ORCID Profile
0000-0002-7411-5375
Current Organisation
University of Manchester
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Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.CLIM.2006.05.003
Abstract: Although idiopathic humoral immunodeficiencies are arbitrarily classified into specific antibody deficiency (SAD) or common variable immunodeficiency (CVID), this distinction does not accurately predict the risk of the bronchiectasis, one of the major long-term clinical complications in these patients. In this study, clinical complications were compared with laboratory markers of cellular and humoral immunity in fifty-five consecutive patients (27 children and 28 adults) attending regional immunology clinics in Manchester, United Kingdom. Reduced CD19(+)CD27(+)IgD(-) B cell percentage but not serum immunoglobulin levels or classification of patients into SAD and CVID was associated with a significantly higher prevalence of bronchiectasis (OR 0.4 (0.2-0.8), P = 0.001), splenomegaly (OR 0.2 (0.1-0.5), P = 0.001) and autoimmunity (OR 0.4 (0.2-0.7), P = 0.003). We conclude that in patients with idiopathic humoral immunodeficiencies assessment of B cell switching more accurately predicts clinical prognosis than either classification of patients into SAD and CVID or serum immunoglobulin concentrations.
Publisher: American Society for Clinical Investigation
Date: 06-06-2019
Publisher: Elsevier BV
Date: 2016
DOI: 10.1038/JID.2015.363
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 08-2015
Publisher: Elsevier BV
Date: 11-2005
Publisher: American Society of Hematology
Date: 19-09-2013
DOI: 10.1182/BLOOD-2013-02-482331
Abstract: The development and survival of mature NKT cells are impaired in DOCK8-deficient mice. DOCK8 is required for antigen-induced NKT cell proliferation and cytokine production.
Publisher: Cambridge University Press (CUP)
Date: 26-05-2005
Publisher: Oxford University Press (OUP)
Date: 22-01-2009
DOI: 10.1111/J.1365-2249.2009.03873.X
Abstract: Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1–10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.
Publisher: American Society of Hematology
Date: 2001
Publisher: Elsevier BV
Date: 2009
Publisher: BMJ
Date: 02-2006
Publisher: Wiley
Date: 17-09-2018
DOI: 10.1111/PAI.12959
Abstract: Peanut allergy is classically managed by food avoidance. Immunotherapy programs are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers. A retrospective, international survey of anonymized case records from seven specialist pediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analyzed. Of the 1634 children aged 1-18 years old included, 525 (32%) failed their peanut challenge. Twenty-eight percent reacted to 25 mg, while 38% only reacted after consuming 1 g or more of whole peanut. Anaphylaxis (55 [11%]) was 3 times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to 25-200 mg of whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity. More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut, was more common in older children. Tailored immunotherapy programs might be considered not only for children with low, but also higher reaction thresholds. Whether these programs could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2016
DOI: 10.1038/NG.3696
Publisher: Wiley
Date: 28-11-2018
DOI: 10.1111/ALL.13657
Abstract: Mast cells are typically linked to immediate hypersensitivity and anaphylaxis. This review looks beyond this narrow role, focusing on how these cells have evolved and ersified via natural selection promoting serine protease gene duplication, augmenting their innate host defense function against helminths and snake envenomation. Plasticity of mast cell genes has come at a price. Somatic activating mutations in the mast cell growth factor KIT gene cause cutaneous mastocytosis in young children and systemic mastocytosis with a more guarded prognosis in adults who may also harbor other gene mutations with oncogenic potential as they age. Allelic TPSAB1 gene duplication associated with higher basal mast cell tryptase is possibly one of the commonest autosomal dominantly inherited multi-system diseases affecting the skin, gastrointestinal tract, circulation and musculoskeletal system. Mast cells are also establishing a new-found importance in severe asthma, and in remodeling of blood vessels in cancer and atherosclerotic vascular disease. Furthermore, recent evidence suggests that mast cells sense changes in oxygen tension, particularly in neonates, and that subsequent degranulation may contribute to common lung, eye, and brain diseases of prematurity classically associated with hypoxic insults. One hundred and forty years since Paul Ehrlich's initial description of "mastzellen," this review collates and highlights the complex and erse roles that mast cells play in health and disease.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/746507
Abstract: Allergen component analysis is now available in many laboratories. The aim of this study was to examine the possible association between peanut allergen IgE components and severity of clinical reactions in patients with a history of peanut allergy. Data and sera collected from 192 patients within the Manchester Allergy Research Database and Serum Bank were used in this retrospective study. Sensitization to peanut specific IgE and Ara h 1, 2, 3, and 8 peanut IgE components, as measured by fluoroenzyme immunoassay, was not associated with anaphylaxis. In contrast, sensitization to the lipid-transfer protein Ara h 9 was significantly more prevalent in patients with peanut-associated bronchospasm (26% versus 9% of patients), even after adjusting for potential confounding effects of age, gender, and severity of concomitant chronic atopic diseases. Patients who were sensitized to Ara h 9 were more likely to have ingested rather than just have had skin contact with peanut and have a more rapid onset of symptoms. These results are consistent with observations that sensitization to heat and protease resistant lipid-transfer protein components of hazelnut, grains, and fruit is predictive of anaphylaxis.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.VACCINE.2006.03.088
Abstract: A heptavalent pneumococcal conjugate vaccine (PCV-7) protects children against invasive pneumococcal disease. The aim of this study was to evaluate immunoglobulin subclass and serotype-specific pneumococcal antibody responses to vaccination in children with a history of recurrent or severe bacterial infections. Pneumococcal IgG, IgG1, IgG2 titres were assayed by ELISA, and nine serotype concentrations measured using a nonaplex bead assay in 145 children investigated for recurrent or severe infections. Children mounted an exclusively IgG1 response after vaccination with two doses of PCV-7 and a dose of 23 valent pneumococcal polysaccharide vaccine (PPV-23), with pneumococcal IgG2 antibody titres remaining low to negligible. Measurement of serotype-specific responses demonstrated that although PCV-7 specific serotype responses increased significantly post-vaccination, specific IgG against two of the serotypes not covered by PCV-7 but only by PPV-23 remained low. We conclude that in contrast to antibody response to natural infection with Pneumococcus or pneumococcal polysaccharide vaccines which are often of a IgG2 subclass, responses in children after PCV-7 are of IgG1 subclass. Serotype-specific IgG were useful in determining the protection against specific pneumococcal strains, and showed that the PPV-23 did not broaden protection against non-PCV-7 serotypes.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.JAAPOS.2012.12.153
Abstract: A 12-year-old boy with severe mixed limbal and palpebral vernal keratoconjunctivitis experienced persistent ocular symptoms despite treatment with topical corticosteroids or cyclosporine. Signs and symptoms resolved completely with monthly subcutaneous omalizumab, an immunomodulating biologic agent. To our knowledge, this is the first report of its use as a monotherapy agent to treat vernal keratoconjunctivitis.
Publisher: Wiley
Date: 05-2006
DOI: 10.1111/J.1399-3038.2006.00392.X
Abstract: Intramuscular adrenaline is the treatment of choice for food-related anaphylactic reactions. Although auto-injectable adrenaline devices are routinely prescribed for patients at risk of serious reactions, previous studies have shown that only one-third to one and a half of patients or their carers are able to properly use these devices. The aim of this study was to determine which factors are most strongly associated with the effective use of these devices. A 122 children with food allergies who had previously been prescribed EpiPens and were attending a single specialist pediatric allergy center in the UK. were studied prospectively. A 69% of parents were unable to use the EpiPen, did not have it available, or did not know when it should be administered. A prior practical demonstration was associated with a 4-5 fold greater chance that parents would be able to use the device (p < 0.005). Prior consultation with an allergy specialist rather than a general physician, and parents who independently sought additional information from the national self-help allergy organization were also four to six times more likely to be competent with these devices (p < 0.005). The study clearly shows that for EpiPens to be used safely and effectively it is essential to educate the carer at the time the device is prescribed.
