systemic lupus erythematosus ( sle ) is an autoimmune disease that is typified by multiple abnormalities of the immune system , and which results in widespread pathology of multiple organs , including skin , kidney , heart , lungs , and joints . in addition to peripheral organ dysfunction in sle , there is a high incidence of neuropsychiatric symptoms especially headaches , cognitive dysfunction , and psychiatric disorders , with roughly 4070% of sle patients demonstrating affective disorders . brain pathology , loss of integrity of the blood - brain barrier and autoantibodies are thought to play a role in neuropsychiatric systemic lupus erythematosus ( np - sle ) , although some patients with behavioral symptoms have histologically normal brain tissue and no identifiable markers in serum or csf [ 311 ] . neuropsychiatric symptoms , particularly affective disorders , may be among some of the earliest manifestations of sle [ 1214 ] . approximately 40% of the np - sle symptoms develop before the onset of sle or at the time of diagnosis and about 60% within the first year of diagnosis [ 13 , 15 , 16 ] , indicating that neuropsychiatric symptoms are reliable indicators of disease activity and are often evident even before gross peripheral organ pathology occurs ( in particular kidney disease ) . symptoms of np - sle may also be independent of active disease in other organs [ 1719 ] . this was found to be the case also in the animal model of lupus which is the subject of this paper , the mrl / lpr mouse , where depressive - like behavior is evident in young animals before significant levels of autoantibody titers and nephritis are evident [ 14 , 20 ] . there are obvious limits to the search for mechanisms of cns disease in human patients , and furthermore the diagnosis is often made after lupus is in late stages of progression . thus , murine models can offer many advantages to elucidate the early mechanisms of neuropsychiatric manifestations of np - sle and help to distinguish between cns - specific mechanisms and nonspecific illness . in this paper we focus on a specific murine model of lupus , the mrl / lpr strain , and the ways in which this model reflects some of the most common manifestations of human np - sle . in addition , we discuss experimental data pointing to viable pathogenic mechanisms that underlie cns involvement in sle . excellent reviews about other aspects of this and other murine models of lupus can be found elsewhere [ 3 , 11 , 2134 ] . to best represent human disease and explore relevant translational aspects of pathogenesis and novel treatment approaches , it is crucial to identify the most appropriate animal model from among the several available mouse strains which spontaneously develop lupus - like disease . although there are induced models of sle in nonautoimmune mouse strains , organ involvement as a rule is less severe than that observed in genetically susceptible animals [ 35 , 36 ] . therefore , spontaneous lupus models are often preferred for modeling of lupus - associated neuropsychiatric or other target organ disease . murine models that spontaneously develop hallmark diagnostic signs of sle include nzb  nzw f1 , nzm2410 , bxsb , and mrl / lpr mouse strains . all of these strains ( to a varying degree ) develop lymphoid hyperplasia , b cell hyperactivity , autoantibodies , circulating immune complexes , complement consumption , and glomerulonephritis . these strains differ from human sle in that they display a high penetrance and relatively uniform disease expression over time . however , the disease course in murine lupus models ( in the absence of extraneous intervention ) is progressive , in contrast to the fluctuating course of flares and remissions typical in human sle [ 26 , 27 , 37 ] . although many of the spontaneous models of sle develop behavioral abnormalities at some point in the disease , the mrl mouse model has some advantages in the investigation of specific cns dysfunction and np - sle . first , nzb- and bxsb - derived strains of mice have a high incidence of inherited brain anomalies   which can confound the assessment of autoimmunity - induced brain damage and the links between lupus - like disease and behavioral changes . thus the mrl / lpr model permits the examination of interrelationships between behavioral outcomes and their underlying mechanisms without the potential confound of pre - existing cns abnormalities [ 3840 ] . as human sle is overwhelmingly more common in females ( about a 9  :  1 female to male ratio ) , mouse models that reflect this sex bias , such as mrl / lpr , are also likely to be useful in elucidating the relationship of hormones , negative outcomes , and potential sex - differences in efficacy of therapeutic agents in autoimmune disease . mrl / lpr mice   also express cardiolipin autoantibodies , one of a class of antiphospholipid autoantibodies thought to be important in the development of behavioral outcomes and cns damage [ 4345 ] . although the molecular defect in the fas gene