Review
Neuroimmunopathology in a murine model of neuropsychiatric lupus

https://doi.org/10.1016/j.brainresrev.2006.12.003Get rights and content

Abstract

Animal models are extremely useful tools in defining pathogenesis and treatment of human disease. For many years researchers believed that structural damage to the brain of neuropsychiatric (NP) patients lead to abnormal mental function, but this possibility was not extensively explored until recently. Imaging studies of NP-systemic lupus erythematosus (SLE) support the notion that brain cell death accounts for the emergence of neurologic and psychiatric symptoms, and evidence suggests that it is an autoimmunity-induced brain disorder characterized by profound metabolic alterations and progressive neuronal loss. While there are a number of murine models of SLE, this article reviews recent literature on the immunological connections to neurodegeneration and behavioral dysfunction in the Fas-deficient MRL model of NP-SLE. Probable links between spontaneous peripheral immune activation, the subsequent central autoimmune/inflammatory responses in MRL/MpJ-Tnfrsf6lpr (MRL–lpr) mice and the sequential mode of events leading to Fas-independent neurodegenerative autoimmune-induced encephalitis will be reviewed. The role of hormones, alternative mechanisms of cell death, the impact of central dopaminergic degeneration on behavior, and germinal layer lesions on developmental/regenerative capacity of MRL–lpr brains will also be explored. This model can provide direction for future therapeutic interventions in patients with this complex neuroimmunological syndrome.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune/inflammatory disease with a broad spectrum of clinical and immunological manifestations (Isenberg et al., 1989). Neurologic and psychiatric (NP) manifestations of unknown etiology are common in SLE and have been proposed to represent a more severe form of the disease, occurring in up to 75% of patients (Scolding and Joseph, 2002, Navarrete and Brey, 2000, Hanly, 2001, Bluestein, 1992, Adelman et al., 1986, Mcnicholl et al., 1994). The manifestations of NP-SLE range from diffuse CNS disorders (i.e. acute confusional state, psychosis, anxiety and depressive disorders, clinical to subclinical cognitive disorder of variable functional significance) to CNS syndromes (i.e. seizures, cerebrovascular disease, chorea and myelopathy, transverse myelitis, demyelinating syndrome and aseptic meningitis, headaches) and PNS disorders (i.e. polyneuropathies and mononeuropathies, autonomic disorders, plexopathy, myasthenia gravis) (Tincani et al., 1996). Approximately 40% of the NP-SLE manifestations develop before the onset of SLE or at the time of diagnosis and about 60% within the first year after diagnosis (van Dam, 1991). While a histologically normal brain with no specific pathognomonic brain lesions is a possible finding in NP-SLE, various abnormalities include hypoperfusion (Colamussi et al., 1995, Handa et al., 2003, Huang et al., 2002, Lopez-Longo et al., 2003) and regional metabolic abnormalities (Komatsu et al., 1999, Sibbitt and Sibbitt, 1993, Brooks et al., 1997, Volkow et al., 1988). Brain atrophy, however, is the most frequent observation on CT scans (Gonzalez-Scarano et al., 1979, Kaell et al., 1986, Miguel et al., 1994, Omdal et al., 1989, Ainiala et al., 2005, Waterloo et al., 1999) and is proposed to reflect widespread and progressive neuronal loss (Sibbitt and Sibbitt, 1993, Sibbitt et al., 1994).

