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Abstract
Almost 25 years ago, the concept of the „mosaic of autoimmunity‟ was introduced to the scientific community, and since then t his concept has continuously evolved, with new pebbles being added regularly. We are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of BMC Medicine, several aspects of autoimmunity have been addressed, suggesting that we are now at the forefront of autoimmunity science. Within the environmental factors generating autoimmunity are now included unsuspected molecules such as vitamin D and aluminum. Some adjuvants such as aluminum are recognized as causal factors in the development of the autoimmune response. An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), has been recently described. This is the new wind blowing within the branches of autoimmunity, adding knowledge to physicians for helping patients with autoimmune disease.

Keywords:
Autoimmunity; Autoantibodies; Autoimmune/inflammatory syndrome induced by adjuvants (ASIA); Systemic lupus erythematosus; Vitamin D; Adjuvant

Introduction
Almost 25 years ago the concept of the „mosaic of autoimmunity‟ [1] was introduced to the scientific community. Since then, it has continuously evolved, with new tiles being added regularly[2], and we are now looking at an era in which the players of autoimmunity have changed names and roles. In this issue of BMC Medicine, several aspects of autoimmunity have been addressed suggesting that we are now at the forefront of autoimmunity science. One of the mainstays of the mosaic concept is that autoimmune diseases (ADs) occur in genetically predisposed individuals [3]. This concept has now been expanded by recent evidence of „familial autoimmunity‟: not only is there familial aggregation for individual ADs [4,5], but there is also a familial aggregation of diverse autoimmune diseases. This was brought to light by evidence from a systematic review and meta-analysis performed by Cárdenas-Roldán et al. [6]. Physicians should be aware that familial autoimmunity is a common finding, especially for some specific disorders, such as autoimmune thyroid disease and systemic lupus erythematosus (SLE), suggesting a stronger shared genetic influence in their development. Strengthening the theory of a genetic basis is the evidence that ADs occur more often in young people [7]. However, although ADs were thought to be rare in older people, the validity of this assumption has been challenged, and a tendency towards more severe autoimmunity in older people has been noted [8]. A possible explanation for this paradox comes from another characteristic of the disease mosaic, namely, the presence of an abnormal immune response. Vadasz et al. [9] suggested that expansion of many protective regulatory mechanisms and especially of peripheral CD4+CD25highFoxP3+ T-regulatory cells, is very characteristic in elderly people. It is possible that during aging, an imbalance between thymic and peripheral regulatory T-cell output occurs, with the ratio favoring the peripheral component, which possibly allows a pro-inflammatory response and increases the susceptibility to autoimmunity. Furthermore, in addition to this disruption of adaptive immunity, it has been shown that disruption of the autoimmune response also occurs in the innate immune system [10]. Pollard et al. [11] suggested that differences in autoimmune responses are mainly mediated by the dichotomy in Toll-like receptor (TLR) signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-kappa B (NFκB)-driven pro-inflammatory cytokine expression. Indeed, TLRs play a crucial role in the activation of both innate and adaptive immunity [12]. By recruiting various protein kinases via several adaptor molecules, such as MyD88, TLRs lead to the activation of NFκB [12]. By contrast, self-reactive antibodies against self-reactive or cross-reactive DNA co-engage antigen receptors and TLRs, leading to a continuous activation of these auto-reactive B cells and the development of autoimmune disease [12]. Nonetheless, environmental factors are still central to autoimmunity [13]. Indeed, it is possible that the discrepancies in the immune system may lead to infections (which are indeed more frequent in elderly people) thus triggering ADs [14]. Thus, on the one hand, a huge number of microorganisms have been identified as associated with the onset of an overt immune-mediated disease, and on the other hand, patients with ADs are at a major risk for infections [15]. Ramagopalan et al. [16] analyzed hospital admissions and death certificates across England, and found that the risk of tuberculosis (TB) is significantly increased in patients with immune-mediated diseases, highlighting the need for TB screening control and treatment policies in these patients. It would be interesting to confirm whether TB is a consequence of the immune system imbalance of the disease per se, or a result of the background therapy, or if it represents another causative factor of ADs [17]. It has been shown that a link exists between the mycobacterium, ADs, and, surprisingly, another component of the puzzle, namely, vitamin D [18]. Vitamin D plays a key role as an immunomodulator in autoimmunity [19,20]. This role of vitamin D seems to be so important that ADs show seasonality (due to different levels of UV exposure), and even the month of birth may influence the risk of onset of an AD, as shown by Disanto et al. [21]. Moreover, Tincani et al. [22], in their review, emphasized that patients affected

