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Mononuclear cells from patients with polymyositis inhibit calcium binding by sarcoplasmic reticulum
Abstract:
We have examined whether peripheral blood mononuclear cells from patients with polymyositis-dermatomyositis (PM-DM) incubated with autologous muscle release mediators that can affect the Ca2+ binding by sarcoplasmic reticulum (SR), the key regulator of muscle contraction. Peripheral blood mononuclear cells from 11 patients with early, active, and untreated PM-DM and from 20 controls were incubated with various dilutions (ranging from 1:60 to 1:4800 wt/vol) of autologous muscle homogenates. Mononuclear cells from eight of 11 patients with PM-DM underwent proliferation as assessed by 3H-thymidine incorporation into mononuclear cells (stimulation indices ranging from 3 to 14). Supernatants from muscle-stimulated mononuclear cells suppressed the adenosine triphosphate-dependent Ca2+ binding by SR membranes derived from rat skeletal muscles. Neither proliferative responses of mononuclear cells nor release of mediators suppressing calcium binding by SR was observed in mononuclear cell cultures of controls. The factor(s) producing suppression of calcium binding by SR was nondialyzable, and its effect on SR was concentration dependent. These results suggest that mononuclear cells in PM-DM are sensitized to autologous muscle and release a soluble factor(s) that inhibits the function of SR muscle membrane. These findings may have important implications in the pathogenesis of muscle weakness in PM-DM.
Insights
Peripheral blood mononuclear cells from polymyositis-dermatomyositis patients proliferate when exposed to muscle. These cells release factors that impair calcium binding in muscle sarcoplasmic reticulum, potentially explaining muscle weakness.
Area of Science:
- Immunology
- Muscle Physiology
- Rheumatology
Background:
- Polymyositis-dermatomyositis (PM-DM) is an autoimmune disease causing muscle inflammation and weakness.
- The precise mechanisms underlying muscle dysfunction in PM-DM are not fully understood.
- Sarcoplasmic reticulum (SR) Ca2+ binding is crucial for muscle contraction regulation.
Purpose of the Study:
- To investigate the immune response of peripheral blood mononuclear cells (PBMCs) from PM-DM patients to autologous muscle antigens.
- To determine if PBMCs from PM-DM patients release mediators affecting SR function.
- To explore the potential role of these mediators in the pathogenesis of muscle weakness in PM-DM.
Main Methods:
- Incubation of PBMCs from 11 PM-DM patients and 20 controls with autologous muscle homogenates.
- Assessment of PBMC proliferation using 3H-thymidine incorporation.
- Measurement of the effect of supernatant from stimulated PBMCs on Ca2+ binding by rat skeletal muscle SR membranes.
Main Results:
- PBMCs from 8/11 PM-DM patients showed significant proliferation (stimulation indices 3-14) when exposed to muscle homogenates.
- Supernatants from muscle-stimulated PM-DM PBMCs suppressed ATP-dependent Ca2+ binding by SR membranes.
- No proliferation or suppressive mediator release was observed in control subjects.
- The suppressive factor was nondialyzable and its effect was concentration-dependent.
Conclusions:
- PBMCs in PM-DM patients are sensitized to autologous muscle antigens.
- A soluble factor released by stimulated PBMCs inhibits SR Ca2+ binding function.
- This immune-mediated inhibition of SR function may contribute to muscle weakness in PM-DM.