underlying abnormal b cell regulation in mrl / lpr mice is not believed to be a cause for human sle [ 46 , 47 ] , it is clear that the b cell dysregulation that characterizes this murine model is also a critical pathological aspect of human sle [ 48 , 49 ] . moreover , the early onset , rapid progression , and other similarities to the human disease state in mrl / lpr mice are also useful features of this model . the mrl lymphoproliferation strain ( lpr ) mrl / tnfrsf6 lpr / lpr ( a.k.a . mrl / lpr ) differs from the congenic ( control ) mrl/+ strain by a defect in membrane apoptotic - signaling fas protein , which is due to a retrotransposon in the fas gene [ 50 , 51 ] . in addition to the typical signs of peripheral sle , including autoantibodies , skin disease , arthritis , lymphadenopathy , and nephritis , mrl / lpr mice develop a constellation of behavioral outcomes referred to as  autoimmunity - associated behavioral syndrome  , particularly in the behavioral domains of emotional reactivity , motivated behavior , and cognitive function [ 14 , 20 , 22 , 24 , 33 , 5275 ] . nervous system involvement in lupus can include seizures , stroke and other cerebrovascular events , psychosis , cognitive dysfunction , and notably a very high incidence of mood disorders , particularly anxiety and depression [ 2 , 18 , 7678 ] . estimations of the prevalence of np - sle in human lupus range from 15% to 75% ( or higher ) , reflecting variable diagnostic methodologies , a lack of standard criteria , and the sensitivity of diagnostic instruments to assess various behavioral outcomes [ 1 , 2 , 79 ] . furthermore , many clinical studies of np - sle address only the most severe cns symptoms , such as seizure , psychosis , and stroke , thus both the prevalence and importance of other neuropsychiatric symptoms are often underestimated . generally , when specific and well - validated cognitive and affective diagnostic batteries are administered , rather than simple quality of life exams , studies consistently indicate that a great majority of sle patients have some cns outcomes , particularly mood disorders and cognitive dysfunction . np - sle is a major determinant of morbidity and mortality and is associated with increased disease severity , poorer prognosis and earlier mortality [ 8085 ] . furthermore , np - sle can necessitate potent and long - term immunosuppressive treatment with attendant side effects , is a detriment to quality of life in lupus patients , may be a major factor in employment disability , and substantially increases the financial and emotional costs of sle [ 86 , 87 ] . comprehensive reviews of np - sle manifestations , diagnosis , pathology , and treatment in humans are outside the scope of the paper , and can be found elsewhere [ 2 , 4 , 9 , 8894 ] . as in humans , development of sle in mrl / lpr mice the most robust and reproducible deficits in mrl / lpr mice are emotional dysfunction , particularly in assays of depressive - like behavior such as the forced swim test and anhedonia . the forced swim test [ 95 , 96 ] assesses behavioral despair as the proportion of immobility when rodents are placed in a tank of water [ 97 , 98 ] . normal rodents placed in a narrow tank of water from which there is no escape will exhibit vigorous swimming and struggling activity for the duration of the test ( typically 612 minutes ) and only rarely adopt a characteristic immobile posture ( floating ) . in contrast , animals treated with either pharmacological agents ( such as hormones or via depletion of the amino acid tryptophan necessary to make serotonin [ 99 , 100 ] ) , environmental manipulations ( unpredictable chronic stress , social isolation [ 101103 ] ) , or genetic alterations ( flinders strain , sert knockouts [ 104 , 105 ] ) thought to be important in the etiology of depression more rapidly become immobile and maintain this immobility for a significantly great proportion of time than control subjects . the forced swim test has been extensively validated , as immobility is reduced by a wide range of clinically active antidepressant drugs   and has predicted the antidepressant efficacy of novel therapeutic agents . mrl / lpr mice develop depression - like behavior in the forced swim test as early as 5 weeks old , and this persists throughout the course of the disease [ 14 , 20 , 58 , 65 ] . in addition to feelings of helplessness and despair , depressed patients report anhedonia  the inability to experience pleasure or reward from events that normally have a positive hedonic value , such as eating , social interaction , or sexual activity . in rodents , a commonly used measure of anhedonia is the failure to prefer sweet solutions [ 107 , 108 ] . mrl / lpr mice exhibit this lack of normal preference for sweet solutions as early as 5 - 6 weeks old   and continue to exhibit anhedonia during the active disease phase ( 4 - 5 months old ) [ 52 , 53 , 55 , 109 ] . further symptoms of depression - like behavior include decreased activity , fatigue , and apathy . in rodents , this can be assessed as decreased voluntary activity and exploration in a novel environment , such as an open field . mrl / lpr mice exhibit reduced exploration and activity during both the nocturnal and diurnal phases [ 63 , 65 ] by 811 weeks old [ 14 , 33 ] .   