Abstract
Interactions of T cells and fibroblasts appear to be important in the development of fibrosis, for example, the restrictive lung disease that follows the inflammatory process of alveolitis in scleroderma (systemic sclerosis, SSc). The intermolecular interactions mediating fibroblast activation are not well characterized. CD154 (CD40 ligand) is an activation-induced T-cell surface molecule which counter-receptor is CD40 expressed on target cells, including fibroblasts. We have found CD154 expression on a number of activated CD8+ T cell clones derived from bronchoalveolar lavage (BAL) fluids from SSc patients. To begin investigating the potential role of CD154-CD40 interactions in fibroblast activation, we co-cultured CD154+ Jurkat D1.1 cells or CD154- Jurkat E6-1 cells with fibroblast lines derived from dermal biopsies or BAL fluids from SSc patients and control donors. Collagen α 2(I) mRNA expression in fibroblasts was measured by RT-PCR, with ribosomal protein S9 as an internal standard. Total soluble collagen was measured in co-culture supernatants, using Sircol Biocolor assay. In fibroblasts co-cultured for 6 h with CD154+ cells, but not CD154- cells, normalized collagen mRNA expression and total soluble collagen production were 2 times higher than in fibroblasts cultured alone. Intracellular fluorescent staining did not detect IL-4, IL-10, IFNγ, or CD95 ligand expression in either D1.1 or E6-1 cells. These data suggest that CD154-CD40 interactions may enhance collagen production in fibroblasts. As this process continues uncontrolled, it may lead to the development of fibrosis.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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