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The impact of perinatal immune development on mucosal homeostasis and chronic inflammation

Nature Reviews Immunology volume 12, pages 9–23 (2012)Cite this article

Subjects

Key Points

  • Here, we discuss emerging evidence that causally links perinatal exposure to microbial and environmental factors with chronic inflammatory diseases of the intestinal and respiratory tracts.

  • Structural and functional changes of the lung and gut mucosal immune systems occur during the pre- and postnatal periods, and are regulated by developmental and environmental factors. Concomitantly, the exposure to environmental stimuli increases and the resident microbiota at mucosal sites is established.

  • Adaptation to these changes is facilitated by complex molecular and cellular regulatory circuits that prevent inappropriate immune stimulation and promote the establishment of a stable microbial–host homeostasis.

  • A failure to acquire tolerance to food and environmental antigens, impaired epithelial barrier formation and an imbalanced mucosal cellular composition promote the development of inflammation. In addition, alterations to the composition of the resident microbiota influence nutrient metabolism, mucosal tissue maturation and immunoregulatory mechanisms.

  • Further insight is required to fully understand the links between early microbial and environmental exposures, perinatal mucosal tissue maturation, postnatal establishment of the mucosal microbiota and disease susceptibility; such information might be used to develop prophylactic and therapeutic strategies to overcome chronic inflammatory diseases.

Abstract

The mucosal surfaces of the gut and airways have important barrier functions and regulate the induction of immunological tolerance. The rapidly increasing incidence of chronic inflammatory disorders of these surfaces, such as inflammatory bowel disease and asthma, indicates that the immune functions of these mucosae are becoming disrupted in humans. Recent data indicate that events in prenatal and neonatal life orchestrate mucosal homeostasis. Several environmental factors promote the perinatal programming of the immune system, including colonization of the gut and airways by commensal microorganisms. These complex microbial–host interactions operate in a delicate temporal and spatial manner and have an important role in the induction of homeostatic mechanisms.

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Figure 1: Postnatal development and maturation of the intestinal mucosal barrier and immune system.
Figure 2: Development of the respiratory mucosal immune system.
Figure 3: The cellular network of gut immune homeostasis and the cellular processes driving mucosal inflammation.

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Acknowledgements

H.R. is supported by the SFB/TR22 DFG-funded network 'Allergic Immune Responses of the Lung' and by the Universities of Giessen and Marburg Lung Centre (UGMLC), a LOEWE excellence initiative of the Hessian Government, Germany. P.B. is supported by the Research Council of Norway, The University of Oslo and Oslo University Hospital, through the joint financing of the Center of Excellence named 'Centre for Immune Regulation'. M.H. is supported by the German Research Foundation (Ho2236/5-3), the Federal Ministry of Education and Research (DLR 01GU0825 and DLR 01KI1003D) and the Collaborative Research Center grants SFB621 and SFB900.

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Authors and Affiliations

  1. Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Medical Faculty, Baldingerstrasse, 35043, Marburg, Germany

    Harald Renz

  2. and Department of Pathology, Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Per Brandtzaeg

  3. Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany

    Mathias Hornef

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Glossary

Oral tolerance

This form of tolerance is established through the intestinal mucosa to avoid local and systemic hypersensitivity to innocuous antigens that have breached the epithelial barrier. It is mediated mainly through the induction of regulatory T cells but probably also through other mechanisms, such as T cell anergy and clonal deletion.

Crypt–villus architecture

Crypts are glandular invaginations of the intestinal epithelium. Paneth cells localize to the base of crypts in the small intestine and secrete antimicrobial peptides. Intestinal stem cells in crypts divide continuously and provide rapid epithelial cell renewal. In the small intestine, villi are finger-like protrusions into the gut lumen, which increase the absorptive surface of the gut epithelium. Villi mainly consist of mature, absorptive enterocytes, but also contain mucus-secreting goblet cells.

Cathelicidin

Cathelicidins are a large family of antimicrobial peptides in ruminants. In mice and humans, only one cathelicidin — CRAMP or LL37, respectively — is expressed. The genes encoding CRAMP and LL37 are expressed by most epithelial cells, as well as granulocytes, and their expression is regulated at the level of transcription. They encode a highly conserved 'cathelin' sequence of 12 kDa at the amino terminus, followed by the mature antimicrobial peptide, which requires enzymatic cleavage to become active.

Defensins

A class of antimicrobial peptides with broad antibacterial, antifungal and, in part, antiviral activity. α-defensins are produced constitutively by small intestinal Paneth cells and, in humans, also by neutrophils, whereas many β-defensins are transcriptionally regulated and expressed by most epithelial cells.

RORγt+NKp46+ lymphocytes

A population of innate lymphoid cells in the intestinal lamina propria that expresses the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and the natural killer cell marker NKp46. RORγt+NKp46+ lymphocytes support the expression of the antimicrobial peptide REG3γ by epithelial cells through secretion of IL-22.

Cryptopatches

Clusters of KIT+IL-7R+THY1+ T cell progenitors found in the murine intestinal lamina propria. Cryptopatches are absent in germ-free mice.

Isolated lymphoid follicles

Small lymphoid aggregates located in the lamina propria of the small and large intestines that contain B cells, dendritic cells, stromal cells and some T cells and that might form germinal centres. In mice, isolated lymphoid follicles were shown to develop from cryptopatches and they are absent in germ-free animals.

Anaphylaxis

A severe and rapid allergic reaction triggered by the activation of high-affinity Fc receptors for IgE in sensitized individuals. Anaphylactic shock is the most severe type of anaphylaxis and can lead to death in minutes if left untreated. In various mouse models, it has been shown that IgG1 rather than IgE antibodies trigger the anaphylactic reaction.

Tight junctions

These are specialized intercellular junctions that seal the apical epithelium, in which two plasma membranes form a sealing gasket around a cell (also known as the zonula occludens). They are formed by several proteins, including occludin and claudin. Tight junctions prevent fluid moving through the intercellular gaps and prevent the lateral movement of membrane proteins between the apical and basolateral cellular domains.

Goblet cells

Mucus-producing cells that are found in the epithelial cell lining of the intestines and lungs.

Clara cells

Dome-shaped cells with short microvilli that are found in the small airways (bronchioles) of the lungs. These cells can secrete glycosaminoglycans to protect the lining of the bronchioles and are also known as bronchiolar exocrine cells.

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Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol 12, 9–23 (2012). https://doi.org/10.1038/nri3112

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