Publisher: Wiley
Date: 17-11-2006
DOI: 10.1111/J.1399-3038.2006.00468.X
Abstract: T lymphocytes accumulating in the skin of patients with atopic dermatitis (AD) have a prolonged survival and are key mediators of this inflammatory disease. The anti-apoptotic bfl-1 gene is unique in that it is the only member of the Bcl-2 family that is transcriptionally regulated by inflammatory cytokines and might therefore be important in promoting the survival of effector T cells in patients with AD. The aim of this study was to determine whether polymorphisms in the bfl-1 gene are associated with a predisposition to childhood AD. Four bfl-1 gene, single nucleotide polymorphisms (SNPs) were studied by ARMS-PCR in 105 Caucasian children with moderately severe AD and 110 non-atopic adult controls. In addition to the known polymorphisms of exon 1 (+141*A/G, +202*G/T, +303*A/G), we described a novel polymorphism in the promoter region of the gene (-1182*G/C). We found a significant difference in bfl-1 +141 genotype [OR (95% CI) 5.1 (1.0-25.2)], as well as bfl-1-1182:+141:+202:+303 G:A:G:A/G:A:G:A diplotype frequencies [3.5 (1.0-12.2)] in AD (p < 0.05). The study thus provides evidence for an association between bfl-1 polymorphisms and the genetic predisposition to AD.
Publisher: Elsevier BV
Date: 05-2005
Publisher: Springer Science and Business Media LLC
Date: 05-08-1996
Abstract: Nephrotic syndrome presenting in the 1st year of life is often associated with a very poor prognosis for normal renal function. A small proportion of patients, particularly boys, presenting after the first 3 months of life with idiopathic-type, steroid-sensitive nephrosis, have a much better prognosis and may achieve sustained remission. We describe three boys with infantile idiopathic nephrotic syndrome of the mesangial proliferative glomerulonephritis type who went into complete remission. The patients, their first-degree relatives or both suffered from atopy (eczema, asthma or hayfever). This is the first report linking infantile nephrotic syndrome and atopy. The literature linking idiopathic nephrotic syndrome and atopy is reviewed, and the implications of our findings discussed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2010
Publisher: BMJ
Date: 06-2000
Abstract: Polymorphisms in transforming growth factor (TGF)-beta(1) associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-beta(1) gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis. Polymorphisms in the TGF-beta(1) gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records. Patients with cystic fibrosis of a TGF-beta(1) high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-beta(1) low producer genotype. The relative risk of accelerated decline in forced expiratory volume in one second (FEV(1)) to 50% predicted and forced vital capacity (FVC) to 70% predicted of patients with a high producer genotype was 1.74 (95% CI 1.11 to 2. 73) compared with 1.95 (95% CI 1.24 to 3.06) for those with a low producer genotype. TGF-beta(1) genotypes may have a role in mediating pulmonary dysfunction in patients with cystic fibrosis. Further work is required to determine whether inhibition of TGF-beta(1) activity in these patients may slow disease progression.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.JAIP.2014.01.016
Abstract: A 7-year-old girl presented with atopic dermatitis (AD) that did not respond to standard therapy. She was avoiding dairy, egg, and wheat in her diet because of a history of skin flares. Her weight gain was poor, and laboratory test results showed low iron and zinc levels. Over the previous 6 months, she had been prescribed numerous courses of antibiotics, but, despite this, she continued to have secondary skin infections as well as deep circumscribed erosions on her shins. She was awake much of the night because of scratching and displayed repetitive and habitual behavior. She also had troublesome allergic rhinoconjunctivitis with positive allergy testing results to house dust mite. Methicillin-resistant Staphylococcus aureus was isolated from her skin, which was successfully treated with appropriate antibiotics and flares controlled with topical antiseptics and better personal and caregiver hygiene. Although milk, egg, and wheat specific IgE were raised, these foods were successfully reintroduced back into her diet with improvement of her nutritional status and no flare of her AD. In view of her habitual behavior and family history of obsessive compulsive disorder, she underwent cognitive behavioral therapy, and her general well-being, sleep, and ulcers over her shins improved. Despite high house dust mite-specific IgE, house dust mite sublingual immunotherapy led to no additional improvement in her AD although it did improve her rhinitis. Although there may be no "quick fixes" in patients with AD, the clinician should be aware of antimicrobial, allergen, and educational and/or behavioral interventions, which may greatly improve eczema severity and the patient's well-being.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.JACI.2012.09.025
Abstract: Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. We sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10/IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled. Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R-deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.
Publisher: Oxford University Press (OUP)
Date: 11-2003
DOI: 10.1111/J.1365-2133.2003.05557.X
Abstract: Exposure to environmental microorganisms is associated with variations in the prevalence and severity of atopic diseases. We have previously shown that administration of a Mycobacterium vaccae suspension significantly reduced the severity of atopic dermatitis (AD) in children aged 5-18 years. This study aimed to extend these observations to younger children. Fifty-six children aged 2-6 years with moderate to severe AD were enrolled in a randomized, double-blind, placebo-controlled trial and given one intradermal injection of either killed M. vaccae suspension or buffer solution (placebo). Skin surface area affected and dermatitis severity score were assessed before and 1, 3 and 6 months after treatment. Although a 38-54% reduction in surface area affected by dermatitis was noted at all time points after M. vaccae administration (P = 0.005), this improvement was not significantly different from that observed in the placebo group. Meta-analysis of this and our previous cohort (97 children aged 2-18 years) showed that M. vaccae was associated with a significant improvement in clinical severity at all ages, whereas within the placebo group, younger but not older children showed a similar improvement. Despite a reduction in clinical severity associated with M. vaccae at all ages, no benefit could be found after administering M. vaccae to children with AD aged 2-6 years when compared with placebo. M. vaccae may offer greater benefit in children over 5 years old, whose AD appears less likely to regress spontaneously.
Publisher: Massachusetts Medical Society
Date: 11-05-2023
Publisher: Massachusetts Medical Society
Date: 30-09-2004
DOI: 10.1056/NEJMOA040036
Publisher: Oxford University Press (OUP)
Date: 03-11-2017
DOI: 10.1111/CEI.13068
Abstract: Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty-nine (70%) of 199 patients aged 1–80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7–74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1–13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2–10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50–91)] than those without this complication [92% (84–101)] (P & 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.
Publisher: Elsevier BV
Date: 2005
Publisher: Medical Journals Sweden AB
Date: 2014
Abstract: Mineral ions in tap water react with fatty acids in soap, leading to the formation of insoluble precipitate (metallic soap) on skin during washing. We hypothesised that metallic soap might negatively alter skin conditions. Application of metallic soap onto the skin of NC/Tnd mice with allergic dermatitis further induced inflammation with elevation of plasma immunoglobulin E and proinflammatory cytokine expression. Pruritus and dryness were ameliorated when the back of mice was washed with soap in Ca2+- and Mg2+-free ultra-pure soft water (UPSW). Washing in UPSW, but not tap water, also protected the skin of healthy volunteers from the soap deposition. Furthermore, 4 weeks of showering with UPSW reduced dryness and pruritus of human subjects with dry skin. Washing with UPSW may be therapeutically beneficial in patients with skin troubles.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2014
DOI: 10.1038/NATURE13386
Publisher: Elsevier BV
Date: 11-2013
Publisher: American Society for Clinical Investigation
Date: 06-08-2018
DOI: 10.1172/JCI97116
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.RESUSCITATION.2010.01.021
Abstract: Anaphylaxis is of increasing prevalence and concern in Western communities. Ambulance services are often called to deal with these emergencies. There are few published studies that examine the demand and management of allergic reactions by emergency services. The aim of this study was to investigate the frequency, severity and outcome of calls, as well as whether intramuscular adrenaline was required for successful management of allergic reactions by paramedics and first aiders. A retrospective study of all emergency calls for allergic reactions within Greater Manchester in a 12-month period by the North West Ambulance Service of the United Kingdom. 816 (0.2%) of 401,152 incidents were due to allergic reactions (32/100,000/year). No patients died. In 457 (56%) patients this was the first allergic reaction. Intramuscular adrenaline was administered to 116 (14%) patients. Patients with respiratory/circulatory compromise were significantly more likely to be given intramuscular adrenaline by paramedics (14 (4.4-45)), but not by first aiders (1.9 (0.98-3.6)). Administration of adrenaline by first aiders was more likely in patients with a past history of allergic reactions (4.3 (2.3-8.1)) and where reactions occurred at non-residential addresses (4.6 (2.6-8.2)). Emergency call-outs for allergic reactions made up <1% of total ambulance workload. Most cases were successfully managed without intramuscular adrenaline. Adrenaline appeared to be used appropriately by paramedics. The lack of correlation between clinical severity and adrenaline use by first aiders suggests that they may often not understand the correct clinical indications for this drug.
