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Identification of the Advanced Glycation End Products Ne 488 EXTENDED REPORT Ann Rheum Dis: first published as 10.1136/ard.61.6.492 on 1 June 2002. Downloaded from Identification of the advanced glycation end products Ne-carboxymethyllysine in the synovial tissue of patients with rheumatoid arthritis S Drinda, S Franke, C C Canet, P Petrow, R Bräuer, C Hüttich, G Stein, G Hein ............................................................................................................................. Ann Rheum Dis 2002;61:488–492 Background: Generation of advanced glycation end products (AGEs) is an inevitable process in vivo and can be accelerated under pathological conditions such as oxidative stress. In serum and synovial fluid of patients with rheumatoid arthritis (RA) raised AGE levels have been found. Objective: To determine the presence of Nå-carboxymethyllysine (CML; marker of oxidative stress) in See end of article for RA synovial tissue by immunohistology. authors’ affiliations Methods: Frozen synovial tissue samples from 10 patients with RA and eight controls (four patients ....................... without joint disease and four patients with osteoarthritis (OA)) were treated with rabbit-anti-CML-IgG Correspondence: to: Dr S and goat-antirabbit-IgG. Immunostaining was visualised by streptavidine-alkaline phosphatase Drinda, Friedrich Schiller (chromogen fuchsin). Cell differentiation was performed with antibodies against CD68, CD45RO, and Universität Jena, Klinik für CD20. Innere Medizin IV, Results: CML was detected in the synovial lining, sublining, and endothelium in 10/10 RA and 4/4 Rheumatologie/Osteologie, OA synovial specimens. In RA some macrophages (CD68+) and T cells (CD45RO+) showed positive Erlanger Allee 101, 07740 Jena, Germany; immunostaining for CML, whereas B cells were negative. Staining in OA synovial sublining was weak stefan.drinda@ compared with RA. med.uni-jena.de Conclusions: CML was detected for the first time in RA and OA synovial tissue. Different patterns of Accepted immunostaining in RA and OA and the presence of CML on macrophages and T cells, suggest a role 7 December 2001 for CML in the pathogenesis of RA. This might be due to presentation of new epitopes which can main- ....................... tain or even trigger an autoimmune response. dvanced glycation end products (AGEs) are formed dur- driven process in this disease, but a specific antigen has not yet ing the Maillard reaction by non-enzymatic glycation been found. Aand oxidation of proteins constituting a heterogeneous To obtain more detailed information on the accumulation of http://ard.bmj.com/ class of structures. The generation of AGEs is an inevitable AGE modified proteins in RA, this study aimed at investigat- process in vivo and their accumulation in different tissues has ing whether CML modifications are present in the synovial been implicated in the process of aging and also in the patho- tissues of patients with RA. genesis of several pathological conditions, including diabetes, atherosclerosis, Alzheimer’s disease, renal failure, and renal MATERIALS AND METHODS replacement treatment with maintenance haemodialysis.1–5 Synovial tissue samples obtained by therapeutic synovectomia AGE modification can lead to tissue damage through from 10 patients with RA (mean age 57 years, range 33–83) on October 1, 2021 by guest. Protected copyright. alterations of tissue protein structure and function, and fulfilling the 1987 revised ACR criteria14 were examined in this stimulates cellular responses mediated by a specific receptor study. Synovial specimens obtained at post mortem from four (RAGE). patients who had no history of joint disease (mean age 52 Not only glucose but also reactive carbonyl intermediates years, range 21–86) and from four patients (mean age 74 derived from the Maillard reaction (3-deoxyglucosone), as years, range 66–80) with osteoarthritis (OA) served as well as the products of sugar oxidation (arabinose, glyoxal, controls. The OA samples were obtained during the surgical methylglyoxal) and lipid peroxidation (malondialdehyde) are implantation of a knee endoprosthesis. All patients were non- precursors causing chemical modification of proteins. Oxida- diabetic. Table 1 shows the patient characteristics. tive stress accelerates the formation of these products.67 The Sample preparation well characterised AGE Ne-carboxymethyllysine (CML) repre- Frozen synovial tissues (2 µm sections) were mounted on sents a chemically modified amino acid and originates in vivo polylysine coated slides (Menzel, Germany), fixed in acetone, from carbohydrate as well as from lipid derived precursors. It and blocked in 4% skimmed milk for 20 minutes. Slides were has been suggested that CML is a general marker of oxidative then incubated with rabbit-anti-CML-IgG (concentration 4 stress and tissue damage through protein alteration.8 Oxida- g/l, dilution 1:10 000; kindly provided by Roche Diagnostics, tive stress plays an important part in acute and chronic Germany) for one hour. Biotinylated goat-antirabbit-IgG con- inflammatory