Absence of functional alternative complement pathway alleviates lupus cerebritis

Eur J Immunol. 2007 Jun;37(6):1691-701. doi: 10.1002/eji.200636638.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen-Antibody Complex / analysis
  • Antigen-Antibody Complex / immunology
  • Apoptosis / immunology
  • Behavior, Animal
  • Brain / immunology
  • Brain / metabolism
  • Brain / pathology
  • Brain Chemistry
  • Caspase 3 / metabolism
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Complement C3 / analysis
  • Complement C3 / immunology
  • Complement C3d / analysis
  • Complement C3d / immunology
  • Complement Factor B / genetics
  • Complement Factor B / metabolism*
  • Complement Pathway, Alternative / genetics
  • Complement Pathway, Alternative / immunology*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression
  • Hippocampus / chemistry
  • Hippocampus / immunology
  • Hippocampus / pathology
  • Immunoglobulin G / analysis
  • Immunoglobulin G / immunology
  • Lupus Vasculitis, Central Nervous System / immunology*
  • Lupus Vasculitis, Central Nervous System / pathology
  • Mice
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Neutrophil Infiltration / immunology
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • Antigen-Antibody Complex
  • Complement C3
  • Extracellular Matrix Proteins
  • Immunoglobulin G
  • Complement C3d
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Complement Factor B
  • Caspase 3