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. 2000 Jun;59(6):439–447. doi: 10.1136/ard.59.6.439

Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment

A Ulfgren 1, L Grondal 1, S Lindblad 1, M Khademi 1, O Johnell 1, L Klareskog 1, U Andersson 1
PMCID: PMC1753152  PMID: 10834861

Abstract

OBJECTIVES—Assessment of the numbers and spatial distribution of cells producing interleukin 1α (IL1α), interleukin 1β (IL1β), tumour necrosis factor α (TNFα), and interleukin 6 (IL6) in the synovial membranes of patients with rheumatoid arthritis (RA).
METHODS—Synovial tissue specimens from 40 patients with RA and eight patients with non-rheumatic disease were obtained by arthroscopy guided biopsy techniques or during joint surgery. A modified immunohistochemical method detecting cytokine producing rather than cytokine binding cells was applied to determine cytokine synthesis in fixed cryopreserved sections. Computerised image analysis methods provided comparative quantitative assessments.
RESULTS—A wide variation between subjects was recorded for both quantities and profiles of expressed cytokines, despite similar macroscopic and histopathological features of inflammation. IL1α and IL1β were the most abundant monokines identified, though produced at different sites. IL1α was predominantly seen in vascular endothelial cells, whereas IL1β staining was mainly shown in macrophages and fibroblasts. Concordant results for the detection of TNFα at protein and mRNA levels were obtained with an unexpectedly low number of TNFα producing cells compared with IL1 expressing cells in many patients with RA. Specimens acquired arthroscopically from areas with maximum signs of macroscopic inflammation showed an increased number of TNFα producing cells in pannus tissue compared with that occurring in synovial villi of a given joint. This clustered distribution was not found for cells expressing any of the other studied cytokines.
CONCLUSION—The recorded heterogeneous profile of proinflammatory cytokine synthesis in the synovial membrane among patients with RA may provide a clue for an understanding of the wide variation in responsiveness to different modes of antirheumatic treatment between patients.



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Figure 1  .

Figure 1  

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Videoprint photographs illustrating brown (diaminobenzidine) immunoperoxidase staining for cytokine producing cells in cryopreserved synovial membrane biopsy specimens obtained from patients with rheumatoid arthritis (RA). The cells were counterstained with haematoxylin. (A) Interleukin 1β producing cells in pannus tissue penetrating bone (dark blue staining) (original magnification ×200, bar represents 40 µm). (B) Interleukin 1α production occurring in both vascular endothelial cells and individual macrophages (original magnification ×320, bar represents 32 µm). (C) Tumour necrosis factor α (TNFα) producing cells in the sublining layer with additional extracellular TNFα staining encompassing producer cells (original magnification ×400, bar represents 20 µm). (D) Interleukin 6 production was seen in scattered cells with minimum additional extracellular staining (original magnification ×400, bar represents 20 µm).

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