Publisher: Oxford University Press (OUP)
Date: 07-06-2005
DOI: 10.1189/JLB.0105042
Abstract: α-1-Acid glycoprotein (AGP) is an acute-phase protein produced by hepatocytes and secreted into plasma in response to infection/injury. We recently assessed the transcriptional program of terminal granulocytic differentiation by microarray analysis of bone marrow (BM) populations highly enriched in promyelocytes, myelocytes/metamyelocytes (MYs), and BM neutrophils. These analyses demonstrated a transient, high mRNA expression of genuine secondary/tertiary granule proteins and AGP in MYs. In agreement with this, immunocytochemistry revealed the presence of AGP protein and the secondary granule protein lactoferrin in cells from the MY stage and throughout granulocytic differentiation. Immunoelectron microscopy demonstrated the colocalization of AGP and lactoferrin in secondary granules of neutrophils. This finding was substantiated by the failure to detect AGP and lactoferrin in blood cells from a patient with secondary/tertiary (specific) granule deficiency. In addition, Western blot analysis of subcellular fractions isolated from neutrophils revealed that neutrophil-derived AGP, localized in secondary granules, was abundant and highly glycosylated compared with endocytosed, plasma-derived AGP localized in secretory vesicles. Exocytosis studies further demonstrated a marked release of AGP and lactoferrin by activated neutrophils. Finally, induction of CCAAT/enhancer-binding protein (C/EBP)-ɛ in a myeloid cell line was shown to increase AGP transcript levels, indicating that AGP expression in myeloid cells, like in hepatocytes, is partially regulated by members of the C/EBP family. Overall, these findings define AGP as a genuine secondary granule protein of neutrophils. Hence, neutrophils, which constitute the first line of defense, are likely to serve as the primary local source of AGP at sites of infection or injury.
Publisher: Oxford University Press (OUP)
Date: 1994
Abstract: Immunosuppressive factors isolated from trophoblast are known to block both innate and major histocompatibility complex (MHC)-dependent cell-mediated immune responses in vitro and, in some cases, in vivo. We investigated the biochemical nature of these factors, which is presently unknown. Immunosuppressive activity, assessed by inhibition of two-way MLR, was extracted from term syncytiotrophoblast microvilli using 3 M KCl. The activity resisted both extensive pronase digestion and heating to 90 degrees C for 1 h, demonstrating that intact membrane proteins were not required. Although purified protein-linked oligosaccharides released by hydrazinolysis from the syncytiotrophoblast membrane were themselves inactive, they blocked the immunosuppressive activity of the KCl extract. After pronase digestion, the activity could be fractionated by TSK 55S gel filtration, followed by C18 reverse-phase chromatography. Sequential exoglycosidase digestion of hydrazine-released sugars of the active fraction demonstrated that it contained neutral N-linked oligomannose and hybrid oligosaccharides, which normally make up < 3% of the total syncytiotrophoblast-derived protein glycan library. These glycopeptides of the active fraction were associated with membrane phospholipid micelles. The possible mechanism by which incompletely processed N-linked oligosaccharides expressed by a variety of syncytiotrophoblast membrane glycoproteins may block allogeneic reactivity when presented as polyvalent sugar groups is discussed.
Publisher: American Society of Hematology
Date: 26-04-2012
DOI: 10.1182/BLOOD-2011-11-392985
Abstract: T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4+ T cells to the Tfh lineage, because IL-12 induces naive human CD4+ T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4+ T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12–induced expression of IL-21 by human CD4+ T cells. Defective expression of IL-21 by STAT3-deficient CD4+ T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4+CXCR5+ T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
Publisher: American Society of Hematology
Date: 26-03-2009
DOI: 10.1182/BLOOD-2008-09-179630
Abstract: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRαβ+ CD4−CD8− T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.
Publisher: Informa UK Limited
Date: 12-04-2012
DOI: 10.3109/09546634.2012.672709
Abstract: Ciclosporin is used to treat severe atopic dermatitis (AD) where conventional therapy is either ineffective or inappropriate. Response to treatment is variable and the factors determining responsiveness are currently unclear. The aim of this study was to determine which children with severe AD are most responsive. A cohort of 35 children with severe AD who were given oral ciclosporin was retrospectively surveyed. SCORAD index was used to assess severity prior to and after treatment. Demographic and clinical data were correlated with clinical response. Ciclosporin resulted in a sustained reduction in SCORAD index of 91 (67-100)% in children where clinical skin infection was the main trigger and in whom the infection was effectively eradicated with antibiotics. If infection persisted or recurred the reduction in SCORAD index was only 44 (41-83)%. Children in whom their AD was triggered by other factors had a poor response to ciclosporin with reduction in SCORAD index of 8 (1-39)%. Oral ciclosporin is most effective in children with infection-driven AD in whom the infection is brought under control. In cases where the infection recurs or where the main triggers are non-infectious, response to ciclosporin is poorer.
Publisher: Elsevier BV
Date: 03-2001
Abstract: Although a doubling in the prevalence of atopic disease, including atopic dermatitis, in the Western world over the last few generations has been paralleled by a marked reduction in infectious diseases, especially tuberculosis, it is unclear whether this increase in atopy is causally related to reduced exposure to mycobacteria. The aim of this study was to determine whether administration of mycobacterial antigens to atopic in iduals might ameliorate their disease. Forty-one children aged 5 to 18 years with moderate-to-severe atopic dermatitis were enrolled in a randomized, double-blind, placebo-controlled trial, where they were given either one intradermal injection of killed Mycobacterium vaccae (SRL 172) or buffer solution (placebo). Changes in skin surface area affected by dermatitis and dermatitis severity score were assessed before treatment and at 1 and 3 months after treatment. Children treated with SRL 172 showed a mean 48% (95% CI, 32%-65%) reduction in surface area affected by dermatitis compared with a mean 4% (95% CI, -29% to 22%) reduction for the placebo group (P <.001) and a median 68% (interquartile range, 46%-85%) reduction in dermatitis severity score compared with 18% (interquartile range, -2% to 34%) for the placebo group (P <.01) at 3 months after treatment. There were no untoward effects of the treatment, apart from a local reaction in 13 of the 21 children, which occurred 1 month after SRL 172 administration and settled spontaneously. SRL 172 was associated with an improvement in the severity of the dermatitis in children with moderate-to-severe disease.
Publisher: Elsevier BV
Date: 03-2015
Publisher: Rockefeller University Press
Date: 02-2010
DOI: 10.1084/JEM.20091983
Abstract: Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1β, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-β, tumor necrosis factor [α], or transforming growth factor β). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.
