Abstract
BackgroundSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors.MethodsTo dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6lpr/lpr mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment.ResultsDespite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity.ConclusionsChimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity.
Highlights
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain
These results strongly suggest, that any development and/or persistence of an neuropsychiatric SLE (NPSLE) phenotype in MRL/+ → MRL/Tnfrsf6lpr/ lpr (MRL/lpr) chimeric mice would less likely be attributable to systemic immune abnormalities
Since we found that MRL/+ → MRL/lpr mice did not have elevated serum autoantibody titers while still exhibiting robust neuropsychiatric disease, it appears that a sustained serum autoantibody response is not strictly required for the initiation or maintenance of a spontaneous NPSLE phenotype
Summary
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors. Treatment of NPSLE has traditionally focused on systemic immune suppression and Central NPLSE manifestations can be broadly categorized into two major groups: focal presentations resulting predominately from cerebrovascular disease and diffuse disorders consisting of depression, memory loss, and cognitive decline. Systemic humoral factors may be responsible for diffuse NPSLE presentations. These include anti-N-methyl-D-aspartate receptor (NMDAR) antibodies [5], anti-ribosomal-
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