despite the high prevalence of depression in lupus patients and recent evidence that antidepressants may reduce symptoms of depression , in part , by reducing inflammatory responses [ 111 , 112 ] , there have been few studies investigating the efficacy of antidepressant therapies in human lupus   or in murine models . immunosuppressive agents typically used to treat sle , such as cyclophosphamide and steroids , do reduce measures of depression - like behavior in mrl / lpr mice [ 33 , 55 , 59 , 114 ] and also typically reduce the other hallmarks of sle , including autoantibody titers , proteinuria ( nephritis ) , and the levels of proinflammatory cytokines [ 55 , 59 ] . however , there have been few systematic studies to determine if these are effective at reducing measures of np - sle , especially cognitive and affective dysfunction , in humans . several studies indicate that high levels of both affective and cognitive disorders are present and persistent in np - sle patients undergoing such therapies [ 115 , 116 ] , though these traditional immunosuppressive agents do seem to be effective to prevent and/or treat the more severe np - sle outcomes , such as seizure and cerebrovascular events [ 13 , 117 , 118 ] . anxiety disorders are also common in np - sle [ 1 , 119 ] and are often comorbid with depressive disorders . several commonly used methods can be applied to assess anxiety in rodents , and these include the elevated plus maze and the acoustic startle test [ 120127 ] . the elevated plus maze ( epm ) essentially assesses a preference between a comparatively safe environment ( the closed arms ) and a risky environment ( elevated open spaces ) . the general principle is that the more  anxious  the subjects are , the less likely they will be to explore the open arms . the epm has been validated pharmacologically , with other tests of anxiety - like behaviors , and physiologically [ 120123 ] . with respect to anxiety in murine models of lupus , some groups have reported increased anxiety in mrl / lpr mice assessed in the elevated plus maze , while others have reported that mrl / lpr mice have normal or less anxiety than mrl/+ controls [ 14 , 20 , 70 ] . the lack of anxiety phenotype is also supported by a generally lower startle reactivity till 11 weeks old . there is also no clear consensus with respect to cognitive dysfunction in murine models of lupus . mild spatial memory deficits have been reported in the water maze , assessed as the latency to find a new platform position after previous training in the water maze   and as deficits in linear maze acquisition as early as 8 weeks . however , behavior in the object placement and novel object recognition tasks [ 128130 ] is normal [ 14 , 20 ] . the predominance and reproducibility of affective dysfunction in mrl / lpr mice are consistent with known pathology and/or dysfunction in several neurotransmitter systems and brain regions important in the regulation of mood . these include altered responses to the dopaminergic drugs amphetamine and apomorphine [ 52 , 109 , 132 ] and higher levels of apoptosis in the dopaminergic neurons in the nucleus accumbens and substantia nigra ( thought to be involved in response to reward and anhedonia ) in mrl / lpr mice [ 52 , 109 ] . there are also decreased levels of serotonin in brain regions such as the hypothalamus , which regulate stress and response to appetitive stimuli ( among other things ) , and increased levels in the hippocampus . this observation is consistent with altered serotonin levels in lupus patients similar to those that occur in depressed patients [ 134136 ] , including those in which depression has been induced by cytokine therapy [ 137139 ] . decreased levels of noradrenaline evident in the prefrontal cortex of mrl / lpr mice would also be consistent with depressive - like behavior [ 58 , 140142 ] . there is also a fascinating  accidental  experimental difference in mrl / lpr mice . over time , this strain of mice displayed a lessening of symptoms such as lymphoproliferation , a greatly delayed development of nephritis , and a longer lifespan . the line was eventually reconstituted and again manifests rapid development of the typical severe autoimmune profile ( http://jaxmice.jax.org/ : re - coding of stock # 485-attenuated disease to stock # 6825-reconstituted severe line ) . this serendipitous circumstance permits the differentiation between negative behavioral outcomes that may result from gross peripheral pathology and specific cns - mediated behaviors [ 14 , 143 ] . a major difference in the disease - attenuated line is the long delay to develop renal disease and profoundly decreased proteinuria [ 14 , 20 ] . the levels of autoantibodies tend to increase earlier and to a greater