Cumulative meta-analysis of interleukins 6 and 1 beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder

Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and Psychlnfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p <0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p <0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-alpha levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1 beta levels and major depression (d = -0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-alpha, interleukin-1 beta and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression. (C) 2015 The Authors. Published by Elsevier Inc.Peer reviewe

Association of circulating metabolites with healthy diet and risk of cardiovascular disease : analysis of two cohort studies

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations-the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 +/- 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 +/- 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.Peer reviewe

Peripheral DNA methylation, cognitive decline and brain aging : pilot findings from the Whitehall II imaging study

Aim: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to beta-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.Peer reviewe

Innate and adaptive immunity in the development of depression: : An update on current knowledge and technological advances

The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.Peer reviewe

Astmapotilaiden hoidossa käytettävät sähköiset ohjausmenetelmät

Opinnäytetyön tarkoituksena oli selvittää astmaa sairastavien aikuispotilaiden hoidossa käytettäviä sähköisiä ohjausmenetelmiä ja erilaisten sähköisten ohjausmenetelmien merkitystä astmaa sairastavien omahoidon hallinnassa. Tutkimuksen tavoitteena on tuottaa uutta tietoa sähköisten sovellusten käytön mahdollisuuksista lisätä astmaa sairastavan aktiivista osallistumista omaan hoitoon liittyviin päätöksiin, hoidon toteutukseen ja omien terveystietojen seurantaan. Opinnäytetyö toteutettiin käyttäen metodina systemaattista kirjallisuuskatsausta. Aineistohakuun käytettiin suomalaisia ja kansainvälisiä tietokantoja PubMed, Cochrane Library, Medline (Ovid), Medline (EBSCO), Arto ja Medic. Sisäänotto- ja poissulkukriteerien perusteella lopulliseen analyysiin valikoitui yhteensä 11 vuosina 2009-2017 julkaistua tutkimusta, joiden sisältö ja tulokset analysoitiin käyttäen laadullista sisällönanalyysiä. Tutkimuksissa käytetyt sähköiset sovellukset olivat puhelimeen ladattavia sovelluksia tai Internet -sivustoja, joita tutkimushenkilöt käyttivät astman omahoidon tukena heille itselleen parhaiten sopivana aikana. Sähköisten sovellusten käyttö mahdollisti mm. oireiden ja keuhkojen toimintaa mittaavien arvojen reaaliaikaisen kirjauksen ja sähköisen kommunikoinnin hoitajan kanssa. Joissakin sovelluksissa oli ominaisuuksina hälytysjärjestelmä, jonka avulla tutkimushenkilöt saivat tiedon astman omahoidon tilasta ja jatkohoito-ohjeet. Tutkimusten laadullisessa sisällönanalyysissä tulokset olivat vaihtelevia, ja osassa tutkimuksia havaittiin sovelluksen käytön liittyvän lisääntyneeseen astman omahoidon hallintaan ja parantuneeseen elämänlaatuun. Ongelmina olivat mm. sovelluksen vähäinen käyttötiheys ja tutkimuksen lyhyt kesto. Tulokset osoittavat, että sähköisillä ohjausmenetelmillä voi olla positiivisia vaikutuksia astmaa sairastavan elämään ja omahoidon toteutumiseen. Jatkotutkimusehdotuksena on systemaattinen analyysi niistä laitteiden ominaisuuksista ja toiminnoista, jotka ovat yhteydessä korkeaan käyttötiheyteen ja suotuisiin vaikutuksiin astman omahoidossa ja astmaan sairastavien elämänlaadussa pitkällä aikavälillä tarkasteltuna. Lisäksi tulisi arvioida astman hoidossa käytettävien sähköisten ohjausmenetelmien kustannustehokkuutta tavanomaisiin hoitomenetelmiin verrattuna.The purpose of this study was to examine the use of electronic applications and their role in patient education and self-management of asthma in adults. A systematic literature review was conducted using six domestic and international databases. A total of 11 articles published between 2009-2017 were included in the review. The content and results of each article was analysed by means of a content analysis. Some electronic applications used in asthma self-management contained the opportunity to monitor lung function or communicate with asthma nurse online while others allowed patients to receive immediate feedback regarding their current asthma control. The content analysis of the included articles revealed that the use of electronic applications may support asthma control and improve asthma-related quality of life compared to usual care, although the results show large variability. The findings of this study indicate that electronic applications may have potential benefits on the wellbeing and self-care of asthmatic patients. More research is needed to gain insight on the specific features and functions of these applications associated with high usability and long-term beneficial outcomes on asthma control and asthma-related quality of life. Further study is also needed to evaluate the cost-effectiveness of these interventions

