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The neonatal window of opportunity – early priming for life
Harald Renz, MD, PhD, Becky D. Adkins, MD, Sina Bartfeld, PhD, Richard S.Blumberg, MD, PhD, Donna L. Farber, MD, PhD, Johan Garssen, MD, PhD, PeterGhazal, MD, PhD, David J. Hackam, MD, Benjamin J. Marsland, MD, PhD, KathyD. McCoy, MD, PhD, John Penders, MD, PhD, Immo Prinz, MD, PhD, ValerieVerhasselt, MD, PhD, Erika von Mutius, MD, MSc, Jeffrey N. Weiser, MD, Duane R.Wesemann, MD, PhD, Mathias W. Hornef, MD
PII: S0091-6749(17)31895-X
DOI: 10.1016/j.jaci.2017.11.019
Reference: YMAI 13161
To appear in: Journal of Allergy and Clinical Immunology
Received Date: 8 June 2017
Revised Date: 23 October 2017
Accepted Date: 15 November 2017
Please cite this article as: Renz H, Adkins BD, Bartfeld S, Blumberg RS, Farber DL, Garssen J, GhazalP, Hackam DJ, Marsland BJ, McCoy KD, Penders J, Prinz I, Verhasselt V, von Mutius E, Weiser JN,Wesemann DR, Hornef MW, The neonatal window of opportunity – early priming for life, Journal ofAllergy and Clinical Immunology (2018), doi: 10.1016/j.jaci.2017.11.019.
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ACCEPTED MANUSCRIPTParadigms and Perspectives 1 2 3 The neonatal window of opportunity – early priming for life 4 5 6 Harald Renz, MD, PhD1; Becky D. Adkins, MD2; Sina Bartfeld, PhD3; 7 Richard S. Blumberg, MD, PhD4; Donna L. Farber, MD, PhD5; Johan Garssen, MD, PhD6; 8 Peter Ghazal, MD, PhD7; David J. Hackam, MD8; Benjamin J. Marsland, MD, PhD9; 9 Kathy D. McCoy, MD, PhD10; John Penders, MD, PhD11; Immo Prinz, MD, PhD12; 10 Valerie Verhasselt, MD, PhD13; Erika von Mutius, MD, MSc14; Jeffrey N. Weiser, MD15; 11 Duane R. Wesemann, MD, PhD16; Mathias W. Hornef, MD17 12 13 14 15 16 1 University of Marburg, Germany 17 2 University of Miami, USA 18 3 University of Würzburg, Germany 19 4 Harvard University, USA 20 5 Columbia University Medical Center, USA 21 6 Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht 22 University, Utrecht, The Netherlands 23 7 University of Edinburgh, United Kingdom 24 8 Johns Hopkins University, Baltimore, USA 25 9 University Hospital of Lausanne, Switzerland 26 10 University of Calgary, Canada 27 11 Care and Public Health Research Institute (Caphri) & NUTRIM School for Nutrition and 28 Translational Research in Metabolism, Dept. of Medical Microbiology, Maastricht University, 29 The Netherlands 30 12 Hannover Medical School, Germany 31 13 Family Larsson-Rosenquist Foundation Chair in Human Lactology, School of Molecular 32 Science, University of Western Australia, Perth, Australia 33 14 Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, 34 Germany, Comprehensive Pneumology Center Munich (CPC-M), Member of the German 35 Center for Lung Research 36 15 New York University School of Medicine, USA 37 16 Harvard University, Brigham and Women’s Hospital, USA 38 17 RWTH University Hospital, Aachen, Germany 39 40 41 42 43 44 45 Correspondence to: 46 Harald Renz, MD 47 Institute of Laboratory Medicine 48 University of Marburg 49 Baldingerstr. 50 35043 Marburg, Germany 51 Phone: +49-6421-5866808 52 Fax: +49-6421-5866102 53 [email protected] 54 55
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List of abbreviations 56 57 58 59 BCR B-cell receptor 60 COPD chronic obstructive pulmonary disease 61 EPEC enteropathogenic Escherichia coli 62 HDM house dust mite 63 IgD immunoglobulin D 64 IgM immunoglobulin M 65 IL interleukin 66 iNKT invariant natural killer T cells 67 LPS lipopolysaccharide 68 NCD non-communicable diseases 69 NEC necrotizing enterocolitis 70 NF-κB nuclear factor kappa-light-chain-enhancer of activated B-cells 71 NKT cells natural killer T cells 72 RNA ribonucleic acid 73 TLR toll-like receptor 74 WHO World Health Organization 75 76
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Abstract 77
78
The concept of the neonatal window of opportunity assigns the early postnatal period a 79
critical role for life-long host-microbial and immune homeostasis. It is supported by 80
epidemiological evidence that links postnatal environmental exposure with disease 81
susceptibility and mechanisms in the neonate host that facilitate the postnatal transposition, 82
establish a stable microbiome and promote immune maturation. During the conference on 83
“The neonatal window of opportunity – early priming for life”, postnatal microbiome and 84
immune maturation, epidemiological evidence and fundamental mechanisms were discussed 85
to identify new targets for future preventive and interventional measures. 86
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From December 5-7, 2016, the Herrenhausen Conference “The neonatal window of 89
opportunity – early priming for life” took place at Hannover, Germany, sponsored by the 90
Volkswagen Foundation. The concept of the “neonatal window of opportunity”, i.e. a critical 91
non-redundant time frame in a newborn’s life during which environmental factors drive 92
immune and tissue maturation and influence the susceptibility to immune-mediated and other 93
diseases in adult life, was discussed. 94
95
