Fibrosis is an important health problem and its pathogenetic principles are still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases. However, irrespective of the primary cause, fibrotic tissue is always infiltrated by mononuclear immune cells. In most instances the reason for the attraction of these cells to fibrotic tissue and their proliferation remains to be determined, however their cytokine profile shows clear-cut proinflammatory and profibrotic characteristics. In this review we discuss the innate and adaptive immune reactions associated with the development of fibrosis and the molecular basis of the profibrotic mechanisms taking place in systemic sclerosis (scleroderma), arteriosclerosis and peri-silicone mammary implant fibrosis. Fibrosis: a disease with an immune-mediated etiologyFibrosis, 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, in response to foreign implants, or from tumors (see Table 1).Although the pathologic processes initiating and perpetuating these processes are rather diverse, from a biochemical and pathohistological view the end stage of the development of fibrosis seems to be very stereotypic. Thus, in all cases studied the early stages of fibrotic conditions are characterized by immunologic-inflammatory hallmarks, viz. a perivascular infiltration by mononuclear cells and the subsequent imbalance of anti-and profibrotic cytokine profiles. In most of these instances, the original antigenic stimuli triggering the lymphoid infiltration have not been identified. The emphasis of this review is placed on the general role of innate and adaptive immunity, and the respective cytokines involved in the development of fibrosis.

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Although astrocytes presumably participate in maintaining the immune privilege of the central nervous system (CNS), the mechanisms behind their immunoregulatory properties are still largely undefined. In this study, we describe the development of regulatory T cells upon contact with astrocytes. Rat T cells pre-incubated with astrocytes completely lost the ability to proliferate in response to mitogenic stimuli. The cells were blocked in G0/G1 phase of the cell cycle, expressed less IL-2R, and produced significantly lower amounts of interferon-gamma (IFN-gamma), but not interleukin-2 (IL-2), IL-10, or tumor necrosis factor (TNF). These anergic cells completely prevented mitogen-induced growth of normal T lymphocytes, as well as CNS antigen-driven proliferation of autoreactive T cells. The suppressive activity resided in both CD4+ and CD8+ T-cell compartments. Heat-sensitive soluble T-cell factors, not including transforming growth factor-beta (TGF-beta) or IL-10, were solely responsible for the observed suppression, as well as for the transfer of suppressive activity to normal T cells. The administration of astrocyte-induced regulatory T cells markedly alleviated CNS inflammation and clinical symptoms of CNS autoimmunity in rats with experimental allergic encephalomyelitis. Finally, the cells with suppressive properties were readily generated from human lymphocytes after contact with astrocytes. Taken together, these data indicate that astrocyte-induced regulatory T cells might represent an important mechanism for self-limitation of excessive inflammation in the brain.

Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis.

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