Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus

被引:118
作者
Donnelly, Suzanne
Roake, Wendy
Brown, Simon
Young, Philip
Naik, Haley
Wordsworth, Paul
Isenberg, David A.
Reid, Kenneth B. M.
Eggleton, Paul
机构
[1] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England
[2] John Radcliffe Hosp, Oxford OX3 9DU, England
[3] Univ Oxford, Oxford OX3 9DU, England
[4] Univ Edinburgh, Sch Med, Edinburgh, Midlothian, Scotland
[5] UCL, London, England
来源
ARTHRITIS AND RHEUMATISM | 2006年 / 54卷 / 05期
关键词
D O I
10.1002/art.21783
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. A deficiency in a subcomponent of C1q can result in increased susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE). The monocyte endocytic receptor CD91 is implicated in the endocytosis of apoptotic neutrophils via interactions with C1q and calreticulin. In this clinical study, we studied the binding of C1q to leukocytes and determined whether C1q bound specifically to calreticulin and CD91 on cells undergoing apoptosis in SLE. Methods. Proximal antibody phage display, calreticulin-transfected cells, and immunocytochemical and confocal techniques were used in a comprehensive analysis of direct binding of C1q to apoptotic neutrophils that were obtained from healthy individuals and from patients with SLE. In addition, apoptotic cellular systems were assessed in vitro. Results. C1q appeared to colocalize to apoptotic blebs on the surface of leukocytes in association with both calreticulin and CD91, as determined by phage display and transfected cell studies. However, C1q did not bind to apoptotic cells isolated from SLE patients, despite the positivity of the cells for both calreticulin and CD91. Surface expression of calreticulin decreased on neutrophils as they aged, but increased on monocytes. In an apoptotic phagocytic assay, the addition of C1q and calreticulin significantly enhanced the phagocytosis of apoptotic cell debris by monocyte-derived cells. Conclusion. These observations indicate that neutrophils from SLE patients have a reduced ability to be recognized and removed by the C1q/calretictilin/CD91-mediated apoptotic pathway, despite the presence of main apoptotic recognition partners. This suggests that an additional component, as yet unidentified, acts as a C1q binding partner on apoptotic cells, and this component may be lacking in cells isolated from SLE patients.
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页码:1543 / 1556
页数:14
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