Toll-like reseptorien aktivaatio kokeellisessa allergisessa astmassa: ihon ja hengitysteiden välinen yhteys

Astman voimakas lisääntyminen viime vuosikymmeninä on erityisesti länsimaissa esiintyvä ongelma. Syyt tähän kehitykseen ovat suurelta osin tuntemattomia, mutta sekä geneettisillä että ympäristötekijöillä tiedetään olevan merkitystä. Yksi allergioiden lisääntymistä selittävä teoria on nk. hygieniahypoteesi, jonka mukaan vähäinen mikrobialtistus varhaisessa lapsuudessa aikaansaa elimistön Th1/Th2 -välittäjäainetasapainon siirtymisen Th2-suuntaiseksi johtaen allergioiden lisääntymiseen. Ympäristössä esiintyvät mikrobit tunnistetaan erilaisten Tollin kaltaisten (Toll-like) reseptorien avulla, jotka tunnistavat virusten ja bakteerien rakenteita ja aktivoivat luonnollisen immuniteetin järjestelmän. Reseptoreihin sitoutuvia ligandeja on käytetty tutkimuksissa suuntaamaan immuunivastetta allergioilta suojaavaan Th1-suuntaan, mutta tulokset ovat olleet vaihtelevia. Tutkimuksen tavoitteena oli luoda uusi hiiren astmamalli, jota käyttämällä voitiin tutkia eri Toll-like reseptoreihin sitoutuvien, bakteeri- ja virusperäisiä sekvenssejä tunnistavien ligandien (CpG, LPS, Pam3Cys ja Poly(I:C)) vaikutuksia astman kehittymiseen. Tutkimuksessa havaittiin, että ihon kautta tapahtuva herkistyminen luonnonkumille ja myöhemmin hengitysteiden kautta tapahtuva altistus samalle allergeenille sai hiirillä aikaan voimakkaan allergisen Th2-tyypin keuhkotulehduksen, hengitysteiden reaktiivisuuden nousun ja allergeenispesifisten IgE -vasta-aineiden lisääntymisen veressä. Hengitysteiden kautta tapahtuva herkistyminen luonnonkumille sen sijaan lisäsi immuunivastetta hillitsevien välittäjäaineiden esiintymistä. Tutkimustulos osoittaa, että ihon kautta tapahtuva altistuminen allergisoivalle aineelle, kuten luonnonkumille, voi olla merkittävässä roolissa myöhemmässä alttiudessa sairastua astmaan ja allergioihin. Ihonsisäisesti annosteltujen CpG:n, LPS:n, Pam3Cys:n ja Poly(I:C):n vaikutukset astmaan olivat riippuvaisia erityisesti annostellun ligandin pitoisuudesta. Bakteeriperäiset CpG, LPS ja Pam3Cys laskivat keuhkojen tulehdusta sekä Th2-sytokiinien tuotantoa, mutta virusperäisellä Poly(I:C):llä ei vastaavaa vaikutusta havaittu. CpG-molekyylien sivuvaikutuksena havaittiin lisäksi lisääntyneestä IFN-γ:n tuotannosta johtuvaa hengitysreaktiviteetin nousua, millä voi olla merkitystä erityisesti astman immunoterapiatutkimuksissa. Saadut tulokset tukevat hygieniahypoteesia, jonka mukaan altistuminen ympäristön endotoksiineille, kuten LPS:lle, voivat ehkäistä astman ja allergioiden myöhempää ilmentymistä.The increasing prevalence of asthma in western countries during the last decades continues to be a significant public health problem causing both economical and social burden to the society. Reason behind this trend remains largely unknown, but both genetic and environmental factors are known to be involved. One of theories attempting to explain the rise in asthma prevalence is related to reduced exposure to microbial load and a change in Th1/Th2 cytokine balance towards Th2 type immunity in early childhood (“hygiene hypothesis”). Micro-organisms present in the environment are recognized by different Toll-like receptors (TLRs), which bind viral and bacterial components and stimulate innate immune responses. TLR ligands have been used as immunotherapeutic agents to modify the response away from allergies and towards Th1 type immune response. In spite of intensive investigation, the role of systemically or locally administered Toll-like receptor ligands in modulating asthmatic response is still controversial and more investigations are needed to establish the detailed mechanisms. The specific approaches of the study included (i) characterization of mouse model of natural rubber latex (NRL) –induced asthma by studying the effects of different exposure routes on airway inflammation and airway reactivity, (ii) investigation of the effects of GpG (ligand for TLR9), and (iii) the effects of LPS (ligand for TLR4), Pam3Cys (ligand for TLR2) and Poly(I:C) (ligand for TLR3), on asthmatic parameters using the mouse model. In the first study of the thesis, mice were sensitized by intracutaneous (IC), intraperitoneal (IP) and intranasal (IN) route with natural rubber latex (NRL), followed by three-day airway NRL challenge. After four weeks of NRL sensitization, mice exhibited a drastic eosinophilic inflammation in BAL fluid, enhanced amount of mucus around the bronchioles and increased airway reactivity to metacholine after IC and IP, nut not after IN NRL exposure. Expression of Th2 type cytokines IL-4 and IL-13 and CC chemokines CCL1, CCL8, CCL11, CCL24 in the lung tissue and total and NRL-specific IgE antibodies in the serum were also significantly elevated only after IC and IP sensitizations. Intranasal NRL exposure, on the other hand, induced the expression of regulatory cytokines IL-10, Foxp3 and TGF-β in the lung tissue. These results show that allergen exposure via the skin and a subsequent airway challenge induces a vigorous Th2 type inflammation and airway hyperreactivity in mice, highlight the role of skin as the primary site of antigen exposure and subsequent development of airway diseases. In the second study of the thesis, the effects of immunostimulatory CpG molecules in the murine asthma model characterized in the first part of the thesis were investigated. CpG was shown to significantly reduce airway inflammation, mucus production and Th2 type cytokines in the lung tissue, while surprisingly enhancing airway hyperreacivity to inhaled metacholine as measured with non-invasive and invasive methods. At the same time, the amount of main Th1 type cytokine, IFN-γ, as well as CD8+ T cells were induced in the lungs after CpG administration. It was shown that CD8+ T cells produced most of the intracellular IFN-γ. Finally, three strains of KO mice (RAG1-/-, STAT4-/- and STAT6-/-) and lung IFN-γ neutralization studies were used to verify the dependence of enhanced AHR on Th1 type immunity and increased production of IFN-γ in the lungs. These results indicate that treatment with Th1-inducing CpG nucleotides may also cause unwanted side-effects and should be taken into consideration when planning immunotherapeutic treatments for asthma. In the third part of the thesis, the effects of intradermally administered LPS, Pam3Cys and Poly(I:C) were studied in the murine model of asthma using ovalbumin as allergen. Administration of LPS and Pam3Cys was shown to reduce total cell counts and eosinophils in BAL fluid, Th2 type cytokines in the lung and airway reactivity to metacholine, while Poly(I:C) had no clear effect on these parameters. During the early phase of the sensitization, both LPS and Pam3Cys reduced the number of CD11c+ DCs in the lymph nodes, and especially LPS enhanced the expression of activation markers CD80 and CD86. Interestingly, the number of CD8+ T cells and their production of IFN-γ were significantly induced after LPS treatment. Using IFN-γ neutralization, we showed that the capacity of LPS to downmodulate inflammatory response in mice was critically dependent on enhanced production of IFN-γ in the airways. These studies are in line with hygiene hypothesis suggesting that bacterial endotoxins, i.e. LPS, may induce Th1 type responses and protect from development of asthma later in life. Also, our results give light to the importance of skin´s barrier function and host-microbe interaction in the development of allergies