96
Please note: An extended version of the manuscript can be found in the supplement. 97
98
99
Non-communicable diseases (NCD) as the grand challenge for 100
prevention 101
Our body is exposed continuously to many danger signals. An effective immune system is 102
essential in order to protect and repair. Unbalanced immune reactivity seems to play a key 103
role in non-communicable diseases (NCDs) such as chronic pulmonary disease (COPD), 104
allergies, asthma, diabetes, cancer, and cardiovascular diseases as well as obesity (Johan 105
Garssen). Prevention is the grand challenge, since causal therapies for NCDs are still not 106
available and prevalences and incidences are currently on the rise. 107
108
109
Maternal/fetal/neonatal interaction 110
The first “window of opportunity” in life is defined as the pre- or perinatal period. Particularly 111
in this period, microbial factors have a strong impact on the development of immune 112
responses. This includes the birth place and mode of delivery, breastfeeding, medication 113
(e.g. antibiotic use), introduction of solid foods, but also the exposure to siblings and pets 114
(John Penders). Challenging the immune tolerance of neonatal mice, germ-free mice 115
exhibited an exaggerated allergic response when exposed to allergens, as compared to 116
conventionally raised mice. Once their airway microbiome had formed after 2 post-natal 117
weeks, the mice were protected against this over-shooting allergic inflammation (Benjamin 118
Marsland) [1]. However, oral antigen administration in early life, even in the presence of 119
protective breast milk-derived factors, does not guarantee the induction of oral tolerance and 120
the prevention of allergic disease. This implies the necessity to identify limiting factors for oral 121
tolerance induction in early life (Valérie Verhasselt) [2]. 122
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Healthy nutrition during pregnancy and early life represents a key factor for proper immune 124
development. Human milk still remains the gold standard (Johan Garssen). 125
126
127
Development of immune tolerance in the neonatal period 128
This goes hand in hand with the ontogeny of the enteric mucosal tissue and its influence on 129
the establishment of the enteric microbiota and long-term host-microbial homeostasis as well 130
as infection susceptibility. Age-dependently expressed features of the innate and adaptive 131
immune system that contribute to the postnatal acquisition of mucosal homeostasis and the 132
particular susceptibility of the neonate host to infection (Mathias Hornef) [3]. 133
134
135
Early events and new insights into mechanisms 136
Streptococcus pneumonia is a leading cause of bacterial infection of the upper and lower 137
respiratory tract in children. This pathogen spreads to its host following acquisition of very 138
few organisms that quickly proliferate and dominate the niche in the upper respiratory tract. 139
This work established a new paradigm for understanding pathogen transmissio n and the 140
initial establishment of the colonizing microbiota in newborns (Jeffrey Weiser). This is also 141
influenced by the exposure to maternal microbiota metabolites in utero and in early life during 142
lactation that prepares the newborn for colonization with its own microbiota and sets the 143
baseline for a regulated immune system (Kathy McCoy) [4]. Important novel mechanisms are 144
summarized in figure 1. Neonates are often highly susceptible to intestinal pathogens. An 145
exception is seen after infection of murine neonates with Yersinia enterocolitica. Here, 146
multiple innate and adaptive components including (surprisingly) CD8+ T lymphocytes 147
cells , participate in protective immunity (Becky Adkins). Natural killer T (NKT) cells function 148
as a kind of checkpoint regulating the crosstalk between the microbiota and the immune 149
system. iNKT cells are resident cells of the gut mucosa that establish their niche during early 150
life when they home to and expand during a restricted period of neonatal life. Studies 151
performed in germ-free mice suggest a critical neonatal time period for the development and 152
proliferation of these immune cells (Richard Blumberg) [5]. γδ cells in mice represent a first 153
line of defense with respect to both early in life during T-cell development and ontogeny as 154
well as in terms of mucosal tissue localization. The human neonate γδ TCR repertoire 155
contains considerable frequencies of innate “public” TCR-δ sequences matching conserved 156
microbial structure (Immo Prinz). Symbiotic bacteria control the selection processes that 157
determine the antibody repertoire of naïve B-cells in neonatal mice. Interestingly, this 158
training event appears to be particularly influential during a narrow window of opportunity 159
after birth as commensal bacteria exposure of adult germ-free mice showed no effect on the 160
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positive selection events (Duane Wesemann). Tissue specific memory T cells are 161
