The role of immune response in the pathogenesis of idiopathic pulmonary fibrosis: far beyond the Th1/Th2 imbalance

ABSTRACT

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown origin characterized by progressive scarring of the lung leading to irreversible loss of function. Despite the availability of two drugs that are able to slow down disease progression, IPF remains a deadly disease. The pathogenesis of IPF is poorly understood, but a dysregulated wound healing response following recurrent alveolar epithelial injury is thought to be crucial.

Areas covered

In the last few years, the role of the immune system in IPF pathobiology has been reconsidered; indeed, recent data suggest that a dysfunctional immune system may promote and unfavorable interplay with pro-fibrotic pathways thus acting as a cofactor in disease development and progression. In this article, we review and critically discuss the role of T cells in the pathogenesis and progression of IPF in the attempt to highlight ways in which further research in this area may enable the development of targeted immunomodulatory therapies for this dreadful disease.

Expert opinion

A better understanding of T cell interactions has the potential to facilitate the development of immune modulators targeting multiple T cell-mediated pathways, thus halting disease initiation and progression.

KEYWORDS:

• Idiopathic pulmonary fibrosis
• interstitial lung disease
• Th1
• Th2
• immune system
• pathogenesis

Article highlights

• Preclinical evidence suggests that both innate and adaptive immune response may contribute to the development and progression of idiopathic pulmonary fibrosis (IPF).

• Within innate immunity, neutrophils, M2 macrophages and monocytes might be involved in the pathogenesis of IPF by regulating the interplay between tissue damage and epithelial repair.

• Preclinical evidence shows that among effectors of adaptive immunity, an imbalanced Th1/Th2 response may contribute to the pathogenesis of IPF: Th2 cytokines promote the activation of fibroblasts while Th1 pathways appear to dampen fibrogenesis.

• Beyond the Th1/th2 imbalance, a more complex interplay between Th1/Th2 and other T cells (e.g. Th17 cells, Th9-cells, Tregs, Tfhs, CTLs, NKTs, and γδ-T cells) may contribute to the pathogenesis IPF.

• Th17 cells exert profibrotic effects by promoting the proliferation and activation of fibroblasts together with an increased inflammatory infiltrate in IPF lungs.

• In the early stage of IPF, Tregs appear to exert prof-fibrotic effects through overexpression of TGF-β and PDGF-β while during the late phase of the disease a protective role has been described through IL-10 secretion and FGF-9 pathway inhibition.

• While the role of T cells adaptive immunity in IPF remains to be elucidated, the interplay between different populations of T cells represents a promising field of research and may allow the identification of potential molecular and cellular therapeutic targets.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

PS: conception of the review, literature search, drafting of the manuscript; RT: literature search, drafting of the manuscript; GC: literature search, drafting of the manuscript; AVS: literature search, drafting of the manuscript; EC: literature search, drafting of the manuscript; SP: literature search, drafting of the manuscript; SC: critical review of the manuscript; NC: literature search, drafting of the manuscript; EC: critical review of the manuscript; MS: critical review of the manuscript; EB: conception of the review, literature search, drafting of the manuscript.

All the authors approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.