Jenmalm EAACI school Dubrovnik March 2018 2018-05-04¢  EAACI Allergy School 2018-03-16 Genome, methylation

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  • EAACI Allergy School 2018-03-16

    Genome, methylation and allergic disease Maria Jenmalm

    Professor of Experimental Allergology, Div of Neuro & Inflammation Sciences,

    Dept of Clinical & Experimental Medicine

    EAACI dedicated to Allergy Science, 
 committed to your Health 2

    Disclosure

    In relation to this presentation, I declare the following, real or perceived conflicts of interest:

    A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (e.g. owning stocks of a related company, having received honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.

    I have received funding for a clinical trial and honoraria for lectures from BioGaia AB, as well as consultant fees, honoraria for lectures and travel support from Nutricia/ Danone.

  • Atopic dermatitis

    (IgE-mediated)

    Asthma Allergic rhino- conjunctivitis

    MJ

    The allergic march

    MJ

    Time and dose of allergen exposure

    Genotype

    Adjuvant factors

    X

    Images: aaaai.org astmaoallergiforbundet.se clipartconnection.com foodallergens.info ornl.gov/hgmis

    Epigenetics

  • 0 6 12 18 24

    20

    40

    60

    80

    100

    0

    CXCL10/IP-10 (pg/ml)

    100

    200

    300

    400

    500

    600

    700

    0

    CCL22/MDC (pg/ml)

    Th2

    Th1

    Age (mo)

    Th2-skewing early in life

    Abrahamsson et al, Clin Exp Allergy 2011; 41: 1729-39

    n=107-120

    CCL22

    Th2

    CCR4

    Th1

    CXCR3

    CXCL10

    MJ

    Immune deviation during pregnancy

    IL-4 IL-10

    via e g progesterone

    IFN-γ

  • IL-13

    Th2 skewing in newborns -

    epigenetic regulation

    8

    Different epigenetic mechanisms

    Chromatine structure

  • Waddington 1957

    One genome – many cell types

    Epigenetic regulation allows cells to maintain their ‘state’

    10

    DNA methylation

    • Covalent modification of DNA

    • Primarily at cytosines

    • Affects the binding of proteins that regulate the activity of genes 


    TF

  • CGC CGA TGA GCT ATG CAT AGC TCA TCG GCGDNMT3

    CH3 CH3

    CH3CH3

    De novo DNA methylation

    Epigenetic inheritance

    DNA methyl transferase 3

    Maintenance DNA methylation, during cell division

    Epigenetic inheritance

    CAT AGC TCA TCG GCG

    CH3CH3

    CGC CGA TGA GCT ATG

    CH3 CH3 CAT AGC TCA TCG GCG

    CGC CGA TGA GCT ATG

    DNMT1 CH3

    DNA methyl transferase 1

  • DNA methylation patterns can be inherited

    Maintenance of DNA methylation patterns during cell division

    De novo DNA methylation

    Maintenance DNA methylation

    14

    DNA methylation allows Th cell differentiation & contributes to flexibility

    Suarez-Alvarez et al: DNA methylation: a promising landscape for immune system-related diseases 2012; 28: 506-514

  • 2018; 45: 48–56


    reprogramming plasticity
 CH2OH

    CH3

    16

    Dysregulation of DNA methylation at MAPK signaling-associated genes during early CD4+ T-cell development may contribute to suboptimal T-lymphocyte responses in early childhood associated with the development of food allergy

  • Prescott & Saffery: The role of epigenetic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2011; 2: 223-32

    18

    Barker’s hypothesis of fetal origins of adult disease: IUGR, low birth weight, and premature birth have a causal relationship to the origins of hypertension, coronary heart disease and non-insulin-dependent diabetes

    Thrifty phenotype: adaptive response for deprived prenatal environment maladaptive for postnatal environment

    Developmental Origins of Health and Disease (DOHaD) hypothesis: early nutrition and growth affects long-term health

  • A

    C

    BCCL22

    CCL17

    CCL22 / CXCL10

    Th2

    Th1

    Cord blood Th2- and Th1-associated chemokines vs sensitisation development to 6 years of age

    Abelius et al: High cord blood levels of the Th2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of life Pediatr Res 2011; 70: 495-500

    Abelius et al: Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy Pediatr Allergy Immunol 2014; 25: 387-93

    Major changes in microbial exposure to children in westernized countries and increasing prevalence of allergic diseases

    - epigenetic effects?

