Pulmonary-intestinal cross-talk in mucosal inflammatory disease

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Abstract

Chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD) are chronic inflammatory diseases of mucosal tissues that affect the respiratory and gastrointestinal tracts, respectively. They share many similarities in epidemiological and clinical characteristics as well as inflammatory pathologies. Importantly, both conditions are accompanied by systemic co-morbidities that are largely overlooked in both basic and clinical research. Therefore, consideration of these complications may maximise the efficacy of prevention and treatment approaches. Here, we examine both the intestinal involvement in COPD and the pulmonary manifestations of IBD. We also review the evidence for inflammatory organ cross-talk that may drive these associations, and discuss the current frontiers of research into these issues.

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Most cited references 197

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Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

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A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

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Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.

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Author and article information

Contributors

School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Journal

Journal ID (nlm-journal-id): 101299742

Journal ID (pubmed-jr-id): 35518

Journal ID (nlm-ta): Mucosal Immunol

Journal ID (iso-abbrev): Mucosal Immunol

Title: Mucosal immunology

ISSN (Print): 1933-0219

ISSN (Electronic): 1935-3456

Publication date Nihms-submitted: 13 December 2011

Publication date (Electronic): 16 November 2011

Publication date (Print): January 2012

Publication date PMC-release: 01 July 2012

Volume: 5

Issue: 1

Pages: 7-18

Affiliations

School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, NSW, Australia

Author notes

[* ]Joint corresponding authors. Correspondence and request for reprints should be addressed to: Dr. Simon Keely/Prof. Philip M. Hansbro, School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, David Maddison Clinical Sciences Building, Newcastle, Australia 2300., Simon.Keely@ 123456newcastle.edu.au / Philip.Hansbro@ 123456newcastle.edu.au , Phone: +612 4913 8817/8819 Fax: +612 4913 8814

Article

Manuscript ID: nihpa337051

DOI: 10.1038/mi.2011.55

PMC ID: 3243663

PubMed ID: 22089028

SO-VID: be616024-402c-4139-898c-828897198eaa