Trends in Immunology
ReviewThe immunology of fibrosis: innate and adaptive responses
Section snippets
Fibrosis: a disease with an immune-mediated etiology
Fibrosis, i.e. excessive extracellular matrix (ECM) formation, with proliferation and activation of myofibroblasts, is a major global health problem, but its etiology, pathogenesis, diagnosis and therapy have yet to be addressed in detail in either basic or clinical research settings. In principle, fibrosis can occur as a consequence of many different pathologic conditions (Figure 1), the most important of which arise either spontaneously, from tissue damage, inflammatory disease, and in
Modulation and amplification of fibrosis by innate immunity
In recent years, an important role of the innate immune system in the development of various fibrotic diseases has become apparent. Early events of fibrosis comprise inflammatory changes, including proliferation of ECM-producing cells and the occurrence of mononuclear inflammatory infiltrates. In this context, macrophages and mast cells have been implicated as important participants in inflammatory processes involving fibrosis. However, the initial events in the activation of host defence
Initiation and regulation of fibrosis by adaptive immunity
Cells and cytokines of the adaptive immune system play a prominent role in the initiation and progression of fibrosis. Traditionally, Th1 cells are thought to mediate tissue damage, whereas Th2 cells and their corresponding cytokines are linked with fibrogenesis. Th1 and Th2 cytokines play opposing roles in fibrosis: the Th2 cytokines IL-4 and IL-13 are strongly pro-fibrotic, whereas the Th1 cytokines IFN-γ and IL-12 suppress the development of tissue fibrosis [21]. In parasitic infections, a
Myofibroblasts: the main culprits of fibrosis
Fibroblasts are key effector cells in fibrosis development, and it has recently been recognized that they form a very heterogeneous cell population. Not only do fibroblasts from diseased tissues differ in their cytokine patterns, and chemokine and ECM synthesis from their healthy counterparts [38], but they also seem to have a very different origin as well. They can be derived from local quiescent connective tissue fibroblasts by proliferation, but there is also ample evidence that at least
Pro- and anti-fibrotic growth factors and cytokines
As mentioned earlier, the pathophysiology of fibrosis is similar in many fibrotic disorders regardless of the underlying primary disease or affected tissue(s). Various stimuli released in the course of the underlying diseases cause the secretion of certain cytokines, chemokines, and growth factors by inflammatory cells and activated resident cells. These cytokines, chemokines, and growth factors perpetuate inflammation, cause further cell injury and induce fibrotic events, e.g. activation,
Therapeutic implications
The best approach to treat fibrotic diseases would be the early identification and subsequent elimination or control of the initial triggering factor of a particular fibrotic disorder. However, the ultimate etiology of many fibrotic diseases is still unknown, and the triggers are diverse. A more feasible approach might be a cytokine-directed therapy. For example, TGF-β1 has been considered as a promising therapeutic target, but a placebo-controlled phase I/II trial with anti-TGF-β1 antibody
Concluding remarks and open questions
The fibrotic consequences of various primary diseases, ranging from tissue damage resulting from inflammatory conditions, reactions against foreign material, to “spontaneous” fibrosis, remains a major unsolved diagnostic and therapeutic medical problem. In our experience, all fibrotic tissues derived from patients and experimental animals with diseases falling into one of these groups display signs of a chronic immune-mediated inflammation during the earliest periods of their development. This
Acknowledgements
The authors would like to thank all former collaborators who contributed to our general research topic of “The Immunology of Fibrosis” the work of whom is cited throughout this review. Financial support on this topic over the years was provided by the Austrian Research Fund (FWF)-Grant P198810-B05 FWF-to Georg Wick; P18726-B05 to Roswitha Sgonc; the European Union, FP7 Large Scale Integrated Project Novel approaches to reconstitute normal immune function at old age (TOLERAGE
References (106)
CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis
Cytokine
(2003)- et al.
Tryptase, a novel link between allergic inflammation and fibrosis
Trends Immunol.
(2003) Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-gamma
Am. J. Pathol.
(2005)Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC
J. Hepatol.
(2006)Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues
Burns
(1997)Immunomodulatory effects of mineral fibres in occupationally exposed workers
Mutat. Res.
(2004)NK and NKT cells in liver injury and fibrosis
Clin. Immunol.
(2009)Human schistosomiasis mansoni: Immune responses during acute and chronic phases of the infection
Acta Trop.
(2008)Time profiles of the expression of metalloproteinases, tissue inhibitors of metalloproteases, cytokines and collagens in hamsters infected with Opisthorchis viverrini with special reference to peribiliary fibrosis and liver injury
Int. J. Parasitol.
(2009)gammadelta T cell: an important source of IL-17
Curr. Opin. Immunol.
(2008)