with Sjögren's syndrome (SS) who have low levels of vitamin D are at a higher risk of developing severe complications such as lymphoma and peripheral neuropathy [23,24]. The need to provide vitamin D supplementation for patients with autoimmune diseases, including SS, is clear. Moreover, the cost–benefit ratio of providing vitamin D as a preventative medicine to the general population should be evaluated, together with the routine monitoring of gestational vitamin D levels [20]. Finally, because (nolonger-just-a-)vitamin D has several physiological properties involved with the innate immune defense against TB, the role of this vitamin in the treatment of TB should be evaluated, especially when associated with autoimmunity [18]. Thus, it is evident that every day, people are exposed to several triggering factors for ADs. People can be exposed to such elements through diet (for example, vitamin D), and other sources. For instance, another defendant, aluminum (alum), is used as an adjuvant in vaccines, and its association with autoimmunity has recently been highlighted [25]. Alum can be viewed as a nanomaterial, that is, a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Alum has a number of mechanisms by which it works as an adjuvant (Table 1). Moreover, it can be detected within monocytelineage cells long after immunization in presumably susceptible individuals who develop systemic/neurologic symptoms. Khan et al. [26] showed that in mice, intramuscular injection of alum-containing vaccines was associated with appearance of aluminum deposits in distant organs such as the spleen and brain, where they were still detected 1 year after injection. The chemokine CCL-2 seems to be implicated in systemic diffusion of aluminum particles captured by monocyte-lineage cells, and in the subsequent neurodelivery of these particles. Table 1. Specific mechanisms relating to the adjuvant properties of aluminum compounds[28] These various lines of evidence reinforce the idea that alum is neurotoxic, and that continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in cases of over-immunization or immature/altered blood–brain barrier or high constitutive CCL-2 production. It is possible that this is part of the explanation for the real new wave in autoimmunity, that of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) [27]. This syndrome comprises four conditions, namely siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, and post-vaccination phenomena, which have in common a history of previous exposure to an adjuvant and a group of similar clinical features. Consequently, the importance of discovering a pathogenic role for alum must be emphasized. This compound has been considered a safe adjuvant for 90 years. However, it is now known to be an inducer of dendritic cells and complement activation, which is capable of increasing the levels of chemokine secretion at the injection site and of enhancing the secretion of key T-helper (Th)1 and Th17-cell polarizing cytokines such as interleukin-12 [28]. All these effects lead to development of an autoimmune response. Because many of the symptoms of ASIA could be neurologically dependent, the possibility that alum might traffic to the brain raises questions about its relevance to autoimmune disease. Indeed, the central nervous system (CNS) is still attracting most of the interest of autoimmune scientists, especially with regard to SLE, the disease considered the forerunner of ADs[29]. Neuropsychiatric (NP)SLE is triggered by multiple mechanisms, including several autoantibodies. One of the leading pathogenic autoantibodies in NPSLE is anti-ribosomal P protein. Carmona-Fernandes et al. [30] found that the specificity, sensitivity, positive predictive value, and negative predictive value of anti-Rib-P for SLE diagnosis were 99.4%, 14.2%, 90%, and 76.4%, respectively. Although, anti-Rib-P was not clearly associated with any clinical condition, including NPSLE, in that study, nonetheless, the effects of these autoantibodies on the CNS have been addressed in several other studies. One of the most interesting investigations showed that intracerebroventricular injection of an anti-DNA antibody carrying the 16/6 idiotype, which induces the production of anti-Rib-P antibodies, provoked deficiencies in olfactory capabilities and depression in mice [31,32]. Likewise, the 16/16 antibody bound to similar areas in the olfactory machinery as those to which anti-P ribosomal antibodies bind. Kivity et al. [33] identified another weapon at the armory of the 16/6 idiotype-expressing antibodies, showing that these antibodies can induce brain inflammation and cognitive impairment in mice. These reports on the effect of this idiotype of the human anti-DNA antibody shed further light on the diverse mosaic pathophysiology of neuropsychiatric lupus, and indicate that there is a possibility of molecularly targeting the disease [34]. This potential for treatment of SLE was addressed by Gono and coworkers [35], who highlighted the possibility that the differences in the cross-reactivity of each autoantibody with the nervous system might explain the diverse clinical features in NPSLE, and that the identification of autoantibody targets could lead to the development of novel therapies; for instance, by protecting specific neuronal cells. One of the autoimmune conditions more clearly associated with CNS involvement is anti-phospholipid syndrome (APS). Katzav et al. [36] have shown that this AD, besides being characterized by the presence of autoantibodies, can be triggered experimentally by coagulopathy. Indeed, this group found that both heterozygous and homozygous Factor V Leiden (FVL) transgenic mice that were immunized with β2-glycoprotein I had significantly higher and longer-lasting immune responses. Furthermore, because these responses were dependent on the FVL mutation allele load, the research suggests that genetically mediated coagulopathies increase