Publisher: Wiley
Date: 28-12-2007
DOI: 10.1002/ART.23123
Abstract: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene. The cellular mechanisms by which mutations in this gene trigger inflammation are currently unclear. Because NF-kappaB is the major intracellular signaling component inducing secretion of proinflammatory cytokines, we sought to determine whether differences in the clinical phenotype of patients with TRAPS may be attributable to variable effects of TNFRSF1A mutations on TNFRI expression, localization, or NF-kappaB activity. Peripheral blood mononuclear cells were obtained from patients (following informed consent), and cellular nuclear and cytosolic fractions were generated by subcellular fractionation. Localization of IkappaBalpha and NF-kappaB was determined by Western blotting of the resultant fractions. NF-kappaB subunit activity was determined by enzyme-linked immunosorbent assay analysis and confirmed by electrophoretic mobility shift assay. Subcellular localization of TNFRI was determined by immunofluorescence confocal microscopy or by immunoblotting following affinity isolation of plasma membrane by subcellular fractionation. Cells from patients with the fully penetrant C73R mutation had marked activation of the proinflammatory p65 subunit of NF-kappaB. In contrast, cells from patients with the low-penetrant R92Q mutation displayed high levels of DNA binding by the p50 subunit, an interaction previously linked to repression of inflammation. Interestingly, although cells from patients with the C73R mutation have no TNFRI shedding defect, there was nonetheless an unusually high concentration of functional TNFRI at the plasma membrane. High levels of TNFRI at the cell surface in patients with the C73R mutation hypersensitizes cells to stimulation by TNF, leading to increased NF-kappaB p65 subunit activation and an exaggerated proinflammatory response.
Publisher: Oxford University Press (OUP)
Date: 24-11-2002
DOI: 10.1046/J.1365-2249.2002.02002.X
Abstract: Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.
Publisher: Springer Science and Business Media LLC
Date: 02-2015
DOI: 10.1007/S10875-015-0137-5
Abstract: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.
Publisher: Elsevier BV
Date: 02-2009
Publisher: BMJ
Date: 10-2000
DOI: 10.1136/ADC.83.4.356
Abstract: The clinical course of 10 children who have been diagnosed with major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) in the UK over the past eight years is described. They have had a generally poor prognosis, with only two of the 10 still alive despite eight attempts at bone marrow transplantation in six patients. Overwhelming viral infection was the predominant cause of death. Alternative transplant strategies or novel therapies are required for these patients.
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0165-0378(92)90043-4
Abstract: Pregnancy serum contains a factor or factors which suppress T lymphocyte proliferation, although the identity of the factor(s) is still unclear. We have demonstrated that the immunosuppressive activity of pregnancy sera can be destroyed by treatment with periodate which oxidises protein-linked oligosaccharides. Similar effects have been noted with uromodulin, a potent immunosuppressive glycoprotein initially isolated from pregnancy urine. We find, however, that uromodulin is present in both pregnancy and non-pregnancy sera, and that removal of uromodulin from pregnancy serum by lectin affinity chromatography is not associated with loss of activity, ruling out this glycoprotein as the immunosuppressive factor. The possible role of protein-linked oligosaccharides of other serum glycoproteins in causing the pregnancy-related immunosuppression is discussed.
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.CELLIMM.2011.02.007
Abstract: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene which encodes the tumor necrosis factor (TNF) receptor, TNFR1. We investigated the effect of three high penetrance and three low penetrance TNFRSF1A mutations upon NF-κB transcription factor family subunit activity, and the resulting impact upon secretion of 25 different cytokines. Whilst certain mutations resulted in elevated NF-κB p65 subunit activity, others instead resulted in elevated c-Rel subunit activity. Interestingly, high p65 activity was associated with elevated IL-8 secretion, whereas high c-Rel activity increased IL-1β and IL-12 secretion. In conclusion, while all six TNFRSF1A mutations showed enhanced NF-κB activity, different mutations stimulated distinct NF-κB family subunit activities, and this in turn resulted in the generation of unique cytokine secretory profiles.
Publisher: American Medical Association (AMA)
Date: 07-2002
DOI: 10.1001/ARCHDERM.138.7.939
Abstract: Skin staphylococci and streptococci are known to exacerbate atopic dermatitis, but the prevalence changes that occur with age are unknown. This study examined the age-related prevalence and antibiotic resistance of these pathogenic bacteria in children with atopic dermatitis and suspected skin infections. Medical records of 150 children with atopic dermatitis referred to a regional center, who had skin swabs taken for suspected infection, were studied retrospectively. All patients carried Staphylococcus aureus. The prevalence of methicillin sodium-resistant (P =.05) and fusidic acid-resistant (P =.001) S aureus tripled from infancy to school age. Lancefield groups A and G streptococci were the other pathogens found. The prevalence of group A streptococci was highest in children aged 3 to 6 (53%), compared with 11% of infants and 21% of patients aged 9 to 16 (P =.002). Significant differences in the age-related prevalence of group A streptococci skin carriage and antibiotic resistance of S aureus isolates occurred in this group of children with atopic dermatitis and suspected skin infections. Skin swabs to determine bacterial type and antibiotic sensitivities provide an important guide to antibiotic prescribing in these children.
Publisher: Oxford University Press (OUP)
Date: 06-10-2008
DOI: 10.1111/J.1365-2249.2008.03778.X
Abstract: Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-γ, IL-2, tumour necrosis factor (TNF)-α, IL-6, transforming growth factor-β, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-γ, TNF-α and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.
Publisher: Oxford University Press (OUP)
Date: 04-01-2010
Publisher: American Society of Hematology
Date: 28-10-2010
DOI: 10.1182/BLOOD-2009-09-238832
Abstract: X-linked lymphoproliferative disease (XLP) is a condition associated with mutations in the signaling lymphocytic activation molecule (SLAM)–associated protein (SAP SH2D1A). SAP functions as an adaptor, binding to and recruiting signaling molecules to SLAM family receptors expressed on T and natural killer cells. XLP is associated with extreme sensitivity to primary Epstein-Barr virus (EBV) infection, often leading to a lethal infectious mononucleosis. To investigate EBV-specific immunity in XLP patients, we studied 5 in iduals who had survived EBV infection and found CD8+ T-cell responses numerically comparable with healthy donors. However, further investigation of in vitro–derived CD8+ T-cell clones established from 2 of these donors showed they efficiently recognized SLAM ligand–negative target cells expressing EBV antigens, but showed impaired recognition of EBV-transformed, SLAM ligand–positive, lymphoblastoid cell lines (LCLs). Importantly, LCL recognition was restored when interactions between the SLAM receptors CD244 and natural killer–, T-, and B-cell antigen (NTBA) and their ligands on LCLs were blocked. We propose that XLP patients' particular sensitivity to EBV, and not to other viruses, reflects at least in part EBV's strict tropism for B lymphocytes and the often inability of the CD8+ T-cell response to contain the primary infection of SLAM ligand–expressing target cells.
Publisher: Hindawi Limited
Date: 02-2010
DOI: 10.1002/HUMU.21156
Abstract: Mutations that impair expression or function of the components of the phagocyte NADPH oxidase complex cause chronic granulomatous disease (CGD), which is associated with life-threatening infections and dysregulated granulomatous inflammation. In five CGD patients from four consanguineous families of two different ethnic backgrounds, we found similar genomic homozygous deletions of 1,380 bp comprising exon 5 of NCF2, which could be traced to Alu-mediated recombination events. cDNA sequencing showed in-frame deletions of phase zero exon 5, which encodes one of the tandem repeat motifs in the tetratricopeptide (TPR4) domain of p67-phox. The resulting shortened protein (p67Delta5) had a 10-fold reduced intracellular half-life and was unable to form a functional NADPH oxidase complex. No dominant negative inhibition of oxidase activity by p67Delta5 was observed. We conclude that Alu-induced deletion of the TPR4 domain of p67-phox leads to loss of function and accelerated degradation of the protein, and thus represents a new mechanism causing p67-phox-deficient CGD.
Publisher: American Thoracic Society
Date: 02-2003
Publisher: American Society of Hematology
Date: 05-12-2013
DOI: 10.1182/BLOOD-2013-06-506865
Abstract: IL21-mediated induction of CD25 expression on naïve human B cells requires STAT3. A lack of response to IL-2 may lify humoral immunodeficiency in patients with STAT3, IL2RG, or IL21R mutations due to unresponsiveness to IL21.
Publisher: Oxford University Press (OUP)
Date: 27-08-2007
DOI: 10.1093/RHEUMATOLOGY/KEM207
Abstract: C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.JAUT.2015.06.002
Abstract: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient in iduals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.
