Effects of conventional immunosuppressive therapy on functional and pathological features of CNS lupus in NZB/W mice

Jessy Alexander,Alexander Jacob,Richard J Quigg

doi:10.12688/f1000research.6568.1

Abstract

Neurological involvement is one of the most devastating complications of the disease, systemic lupus erythematosus (SLE). To understand the effect of the drugs, cyclophosphamide (CY) and prednisolone (PD) on CNS manifestations, the New Zealand Black/White (NZB/W) lupus mice, were given a cocktail of both drugs by intraperitoneal injections daily from 22 to 44 weeks of age. The treatment prolonged survival (10% of the treated 20 NZB/W mice died compared to 50% of the 30 NZB/W mice, with no mortality in the control NZW mice). Real-time PCR analysis showed a three- to fifteen-fold increase in the expression of GFAP, vimentin and syndecan4 in the cerebral cortex of 44 week NZB/W mice. These alterations were prevented by CY and PD treatment. Immunostaining revealed increased GFAP expression in NZB/W mice compared to congenic, nondiseased NZW mice, which was prevented by treatment. In addition, concomitant changes were observed in the expression of extracellular matrix proteins, collagen IV and fibronectin. To determine the impact of these alterations on the neurological manifestations of SLE, behavior was studied in these mice. The NZB/W mice were spontaneously less active in the open field and exhibited a decrease in distance traveled (58% of control, p<0.01) and ambulatory measurements (52% of control, p<0.01). They took more time (8.8+1.2min) to escape from the maze compared to the control NZW mice (2.6+0.8min). Even more striking was that the behavioral deficits were alleviated in these mice by CY and PD treatment. These results support the hypothesis that increased astrogliosis and altered extracellular matrix proteins may be two of the critical factors that mediate lupus brain disease.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disease in which one third of patients exhibit neuropsychiatric (NP) disturbances
Our studies show that alterations in gliosis and extracellular matrix proteins tracked with behavioral changes in New Zealand Black/White (NZB/W) mice, both of which were ameliorated by CY/PD treatment
As expected in the setting of an autoimmune disease, IgG deposits were significantly increased in NZB/W lupus mice compared to the NZW controls, which was prevented by CY and PD treatment

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease in which one third of patients exhibit neuropsychiatric (NP) disturbances. Patients with NP-SLE have a variety of behavioral and cognitive impairments[1,2,3]. These are likely to track with pathological alterations occur in the brain, subtle. The most accurate SLE model occurs in females of the F1 cross between New Zealand Black and New Zealand White mice (NZB/W)[4,5]. Among the finest examples of translational research occurred over a several decade period in work done at the National Institutes of Health by Alfred Steinberg, James Balow and colleagues; they first showed cyclophosphamide (CY) and methylprednisolone (PD) were efficacious in NZB/W mice[6,7], followed by clinical studies in human SLE8 with this therapy remaining the “gold standard” by which all else is compared

Methods

Results

Conclusion