Research has helped to distinguish the role of autoimmune disease as the primary factor inducing NP-SLE, apart from complications of kidney damage, infections, and steroid therapy. Autoantibodies in the serum and cerebrospinal fluid (CSF) of lupus patients have been proposed as an important factor in the etiology of CNS damage (Jennekens and Kater, 2002). Increased intrathecal synthesis (as revealed by an elevated IgG index and oligoclonal banding) in patients with CNS dysfunction (McLean et al., 1995, Hirohata et al., 1985, Winfield et al., 1983) and antigen-specific autoantibodies in the CSF (Yoshio et al., 2005) are associated with NP manifestations (Greenwood et al., 2002). For example, evidence suggests that neuronal antibodies are involved in the pathogenesis of psychiatric disease (Quismorio and Friou, 1972, Vincent et al., 2003, Diederichsen and Pyndt, 1970, Bluestein and Zvaifler, 1983), and parenchymal lesions associated with movement disorder have recently been documented in these patients (Rocca et al., 2006), supporting the link between autoimmunity, neuronal death, and neurologic manifestations. In many cases however, the correlational nature of clinical data has lead to the necessity for animal models. Using animal models, interactions between autoimmune/inflammatory phenomena and brain function can be examined in a more systematic and direct way. Several animal models develop a fatal immune complex-mediated glomerulonephritis associated with immunological abnormalities (i.e. autoantibody production) very similar to the salient features of human SLE (Theofilopoulos, 1992). The existence of murine models for this disease (both induced and spontaneous) have been extremely valuable to researchers in evaluating the various behavioral manifestations and autoimmune abnormalities which present in this syndrome.

The most commonly studied spontaneous models of lupus include the (NZB × NZW)F1(BWF1) hybrid, BXSB, and MRL mice. These strains are characterized by a wide spectrum of autoimmune manifestations (Dixon et al., 1978) and share common characteristics such as hypergammaglobulinemia and antinuclear antibodies (ANA). However, no animal model is a pure representation of an entire clinical syndrome, and each strain has distinct features which make them beneficial for examining certain aspects of disease (Dixon et al., 1978, Andrews et al., 1978). Considering that the NZB and BXSB strains of mice have a high incidence of inherited brain anomalies (Sherman et al., 1990) which can confound the assessment of autoimmunity-induced brain damage and the links between lupus-like disease and behavioral changes, the MRL model permits the examination of interrelationships between systemic autoimmunity, brain pathology, and aberrant behavior in a more controlled manner. Due to profound deficits in behavior, which appear at a high frequency during the onset of spontaneous CNS-lupus-like disease in MRL/MpJ-Tnfrsf6lpr (MRL–lpr) mice (Szechtman et al., 1997, Sakic et al., 1997), this review focuses on the validity of the MRL model in exploring organic causes of NP manifestations in SLE.

When studied together, MRL–lpr and MRL/MpJ+/+ (MRL+/+) congenic mice (sharing > 99.9% of their genome) are considered to be a natural, well controlled model of NP-SLE (Sakic et al., 1997). These substrains are comparable in many respects (appearance, size and reproductive age), except in the onset of autoimmunity and neurobehavioral dysfunctions. While MRL–lpr mice have rapid onset of disease beginning around 7 weeks of age, MRL+/+ controls develop milder symptoms much later in life (Theofilopoulos, 1992). A mutation of a single autosomal recessive gene, designated lymphopoliferation (lpr), on chromosome 19 results in massive lymphoadenopathy, induced by the accumulation of abnormal T-lymphocytes in the MRL–lpr strain (Theofilopoulos, 1992). There is also a spontaneous loss-of-function mutation in Fas (Nagata, 1994) which leads to a deficit in apoptotic Fas receptor expression in MRL–lpr animals (Nagata, 1994, Singer et al., 1994). The main function of Fas is to bind to its ligand (FasL), and transduce signals leading to cell death (Nagata and Suda, 1995). Similar to various CNS cell death mechanisms and compensatory processes, the pathogenic etiology of behavioral deficits in this model of NP-SLE appears to be multi-factorial. Therefore, this review article examines the interplay between underlying genetics, autoimmunity and inflammation, hormones, and a number of secondary factors leading to nervous tissue injury, death and behavioral dysfunction in MRL–lpr mice.

