title: Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus.
abstract: 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.
  
  
  CONCLUSIONS
  These observations indicate that neutrophils from SLE patients have a reduced ability to be recognized and removed by the C1q/calreticulin/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.
authors.affiliation: John Radcliffe Hospital and University of Oxford, Oxford, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Donnelly
authors.forename: Wendy
authors.initials: W
authors.lastname: Roake
authors.forename: Simon
authors.initials: S
authors.lastname: Brown
authors.forename: Philip
authors.initials: P
authors.lastname: Young
authors.forename: Haley
authors.initials: H
authors.lastname: Naik
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
authors.forename: Kenneth B M
authors.initials: KB
authors.lastname: Reid
authors.forename: Paul
authors.initials: P
authors.lastname: Eggleton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis; D037282:Calreticulin / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D037282:Calreticulin; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1