    Abrahamsson TR, Wu RY, Jenmalm MC: Gut microbiota and allergy: the importance of the pregnancy period. Pediatr Res 2015; 77: 214-219

  • M J

    Decreased microbial stimulation

    Delayed immune maturation Impaired immune regulation

    Large, diverse and continuous microbial pressure from the gut microbiota

    1013-1014 organisms

    400-1000 species (many unknown)

    1-2 kg (60% of faeces)

    West CE, Jenmalm MC, Prescott SL. The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin Exp Allergy 2015; 45: 43-53

    Björkstén B. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immun 2004; 25: 257

    West CE, Renz H, Jenmalm MC, Kozyrskyj AL, Allen KJ, Vuillermin P, Prescott SL. The gut microbiota and inflammatory non-communicable diseases: associations and potentials for gut microbiota therapies. J Allergy Clin Immunol 2015; 135: 3-13

  • Commensals

    Treg TGF-β IL-10

    Gut mucosal environment normally tolerance promoting

    eg butyrate

    epigenetic effects HDAC inhibition

    GPR43

    GPR109a

    Modified from Ohland CL, Jobin C: Microbial activities and intestinal homeostasis: A delicate balance between health and disease. Cell Mol Gastroenterol Hepatol 2015; 1: 28-40

    SCFA mediated immunomodulatory effects

  • 29/09/2014

    3

    A stable microbiota assembles in the first years of life and, barring major insults, remains relatively stable until old age

    Loss of diversity and stability in old age are associated with deteriorating health

    C section

    Vaginal birth

    Diet

    Formula More complex

    B. fragilis E. coli

    C. difficile

    Breast

    Bifidobacterium Ruminococcus

    Stable core genome

    Bacteroides Clostridium

    Ruminococcus Eubacterium

    Parabacteroides Coprococcus

    Dorea Alistipes Collinsella Lachnospira Roseburia

    Faecalibacterium

    Diet, Antibiotics,

    Illness

    Old age Fusobacterium Clostridium Eubacterium

    Facultative anaerobes

    Bacteroides Bifidobacterium

    SCFA

    After Power et al, BNJ (2014) 111:387

    Low diversity and stability of the gut microbiota in infants and elderly

    Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, Coakley M, …, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O'Toole PW: Gut microbiota composition correlates with diet and health in the elderly. Nature 2012; 488: 178-84

    Rodriguez JM , Murphy K, Stanton C, Ross RP, Kober O, Juge N, Avershina A, Rudi K, Narbad A, Jenmalm MC, Marchesi JR, Collado MC: The composition of the gut microbiota throughout life, with an emphasis on early life. Microbial Ecol Health Dis 2015; 26: 26050

    26

    Reduced Bacteroidetes diversity in children developing allergic disease

    0,00!

    0,10!

    0,20!

    0,30!

    0,40!

    0,50!

    0,60!

    1 week! 1 month! 12 months!

    Allergic!

    Non-allergic!

    Shannon diversity

    index

    *

    n=20

    n=20

    Abrahamsson et al, J Allergy Clin Immunol 2012; 129: 434-40

  • 27 sh

    an no

    n_ 1w

    sh an

    no n_

    1w _A

    sh an

    no n_

    1m

    sh an

    no n_

    1m _A

    sh an

    no n_

    12 m

    sh an

    no n_

    12 m_

    A 0

    1

    2

    3

    4

    Sh an

    no n

    D iv

    er si

    ty In

    de x

    1 week 1 month 12 months

    no yes no yes no yes

    * **

    Age

    Asthma

    doi: 10.1111/cea.12253 Clinical & Experimental Allergy, 44, 842–850

    ORIGINAL ARTICLE Clinical Mechanisms in Allergic Disease © 2013 John Wiley & Sons Ltd

    Low gut microbiota diversity in early infancy precedes asthma at school age T. R. Abrahamsson1, H. E. Jakobsson2, A. F. Andersson3, B. Bj€orkst"en4,5, L. Engstrand2,3 and M. C. Jenmalm1,6

    1Division of Pediatrics, Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden, 2Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden, 3Division of Gene Technology, Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Swe