Complement activated C4d immunoreactive oligodendrocytes delineate small cortical plaques in multiple sclerosis.
C4d-immunoreactive complement-activated oligodendrocytes (C4d-CAOs) have been described in several neurodegenerative diseases but have not been studied in multiple sclerosis (MS). Here we report that such CAOs delineate miniature MS plaques of 300-500 mum diameter. They are devoid of myelin and are surrounded by a rim of activated microglia intermingled with the C4d-CAOs. Although C4d-immunostained periaxonal oligodendroglial processes are often swollen, the axons of passage appear undamaged and extend through the demyelinated plaque area. No immunostaining with other components of the complement cascade (C1q-C9) was observed in association with these miniature plaques. However, in large MS lesions, C1q-C9 immunoreactive fibers were present, indicating complete activation of the complement cascade in these more developed lesions. It is possible that the miniature plaques, bordered by C4d-CAOs, represent the earliest stage of plaque development, preceding even the larger, transient plaques frequently observed in serial MRI studies. The association of CAOs with miniature areas of demyelination suggests a direct attack on oligodendroglial cells by the early complement components as an initiating event in MS. Incomplete complement activation indicates that this step may be reversible, whereas full and persistent activation as observed in large MS lesions may lead to death of oligodendroglia with permanent axonal damage.
Schwab
Claudia
C
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
McGeer
Patrick L
PL
D000368:Aged; D000369:Aged, 80 and over; D002540:Cerebral Cortex / Q000473:pathology*; D003181:Complement C4 / Q000096:biosynthesis*; D015935:Complement C4b; D003165:Complement System Proteins / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000473:pathology; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis*; D013494:Supranuclear Palsy, Progressive / Q000473:pathology
D003181:Complement C4; D006684:HLA-DR Antigens; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d; D003165:Complement System Proteins