Toll-like reseptorien aktivaatio kokeellisessa allergisessa astmassa: ihon ja hengitysteiden välinen yhteys

Astman voimakas lisääntyminen viime vuosikymmeninä on erityisesti länsimaissa esiintyvä ongelma. Syyt tähän kehitykseen ovat suurelta osin tuntemattomia, mutta sekä geneettisillä että ympäristötekijöillä tiedetään olevan merkitystä. Yksi allergioiden lisääntymistä selittävä teoria on nk. hygieniahypoteesi, jonka mukaan vähäinen mikrobialtistus varhaisessa lapsuudessa aikaansaa elimistön Th1/Th2 -välittäjäainetasapainon siirtymisen Th2-suuntaiseksi johtaen allergioiden lisääntymiseen. Ympäristössä esiintyvät mikrobit tunnistetaan erilaisten Tollin kaltaisten (Toll-like) reseptorien avulla, jotka tunnistavat virusten ja bakteerien rakenteita ja aktivoivat luonnollisen immuniteetin järjestelmän. Reseptoreihin sitoutuvia ligandeja on käytetty tutkimuksissa suuntaamaan immuunivastetta allergioilta suojaavaan Th1-suuntaan, mutta tulokset ovat olleet vaihtelevia. Tutkimuksen tavoitteena oli luoda uusi hiiren astmamalli, jota käyttämällä voitiin tutkia eri Toll-like reseptoreihin sitoutuvien, bakteeri- ja virusperäisiä sekvenssejä tunnistavien ligandien (CpG, LPS, Pam3Cys ja Poly(I:C)) vaikutuksia astman kehittymiseen. Tutkimuksessa havaittiin, että ihon kautta tapahtuva herkistyminen luonnonkumille ja myöhemmin hengitysteiden kautta tapahtuva altistus samalle allergeenille sai hiirillä aikaan voimakkaan allergisen Th2-tyypin keuhkotulehduksen, hengitysteiden reaktiivisuuden nousun ja allergeenispesifisten IgE -vasta-aineiden lisääntymisen veressä. Hengitysteiden kautta tapahtuva herkistyminen luonnonkumille sen sijaan lisäsi immuunivastetta hillitsevien välittäjäaineiden esiintymistä. Tutkimustulos osoittaa, että ihon kautta tapahtuva altistuminen allergisoivalle aineelle, kuten luonnonkumille, voi olla merkittävässä roolissa myöhemmässä alttiudessa sairastua astmaan ja allergioihin. Ihonsisäisesti annosteltujen CpG:n, LPS:n, Pam3Cys:n ja Poly(I:C):n vaikutukset astmaan olivat riippuvaisia erityisesti annostellun ligandin pitoisuudesta. Bakteeriperäiset CpG, LPS ja Pam3Cys laskivat keuhkojen tulehdusta sekä Th2-sytokiinien tuotantoa, mutta virusperäisellä Poly(I:C):llä ei vastaavaa vaikutusta havaittu. CpG-molekyylien sivuvaikutuksena havaittiin lisäksi lisääntyneestä IFN-γ:n tuotannosta johtuvaa hengitysreaktiviteetin nousua, millä voi olla merkitystä erityisesti astman immunoterapiatutkimuksissa. Saadut tulokset tukevat hygieniahypoteesia, jonka mukaan altistuminen ympäristön endotoksiineille, kuten LPS:lle, voivat ehkäistä astman ja allergioiden myöhempää ilmentymistä.The increasing prevalence of asthma in western countries during the last decades continues to be a significant public health problem causing both economical and social burden to the society. Reason behind this trend remains largely unknown, but both genetic and environmental factors are known to be involved. One of theories attempting to explain the rise in asthma prevalence is related to reduced exposure to microbial load and a change in Th1/Th2 cytokine balance towards Th2 type immunity in early childhood (“hygiene hypothesis”). Micro-organisms present in the environment are recognized by different Toll-like receptors (TLRs), which bind viral and bacterial components and stimulate innate immune responses. TLR ligands have been used as immunotherapeutic agents to modify the response away from allergies and towards Th1 type immune response. In spite of intensive investigation, the role of systemically or locally administered Toll-like receptor ligands in modulating asthmatic response is still controversial and more investigations are needed to establish the detailed mechanisms. The specific approaches of the study included (i) characterization of mouse model of natural rubber latex (NRL) –induced asthma by studying the effects of different exposure routes on airway inflammation and airway reactivity, (ii) investigation of the effects of GpG (ligand for TLR9), and (iii) the effects of LPS (ligand for TLR4), Pam3Cys (ligand for TLR2) and Poly(I:C) (ligand for TLR3), on asthmatic parameters using the mouse model. In the first study of the thesis, mice were sensitized by intracutaneous (IC), intraperitoneal (IP) and intranasal (IN) route with natural rubber latex (NRL), followed by three-day airway NRL challenge. After four weeks of NRL sensitization, mice exhibited a drastic eosinophilic inflammation in BAL fluid, enhanced amount of mucus around the bronchioles and increased airway reactivity to metacholine after IC and IP, nut not after IN NRL exposure. Expression of Th2 type cytokines IL-4 and IL-13 and CC chemokines CCL1, CCL8, CCL11, CCL24 in the lung tissue and total and NRL-specific IgE antibodies in the serum were also significantly elevated only after IC and IP sensitizations. Intranasal NRL exposure, on the other hand, induced the expression of regulatory cytokines IL-10, Foxp3 and TGF-β in the lung tissue. These results show that allergen exposure via the skin and a subsequent airway challenge induces a vigorous Th2 type inflammation and airway hyperreactivity in mice, highlight the role of skin as the primary site of antigen exposure and subsequent development of airway diseases. In the second study of the thesis, the effects of immunostimulatory CpG molecules in the murine asthma model characterized in the first part of the thesis were investigated. CpG was shown to significantly reduce airway inflammation, mucus production and Th2 type cytokines in the lung tissue, while surprisingly enhancing airway hyperreacivity to inhaled metacholine as measured with non-invasive and invasive methods. At the same time, the amount of main Th1 type cytokine, IFN-γ, as well as CD8+ T cells were induced in the lungs after CpG administration. It was shown that CD8+ T cells produced most of the intracellular IFN-γ. Finally, three strains of KO mice (RAG1-/-, STAT4-/- and STAT6-/-) and lung IFN-γ neutralization studies were used to verify the dependence of enhanced AHR on Th1 type immunity and increased production of IFN-γ in the lungs. These results indicate that treatment with Th1-inducing CpG nucleotides may also cause unwanted side-effects and should be taken into consideration when planning immunotherapeutic treatments for asthma. In the third part of the thesis, the effects of intradermally administered LPS, Pam3Cys and Poly(I:C) were studied in the murine model of asthma using ovalbumin as allergen. Administration of LPS and Pam3Cys was shown to reduce total cell counts and eosinophils in BAL fluid, Th2 type cytokines in the lung and airway reactivity to metacholine, while Poly(I:C) had no clear effect on these parameters. During the early phase of the sensitization, both LPS and Pam3Cys reduced the number of CD11c+ DCs in the lymph nodes, and especially LPS enhanced the expression of activation markers CD80 and CD86. Interestingly, the number of CD8+ T cells and their production of IFN-γ were significantly induced after LPS treatment. Using IFN-γ neutralization, we showed that the capacity of LPS to downmodulate inflammatory response in mice was critically dependent on enhanced production of IFN-γ in the airways. These studies are in line with hygiene hypothesis suggesting that bacterial endotoxins, i.e. LPS, may induce Th1 type responses and protect from development of asthma later in life. Also, our results give light to the importance of skin´s barrier function and host-microbe interaction in the development of allergies

