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Early life development of the immune system

Speaker: Susan L Prescott

29 September 2012


Early development of the immune system

PROF SUSAN PRESCOTT


Disclosures Prof Susan Prescott, UWA •

Lecture Fees: Nestle Nutrition (NNI) Nutricia (Danone) ALK (SOSA)

Industry-sponsored grant (institution): Probiomics (VRI) 2002

Consultancy: Fonterra


Overview  Immune development  Overview of T cell ontogeny • Epigenetics changes with age

 Innate immune development (TLR responses) • New data on NLR responses

 Treg ontogeny

 Differences in allergic children  Differences in developing world regions


T cell development: allergen-specific responses


IL-13

IFNg HDM

T cell development allergen-specific responses

OVA Non allergic Allergic disease Adult

Non allergic children: Initial Th2 skewed responses Postnatal IFNg maturation

Tulic, Prescott et al. JACI 2011 127:470-478


IL-13

IFNg HDM

T cell development allergen-specific responses

OVA Non allergic Allergic disease Adult

Allergic children: Impaired IFNg maturation Increasing IL-13 responses

Tulic, Prescott et al. JACI 2011 127:470-478

Differences in T cell responses evident in the first months of life


T cell development under epigenetic control (alters DNA accessibility to transcription)

• Th1 development: - determined by demethylation of IFNg promotor • Treg differentiation - determined by demethylation of FOXP3 locus • Th2 / Th17 development: - demethylation of IL-4 / other genes - acetylation of GATA-3


Developmental changes in gene methylation and gene expression (in CD4+ T cells from 60 children with age)

birth

birth

1 year

1 year

age Gene methylation

Gene expression (mRNA)

Martino et al. Allergy 2012, 67: 191-200 Martino et al. Genes Immun 2012, 13: 388-98.


Epigenetic differences in food allergy Differences in methylation patterns evident at birth

Global methylation patterns in CD4+ T cells 2090 probes differentially methylated 122 vary >15% (biologically meaningful)

Differences present at birth and consistent with differences at 1 year when symptomatic Genes of interest include, Protein Kinases and T cell signaling pathways, class II genes, IL5R (Th2) Martino, Saffery, Prescott et al. in prep 2012

Nonallergic (n=30)

Food allergic (n=30)

Further highlights antenatal events


Innate immune development Toll-like receptor Nod-like receptor responses


IL-1b (pg/ml) (geometric mean + 95% CI)

Patterns of “innate” immune development Non allergic children: • Immature at birth with age-related maturation

Non allergic Allergic disease Adult

Tulic, Prescott et al. JACI. 2011; 127:470-478


IL-1b (pg/ml) (geometric mean + 95% CI)

Patterns of “innate” immune development Non allergic children: • Immature at birth with age-related maturation Allergic children: • Perinatal: Higher inflammatory responses

• Postnatal: relative decline with relative deficiency in responses Difference present at birth suggests in utero effects Non allergic Allergic disease Adult

Tulic, Prescott et al. JACI. 2011; 127:470-478


New data: infants in developing region (PNG) show similar pattern to nonallergic infants

Ontogeny of TLR in Papua New Guinean infants

Lisciandro, Prescott, et al. PLoS One 2012; 7:e36793


Development of other innate pathways NOD-like Receptors (NLR)? Pattern recognition receptors (PRR): >20 NLR-type proteins identified In humans NLRs broadly classified:

‘Nodosome’ subfamily – e.g. NOD1/2 Variants associated with susceptibility to asthma, atopic eczema

‘Inflammasome’ subfamily – e.g. NLRP3 (NALP3) detect viral, bacterial and fungal PAMPs, endogenous stress-related danger signals, environmental pollutants and aluminium salts (vaccines)


New data: First study of NLR ontogeny

Ontogeny of NLR in PNG infants ‘Nodosome’ subfamily

Age-related decline in inflammatory responses (IL-1b & CXCL8) to alum

‘Inflammasome’ subfamily

Th2-assoc. inflammation (Implications for vaccination responses)

Th2 responses Lisciandro, Prescott, et al. PLoS One 2012; 7:e36793


New data: differences between neonates from developed (AUS) vs developing (PNG) regions Lisciandro, Prescott, et al. JACI 2012; ePub ahead of print

Australian neonates: • Enhanced antigen processing & proliferation • Increased upregulation activation markers

PNG newborns AUS newborns

PNG neonates: Higher baseline activation & inhibitory markers But quiescent following activation: • process less antigen • less responsive to stimulation Not explained by differences in T effector or Treg (Treg also reduced in PNG neonates)

Adaptive response to high microbial environmental?

