Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Zhou, Xiaodong; Tan, Filemon K.; Milewicz, Dianna M.; Guo, Xinjian; Bona, Constantin A.; Arnett, Frank C.

doi:10.4049/jimmunol.175.7.4555

Cited by 80 publications

(54 citation statements)

References 34 publications

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“…Therefore, one may consider that anti-fibrillin autoantibodies are present and play a role in liver fibrosis. It was recently shown that anti-fibrillin-1 autoantibodies from scleroderma patients may play a pathogenic role by increasing the transcription and production of ECM components in normal human fibroblasts via the release of sequestered TGF-β1 from fibrillin-1 (26).…”

Section: The Mechanism Of B Cell Involvement In Liver Fibrosis Remainmentioning

confidence: 99%

B cells: no longer bystanders in liver fibrosis

Bhogal¹

2005

Journal of Clinical Investigation

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Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts. Overexpression and deposition of ECM components are dominant features of fibrotic diseases, including hepatic fibrosis. The contribution of CD4 + Th2 cells to hepatic fibrosis has been well described. Now, in this issue of the JCI, Novobrantseva et al. provide data to suggest that hepatic B cells also play a role in liver injury (see the related article beginning on page 3072). In a carbon tetrachloride-induced mouse model of hepatic fibrosis, T cell-deficient mice developed severe liver fibrosis; however, in B cell-deficient animals, hepatic fibrosis was attenuated. This study provides new insight into our understanding of the cells involved in mediating the adaptive immune response that leads to hepatic fibrosis.The ECM is composed of a variety of molecules including the fibrous proteins collagen and fibrillin, adhesion molecules, glycoproteins, proteoglycans, and metalloproteinases, which together form a scaffold on which cells adhere, grow, and differentiate. The most abundant proteins in the ECM belong to the collagen family. In general, ECM molecules are synthesized by fibroblasts; in the liver, they are synthesized by activated hepatic stellate cells (HSCs), portal fibroblasts, and myofibroblasts of bone marrow origin.Maintenance of the normal structure and function of the ECM involves constant remodeling, which results from regulated, low levels of ECM synthesis and degradation. During wound healing, there is a short-lived shift in the balance of synthesis and degradation, which leads to a transient increase in collagen production and deposition. Chronic collagen production can result in keloid scars. A permanent imbalance resulting in major alterations in both the quantity and composition of the ECM causes fibrosis. Excessive accumulation of type I collagen is a major pathological feature in diseases such as scleroderma, osteogenesis imperfecta, and scurvy as well as other conditions of the lung, kidney, and liver characterized by tissue fibrosis (1). The main causes of liver fibrosis include chronic HCV infection, alcohol abuse, and nonalcoholic steatohepatitis. We note that exposure to carbon tetrachloride (CCl 4 ), the most commonly used model of chemically induced hepatic fibrosis in rodents, is not considered to be a main cause of hepatic fibrosis in humans.The cellular and molecular mechanisms underlying fibrotic disorders are similar regardless of the tissue involved. First, excessive collagen production results from the increased expression of the collagen gene. Second, decreased activity of ECM-removing metalloproteinases, primarily due to the overexpression of tissue inhibitors of metalloproteinases (TIMPs), results in decreased ECM (including collagen) degradation. Third, acquisition of a novel phenotype by fibroblasts is related to abnormal activation of receptors and signaling pathways (2, 3), leading to autocrine synthesis of c...

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Section: The Mechanism Of B Cell Involvement In Liver Fibrosis Remainmentioning

confidence: 99%

B cells: no longer bystanders in liver fibrosis

Bhogal¹

2005

Journal of Clinical Investigation

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“…Other investigators have identified AFAs in patients with SSc, mostly in those with the diffuse form of the disease (23), and it was observed that IgG in patients with SSc and pulmonary arterial hypertension (PAH) recognized fibroblast components that were distinct from those in patients with primary PAH (24). In addition, SSc autoantibody binding to the nonstructural matrix component fibrillin 1 (25), as well as to the adhesion molecule NAG-2 (26,27) and to the platelet-derived growth factor (PDGF) receptor (28) expressed on fibroblasts, results in activation of these components, accompanied by increased collagen synthesis. Upon PDGF receptor binding, SSc autoantibodies enhance production of reactive oxygen species and induce phosphorylation of ERK-1/2 (28).…”