Publisher: American Society for Clinical Investigation
Date: 12-03-2020
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1016/S0165-0378(01)00069-9
Abstract: Approximately one in 300 women experience recurrent pregnancy loss (RPL), the aetiology of which is unknown in at least 40% of cases. Previously, some studies have shown increased production of pro-inflammatory cytokines (tumour necrosis factor-alpha and interferon-gamma) and reduced production of anti-inflammatory cytokines (interleukin-10) by circulating blood lymphocytes isolated from these patients when compared with controls. The reasons for this are unclear. The production of these cytokines are partly under genetic control. This study investigated whether polymorphisms in these three cytokine genes known to be associated with either high or low production, are associated with idiopathic RPL. No association was found. It may be that genetic factors are not a major determinant of cytokine production during pregnancy, or alternatively it may be that the observed differences in cytokine production by peripheral lymphocytes do not accurately indicate what is occurring at the local maternofoetal interface during successful and abortive pregnancies.
Publisher: Oxford University Press (OUP)
Date: 25-05-2018
DOI: 10.1111/CEI.13125
Abstract: This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0091-6749(03)01797-4
Abstract: Genetic factors are known to be important in determining an in idual's predisposition to atopic dermatitis. The specific genes that are clinically important in this process are still largely unknown. Because dendritic cells initiate immune responses and thus are critical to the priming of an in idual to potential allergens, we hypothesized that genetic factors controlling the activity of these cells determine an in idual's propensity to atopic dermatitis. We studied known functional polymorphisms of the IL-1beta and TNF-alpha genes and describe novel polymorphisms of the GM-CSF gene in 113 children with atopic dermatitis and 114 controls. All 3 factors are known to be important modulators of the function of skin Langerhans' (dendritic) cells. The inheritance of a homozygous GM-CSF -677*C/C genotype was associated with complete absence of severe atopic dermatitis within this cohort of children (P <.001). Furthermore, the odds ratio of having atopic dermatitis in children who were not of this genotype was 7.5 (2.2-25). The GM-CSF genotype is an important genetic marker predicting an in idual's predisposition to atopic dermatitis.
Publisher: Oxford University Press (OUP)
Date: 24-02-2005
DOI: 10.1111/J.1365-2249.2005.02743.X
Abstract: The increasing prevalence of atopic diseases over the last few decades is thought to be due to reduced exposure to environmental microbes that normally down-regulate allergic responses (hygiene hypothesis). We have shown previously that administration of the environmental microbe Mycobacterium vaccae ameliorates atopic dermatitis in school-age children at 3 months post-treatment. The present study tested the hypothesis that M. vaccae suppresses Th2-type cytokine activity and increases transforming growth factor (TGF)-β1 immunomodulatory activity in these children. Interleukin (IL)-4, IL-5, TGF-β1 and interferon (IFN)-γ activity were assessed in resting and stimulated peripheral blood mononuclear cells (PBMC) isolated from 12 of the children who received M. vaccae in our original clinical trial. A cDNA expression array was used to examine a broader range of cytokine pathway transcripts. There were no significant changes in either Th2-type or TGF-β1 activity. A 5- to 10-fold increase in Th1-type activity was found at 1 month post-M. vaccae administration (P & 0·05), but it had returned to baseline by 3 months. The results do not support the hypothesis that M. vaccae reduces Th2-type or increases TGF-β1 activity of PBMC isolated from children with atopic dermatitis. The transient surge in IFN-γ at 1 month is unlikely to explain any improvement in eczema score at 3 months.
Publisher: Oxford University Press (OUP)
Date: 26-01-2006
DOI: 10.1111/J.1365-2133.2005.07082.X
Abstract: The psychological impact of childhood atopic eczema on parents and carers is poorly quantified. Objectives To compare the impact of caring for a child with atopic eczema vs. asthma on parents' sleep and well-being. Ninety-two parents of 55 children who had moderate to severe atopic eczema or asthma took part in this prospective, questionnaire-based study. It was conducted at regional eczema and asthma outpatient clinics within a U.K. tertiary paediatric hospital. The main outcome measures were the number and duration of parents' sleep disturbances, as well as their anxiety and depression scores. Mothers caring for children with atopic eczema lost a median of 39 min of sleep per night and fathers lost 45 min sleep per night. This compared with a median of 0 min sleep lost by parents who had children with asthma (P < 0.001). These differences were independent of the age of the children, and whether the child came from a single-parent or two-parent family. There was a direct correlation between the severity of sleep disturbance and the level of maternal anxiety (rho = 0.58 P = 0.002) and depression (rho = 0.73 P < 0.001), as well as the level of paternal anxiety (rho = 0.59 P = 0.01). Compared with looking after a child with chronic asthma, caring for a child with chronic atopic eczema was associated with greater parental sleep disturbances. Disruption to parental sleep correlated with anxiety levels and, in the case of mothers, depression scores.
Publisher: The American Association of Immunologists
Date: 12-2020
Abstract: Extensive activation of mast cells is the major switch that triggers systemic anaphylaxis, resulting in the subsequent release of anaphylactic mediators into circulation. We previously demonstrated that rapid changes in oxygen tension lead to mast cell degranulation, and the released tryptase triggers retinal angiogenesis in a murine oxygen-induced retinopathy model. However, whether a rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk factor for systemic anaphylaxis remains unknown. In this study, we demonstrated that the relative hypoxia stress induces systemic mast cell activation via transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads to hypothermia and increased vascular permeability in adult mice. Although mast cell–deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms following a rapid sift to normoxia, preinjection with bone marrow–derived cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice restored anaphylactic responses. In addition, we found that the rapid reductions in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor. Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms. Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylactic shock without Ag–Ab reactions. These findings introduce a potential role for oxygen in inducing mast cell–dependent anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for anoxic diseases.
Publisher: BMJ
Date: 03-2002
DOI: 10.1136/ADC.86.3.200
Abstract: The clinical outcome of 42 acutely unwell infants <3 months old with lymphopenia was retrospectively compared with that of 42 controls. Lymphopenic infants were significantly more likely to require active resuscitation and intensive care, independent of total leucocyte count, gender, degree of prematurity, and diagnosis.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.HUMIMM.2010.01.018
Abstract: Toll-like receptors (TLRs) are important in the initiation of immune responses in both health and disease. How TLR activity alters with age, gender, and also with immunosuppressive agents is still largely unexplored. We studied TLR activity in 49 healthy in iduals as well as in 26 patients receiving immunosuppressive drugs. TLR activity did not alter significantly between the ages of 2 and 67 years. However, females had twice the TLR7 ligand-induced interferon-I response of males (OR [95% CI] 2.7 [1.4-5.1]), whereas TLR3 and four activities were not significantly different between the sexes. The T-cell immunosuppressant agents cyclosporine, tacrolimus, and azathioprine, as well as low dose glucocorticosteroids did not significantly alter TLR pathway responses. In contrast, high dose glucocorticosteroids reduced in vivo TLR responses by 70%-90%. We suggest that gender differences in TLR responses may help to explain the female preponderance of some autoimmune disorders. Furthermore, an understanding the effects of immunosuppressive agents on TLR-pathway activity should allow more focused therapy for autoimmune disorders.