Suggest APC function modified by maternal exposures in utero


Higher cord blood serum IL-6 levels in PNG newborns cord blood serum levels

IL-6

IFNg

CB IL-6

CB IFNg 600 500

3000

pg/ml

2000 1000

400 300 200 100

0

PNG g

N

IF

N

co rd

IF

S

ta ( to

G

co l)

G PN

AUS

co rd

rd

co rd

IL

IL -6

AUS

A U

6

PNG

g

0

PN

pg/ml

4000

A

U

S

In utero exposures (PNG): Intestinal parasites (Giardia lamblia) the largest determinants of neonatal innate responses: •Higher neonatal TLR responses (IL-10 and IFNγ production) •Higher neonatal NLR (inflammasome) responses IL10, IL6, TNF-α and IL1β Lisciandro, Prescott, et al. submitted


Regulatory T cell development


Fetus: highly developed regulatory responses • Not inert or passively unresponsive! • Not an ‘immature’ version of adults 1-2 • Highly responsive to antigens • Strong bias to Treg differentiation

(tolerogenic milieu : TGFb, TSLP) • Higher % circulating Treg than adults3

 Wave of promiscuously responsive cells  Gives rise to a broad repertoire of Treg (self antigens) 1. Betz, A. G. (2010). Science 330(6011): 1635-6. 2. Mold, J. E. and J. M. McCune (2011).." Chimerism 2(2): 35-41 3. Darrasse-Jeze, G., G. Marodon, et al. (2005). Blood 105(12): 4715-21..

Dispels myth that the fetus has ‘reduced ability’ to respond


Tolerance to exogenous antigens also begins during this period • Fetus can generate long-lived CD4+CD25+FoxP3+ Tregs

 to exogenous antigens (alloantigens, microbial Ag)1,2  can modulate postnatal responses • Fetal allergen-specific responses

Fetal Treg response

 generate Treg in vitro3 • Alloantigens • Microbial antigens • Allergens

1. Mold JE, et al. Science 2008; 322:1562–1565 2. Mackroth, M. S. et al. J Immunol 2011:186(5): 2780-91. 3. Thornton C. et al. J Immunol 173(5): 3084-92.

Role of antenatal allergen exposure in initiation of allergen-specific tolerance?


Developmental differences in Treg function?

% Tregs (CD4+CD25+CD127loFoxp3+)

Tregs **

Non-atopic

10

Atopic 8

*

6 4 2 0

< 6 mon

6-12 mon

1-5 yrs

> 5 yrs

FOXP3 0.20

Foxp3 mRNA (UBC normalised)

Crossectional study using Treg isolated from thymus samples in otherwise healthy infants undergoing cardiac surgery.

** 0.15

* *

0.10

Allergic children: • Reduced % Treg • Reduced FOXP3 expression • Reduced suppressive capacity in vitro (when T regulatory titrated into culture systems)

0.05

0.00

< 6 mon

6-12 mon

1-5 yrs

> 5 yrs

Tulic, Moqbel, Prescott et al. JACI 2012 129: 199-206


Early differences in the thymic cytokine milieu in those who develop allergy IL-7

TSLP Treg

‘Th2-skewed’ milieu in neonatal thymus Capacity for Treg:

∞ TSLP level

Subsequent atopy1 - Reduced Treg (% and function) - Reduced TSLP neonatal in period

 reflects in utero environment Human neonatal thymus Tulic M, et al. JACI 2012 129: 199-206