extent in the reconstituted severe line . furthermore , the disease - attenuated line has normal open field activity from 8 to 18 weeks   while in the reconstituted severe line , the females have lower activity levels from 5 weeks , although mrl / lpr males exhibit normal open field activity until at least 18 weeks old [ 14 , 20 ] . cognitive functions assessed in novel object exploration and placement tasks were normal in mice 518 weeks old in both sexes and both lines [ 14 , 20 ] . motor coordination in the balance beam and anxiety in the elevated plus maze were also comparable in both lines from 5 to 18 weeks old [ 14 , 20 ] . interestingly , there was no evidence of social withdrawal assessed in the social preference test   in either line from 5 to 18 weeks compared to age- and sex - matched controls [ 14 , 20 ] . however these results were likely due to the very low social preference evident in both mrl/+ female controls and female mrl / lpr mice . it is thus not clear if social withdrawal , a typical symptom of affective disorders , is evident in the mrl / lpr females due to sle or if there is some influence of the background strain that induces social withdrawal by some other route in females . depression - like behavior is robustly evident in disease - attenuated line in the forced swim test by 8 weeks   and in reconstituted severe line by 5 weeks , although earlier time points were not tested in the disease - attenuated line . given that there is no evidence of kidney pathology in the disease - attenuated mice , these data confirm the robustness of emotional dysfunction and provide further support that such outcomes are likely a primary manifestation of autoimmunity rather than arising from nonspecific illness and peripheral organ pathology . finally , the presence of two mrl / lpr strains that share a mutated fas yet which differ in their autoantibody profile and neurobehavioral manifestations [ 14 , 143 ] is strong evidence that the cns manifestations in these mice are primarily immunologically mediated , rather than resulting from possible effects of abnormal fas - mediated apoptosis on brain development or glial function . these include b cell / autoantibody - mediated nervous system compromise , immune complex deposition , vasculitis , microthrombosis and vasculopathy , aberrant mhc class ii antigen expression with t - cell mediated disease , autoactivated t - cells , and cytokine - induced brain inflammation [ 145 , 146 ] . however , as there are multiple and quite disparate expressions of lupus involving the nervous system , it is unlikely that a single mechanism can account for every clinical manifestation of np - sle . as the most common behavioral manifestations of np - sle in both patients and murine models are affective and cognitive disorders , especially in the early stages of sle , we focus on below mechanisms thought to be involved in the etiology of affective and cognitive dysfunction . mrl / lpr mice express a range of autoantibodies   including antinucleosome , antiribosomal   antiphospholipid , and phosphoprotein ( such as anticardiolipin   and antinucleolin )   autoantibodies . a critical role of autoantibodies in the etiology of lupus - associated nephritis has been well documented . nephritogenic lupus autoantibodies initiate immune deposit formation through direct or indirect interaction with glomerular antigens [ 152 , 153 ] and result in kidney pathology that can be prevented by administration of an immunoglobulin - binding peptide [ 151 , 154 ] . it has been suggested that autoantibodies reacting with brain antigens may similarly play a role in cns pathology and negative behavioral outcomes in np - sle [ 90 , 155 ] . evidence supporting the role of autoantibodies in the pathogenesis of np - sle includes the increased titer of autoantibodies in serum of diseased mrl / lpr mice [ 156158 ] , which occurs earlier in females [ 156 , 159 ] , consistent with the earlier onset of depressive - like behavior in mrl / lpr females . there is also evidence that some of these serum autoantibodies react with brain antigens [ 160 , 161 ] and occur in serum of as early as 2 - 3 months old in mrl / lpr mice   and in csf as early as 4 - 5 months . nevertheless , as further discussed below , the fact that behavioral deficits are present before major rises in serum autoantibody titers or detectable breaches in the blood - brain barrier indicates that serum antibodies alone are clearly not the sole important pathogenic factor in np - sle , at least early in the disease . the relationship of serum and csf levels of autoantibodies to the disease process is complex , but it is likely that intrathecal autoantibodies are likely to be more critically related to np - sle than are serum autoantibody titers . some evidence does suggest a role for serum autoantibody levels in np - sle , as mice with more severe peripheral and behavioral manifestations of sle also have more pronounced changes in hippocampal and cortical morphology and increased indices of