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Defective mononuclear phagocyte function in systemic lupus erythematosus: dissociation of Fc receptor-ligand binding
Abstract:
Fc receptor-mediated mononuclear phagocyte system (MPS) clearance is impaired in systemic lupus erythematosus (SLE) and may contribute to the pathogenesis of the immune complex disease. To investigate the basis of MPS dysfunction, we have examined concurrent in vivo and in vitro Fc receptor function in 22 patients with SLE and 23 disease-free adults. Blood monocyte Fc receptor binding was increased rather than decreased as predicted by the saturation hypothesis of MPS blockade. Rosette formation of IgG-sensitized bovine erythrocytes (EA) with monocytes demonstrated increased Fc receptor-ligand binding in SLE (percent rosettes: 40 +/- 12 vs 27 +/- 8, p less than 0.001). Scatchard analysis of the binding of radiolabeled IgG oligomers to SLE monocytes indicated a mean receptor number 30% higher than control, although this did not reach statistical significance. Despite enhanced Fc receptor-ligand (EA) binding, Fc-mediated phagocytosis of EA was decreased in SLE (1.7 +/- 0.7 erythrocytes/monocytes/hour vs 2.6 +/- 1.0, p less than 0.004). This decrease in phagocytosis by blood monocytes from SLE patients was significantly greater than that attributable to the predominance in SLE of individuals with certain HLA B cell alloantigens and intrinsically lower phagocytic rates (p less than 0.05 for all groups). This decrease therefore represents a disease-acquired characteristic. Furthermore, the phagocytic rate of the four SLE patients with marked prolongation in MPS clearance was significantly lower than that of the eight patients with near normal clearance values (p less than 0.01). Saturation of Fc receptors by immune complexes does not explain impaired immune clearance in SLE. Our results indicate that despite increased binding of the EA ligand, Fc receptor-mediated phagocytosis is markedly impaired in SLE monocytes. This impairment cannot be explained on the basis of HLA-related differences in phagocytosis among lupus patients. The defect in phagocytosis of EA is most profound in those patients with the most significantly impaired MPS clearance. Thus, the dissociation of receptor-ligand binding and receptor-mediated internalization may contribute significantly to the in vivo clearance defect in SLE.
Insights
Systemic lupus erythematosus (SLE) impairs Fc receptor function in monocytes, leading to decreased immune complex clearance. Despite increased binding, phagocytosis is reduced, indicating a defect in immune clearance in SLE patients.
Area of Science:
- Immunology
- Rheumatology
Background:
- Impaired mononuclear phagocyte system (MPS) clearance is observed in systemic lupus erythematosus (SLE).
- This dysfunction may contribute to the pathogenesis of SLE, an immune complex-mediated disease.
Purpose of the Study:
- To investigate the basis of MPS dysfunction in SLE by examining Fc receptor function.
- To concurrently assess in vivo and in vitro Fc receptor function in SLE patients and healthy controls.
Main Methods:
- Evaluated Fc receptor binding and rosette formation of IgG-sensitized erythrocytes (EA) with monocytes.
- Utilized Scatchard analysis to assess IgG oligomer binding to monocytes.
- Measured Fc-mediated phagocytosis rates of EA by monocytes.
Main Results:
- Monocyte Fc receptor binding was increased in SLE patients, contrary to the saturation hypothesis.
- Fc-mediated phagocytosis of EA was significantly decreased in SLE patients.
- The observed phagocytic defect was a disease-acquired characteristic, not solely attributable to HLA-related factors.
- Impaired phagocytosis correlated with more prolonged MPS clearance times in SLE patients.
Conclusions:
- Fc receptor-mediated phagocytosis is markedly impaired in SLE monocytes, despite increased receptor-ligand binding.
- The dissociation between Fc receptor binding and internalization contributes to impaired immune clearance in SLE.
- This defect in phagocytosis represents a significant factor in the pathogenesis of SLE's immune clearance dysfunction.