Exogenous exposures may alter fetal tissue (thymic) milieu to influence immune development


The importance of the tissue milieu:

Tissue milieu provides conditioning signals to resident APC

INFLAMMATION

TOLERANCE

Critically determines of the pattern of response

- Peripheral tissues Gut, skin airways - Lymph nodes - Thymus

Tissue context will determine 2 things: 1) If there is a response (classical â&#x20AC;&#x2DC;danger modelâ&#x20AC;&#x2122;) Matzinger (1994) Annu Rev Immunol

2)The type of response (extended model of tolerance) Tissue-based class control: (DTH, Th1, Th2, Treg etc) Matzinger, & Kamala (2011). Nat Rev Immunol

The same cells will behave differently in different tissues (gut, thymus, eye, testis)


Early environmental exposures can alter the tissue milieu (pregnancy and early postnatal period)

Influence the patterns of response to ‘new’ antigens Factors known to alter immune function 1,2 also have known effects of TSLP and other tissue factors

Epigenetic effects

- Smoking / pollutants 3 - Dietary patterns / nutrients 4 - Microbial exposure 5,6

Effects on milieu

May contribute to emergent differences in immune function at birth 1. Martino and Prescott (2010). Allergy 65(1): 7-15. 2. Martino and Prescott (2011). Chest 139(3): 640 – 647 3. Nakamura Y, et al. JACI 2008; 122:1208-14..

(TSLP)

4. Weise C, et al. PAI 2011; 22:497-504. 5. Mileti E, et al. PLoS One 2009; 4:e7056. 6. Kawasaki J, et al. J Dermatol Sci 2011; 62:131-4.


Summary (1): Perinatal differences contributing allergy

Increased inflammatory responses

TLR

Prescott JACI 2008;122:391

Innate inflammatory responses (IL-6, TNFa)

Immature Th1 function Tang 1994, Warner 1994, Kondo 1998, Prescott 1998, and others

Th1 Immature T reg function (?) Smith/Prescott JACI 2008;121:1460 Schaub 2008; JACI 121:1491 Tulic/Prescott JACI 2011:129

Gene-environmental interactions in utero. Epigenetic influences?

IgE

Treg

Th2

B

Th2

Subsequent Allergic response

?


Summary (2): The pathways to early sensitisation Amniotic fluid

Fetal blood

Cutaneous

Breast milk

ALLERGEN EXPOSURE Dose, timing, route

+ GENETIC Predisposition

(FIXED)

VARIATIONS IN TISSUE MILIEU (TSLP/ IL-7 / TGFb other)

ENVIRONMENTAL INFLUENCES (VARIBLE) • Diet /nutrients • Pollutants • Microbes

Can all alter tissue milieu incl. TSLP

APC/DC

REGULATORY phenotype TOLERANCE

Pattern of T cell response PLASTICITY (responsive to environmental conditions

EFFECTOR phenotype Th2 Th1

Altered breast milk composition (TSLP/IL-7/TGFb )

(if consolidated) SENSITISATION


Conclusion: Early life: critical for all aspects of development pregnancy “sets the scene”

Nutrition Microbiome Activity patterns Modern pollutants

postnatal “culminating events”

Allergy Asthma Obesity T2 diabetes Heart disease Mental ill health

Opportunities for prevention (not just for allergy, but for many NCDs) Common risk factors = mean common solutions (interdisciplinary collaboration)


“The Allergy Epidemic” (all author proceeds donated to research)  To raise awareness  To educate, inform and inspire  To engage the public (international) •

Paperback -

• -

‘Good bookshops’ Order on-line: Publisher (UWAP) http://uwap.uwa.edu.au/books-andauthors/book/the-allergy-epidemic/ Amazon / other on-line outlets

E-Books http://ebooks.readings.com.au/product/9781742583303

Wide target audience: Families, students & health care professionals (primer), health policy makers, anyone who wants to understand more.


The Allergy Epidemic A Mystery of Modern Life

PROF SUSAN PRESCOTT

Susan L Prescott  
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