Intradermal Cytosine-Phosphate-Guanosine Treatment Reduces Lung Inflammation but Induces IFN-gamma-Mediated Airway Hyperreactivity in a Murine Model of Natural Rubber Latex Allergy

Asthma and other allergic diseases are continuously increasing, causing considerable economic and sociologic burden to society. The hygiene hypothesis proposes that lack of microbial T helper (Th) 1-like stimulation during early childhood leads to increased Th2-driven allergic disorders later in life. Immunostimulatory cytosine-phosphate-guanosine (CpG)-oligodeoxynucleotide motifs are candidate molecules for immunotherapeutic studies, as they have been shown to shift the Th2 response toward the Th1 direction and reduce allergic symptoms. Using natural rubber latex (NRL)-induced murine model of asthma, we demonstrated that intradermal CpG administration with allergen reduced pulmonary eosinophilia, mucus production, and Th2-type cytokines, but unexpectedly induced airway hyperreactivity (AHR) to inhaled methacholine, one of the hallmarks of asthma. We found that induction in AHR was dependent on STAT4, but independent of STAT6 signaling. CpG treatment increased production of IFN-γ in the airways and shifted the ratio of CD4(+):CD8(+) T cells toward CD8(+) dominance. By blocking soluble IFN-γ with neutralizing antibody, AHR diminished and the CD4(+):CD8(+) ratio returned to CD4(+) dominance. These results indicate that increased production of IFN-γ in the lungs may lead to severe side effects, such as enhancement of bronchial hyperreactivity to inhaled allergen. This finding should be taken into consideration when planning prophylaxis treatment of asthma with intradermal CpG injections

Peripheral DNA methylation, cognitive decline and brain aging: pilot findings from the Whitehall II imaging study.

AIM: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. METHODS: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. RESULTS: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. CONCLUSION: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.. The study was funded by the National Institute of Health Research (NIHR) Academic Clinical Fellowship programme (ACF; LC) the Oxfordshire Health Services Research Committee (OHSRC; LC), the Oxford University Clinical Academic Graduate School (OUCAGS; LC), the UK Medical Research Council (G1001354; KPE; K013351; MK), the Gordon Edward Small’s Charitable Trust (SC008962; KPE), the HDH Wills 1965 charitable trust (charity No: 1117747; KPE), the Medical Research Council (MRC) (Grant number: MR/N027973/1; KL, EP) as part of the Joint Programme—Neurodegenerative Disease Research (JPND) grant for the EPI-AD consortium