Section snippets

Prelude to CNS damage: disruption of the blood–brain barrier

The blood–brain barrier (BBB) is formed by brain capillary endothelial cells that line cerebral microvessels and has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling in the CNS (Abbott et al., 2006). Some chronic neuropathologies may involve an early phase of BBB disturbance preceding neuron damage, which suggests that vascular damage can lead to secondary neuronal disorder (Minagar and Alexander, 2003). For example, autoantibodies may

Evidence of neuroinflammation in CNS disease

Recently, the role of neuroinflammation is emerging as an important component in lupus-like disease. It has been documented that there is an age-related increase in the frequency of T-cells and perivascular leakage of IgG around brain vessels (Vogelweid et al., 1991), upregulation of adhesion molecules (McHale et al., 1999, Zameer and Hoffman, 2003), the expression of mRNA for pro-inflammatory cytokines (Tomita et al., 2001a, Tomita et al., 2001b), and deposition of complement proteins (

Evidence of neuronal death and impaired brain growth/atrophy

The MRL strain does not show a high incidence of inherited neuroanatomical abnormalities (Sherman et al., 1987) which minimize the possibility of congenital defects confounding the study of disease-induced neurodegeneration. At the onset of autoimmune symptoms in MRL–lpr mice, reports of reduced complexity of pyramidal neurons, reduced brain weights (Sakic et al., 1998b), and selectively neurotoxic CSF (Maric et al., 2001) provided indirect evidence of neuronal damage in diseased animals.

Stress-like behavior is associated with autoimmune disease

The onset and progression of disease in MRL–lpr mice parallels the emergence of aberrant stress-like behaviors (Szechtman et al., 1997). The nature of this autoimmune-associated behavioral syndrome (AABS) suggests a progressive anxious- and depressive-like state (and differences in emotionality), as indicated by increased thigmotaxic behavior, impaired exploration of novel objects and spaces, performance deficits in the plus-maze and step-down tests, excessive floating in the forced swim test

Corticosteroids: the permissive factor for cell death?

Similar to chronic cerebral ischemia, corticosteroid therapy has been linked to cerebral atrophy (Ainiala et al., 2005) and cognitive decline often documented in NP-SLE patients (Yamauchi et al., 1994, Chinn et al., 1997). Similar to the effects of chronic stress, NP-lupus mice show brain atrophy and deficits in cognition at the onset of disease (Sakic et al., 1993b, Sakic et al., 1998b, Ballok et al., 2004b). In addition to the peripheral dysregulation of glucocorticoids, studies have also

Behavioral consequences of CNS damage

Clinical studies have reported that NP manifestations are accompanied by cerebral atrophy (Chinn et al., 1997), progressive neuronal loss (Brooks et al., 1997, Sibbitt and Sibbitt, 1993), and parenchymal lesions associated with movement disorder (Rocca et al., 2006). In MRL–lpr mice, despite parallels between the emergence of behavioral dysfunction and systemic autoimmunity, there has been no direct evidence that brain pathology can account for aberrant behavior. Recently, the phenomena and

Possible mechanisms and targets of brain cell death

The well-characterized apoptotic pathway defect in MRL–lpr mice has lead to much speculation as to which compensatory processes most likely predominate in CNS disease. One consequence of impaired apoptotic mechanisms may be the accumulation of unwanted proteins which often underlie the pathogenesis of several major human neurodegenerative diseases. For example, as a result of defective ubiquitin-dependent proteolysis, neurodegeneration can occur (Layfield et al., 2001). Indeed, the

Conclusions and future perspectives

Neurodegenerative disorders are characterized by a gradual and relentlessly progressive neuronal loss that is often selective in that it occurs in anatomically and physiologically related brain areas. Progressive neuronal death and microglial activation are concomitant with the onset and development of systemic autoimmune/inflammatory disease and behavioral deficits in the MRL–lpr model of NP-SLE. The initial role of corticosterone appears to be important in SLE-like disease given that

Acknowledgments

This work was supported by the doctoral research award grant MOP 38065 from the Canadian Institutes of Health Research (CIHR) awarded to D.A. Ballok.

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