIVER DISEASE, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S389-S390, ISSN: 0168-8278

Conference paper

Liberal R, Grant CR, Holder BS, Ma Y, Mieli-Vergani G, Vergani D, Longhi MSet al., 2013, PHENOTYPIC AND FUNCTIONAL PLASTICITY OF CD4(pos)CD25(high)CD127(pos) AND CD4(pos)CD25(high)CD127(neg) T CELLS IN AUTOIMMUNE HEPATITIS, International Liver Congress / 48th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S389-S389, ISSN: 0168-8278

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Liberal R, Grant CR, Holder BS, Longhi MS, Mieli-Vergani G, Vergani Det al., 2012, In autoimmune sclerosing cholangitis and autoimmune hepatitis a high proportion of circulating T and B lymphocytes express the gut-homing integrin alpha 4 beta 7, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 721A-721A, ISSN: 0270-9139

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Holder BS, Grant CR, Liberal R, Ma Y, Mieli-Vergani G, Vergani D, Longhi MSet al., 2012, Retinoic acid restores CD25 expression and boosts suppressive function of antigen-specific regulatory T cells in autoimmune hepatitis, 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 196A-197A, ISSN: 0270-9139

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