Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease.
Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented.
Sakic
Boris
B
Department of Psychiatry and Behavioural Neurosciences, HSC Rm 4N81, McMaster University, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
Kirkham
David L
DL
Ballok
David A
DA
Mwanjewe
James
J
Fearon
Ian M
IM
Macri
Joseph
J
Yu
Guanhua
G
Sidor
Michelle M
MM
Denburg
Judah A
JA
Szechtman
Henry
H
Lau
Jonathan
J
Ball
Alexander K
AK
Doering
Laurie C
LC
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D034961:Antigens, Nuclear / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D002308:Cardiolipins / Q000276:immunology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000502:physiology*; D003952:Diagnostic Imaging / Q000379:methods; D019075:Electrophoresis, Capillary / Q000379:methods; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005260:Female; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000134:cerebrospinal fluid / Q000473:pathology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000134:cerebrospinal fluid; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009929:Organ Size / Q000502:physiology; D009930:Organic Chemicals / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors
D034961:Antigens, Nuclear; D001323:Autoantibodies; D002308:Cardiolipins; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D009930:Organic Chemicals; C435731:fluoro jade