.2015 Jan 17;17(1):6.

doi: 10.1186/s13075-015-0518-4.

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

Olga N Karpus¹, Hans P Kiener², Birgit Niederreiter³, A Seda Yilmaz-Elis⁴, Jos van der Kaa⁵, Valeria Ramaglia⁶, Ramon Arens⁷, Josef S Smolen⁸, Marina Botto⁹, Paul P Tak^{10 11}, J Sjef Verbeek¹², Jörg Hamann¹³

Affiliations

¹ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. o.karpus@amc.uva.nl.
² Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. hans.kiener@meduniwien.ac.at.
³ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. birgit.niederreiter@meduniwien.ac.at.
⁴ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. a.s.yilmaz-elis@lumc.nl.
⁵ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. j.van_der_kaa@lumc.nl.
⁶ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. v.ramaglia@amc.uva.nl.
⁷ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. r.arens@lumc.nl.
⁸ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. josef.smolen@wienkav.at.
⁹ Centre for Complement & Inflammation Research, Department of Medicine, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. m.botto@imperial.ac.uk.
¹⁰ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. p.p.tak@amc.uva.nl.
¹¹ GlaxoSmithKline Pharmaceuticals Research and Development, Gunnels Wood Road, Stevenage, SG1 2NY, UK. p.p.tak@amc.uva.nl.
¹² Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. j.s.verbeek@lumc.nl.
¹³ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.hamann@amc.uva.nl.

PMID:25596646
PMCID: PMC4325944
DOI: 10.1186/s13075-015-0518-4

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

Olga N Karpus et al. Arthritis Res Ther.2015.

.2015 Jan 17;17(1):6.

doi: 10.1186/s13075-015-0518-4.

Authors

Affiliations

¹ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. o.karpus@amc.uva.nl.
² Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. hans.kiener@meduniwien.ac.at.
³ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. birgit.niederreiter@meduniwien.ac.at.
⁴ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. a.s.yilmaz-elis@lumc.nl.
⁵ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. j.van_der_kaa@lumc.nl.
⁶ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. v.ramaglia@amc.uva.nl.
⁷ Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. r.arens@lumc.nl.
⁸ Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, A-1090, Vienna, Austria. josef.smolen@wienkav.at.
⁹ Centre for Complement & Inflammation Research, Department of Medicine, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. m.botto@imperial.ac.uk.
¹⁰ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. p.p.tak@amc.uva.nl.
¹¹ GlaxoSmithKline Pharmaceuticals Research and Development, Gunnels Wood Road, Stevenage, SG1 2NY, UK. p.p.tak@amc.uva.nl.
¹² Departments of Human Genetics and Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. j.s.verbeek@lumc.nl.
¹³ Departments of Experimental Immunology, Internal Medicine, and Genetics, Room K0-140, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.hamann@amc.uva.nl.

PMID:25596646
PMCID: PMC4325944
DOI: 10.1186/s13075-015-0518-4

Abstract

Introduction: CD55, 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.

Methods: Synovial 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.

Results: Abundant 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.

Conclusions: CD55 is produced by FLS and deposited on the local collagen fiber meshwork, where it protects the synovial tissue against immune complex-mediated arthritis.

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Figures

**Figure 1**
**CD55 is expressed in the intimal lining layer of rheumatoid arthritis (RA) synovial tissue. (A)** Sections of RA synovial tissue were stained with a fluorescein isothiocyanate (FITC)-labeled CD55 antibody (clone IA10) and analyzed by confocal microscopy. Note the fibrillar appearance of the fluorescent signal; magnification 20 x.(B) RA synovial tissue sections were stained with a CD55 antibody (clone 143–30) and visualized by immunohistochemistry and light microscopy; magnification 20 x.(C)*In situ* hybridization, using an antisense locked nucleic acid (LNA) oligomer, detects CD55 transcripts primarily in the synovial lining. Representative images are shown; magnification 10 x.

**Figure 2**
**Expression pattern of CD55 and collagen III coincides with collagenous structures in rheumatoid arthritis (RA) synovial tissue.** Sections of RA synovial tissue first were stained with(A) anti-collagen antibody or(C) anti-CD55 antibody and then processed to(B/D) Gomori silver impregnation. Red arrowheads indicate localization of CD55 to collagenous fibers. Shown are representative stainings derived by light microscopy; magnification 20 x.

**Figure 3**
**Expression pattern of CD55 coincides with collagenous structures in three-dimensional fibroblast-like synoviocytes (FLS) micromasses. (A, B, E, F)** Sections of three-dimensional FLS micromasses were stained with anti-CD55 antibody at day 14(A) and day 28(E), and then processed to Gomori silver impregnation (**B and F,** respectively).(C, D, G, H) Sections of three-dimensional FLS micromasses, which were cultured with 10 ng/ml tumor necrosis factor (TNF), were stained with anti-CD55 antibody at day 14(C) and day 28(G), and then processed to Gomori silver impregnation (**D and H**, respectively). Red arrowheads indicate a similar distribution of CD55 and collagenous fibers. Shown are representative stainings derived by light microscopy; magnification 40 x.

**Figure 4**
**CD55 colocalizes with collagen I and collagen III, but not with ER-TR7 or CD90 in rheumatoid arthritis (RA) synovial tissue.** Sections of RA synovial tissue were costained for CD55 (green) and(A) collagen I,**(B)** collagen III(C) CD90, or(D) ER-TR7 (all red, overlay yellow) and analyzed by confocal microscopy. Shown are representative stainings, magnification 63 x.

**Figure 5**
**CD55 either on immune or stromal cells protects from K/BxN serum transfer-induced arthritis in the absence of FcγRIIB (CD32).** Mice were injected at day 0 with 12.5 μl/g K/BxN serum and followed for disease development. At day 10, animals were sacrificed for further analysis.(A) Collagen III staining in representative knee joint sections of non-diseased and arthriticFcgr2b^−/− mice. Magnification 20 x.(B) Development of arthritis evaluated by measuring clinical scores and ankle thickness. Depicted are mean ± standard error of the mean (SEM) of five animals per group.^***,P <0.001;^**,P <0.01;^*,P <0.05(C) Histological evaluation of knee joints for proteoglycan loss (toluidine blue; above) and cell infiltration (hematoxylin and eosin; below). Photographs are representative of mice with no or highest disease activity in the experiment, respectively. Joint structures are labeled as F, femur; M, meniscus; S, synovium; T, tibia. Magnification 5 x.(D) Flow cytometry plots of isolated synovial tissue cells stained for CD11b⁺Gr1⁺ granulocytes, representative of mice with no or highest disease activity in the experiment, respectively.(E) Development of arthritis evaluated by measuring clinical scores and ankle thickness in bone marrow chimeric mice that lacked CD55 on stromal cells (*Fcgr2b*^−/− xCd55^{host−/−BM+/+}, depicted as a dark green line), on immune cells (*Fcgr2b*^−/− xCd55^{host+/+BM−/−}, depicted as a light green line), or on none of the two compartments (*Fcgr2b*^−/− xCd55^host+/+BM+/+, depicted as a red line). Depicted are mean ± SEM values of five animals per group.(F) Flow cytometry plots of isolated synovial tissue cells stained for CD11b⁺Gr1⁺ granulocytes, representative of mice with no or highest disease activity in the experiment, respectively. Quantifications provided to the right in(C),**(D)**, and(F) show individual mice (dots) with a horizontal line indicating the mean per group (n = 5).

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

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

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