Publisher: Public Library of Science (PLoS)
Date: 14-12-2011
Publisher: Elsevier BV
Date: 02-2010
Publisher: Elsevier BV
Date: 02-2013
Publisher: Wiley
Date: 09-2006
DOI: 10.1111/J.1365-2222.2006.02558.X
Abstract: The hygiene hypothesis is often proposed to explain the high prevalence of atopy in the western world. Dysregulation of the immune system may result from inadequate exposure to micro-organisms such as mycobacteria. A small trial suggested that a killed extract of Mycobacterium vaccae ameliorates atopic dermatitis (AD). To confirm in a large clinical trial whether killed M. vaccae ameliorates AD in 5-16-year-old children. This was a randomized, placebo-controlled, double-blind, multi-centre study of the effect of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate-to-severe AD. Patients were followed up for 24 weeks. The primary end point was the change in severity of AD at 12 weeks, assessed using the six area, six-sign, atopic dermatitis (SASSAD) score. Secondary end points included changes in disease extent, patient's global assessment and children's dermatology life quality index. There were 166 patients randomized. The mean SASSAD score fell to a similar degree at week 12 in all treatment arms: from 33 to 24, (26%) in the high-dose group, from 30 to 23 (25%) in the low-dose group and from 36 to 27 (24%) in the placebo group (P>0.05). Secondary end points followed the same trend. Adverse events were generally those expected to occur in this population. Injection site reactions occurred in 32 patients at week 4. M. vaccae was no more effective than the placebo in ameliorating the severity of AD.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2022
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.YMGME.2012.12.001
Abstract: The deficiency of ubiquitously expressed glucose-6-phosphatase (G6PC3) enzyme is known to result in a syndrome characterized by severe congenital neutropenia, prominent superficial venous pattern, congenital heart defects and genito-urinary malformations. Here, we describe four patients from three families with non-syndromic severe congenital neutropenia and identify four G6PC3 mutations as causative in these cases. Thus we demonstrate that G6PC3 mutations also result in a non-syndromic form of severe congenital neutropenia. We propose that G6PC3 deficiency should be considered as part of the differential diagnoses in any patient with unexplained congenital neutropenia. Additionally, we show a relationship between the genotype and non-hematological phenotype of G6PC3 deficiency. These findings may provide an insight into the role of the G6PC3 enzyme and glucose metabolism in developmental pathways.
Publisher: Oxford University Press (OUP)
Date: 08-2001
DOI: 10.1046/J.1365-2249.2001.01620.X
Abstract: Toxin-positive strains of Staphylococcus aureus (T + S. aureus) are present on the skin of some but not all patients with atopic dermatitis. Many staphylococcal toxins are superantigens, which can stimulate the immune response and thus may potentially lead to the very high levels of IgE characteristic of this condition, as well as exacerbating the clinical disease. The aim of this study was to determine whether the presence of T + S. aureus on the skin of children with atopic dermatitis was associated with in vivo evidence of a heightened humoral immune response, higher IgE levels and more severe clinical disease. Toxin gene expression in S. aureus isolated from the eczematous lesions of 28 children with atopic dermatitis was assessed by PCR. Clinical and immune data were also collected from this cohort. Thirteen of the 28 children (46%) were colonized with T + S. aureus strains. The presence of T + S. aureus was associated with a significant expansion in peripheral blood CD5− B cells (P = 0·01), and the more toxin types identified the greater the B-cell expansion (P = 0·002). However, in this cohort of children with atopic dermatitis, despite th in vivo expansion of B cells in children harbouring T + S. aureus, there was no associated increase in IgE levels or in clinical disease severity scores.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1984
Publisher: BMJ
Date: 02-2010
Abstract: Although poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome. Clinical and laboratory parameters from 64 patients with 22q11.2 deletion syndrome referred to two immunology centres in the north of England were studied retrospectively. 31 (48%) patients had no problems with infection, 21 (33%) had bacterial infections, and 12 (19%) had recurrent or persistent thrush and/or viral enteritis and bronchiolitis, the latter suggestive of a significant T cell immunodeficiency. Patients with a history of thrush/viral infections, but not those with bacterial infections, had significantly lower CD4+ and CD8+ T lymphocyte numbers (relative risk (95% CI) 0.3 (0.1 to 0.8)) and phytohaemagglutinin mitogen responses (0.4 (0.2 to 0.8)) adjusted for age at testing. Hypoparathyroidism was associated with low T lymphocyte numbers and function (p<0.05) as well as an increased risk of thrush/viral infections (p<0.0001) after adjusting for age at testing. 22q11.2 syndrome patients with hypoparathyroidism are more likely to have a clinically significant T cell immunodeficiency and lower laboratory parameters of T cell function, with a higher risk of thrush and viral bronchiolitis and enteritis. Measurement of absolute CD3 count is a simple and accurate predictor of fungal/viral infection risk, with phytohaemagglutinin mitogen responses providing little or no further value in most patients.
Publisher: Rockefeller University Press
Date: 11-11-2013
DOI: 10.1084/JEM.20130323
Abstract: Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5 ERK PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.VACCINE.2007.06.021
Abstract: Current guidelines recommend up to two doses of the pneumococcal conjugate heptavalent vaccine (PCV-7) in children up to 5 years old followed by and a dose of the polysaccharide vaccine (PPV-23) for patients over 2 years old to broaden serotype immunity. We assessed the serotype responses to two doses of PCV-7 and a dose of PPV-23 in a cohort of children in the 2-16-year age range in order to determine whether PPV-23 induced effective immunity to non-PCV-7 serotypes. Pneumococcal antibody concentrations to the seven serotypes covered by PCV-7 and five additional serotypes covered by PPV-23 but not PCV-7 were measured in 60 children aged 2-16 years. None of the children had a primary antibody immunodeficiency. Vaccinated children had 7-30-fold higher antibody concentrations than unvaccinated children to all serotypes contained in the PCV-7 (P or =0.35 mcg/ml) against these serotypes. In this cohort of children, PPV-23 vaccine did not broaden the protection in vitro against potentially pathogenic strains of Streptococcus pneumoniae. We call into question the recommendation to use the PPV-23 in children.
Publisher: American Academy of Pediatrics (AAP)
Date: 05-2011
Abstract: The 10 warning signs of primary immunodeficiency diseases (PID) have been promoted by various organizations in Europe and the United States to predict PID. However, the ability of these warning signs to identify children with PID has not been rigorously tested. The main goal of this study was to determine the effectiveness of these 10 warning signs in predicting defined PID among children who presented to 2 tertiary pediatric immunodeficiency centers in the north of England. A retrospective survey of 563 children who presented to 2 pediatric immunodeficiency centers was undertaken. The clinical records of 430 patients with a defined PID and 133 patients for whom detailed investigations failed to establish a specific PID were reviewed. Overall, 96% of the children with PID were referred by hospital clinicians. The strongest identifiers of PID were a family history of immunodeficiency disease in addition to use of intravenous antibiotics for sepsis in children with neutrophil PID and failure to thrive in children with T-lymphocyte PID. With these 3 signs, 96% of patients with neutrophil and complement deficiencies and 89% of children with T-lymphocyte immunodeficiencies could be identified correctly. Family history was the only warning sign that identified children with B-lymphocyte PID. PID awareness initiatives should be targeted at hospital pediatricians and families with a history of PID rather than the general public. Our results provide the general pediatrician with a simple refinement of 10 warning signs for identifying children with underlying immunodeficiency diseases.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.JACI.2010.08.027
Abstract: Accumulating evidence implicates T(H)17 cytokines in protection against Candida species infections, but the clinical relevance is not clear. Chronic mucocutaneous candidiasis (CMC) is a heterogeneous syndrome with the unifying feature of selective susceptibility to chronic candidiasis. Different subgroups with distinct clinical features are recognized, including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), CMC with hypothyroidism, and isolated CMC. Understanding immune defects in patients with CMC will define cellular and molecular mechanisms crucial for protection against Candida species in human subjects. We sought to determine whether impaired T(H)17 responses underlie susceptibility to Candida species infections and whether the same defect is present in different CMC subgroups. We assessed T(H)17 responses of PBMCs to Candida and non-Candida species stimuli by measuring IL-17, IL-22, IL-21, IL-6, IL-23, and IFN-γ cytokine production using cytokine arrays and intracellular cytokine-producing cell numbers and proliferation with flow cytometry. PBMCs from healthy subjects and unaffected family members served as controls. In patients with CMC with hypothyroidism, T(H)17 cells demonstrated decreased proliferation and IL-17 production in response to Candida species. In contrast, in patients with APECED, T(H)17 cell proliferation and IL-17 production were normal unless exposed to APECED plasma, which inhibited both functions in both APECED and normal PBMCs. Candida species-stimulated IL-22 production was impaired in all patients with CMC, whereas IL-6 and IL-23 responses were unaltered. An impaired T(H)17 response to Candida species, although mediated by different mechanisms, was present in all CMC subgroups studied and might be a common factor predisposing to chronic candidiasis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2008
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.JACI.2014.11.029
Abstract: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. We sought to define the outcomes of HSCT for patients with CVID. Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.
