Journal ArticleDOI
Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus.
Suzanne Donnelly,Wendy Roake,Simon Brown,Philip J. Young,Haley B. Naik,Paul Wordsworth,David A. Isenberg,Kenneth B.M. Reid,Paul Eggleton +8 more
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TLDR
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.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.
Conclusion
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.read more
Citations
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Journal ArticleDOI
Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum
TL;DR: Calreticulin has been implicated to play a role in many biological systems, including functions inside and outside the ER, indicating that the protein is a multi-process molecule.
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The role of defective clearance of apoptotic cells in systemic autoimmunity
TL;DR: The accumulation of postapoptotic remnants and fragments derived from secondary necrotic cells in the presence of autoantibodies against apoptotic cells or adaptor molecules obliges their pathological elimination and maintains autoinflammation.
Journal ArticleDOI
Calreticulin: non-endoplasmic reticulum functions in physiology and disease
Leslie Gold,Paul Eggleton,Mariya T. Sweetwyne,Lauren B. Van Duyn,Matthew R. Greives,Sara Megumi Naylor,Marek Michalak,Joanne E. Murphy-Ullrich +7 more
TL;DR: It has become clear that CRT is a multicompartmental protein that regulates a wide array of cellular responses important in physiological and pathological processes, such as wound healing, the immune response, fibrosis, and cancer.
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Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.
Sabina Sangaletti,Claudio Tripodo,Claudia Chiodoni,Carla Guarnotta,Barbara Cappetti,Patrizia Casalini,Silvia Piconese,Mariella Parenza,Cristiana Guiducci,Caterina Vitali,Mario P. Colombo +10 more
TL;DR: It is shown that myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity when injected into naive mice, providing the first demonstration that NET structures are highly immunogenic such to trigger adaptive immune response relevant for autoIMmunity.
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Clearance of apoptotic and necrotic cells and its immunological consequences
TL;DR: Recent findings on genetic pathways participating in apoptotic cell clearance, mechanisms of internalization, and molecules involved in engulfment of apoptotic versus necrotic cells are reviewed, as well as their immunological consequences and relationships to disease pathogenesis.
References
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Journal ArticleDOI
The 1982 revised criteria for the classification of systemic lupus erythematosus
Eng M. Tan,Alan S. Cohen,James F. Fries,Alfonse T. Masi,Dennis J. McShane,Naomi F. Rothfield,Jane G. Schaller,Norman Talal,Robert Winchester +8 more
TL;DR: The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification and showed gains in sensitivity and specificity.
Journal ArticleDOI
Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.
Seamus J. Martin,Chris P. M. Reutelingsperger,A J McGahon,J. A. Rader,R. C. A. A. Van Schie,Drake LaFace,Douglas R. Green +6 more
TL;DR: It is shown that PS externalization is an early and widespread event during apoptosis of a variety of murine and human cell types, regardless of the initiating stimulus, and precedes several other events normally associated with this mode of cell death.
Journal ArticleDOI
Corpse clearance defines the meaning of cell death
John Savill,Valerie A. Fadok +1 more
TL;DR: Appoptosis marks unwanted cells with 'eat me' signals that direct recognition, engulfment and degradation by phagocytes allow scavenger cells to confer meaning upon cell death.
Journal ArticleDOI
Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.
John Savill,Andrew H. Wyllie,Janet E. Henson,Mark Walport,Peter M. Henson,Christopher Haslett +5 more
TL;DR: Changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation, and these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.
Journal ArticleDOI
C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells
Carol Anne Ogden,Aimee deCathelineau,Peter R. Hoffmann,Donna L. Bratton,Berhane Ghebrehiwet,Valerie A. Fadok,Peter M. Henson +6 more
TL;DR: Evidence is provided that C1q and mannose binding lectin (MBL), a member of the collectin family of proteins, bind to apoptotic cells and stimulate ingestion of these by ligation on the phagocyte surface of the multifunctional protein, calreticulin.
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