Absence of functional alternative complement pathway alleviates lupus cerebritis
Copyright policy )Absence of functional alternative complement pathway alleviates lupus cerebritis
AbstractThe complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ‐Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB‐deficient (fB–/–MRL/lpr) compared to fB‐sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase‐3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)‐Akt (0.16 ± 0.02 vs. 0.35 ± 0.13, p <0.03) was increased, while expression of p‐PTEN (0.40 ± 0.06 vs. 0.11 ± 0.07, p <0.05) was decreased in fB–/–MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB–/–MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.
- Hollings Cancer Center United States
- VA Southeast Network United States
- University of Chicago United States
- Ralph H Johnson VA Medical Center United States
- Medical University of South Carolina United States
Brain Chemistry, Cerebral Cortex, Mice, Knockout, Extracellular Matrix Proteins, Mice, Inbred MRL lpr, Behavior, Animal, Caspase 3, Complement Pathway, Alternative, Lupus Vasculitis, Central Nervous System, Brain, Gene Expression, Apoptosis, Antigen-Antibody Complex, Complement C3, Hippocampus, Mice, Complement C3d, Immunoglobulin G, Animals, Complement Factor B
Brain Chemistry, Cerebral Cortex, Mice, Knockout, Extracellular Matrix Proteins, Mice, Inbred MRL lpr, Behavior, Animal, Caspase 3, Complement Pathway, Alternative, Lupus Vasculitis, Central Nervous System, Brain, Gene Expression, Apoptosis, Antigen-Antibody Complex, Complement C3, Hippocampus, Mice, Complement C3d, Immunoglobulin G, Animals, Complement Factor B
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