cell death [ 163166 ] . this can be prevented with doses of cyclophosphamide that reduce serum autoantibody titers , although csf levels of autoantibodies were not assessed . however , igg levels in serum , but not csf , are positively correlated with spleen weight , suggesting that central autoimmune processes are relatively independent from systemic manifestations . this is supported by the fact that the patterns of autoantibody expression in serum and csf is not correlated over time in patients with np - sle . finally , csf from diseased mrl / lpr mice which was treated to remove cytokines is cytotoxic to cultured cells [ 71 , 169 ] and was more cytotoxic than serum derived from diseased animals , indicating a primary intrathecal source of cytotoxic autoantibodies . cytotoxicity in culture was correlated with the extent of apoptosis in the brains of aged lpr mice from which the csf was derived , thus toxic mediators produced by the cns of diseased mrl / lpr mice are likely to be more pathogenic than those in serum the site of production of brain reactive antibodies in mrl - lpr mice is however not conclusively identified , although this remains a subject of intense research interest . autoantibodies recognizing brain antigens , such as the nmda receptor subtype of the excitatory neurotransmitter , glutamate , are also present in the serum and csf of patients with np - sle [ 168 , 170 ] . when injected directly into the brain of otherwise healthy mice , or when injected peripherally to animals with a compromised blood - brain barrier , in addition , intrathecal administration of antiribosomal p antibodies induces depression - like behavior in the forced swim test . there have also been reports of positive correlations between serum levels of brain reactive autoantibodies and cognitive dysfunction and depression - like behavior [ 90 , 155 , 175 ] although other studies have failed to find such relationships [ 61 , 161 , 176 ] in patients with np - sle . it has thus been suggested that csf levels of brain - reactive autoantibodies may be more important factors than serum titers to the genesis of np - sle pathology and symptoms [ 90 , 177 ] . these data further support the notion that cns - derived specific factors and possibly intrathecal production of autoantibodies can lead to brain pathology and corresponding negative behavioral outcomes [ 52 , 162 , 169 ] . however , the blood - brain barrier restricts the influx of circulating factors , including lymphocytes and antibodies , from entering the brain and cerebral circulation . generally , influx of antibodies or lymphocytes requires disintegration of the blood - brain barrier as general or localized lesions . there is no convincing evidence to date that this occurs as early as the earliest manifestations of the negative behavioral outcomes . therefore , while it is probable that the loss of integrity of the blood - brain barrier eventually occurs and obviously plays role in the resulting cns pathology [ 9 , 178181 ] , possibly in part by permitting the entry of autoantibodies and antibody - producing cells , negative behavioral outcomes might rather be initiated by different mechanisms than those that regulate pathology in peripheral organs and later onset , more severe symptoms of np - sle . thus , autoantibodies are possibly not the sole or primarily etiology of several of the symptoms of np - sle , especially given the notable role of cytokines and chemokines in affective and cognitive disorders [ 182186 ] .    indeed , several lines of evidence suggest that autoantibodies may not be sufficient to induce np - sle in the mrl / lpr strain . first , increased secretion of chemokines and cytokines ( such as interferons ) cause inflammatory pathology in kidney [ 187 , 188 ] , even in the absence of autoantibody deposits . furthermore , the high proinflammatory cytokine levels in mrl / lpr mice are progressive and correlated with increasing disease severity . in fact , numerous anti - inflammatory agents with a wide variety of underlying mechanisms of action increase survival , reduce peripheral organ pathology , and normalize t - cell phenotypes in mice without altering the level of autoantibodies [ 192197 ] . however , neuropsychiatric symptoms have not been systematically assessed in most of these studies so it is not clear if there are also similar benefits to behavioral outcomes . further evidence suggesting that autoantibodies are not sufficient to produce np - sle includes the fact that dna - binding antibodies derived from autoimmune mrl mice fail to induce sle - like changes when administered to healthy animals . actually , all strains of mice thus far tested show some brain reactive autoantibodies in serum   even in the absence of abnormal behavior . last , mrl / lpr mice that express a mutant transgene that prevents the secretion of circulating igg still develop nephritis despite the lack of soluble autoantibody production , indicating that circulating autoantibodies are neither requisite nor sufficient to induce pathology .   