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confidence: 99%

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Fineschi¹,

Goffin²,

Rezzonico³

et al. 2008

Arthritis & Rheumatism

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Objective. Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved.Methods. AFA-positive and AFA-negative IgG were tested on fibroblasts. Chemokine messenger RNA expression was screened by microarray and quantitative reverse transcription-polymerase chain reaction. Production of CCL2, CXCL8, and CXCL10 proteins was assessed by enzyme-linked immunosorbent assay. Pharmacologic inhibitors were used to study signal transduction, with results assessed by Western blotting and immunofluorescence analysis. Fibroblasts with defective expression of Toll-like receptors (TLRs) and anti-TLR monoclonal antibodies (mAb) were used to assess AFA specificity.Results. In human fibroblasts, AFA-positive IgG induced the preferential transcription of chemokines with profibrotic and proangiogenic potential, including, but not exclusively, CCL2, CXCL1, CXCL8, CKLF, and ECGF1, which were distinctly different from those induced by interferon-␥. Levels of CCL2 and CXCL8 proteins were increased in AFA-stimulated fibroblast culture supernatants. AFA binding to fibroblasts resulted in concomitant activation of ERK-1/2, c-Jun, and NF-B. CCL2 production was sensitive to inhibition of both proteasome and JNK, while CXCL8 production was sensitive only to inhibition of proteasome. AFAs failed to up-regulate CCL2 expression in TLR-4-deficient fibroblasts but not in TLR-6-or TLR-2-deficient fibroblasts. Moreover, anti-TLR-4 mAb, but not anti-TLR-2 mAb, partially inhibited the production of CCL2 induced by AFAs in human fibroblasts. Conclusion.Autoantibodies that bind to the surface of fibroblasts may contribute to the pathogenesis of SSc by up-regulating the fibroblast production of profibrotic and proangiogenic chemokines, in a proteasomeand TLR-4-dependent manner.

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“…Antikörper gegen Matrix-Metalloproteinasen können ihre Zielantigene hemmen und dadurch die Balance zwischen Kollagenauf-und -abbau zuungunsten der Degradation verschieben [33,38]. Fibrillin-Antikörper sollen durch Interferenz mit extrazellulären Mikrofibrillen die Freisetzung von latentem TGF-β und eine durch diesen vermittelte profibrotische Genregulation auslösen [48]. …”

Section: Pathogenetische Bedeutung Sklerodermie-assoziierter Autoantiunclassified

Sklerodermie-assoziierte Autoantikörper – klinische und diagnostische Relevanz

Mierau

Genth²

2006

Z. Rheumatol.

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In systemic sclerosis (SSc) and its variants, autoantibodies are the best known immunological aberration. In more than 95% of the patients, antinuclear antibodies or other autoantibodies can be detected. In about 90% of SSc patients with antinuclear antibodies, scleroderma associated autoantibodies highly specific for systemic sclerosis are found. These autoantibodies usually exclude each other in individual patients, and they are detectable early, persisting during the course of the disease. SSc patients characterized by scleroderma associated autoantibodies belong to disease subsets which are relatively homogeneous in clinical, genetic and prognostic terms. Besides these diagnostically relevant autoantibodies, numerous additional ones have also been described. These are neither SSc specific nor mutually exclusive, and their antigens have only been partially characterized. Some, however, are thought to be relevant to the as yet unanswered question of whether autoantibodies are directly involved in SSc pathogenesis.

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Autoantibodies to Fibrillin-1 Activate Normal Human Fibroblasts in Culture through the TGF-β Pathway to Recapitulate the “Scleroderma Phenotype”

Cited by 80 publications

References 34 publications

B cells: no longer bystanders in liver fibrosis

B cells: no longer bystanders in liver fibrosis

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Sklerodermie-assoziierte Autoantikörper – klinische und diagnostische Relevanz

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