Hippocampal damage in mouse and human forms of systemic autoimmune disease.
Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJB-positive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada.
David A
DA
Ballok
John
J
Woulfe
Monalisa
M
Sur
Michael
M
Cyr
Boris
B
Sakic
D000375:Aging / Q000378:metabolism; D000818:Animals; D002831:Choroid Plexus / Q000473:pathology / Q000503:physiopathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005911:Gliosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007859:Learning Disabilities / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008875:Middle Aged; D009410:Nerve Degeneration / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology; D009930:Organic Chemicals; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D005452:Fluoresceins; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D009930:Organic Chemicals; D019014:fas Receptor; C435731:fluoro jade; D003520:Cyclophosphamide