Publisher: Massachusetts Medical Society
Date: 27-09-2007
DOI: 10.1056/NEJMC072018
Publisher: Oxford University Press (OUP)
Date: 09-10-2020
DOI: 10.1111/BJD.19460
Publisher: Wiley
Date: 17-11-2006
Publisher: The American Association of Immunologists
Date: 07-2021
Abstract: Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette–Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.
Publisher: Wiley
Date: 19-12-2011
DOI: 10.1111/J.1365-2222.2011.03912.X
Abstract: Although adrenaline is recommended as first line treatment for anaphylaxis, it is often not utilized. There has been a debate about when adrenaline autoinjectors should be prescribed and how many should be dispensed. To see how many adrenaline autoinjectors were used during anaphylactic reactions and to determine why they were not used in situations where they were clinically indicated. Patients were recruited prospectively at 14 paediatric allergy clinics throughout UK. Participants completed a questionnaire covering demographic data, atopic status and details of allergic reactions in the previous year and reasons for using more than one device. A total of 969 patients were recruited of whom 466 (48.1%, 95% CI: 37.9-58.2) had had at least one reaction in the previous year 245 (25.3%, 95% CI: 16.2-34.4) of these reactions were anaphylaxis. An adrenaline autoinjector was used by 41 (16.7%, 95% CI: 11.7-21.3) participants experiencing anaphylaxis. Thirteen participants received more than one dose of adrenaline, for nine of these a health professional gave at least one. The commonest reasons for using more than one were severe breathing difficulties (40%), lack of improvement with first dose (20%) and miss-firing (13.3%). The commonest reasons for not using adrenaline in anaphylaxis were 'thought adrenaline unnecessary' (54.4%) and 'unsure adrenaline necessary' (19.1%). Many with wheeze did not use their autoinjector. Adrenaline is used by only a minority of patients experiencing anaphylaxis in the community. Thirteen of the 41 patients with anaphylaxis who used their autoinjector needed another dose of adrenaline. Further research is needed to consider how to best encourage the usage of adrenaline when clinically indicated in anaphylaxis.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-08-2015
Abstract: The immune system needs its full array of soldiers—including cells and the molecules they secrete—to optimally protect the host. When this isn't the case, minor infections can become chronic or even deadly. Markle et al. report the discovery of seven in iduals carrying loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. These in iduals lacked immune cells that produce the cytokine interleukin-17, causing them to suffer from chronic candidiasis. RORC-deficient in iduals also exhibited impaired immunity to mycobacterium, probably due to reduced production of the cytokine interferon-γ, a molecule not known to require RORC for its induction. Science , this issue p. 606
Publisher: Elsevier BV
Date: 03-2022
Publisher: Rockefeller University Press
Date: 17-10-2011
DOI: 10.1084/JEM.20110345
Abstract: In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7− phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell ision. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.
Publisher: Elsevier BV
Date: 2014
Publisher: Oxford University Press (OUP)
Date: 03-2007
DOI: 10.1111/J.1365-2230.2006.02313.X
Abstract: There is little information on the relative efficacy of topical tacrolimus and corticosteroids in the treatment of atopic dermatitis (AD) in children. In a single-centre, prospective, observer-blinded, side-to-side comparative study (ISRCTN65507338), 96 children with moderately severe AD were enrolled. The study aimed to compare the relative effectiveness of the child's usual topical corticosteroid with 0.03% tacrolimus ointment applied for 1 week, and if there was no difference, 0.1% tacrolimus ointment applied for a further week. Topical tacrolimus was found to be more effective than topical corticosteroid in 72 of the 93 children (77%) who completed the study. Using multiple-regression analysis with age, gender, pretreatment surface area affected and pretreatment corticosteroid potency as covariants, the only factor that reduced the chance of observing a beneficial effect with tacrolimus was moderate or potent topical corticosteroid use (OR = 0.13 95% CI 0.02-0.74).
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.JACI.2007.12.003
Abstract: Although acute allergic reactions after ingestion of peanuts and tree nuts are common, fatalities are rare. Other than patients with coexisting asthma, it is currently not possible to predict which patients are most likely to develop severe reactions. The aim of this study was to determine which clinical and laboratory parameters best predict the likelihood of severe allergic reactions. From 1992 to 2004, we collected detailed information on the clinical severity and allergy test results of 1094 patients with peanut and tree nut allergy attending a regional allergy center. In a subgroup of 122 patients, sera were assayed for activity of enzymes involved in the catabolism of bradykinin. Severe pharyngeal edema was 3.8 (2.1-6.9) times more common in patients with severe rhinitis and 2.6 (1.8-3.7) more common after ingestion of tree nuts compared with peanuts. Patients with serum angiotensin-converting enzyme concentrations <37.0 mmol/L had a 9.6 (1.6-57)-fold risk of severe pharyngeal edema. Life-threatening bronchospasm was most likely in patients with severe asthma (relative risk, 6.8 [4.1-11.3]) and less so in patients with milder asthma (2.7 [1.7-4.0]). Altered levels of consciousness were more likely in patients with severe eczema (3.1 [1.1-8.4]). Severity of coexisting atopic diseases predicted which patients attending a tertiary referral clinic were most likely to develop life-threatening allergic reactions to peanuts and tree nuts. Patients with the lowest serum angiotensin-converting enzyme concentrations were more likely to develop life-threatening pharyngeal edema, suggesting that this complication may be partly mediated by bradykinin.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Rockefeller University Press
Date: 04-01-2010
DOI: 10.1084/JEM.20091706
Abstract: Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2009
DOI: 10.1038/CR.2009.112
Publisher: Elsevier BV
Date: 11-1991
DOI: 10.1016/0143-4004(91)90498-5
Abstract: The fetally derived syncytiotrophoblast in the placenta form the major interface with the maternal circulation. Cell surface N-linked oligosaccharides are known to influence cell-cell interactions in a variety of ways. The N-linked oligosaccharide component of the human syncytiotrophoblast membrane has been purified from term placentae, and its biochemical structure analysed. Ninety-five per cent of structures were complex N-linked oligosaccharides, with the remaining 5 per cent being of the oligomannose type. Seventy-two per cent of oligosaccharides were sialylated 50 per cent having two or more sialic acid residues. Such a population of N-linked oligosaccharides would be expected to provide a surface which inhibits interactions between trophoblast and maternal leukocytes. The temporal changes in syncytiotrophoblast N-linked oligosaccharides from the end of the second, and through the third trimester (25-41 weeks) were analysed, as were the changes which occur during parturition. There was no change in the degree of sialylation of these structures. The only significant change was a 37 per cent decrease in core fucosylation of complex N-linked sugars during gestation (P less than 0.005). Women delivered by caesarean section at term, had significantly higher levels of fucosylation (equivalent to women with a gestational age of 31-36 weeks), than those who laboured at term. Present knowledge of core fucosylation of N-linked oligosaccharides is discussed in relation to trophoblast functioning.
Publisher: American Society of Hematology
Date: 07-2006
DOI: 10.1182/BLOOD-2005-09-3890
Abstract: Haptoglobin (Hp) is a plasma protein synthesized primarily by hepatocytes. It exerts a broad range of anti-inflammatory activities and acts indirectly as a bacteriostatic agent and an antioxidant by virtue of its ability to bind free hemoglobin (Hb) and to facilitate its immediate clearance by macrophages. We identified Hp as a novel specific granule protein of neutrophils by means of immunoelectron microscopy, subcellular fractionation, and exocytosis studies. Consistent with these findings, blood cells from a patient with specific granule deficiency (SGD) lacked neutrophil-derived Hp. Neutrophils contained a large amount of highly glycosylated Hp (beta-chain 45-65 kDa) synthesized in neutrophil precursors and stored in specific granules and a small amount of Hp (beta-chain 39 kDa) endocytosed from plasma and stored in secretory vesicles. Subsequent binding studies revealed that Hp from specific granules binds to Hb. Finally, the CCAAT enhancer binding protein-epsilon (C/EBPepsilon) induced Hp transcription in a myeloid cell line, suggesting that Hp expression in myeloid cells, as in hepatocytes, is at least partially regulated by members of the C/EBP transcription factor family. Collectively, these findings demonstrate that Hp is stored in specific granules and is released by neutrophils in response to activation. Hence, neutrophil-derived Hp might reduce tissue damage and bacterial growth at sites of infection or injury by propagating anti-inflammatory activities and Hb clearance.