diseases, including rheumatoid arthritis (RA).9 jugated with streptavidine/alkaline phosphatase was used for Recently reported studies have provided evidence that the AGE pentosidine is raised in the articular cartilage as well as in the serum and synovial fluid of patients with RA.10–12 ............................................................. Furthermore, the raised autoantibody level against CML in Abbreviations: AGEs, advanced glycation end products; CML, patients with diabetic renal failure indicates that CML Ne-carboxymethyllysine; IL, interleukin; OA, osteoarthritis; RA, rheumatoid 13 accumulated in vivo serves as an immunological epitope. On arthritis; RAGE, receptor for AGEs; TNFα, tumour necrosis factor α; TRX, the other hand, many findings in RA indicate an antigen thioredoxin www.annrheumdis.com Carboxymethyllysine (CML-AGE) in RA synovial tissue 489 Table 1 Clinical data on investigated patients Ann Rheum Dis: first published as 10.1136/ard.61.6.492 on 1 June 2002. Downloaded from Duration/ exacerbation of Radiological WBC BSG Patient Diagnosis disease (years) Age (years) Sex signs* Treatment† (×109/l) CRP (mg/l) (mm) 1RA3064FL41,2,3105238 2 RA 5 54 F L5 2 10 55.9 68 3 RA 1 75 F L4 4 10.2 21.5 19 4 RA 10 52 F L5 1, 2 5.6 34.7 52 5 RA 10 44 F L4 2 9.8 41.4 38 6 RA 2 63 F NA 1,2,3,5 6.8 <5 12 7 RA 2 37 F L3 1, 2, 3, 6 12.1 63.2 27 8 RA 2 62 F L4 1, 2, 3 10.1 7.7 18 9 RA 1.5 83 F L4 No 8.4 46.8 50 10 RA 1.5 33 M NA 2 8.7 7,. 24 11 OA 0.17 (2 m) 77 F K4 2 4.9 <5 10 12 OA 0.75 66 F K4 2 7.7 8,5 13 13 OA 0.5 74 F K4 No 5.2 <5 17 14 OA 1 80 F K4 2 4.9 <5 24 15 Liver cirrhosis NA 28 M – – – – – 16 Cardiac failure NA 74 F – – – – – 17 Gastric sarcoma NA 21 F – – – – – 18 Peritonitis NA 86 M – – – – – *Radiological signs: grading after Larsen (L) and Kellgren (K)28; †treatment: 1, MTX; 2, NSAID; 3, cortisone; 4, etanercept; 5, azathioprine; 6, leflunomide. NA, not applicable; F, female; M, male. detection (concentration 1 mg/ml, dilution 1:400, incubation DAKO Denmark), and CD45RO (activated T lymphocytes; time 40 minutes; DAKO Denmark). Immunostaining was DAKO Denmark). Tissue samples were examined in two visualised using the streptavidine/alkaline phosphatase tech- staining steps: in the first step slides were incubated with nique with the chromogen fuchsin. Negative controls included rabbit-anti-CML-IgG (see above), staining was visualised by (a) omission of the primary antibody; (b) treatment of the alkaline phosphatase anti-alkaline phosphatase technique sections with rabbit immunoglobulin of irrelevant specificities (chromogen neufuchsin). In the second staining step, slides at the same concentration as the primary antibody; (c) were treated with antibodies against CD20 and CD68 by non-arthritic synovial tissue (table 1). applying the peroxidase technique (chromogen diaminoben- For cell differentiation we used antibodies against CD68 zidine) or CD45RO using the streptavidine-biotin- (macrophages; DAKO Denmark), CD20 (B lymphocytes; immunogold-silver technique. For monostaining the semiquantitative measurement was assigned to the following ranges: no positive cells, <5% positive http://ard.bmj.com/ on October 1, 2021 by guest. Protected copyright. Figure 1 RA synovial tissue showing CML-expression (red) in the lining layer, the subsynovial interstitium, and in endothelial cells Figure 2 RA synovial tissue with macrophage, which shows double (×20). staining: CML (red) and CD68+ (brown) (×40). www.annrheumdis.com 490 Drinda, Franke, Canet, et al Table 2 Immunohistological staining of structures in synovial tissue Ann Rheum Dis: first published as 10.1136/ard.61.6.492 on 1 June 2002. Downloaded from Immunohistology Staining in Staining in Patient Staining in synovial vascular No/disease synovial lining sublining endothelium 1/RA NA +++ ++ 2/RA +++ +++ +++ 3/RA ++ ++ ++ 4/RA +++ ++ +++ 5/RA ++ +/− +++ 6/RA +++ +++ +++ 7/RA +++ ++ +++ 8/RA NA + +/− 9/RA NA +/− ++ 10/RA ++ +++ +++ 11/OA ++ +/− +++ 12/OA ++ +/− +++ 13/OA ++ +/− ++ 14/OA +++ + + 15/Control NA +/− +/− 16/Control −− + 17/Control −− ++ 18/Control −− + Semiquantitative; −, no positive cells; +/−, <5% positive cells; ++, 30–60% positive cells; +++, >60% positive cells; NA not applicable. Figure 3 RA synovial tissue with activated T cells, which shows double staining: CML (red) and CD45RO+ (black) (×40). http://ard.bmj.com/ on October 1, 2021 by guest. Protected copyright. Figure 5 OA synovial tissue showing CML expression (red) in the lining layer, the subsynovial interstitium, and in endothelial cells (×20). Overall, fewer inflammation cells are present compared with RA tissue. numerous sublining and stroma cells as well as in the Figure 4 RA synovial tissue with follicle of B cells (brown staining). endothelium of synovial vessels (fig 1). Some macrophages CML positive cells are organised outside the follicle (×20). (CD68+) and activated T cells (CD45RO+) showed positive immunostaining for CML (figs 2 and 3), whereas B cells were cells, 30–60% positive cells, >60% positive cells, and not negative (fig 4). About 10% of CML positive cells were found in applicable.
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