thus , serum antibodies could be neurotoxic , but they can only access brain tissue after a compromise of blood - brain barrier integrity . furthermore , insults to the blood - brain barrier are likely to be regional rather than global and may occur later in the disease than the onset of robust emotional disturbances . so if brain - reactive autoantibodies are not engendering such symptoms early in np - sle , then what is ? cytokines and chemokines are likely to be critical early factors regulating the negative behavioral outcomes , as they need not pass the blood - brain barrier to regulate neural function [ 57 , 183 , 201 ] . detection of increased secretion of peripheral inflammatory cytokines can occur across an intact blood - brain barrier , in part via the vagus nerve . this induces glia and microglia to produce cytokines and other inflammatory and cytotoxic agents ( including prostaglandins and nitric oxide ) . these are well documented to elicit the physiological and behavioral symptoms of mood disorders , including lethargy , decreased social interaction , immobility in the forced swim test , and anhedonia [ 183 , 184 , 202204 ] . finally , cytokines have been linked to depression in humans [ 205213 ] and to neuropsychiatric symptoms in np - sle patients [ 8 , 12 , 170 , 185 , 214 , 215 ] . the role of cytokines in emotional disturbances in mrl / lpr mice is supported by numerous studies . in very large samples , the severity of behavioral deficits in mrl / lpr mice does not relate strictly to autoantibody titers or brain infiltration by t cells , which would indicate a compromised blood - brain barrier . cytokine , chemokine , and prostaglandin dysregulation occurs as early as 14 weeks in mrl / lpr mice , well before disease onset and upregulation of autoantibodies [ 26 , 30 , 216223 ] . clinically , cytokine - mediated depression has certainly resulted from cytokine administration when used as treatments in cancer and viral infections [ 224228 ] . increased levels of il-6 and other cytokines have been found in the cerebrospinal fluid and brains of patients with np - sle . in mrl / lpr mice , treatment with anti - inflammatory cytokines reduces disease severity [ 189 , 230237 ] while administration of proinflammatory cytokines accelerates glomerulonephritis , vasculitis , and other disease manifestations [ 231 , 233 ] . mrl / lpr mice lacking the il-6 receptor have delayed mortality and nephritis and a reduction of autoantibody complex deposition , though these mice have not been behaviorally tested , so the affect on symptoms of np - sle is not known . the early dysregulation of cytokine production , especially tnf - alpha , il-1 , il-2 , and il-6 [ 188 , 223 , 239 , 240 ] , corresponds to the onset of symptoms of depressive - like behavior , such as anhedonia and behavioral despair in mrl / lpr mice   and in other rodent strains [ 241 , 242 ] . anhedonia can be ameliorated by cyclophosphamide , which abolishes the typically early and significant rise of cytokines , particularly il-6 . notably , anhedonia and other behavioral indices of depressive - like behavior in mice can be replicated by exogenous il-6   and are prevented by knockout of the il-6 receptor . other proinflammatory immunomodulators , such as tnf - alpha , also increase behavioral indices of depressive - like behavior in mice   while blocking their secretion or receptors decreases depressive - like behavior [ 242 , 243 ] . high levels of proinflammatory cytokines may also impair the function of the blood - brain barrier [ 244 , 245 ] and may thus be permissive to the negative effects of autoantibodies and lymphocytes . finally , cytokine dysregulation is a shared characteristic of murine lupus models with different underlying genetic mechanisms . thus , while recent and substantial evidence indicates a role for cytokines in the early mechanisms of np - sle , several obstacles have prevented the further studies needed to elucidate the specific underlying etiology . first , it is important to recognize that local alterations in brain cytokine levels that can be very relevant to np - sle pathogenesis may be present early in the disease course , yet these may not necessarily be reflected in abnormal serum levels . second , there are numerous cytokines , and it is a gross oversimplification to assume that an individual cytokine is pro- or anti - inflammatory . rather , the precise proportions of cytokine levels in serum and brain are likely to be more important than absolute levels of a single cytokine . furthermore , cytokines are necessary for normal brain development and cognitive function [ 247250 ] , and thus global knock - outs of specific cytokine receptors can be problematic , as these can cause cognitive , reproductive , and other deficits [ 248 , 251 ] and also require large breeding colonies to achieve appropriate genotypes . more precise timing of cytokine receptor knockdown can be accomplished by viral vectors , but these are also less than