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Complement C4-derived monocyte-directed chemotaxis-inhibitory factor. A molecular mechanism to cause
S Matsubara1, T Yamamoto, T Tsuruta
1Department of Orthopaedic Surgery, Kumamoto University Medical School, Japan.
Abstract:
To reveal the mechanism of the lesser infiltration of monocytes in synovial cavities with rheumatoid arthritis despite the presence of chronic inflammation, the synovial fluid from 15 rheumatoid arthritis patients was analyzed with respect to leukocyte chemotaxis. The synovial fluid possessed strong chemotactic activity to polymorphonuclear leukocytes but rather suppressed one to monocytes. The synovial fluid contained two different inhibitory activities in monocyte chemotaxis. One, which also suppressed polymorphonuclear leukocyte chemotaxis, was identified as alpha 1 protease inhibitor. The other, with molecular weight of 8 kd, possessed the specificity to monocytes and shared the antigenicity with complement C4 but not with C3 or C5. A similar inhibitor was generated in normal human plasma when the classical pathway of the complement system was initiated with aggregated human IgG, while it was not when alternative pathway was initiated with zymosan. The small size factor in the synovial fluid, apparently derived from C4, seemed to be a cyto-directed factor that might block an early part of signal transduction system of monocytes in the chemotaxis. After removal of the small-size inhibitor, the synovial fluid exhibited chemotactic ability to monocytes. Therefore the apparent C4-derived factor might play a key role in the polymorphonuclear leukocyte-predominant infiltration in the synovial fluid of rheumatoid arthritis.
Insights
Rheumatoid arthritis synovial fluid suppresses monocyte infiltration via a complement C4-derived factor. This factor may explain why polymorphonuclear leukocytes dominate, driving chronic inflammation in joints.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Rheumatoid arthritis (RA) is characterized by chronic joint inflammation.
- Monocyte infiltration into synovial cavities is typically crucial in inflammatory processes.
- The mechanism behind reduced monocyte infiltration in RA despite inflammation is unclear.
Purpose of the Study:
- To investigate the mechanism limiting monocyte infiltration in rheumatoid arthritis synovial fluid.
- To identify factors within synovial fluid that modulate leukocyte chemotaxis.
Main Methods:
- Analysis of synovial fluid from 15 RA patients for leukocyte chemotactic activity.
- Identification of inhibitory factors affecting monocyte chemotaxis using molecular weight and antigenicity assays.
- Generation of inhibitors in normal plasma via complement system activation.
Main Results:
- Synovial fluid showed strong chemotaxis for polymorphonuclear leukocytes but suppressed monocyte chemotaxis.
- Two inhibitors were identified: alpha 1 protease inhibitor and an 8 kd factor sharing antigenicity with complement C4.
- The C4-derived factor specifically inhibited monocyte chemotaxis, potentially by blocking signal transduction.
- Removal of the C4-derived factor restored monocyte chemotactic ability.
Conclusions:
- A C4-derived factor in RA synovial fluid significantly inhibits monocyte chemotaxis.
- This inhibitor may be responsible for the predominant infiltration of polymorphonuclear leukocytes in RA joints.
- Understanding this mechanism could offer new therapeutic targets for rheumatoid arthritis.