Publisher: American Society for Clinical Investigation
Date: 06-1993
DOI: 10.1172/JCI116515
Publisher: Springer Science and Business Media LLC
Date: 23-09-2015
Publisher: The American Association of Immunologists
Date: 15-10-2010
Abstract: Almost all humans with homozygous deficiency of C1q develop systemic lupus erythematosus (SLE). The precise cellular mechanism(s) by which C1q prevents the development of SLE remains unclear. In this study, we tested the role of C1q in the regulation of IFN-α induced by immune complexes (ICs) in vitro, as well as the consequences of lack of C1q in vivo. Our experiments revealed that C1q preferentially promotes the binding of SLE ICs to monocytes rather than plasmacytoid dendritic cells, but this inhibition was not due to the induction of inhibitory soluble factors. The presence of C1q also altered the trafficking of ICs within monocytes such that ICs persisted in early endosomes. In patients with C1q deficiency, serum and cerebrospinal fluid levels of IFN-α and IFN-γ–inducible protein-10 levels were elevated and strongly correlated with Ro autoantibodies, demonstrating the clinical significance of these observations. These studies therefore associate C1q deficiency with defective regulation of IFN-α and provide a better understanding of the cellular mechanisms by which C1q prevents the development of IC-stimulated autoimmunity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1982
Abstract: Thirty pairs of drinking and nondrinking men, matched for age and weight, were drawn from a working population in which a close relationship between alcohol consumption and blood pressure had been demonstrated. In this smaller s le, men who drank an average of 408 ml of ethanol/week had higher supine (126.9 +/- 2.3 mm Hg) and standing (113.3 +/- 2.5 mm Hg) systolic and supine diastolic blood pressure (75.5 +/- 2.2 mm Hg) than nondrinkers (117.5 +/- 2.0, 107.4 +/- 2.2 and 68.9 +/- 1.8 mm Hg, respectively). Resting plasma concentrations of free and sulfated norepinephrine and epinephrine, renin activity, angiotensin II, aldosterone and cortisol were similar in drinkers and nondrinkers. To investigate differences that may arise when sympathoadrenal activity was stimulated, the subjects underwent a series of standardized physiologic stresses: isometric hand grip, mental arithmetic, cold pressor testing, standing and bicycle exercise. Blood pressure and heart rate responses were similar in drinkers and nondrinkers, although the differences in blood pressure between the two groups tended to become smaller after certain stresses. No differences in the plasma levels of free or conjugated catecholamines were apparent after these stresses. Plasma renin activity increased only after bicycle exercise, and this was similar in both groups. Plasma cortisol levels did not increase. The higher blood pressure in drinkers, therefore, cannot be explained by increased activity of the sympathoadrenal and renal pressor mechanisms.
Publisher: Elsevier BV
Date: 08-2001
Abstract: Atopic dermatitis (AD) is associated with hyperresponsiveness of lymphocytes to allergens. In acute AD only T(H)2-type lymphocytes are activated, whereas in more chronic forms of AD, the activity of both T(H)1- and T(H)2-type lymphocytes increases. IL-10 and transforming growth factor beta(1) (TGF-beta(1)) are immunosuppressive cytokines that inhibit the activity of both T(H) cell types in human subjects. The aim of this study was to determine whether children with moderately severe chronic AD had IL10 or TGFB1 genotypes known to be associated with low cytokine production. Using lification refractory mutation screening PCR, we examined TGFB1 and IL10 gene polymorphisms, which are known to affect cytokine production, in 68 children with moderately severe AD and in 50 nonatopic children. The odds ratio of children with AD having a low TGFB1 producer genotype was 4.8 (95% CI, 2.4--9.7) compared with the control subjects (P <.0001). There were no differences in the frequency of IL10 gene polymorphisms between groups. TGFB1 genotype may partly explain the strong genetic predisposition to AD.
Publisher: Rockefeller University Press
Date: 04-05-2015
DOI: 10.1084/JEM.20141992
Abstract: Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that in iduals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic in iduals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
Publisher: American Society of Hematology
Date: 15-04-2002
Abstract: Human primary immunodeficiency diseases are experiments of nature characterized by an increased susceptibility to infection. In many cases, they are also associated with troublesome and sometimes life-threatening autoimmune complications. In the past few years, great strides have been made in understanding the molecular basis of primary immunodeficiencies, and this had led to more focused and successful treatment. This review has 3 aims: (1) to highlight the variety of autoimmune phenomena associated with human primary immunodeficiency diseases (2) to explore how primary immunodeficiencies predispose patients to autoimmune phenomena triggered by opportunistic infections and (3) to consider the rationale for the current treatment strategies for autoimmune phenomena, specifically in relation to primary immunodeficiency diseases. Reviewing recent advances in our understanding of the small subgroup of patients with defined causes for their autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.
Publisher: The Endocrine Society
Date: 11-2008
DOI: 10.1210/JC.2008-0935
Abstract: Context: In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. Design: The study was designed to detect autoantibodies against interferon-α2 and interferon-ω in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. Outcome: The diagnostic value of anti-interferon autoantibodies was assessed. Results: We found antibodies against interferon-α2 and/or interferon-ω in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-ω, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.
Publisher: The American Association of Immunologists
Date: 15-04-2006
DOI: 10.4049/JIMMUNOL.176.8.5078
Abstract: The autosomal recessive form of human complete Stat-1 deficiency is a rare disorder, thus far reported in two unrelated patients, both of whom developed disseminated bacillus Calmette-Guérin (BCG) and subsequently died of viral illnesses before detailed studies of the condition could be performed. It is associated with impaired cellular responses to both IFN-γ and IFN-αβ via Stat-1-containing complexes. We describe a third patient with complete Stat-1 deficiency and disseminated BCG infection, who died 3 mo after bone marrow transplantation. The patient’s EBV-transformed B cells did not express Stat-1 protein and did not activate Stat-1-containing transcription factors. We also report the ex vivo responses of a Stat-1-deficient patient’s fresh blood cells to IFN-γ and the in vitro responses of a SV40-transformed fibroblastic cell line to IFN-γ and IFN-αβ. There was no response to IFN-γ in terms of IL-12 production and HLA class II induction, accounting for vulnerability to BCG. Moreover, IFN-αβ did not suppress HSV and vesicular stomatitis virus replication in fibroblasts, although in vivo the patient was able to successfully clear at least some viruses. This study broadens our understanding of complete Stat-1 deficiency, a severe form of innate immunodeficiency. Stat-1 deficiency should be suspected in children with severe infections, notably but not exclusively patients with mycobacterial or viral diseases.
Publisher: Oxford University Press (OUP)
Date: 08-10-2019
DOI: 10.1111/BJD.18476
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-08-2018
Abstract: Mice are a convenient model for exploring the functions of cellular signaling pathways. Occasionally, however, an “experiment of nature” highlights the perils of overreliance on mice. RIPK1 is a well studied protein kinase that regulates cell death. Mice deficient in RIPK1 die soon after birth because of the protein's widespread role in multiple tissues and organs. Cuchet-Lourenço et al. studied patients with inherited immunodeficiency of unknown cause (see the Perspective by Pasparakis and Kelliher). They identified inactivating mutations in the RIPK1 gene in four in iduals. Unlike what has been seen in mice, the deleterious effects of RIPK1 loss in humans were confined to the immune system, a finding with potential therapeutic implications. Science , this issue p. 810 see also p. 756
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Peter Arkwright.