ideal in studies of sle as they are thought to induce immune responses . moreover , females with autoimmune disease have a higher risk of psychiatric disorders , particularly depression . disease severity and rate of progression are also accelerated in female mrl / lpr mice as compared to males of this strain . serum autoantibodies appear earlier in female mrl / lpr mice [ 14 , 156 ] . female mrl / lpr mice also have higher levels of igg in the csf compared to males . symptoms of depressive - like behavior are also worse in female mrl / lpr mice . one possible mediator of sex differences in the prevalence and outcomes of sle is sex steroid hormones , such as estrogens [ 254263 ] . administration of exogenous estrogens can induce a lupus - like syndrome in otherwise healthy mice   and exacerbate symptoms in mrl / lpr mice , in which estrogens globally increase igm levels   autoantibody titers , glomerulonephritis , lymphoproliferation , mortality , and cytokine levels . conversely , treatment with the estrogen receptor antagonist , tamoxifen , reduces proteinuria , serum tiers of anti - dsdna autoantibodies and increases survival . estrogens also differentially affect b and t cell - mediated immune responses in mrl / lpr mice [ 255 , 256 ] . immune complex - mediated glomerulonephritis is significantly accelerated by estrogens whereas t cell - mediated lesions , such as renal vasculitis and periarticular inflammation , are reduced in mrl / lpr mice after estrogen treatment [ 255 , 256 ] . estrogens can also modulate blood - brain barrier permeability [ 267 , 268 ] and increase cytokine levels in patients with sle [ 259 , 262 , 269 , 270 ] . moreover , the myriad effects of estrogen on neuroprotection are being increasingly recognized [ 271273 ] . while space constraints prevent going into further details about the role of sex hormones in maintaining the integrity of the blood - brain barrier and providing neuroprotection , the interested reader can find additional details in some recent comprehensive reviews [ 267 , 271 , 272 , 274 , 275 ] . these sex and hormone differences may have clinical implications for treatment of sle , as cyclophosphamide prevents pulmonary disease in male but not female mrl / lpr mice . similarly , sex differences in the efficacy of treatment in autoimmune disorders is not uncommon . furthermore , there are notable sex differences in both humans and in animal models in the susceptibility of depression , responses to antidepressant treatments , and in underlying hormonal , immune , and neurochemical alterations in affective disorders [ 278 , 279 ] . cns disease in np - sle may share common mechanisms with peripheral organ pathology in sle , especially in the latter stages of the disease , but the distinct nature of cns - mediated immunity and the blood - brain barrier indicates that early manifestations of particularly mood disorders may be derived from some unique mechanisms . additionally , agents critical to the pathology of np - sle , such as cytokines , are regulated by sex and steroid hormones , which is consistent with the predominance of sle and mood disorders in females . altered cytokine profiles in serum and/or cns can result in the activation of astrocytes , microglia , and changes in neuronal function and morphology and dysregulation of the blood - brain barrier pathology of the blood - brain barrier could lead to altered homeostasis and play a significant role in impairment of cns function seen in later onset of np - sle as well many other immune disorders .   despite the importance of the mrl / lpr and other murine models for elucidating the underlying mechanisms of np - sle , there are yet many questions that have not been conclusively answered . these include relating measures of the earliest onset of negative behavioral outcomes with intrathecal levels of cytokines and native brain - reactive autoantibodies , systematic study of the efficacy of alternative therapeutics ( such as traditional and novel antidepressants ) , and comprehensive analysis of the time course of blood - brain barrier dysfunction .
to date , cns disease and neuropsychiatric symptoms of systemic lupus erythematosus ( np - sle ) have been understudied compared to end - organ failure and peripheral pathology . in this review , 
 we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human np - sle . the mouse mrl lymphoproliferation strain ( a.k.a . 
 mrl / lpr ) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of np - sle , which may be among the earliest symptoms of lupus . 
 we suggest that although np - sle may share common mechanisms with peripheral organ pathology in lupus , especially in the latter stages of the disease , the immunologically privileged nature of the cns indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms . 
 these include altered cytokine profiles that can activate astrocytes , microglia , and alter neuronal function before dysregulation of the blood - brain barrier and development of clinical autoantibody titres .