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Abstract Number: 664

The Pathogenesis of Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Brain Intrinsic Factors

Ariel Stock1, Jing Wen2, Jessica Doerner2 and Chaim Putterman3, 1Albert Einstein College of Medicine, Bronx, NY, 2Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 3Rheumatology, Albert Einstein College of Medicine, Bronx, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Lupus, SLE and neuropsychiatric disorders

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Session Information

Session Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Neuropsychiatric disease is a common manifestation of systemic lupus erythematosus (SLE). Frequent presentations include depression, anxiety, memory loss and cognitive decline. The pathogenesis of neuropsychiatric SLE (NPSLE), however, remains unclear; several potential mechanisms include thrombosis, complement deposition, brain reactive autoantibodies, and cytokine mediated inflammation. The MRL-faslpr/lpr (MRL/lpr) mouse has proven quite valuable to the study of SLE in general, including NPSLE. This is due to development of a disease profile similar to humans including renal and cutaneous manifestations, as well as an early neuropsychiatric phenotype characterized by depression and spatial memory deficit. However, it is not clear whether the neuropsychiatric manifestations of SLE are secondary to systemic disease or a primary pathogenic process.

Methods: In order to distinguish between the relative contributions of the central nervous system (CNS) vs hematopoietic compartments, we generated three groups of bone marrow chimeras between MRL/lpr mice and the congenic control MRL/+ mouse (Table 1). We monitored systemic disease progression through titers of autoantibodies and levels of proteinuria. The mice underwent extensive behavioral testing to characterize their motor, cognitive and emotional states, including open field, object placement, object recognition and the forced swim tests.

Results: MRL/lpràMRL/lpr mice showed increasing autoantibody titers over time, consistent with untransplanted MRL/lpr mice. MRL/+àMRL/+ mice showed consistently low or undetectable levels of autoantibodies. MRL/+àMRL/lpr mice showed early increases in autoantibody titers that decreased over time, indicative of MRL/+ bone marrow engraftment and abrogation of the MRL/lpr systemic disease phenotype. Behaviorally, MRL/+àMRL/lpr mice displayed a phenotype remarkably consistent with MRL/lpràMRL/lpr (as well as untransplanted MRL/lpr) mice, including depression like behavior (Fig 1) and increased spatial memory deficits. MRL/+àMRL/+ mice displayed no behavioral deficits, consistent with untransplanted MRL/+ mice.

Conclusion: Previous studies have shown that MRL/lpr mice develop neuropsychiatric disease similar to human lupus, though have not determined whether this is a primary CNS manifestation or secondary to peripheral immune abnormalities and systemic disease. The data presented herein indicate that the MRL/lpr CNS is responsible for NPSLE development, which can occur absent hematopoietic contributions.

Donor

Host

Chimera

Source of CNS Cells

Source of Hematopoeitic Cells

MRL/+

MRL/+

MRL/+→MRL/+

MRL/+

MRL/+

MRL/lpr

MRL/lpr

MRL/lpr→MRL/lpr

MRL/lpr

MRL/lpr

MRL/+

MRL/lpr

MRL/+→MRL/lpr

MRL/lpr

MRL/+

Table 1. Bone marrow transplant scheme.


Disclosure:

A. Stock,
None;

J. Wen,
None;

J. Doerner,
None;

C. Putterman,
None.

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