CD55 deposited on synovial collagen fibers protects from immune complex-mediated arthritis

Abstract

IntroductionCD55, a glycosylphosphatidylinositol-anchored, complement-regulating protein (decay-accelerating factor), is expressed by fibroblast-like synoviocytes (FLS) with high local abundance in the intimal lining layer. We here explored the basis and consequences of this uncommon presence.MethodsSynovial tissue, primary FLS cultures, and three-dimensional FLS micromasses were analyzed. CD55 expression was assessed by quantitative polymerase chain reaction (PCR), in situ hybridization, flow cytometry, and immunohistochemistry. Reticular fibers were visualized by Gomori staining and colocalization of CD55 with extracellular matrix (ECM) proteins by confocal microscopy. Membrane-bound CD55 was released from synovial tissue with phospholipase C. Functional consequences of CD55 expression were studied in the K/BxN serum transfer model of arthritis using mice that in addition to CD55 also lack FcγRIIB (CD32), increasing susceptibility for immune complex-mediated pathology.ResultsAbundant CD55 expression seen in FLS of the intimal lining layer was associated with linearly oriented reticular fibers and was resistant to phospholipase C treatment. Expression of CD55 colocalized with collagen type I and III as well as with complement C3. A comparable distribution of CD55 was established in three-dimensional micromasses after ≥3 weeks of culture together with the ECM. CD55 deficiency did not enhance K/BxN serum-induced arthritis, but further exaggerated disease activity in Fcgr2b−/− mice.ConclusionsCD55 is produced by FLS and deposited on the local collagen fiber meshwork, where it protects the synovial tissue against immune complex-mediated arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0518-4) contains supplementary material, which is available to authorized users.

Stromal cell markers are differentially expressed in the synovial tissue of patients with early arthritis

“…The most prominent stromal cell of the ST is the fibroblast-like synoviocyte (FLS) [ 7 , 32 ]. We previously showed that CD55 is a defining marker for FLS in the intimal lining layer where it can mediate contacts with CD97 on other immune cells and may be of primary importance in maintaining and amplifying synovial inflammation [ 13 , 14 , 33 , 34 ]. Other molecules markedly expressed by FLS in ST of patients with established RA are CD248 (also known as endosialin or TEM1) and podoplanin (gp38) [ 16 , 21 ].…”

“…We therefore hypothesised that subpopulations within the stromal compartment might become activated and expanded during the inflammatory processes occurring in early disease, defining a profile that may be specific for RA. We chose to examine an established intimal lining layer stromal marker (CD55) [ 13 , 14 ], and more recently discovered markers described both in RA and cancer, where the role of tumour-associated fibroblasts has become prominent. These include CD248 [ 15 , 16 ], a synovial sublining glycoprotein marker expressed in perivascular and cancer stromal cells and in the RA synovium; fibroblast activation protein (FAP) [ 17 – 19 ], a cell surface protein that is highly expressed in established RA synovium with ectoenzyme activity and an important role in epithelial cancers; and podoplanin (gp38) [ 20 – 22 ], an intimal lining layer glycoprotein marker with roles in lymph node stromal networks and epithelial to mesenchymal transition.…”

Beyond the Role of CD55 as a Complement Component

“…It is likely that expression of CD55 is not a cause but the failure of RA to protect synovial tissue from activation of the complement. Depletion of CD55 exacerbated arthritic mouse model ( 85 ). Furthermore, CD55 preserved the synovial tissue from immune complex-mediated arthritis ( 85 ).…”

“…Depletion of CD55 exacerbated arthritic mouse model ( 85 ). Furthermore, CD55 preserved the synovial tissue from immune complex-mediated arthritis ( 85 ). These outcomes indicate that soluble CD55 may be a strategy to treat RA.…”

“…The seemingly opposite result might be caused by the fact that CD55 plays a different role depending on cellular context. While Karpus et al ( 85 ) looked into the effect of CD55 depletion in Fcgr2b −/− mice through knockdown of Fcγr2b gene related to lupus susceptibility, Hoek et al ( 86 ) observed it using collagen-induced RA models.…”