Absence of functional alternative complement pathway alleviates lupus cerebritis.
The 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.
Alexander
Jessy J
JJ
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Jacob
Alexander
A
Vezina
Paul
P
Sekine
Hideharu
H
Gilkeson
Gary S
GS
Quigg
Richard J
RJ
D000818:Animals; D000936:Antigen-Antibody Complex / Q000032:analysis / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001522:Behavior, Animal; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D015933:Complement C3d / Q000032:analysis / Q000276:immunology; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis / Q000276:immunology; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000936:Antigen-Antibody Complex; D003176:Complement C3; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D015933:Complement C3d; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D011415:Complement Factor B; D053148:Caspase 3