established as non-circulating resident memory T cells at various tissue sites in response to 162
microbial stimulation (Donna Farber) [6]. Necrotizing enterocolitis (NEC) is the leading cause 163
of death from gastrointestinal disease in premature infants and develops after an exuberant 164
proinflammatory response to the colonizing microbiota and this requires activation of the 165
lipopolysaccharide (LPS) receptor, Toll like receptor (TLR) 4 (David Hackam) [7]. 166
167
168
Role of environmental microbes 169
Epidemiological studies show a strong correlation between early microbial exposure to 170
allergens and a reduced risk of hypersensitivity leading to asthma or hay fever later in life 171
(Erika von Mutius) [8]. The diversity and duration of microbial exposure early in life is 172
important for the development of tolerogenic immune functions. In this regard, mild 173
proinflammatory signals including IL-6 play a critical role to orchestrate early activation 174
signals (Harald Renz) [9]. 175
176
177
New methods 178
Stem cell-derived organoids represent a new three-dimensional model system of the gut 179
epithelium that allows the study of organ development, immune homeostasis and tissue 180
regeneration. Moreover, epithelial stem cell organoids now also open the possibilities to 181
study host-microbe-interaction (Sina Bartfeld). 182
183
System biology approaches applied to the global transcriptome generated from the RNA 184
isolated from a few drops of blood from pre-term babies have helped to reveal how 185
regulatory mechanisms determine the set-point for immune homeostasis in early life by 186
integrating specific immune and metabolic pathways that inter-patient differences can be 187
overcome and uncovered a novel immune-metabolic axis that accurately predicts sepsis in 188
neonates and infants. These studies lay the foundation for future translation of host pathways 189
in advancing diagnostic, prognostic, and therapeutic strategies for neonatal sepsis (Peter 190
Ghazal) [10]. 191
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Conclusion 194
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We are only starting to appreciate the critical impact of the postnatal period for lifelong health 196
and disease susceptibility. Recent discoveries provide the proof of principle, characterize the 197
critical time window(s) and identify underlying mechanisms. However, a number of important 198
questions remain: The cause-effect relationship between microbial exposure and health 199
needs to be established and the mechanisms operating during this “window of opportunity” 200
need to be elucidated. This must consequently lead to effective primary prevention 201
strategies. Future research will further deepen our understanding and extend from animal 202
models to human studies in order to develop interventional strategies to foster immune 203
homeostasis and prevent the development of diseases. 204
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Figure legend 208
Figure 1 New mechanisms of microbe-immune interaction. For details please see text. 209
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Acknowledgements 211
212
The conference and the preparation of this manuscript were supported by an unrestricted 213
grant of the Volkswagen Foundation, Hannover, Germany. 214
215
Johan Garssen receives grants from Nutricia-research foundation, Dutch government 216
funding (NWO, CCC,STW, RAAK/PRO, TKI), EU, and EDB. 217
218
Research in Mathias Hornef’s laboratory is supported by the German Research Foundation 219
(SPP1656, SPP1580, IRTG1273 and Ho-2237/12-1 ) and the Niedersachsen Research 220
Network on Neuroinfectiology (N-RENNT). 221
222
Kathy McCoy is supported by a grant from the SNSF (SNSF310030_134902) and the 223
European Research Council (ERC, FP/2007-2013) Agreement no 281785. 224
225
John Penders is supported by a VIDI grant from the Netherlands Organisation for Scientific 226
Research and a Joint Programme Initiatives grant (Intestinal Microbiomics GI-MDH) within 227
the Healthy Diet for Healthy Living programme. 228
229
Immo Prinz is supported by the grant of the SFB900 (project B8). 230
231
Harald Renz is supported by the German Lung Center, Disease Area of Allergy and Asthma. 232
233
Erika von Mutius receives research grants from the German Research Foundation (DFG) 234
and the German Federal Ministry of Education and Research (BMBF) 235
236
We would like to thank Susanne Zapf for her excellent editorial assistance. 237
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Yersinia
enterocolitica
Commensal
mircobiota
Symbiotic
bacteria
Microbiota
LPS
CD8 iNKTγδ T
cellsB cells
TLR 4
positive
cells
Provide
protective
immunity
Development
of iNKT cells is
controlled
during time-
window in
neonatal
period [high
in
(auto)inflam-
mation]
Evolutionary
imprinted γδ
TCR
repertoire
matches
conserved
microbial
structures
[first line
defense]
T-cell
independent
control of B-
cell repertoire
(B2-cells);
Decrease of
self-reactive
cells
Necrotizing
enterocolitis
develops as a
result of LPS-
TLR 4-NF-κB
activation
Figure 1