the risk of developing coagulation-targeted autoimmune responses. Moreover, raised levels of circulating anti-phospholipid antibodies seem to lead inevitably to neurodegeneration. The thrombophilic network is also involved in another autoimmune disorder, celiac disease. Lerner et al. [37] showed that in addition to the well-known thrombogenic factors, the presence of anti-phospholipid antibodies, namely anti-phosphatidylserine/prothrombin and anti-prothrombin, might play a pathogenic role by increasing the risk of intestinal injury, endothelial dysfunction, platelet abnormality, and enhanced apoptosis. Studies are urgently awaited to address the potential of treating patients with ADs by targeting these antibodies. A further component in the mosaic of autoimmunity is the question of what stays in the renal pyramids. Renal involvement represents a major issue in autoimmune connective tissue diseases (CTDs). The main question is whether renal damage is caused by the underlying disease or by interventions, particularly by drug reactions as described by Kronbichler and Mayer [38]. Consequently, physicians should always take kidney function into account when treating CTDs[39]. Nonetheless, recent evidence suggests that the real hub for presenting T cells is in the lung[40]. Indeed, T-cell blasts do not enter the CNS efficiently, and they gain this capacity only after residing transiently within the lung tissues. In these tissues, the T cells are stimulated, after which they proliferate strongly, acquire migratory properties by rearranging specific genes and producing targeting chemokines, and can then enter the circulation and induce CNS disease. There are several implications for such phenomena. For instance, the role of smoke as a risk factor in ADs becomes even more important when we consider the exposure of disease-inducing immune cells to tobacco smoke drawn into the lungs. Second, the development of drugs based on the concept of arresting T cells at a hub (that is, in the lung), is a potential therapy and should be encouraged[41]. Phosphodiesterase-targeted therapies 4 are also a promising tool for treating patients with a variety of autoimmune diseases. Intriguingly, these inhibitors have been used to treat both diseases of the CNS (such as Parkinson‟s disease) and of the lung (such as chronic obstructive pulmonary disease), suggesting a common soil between the lung and the CNS. Finally, the revolutionary roads traced by biologic therapies continue to provide benefits for patients with ADs. Rosman et al. [42], in their review of the advantages and drawbacks of biologic therapies for autoimmune disease, focused on the importance of having a range of drugs available to treat patients with severe or resistant disease. The important issue here is having a range of different targets, allow personalization of therapy not only for the individual, but also on the basis of the pathogenic mechanisms underlying each specific disorder.

Conclusion
In conclusion, a new wind is blowing within the branches of autoimmunity, from the unexplored continent of ASIA syndrome [27], which is reaching the arduous banks of personalized medicine and bringing new hope to the leaves of autoimmunity.

Competing interests
The authors declare that they have no competing interests.

Financial disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Clinical medicine has neglected the fact that the make-up of organs and body functions, as well as the human-specific repertoire of behaviors and defenses against pathogens or other potential dangers are the product of adaptation by natural and sexual selection. Even more, for many clinicians it does not seem straightforward to accept a role of evolution in the understanding of disease, let alone, treatment and prevention. Accordingly, this Editorial seeks to set the stage for an article collection that aims at dealing precisely with the question of why evolutionary aspects of health and disease are not only interesting, but necessary to improve clinical medicine.

Editorial
Clinicians take for granted that any body part can go wrong at some point in life, as much as a faulty gadget that is poorly adapted to the burden of life [1]. Why is this so? From an evolutionary perspective, it is all but straightforward to assume that the human body is fraught with thousands of flaws that make us vulnerable to disease. Selection has shaped the functional properties of organs over eons close to optimum to convey fitness advantages in terms of survival and reproduction. If evolution by natural selection has sculpted our exquisite design, why do our lungs, hearts, brains and other parts of the body become so often disarrayed? For example,

if organs operate well for 50 years, why cannot they continue to do so for another 50 years? Why do our built-in defense mechanisms break down from time to time? After all, why do we get sick at all, as Nesse and Williams inquired some 20 years ago [2]? Evolutionary medicine offers important insight to these and similar questions; in fact, we assert that questions concerning the causes of sickness and disease cannot be answered without an evolutionary approach. Nor can medicine promote preventive action to help people maintain health without a profound knowledge of gene-environment interactions that were shaped in our distant past. A common medical misconception is to assume that any organ or body part is meant to be perfect by design, ultimately to ascertain longevity, whereas the view offered by Darwinian evolution is that organisms are „designed‟ to secure the propagation of gene s coded in the DNA. Design compromises, produced by opposing selection pressures on the same structure, may cause apparent suboptimal design. The most famous example in the evolutionary literature is probably that of the peacock‟s tail, which makes peacocks sexually attractive to peahens, but also puts the peacock at risk of being devoured by predators [3], an evolutionary process referred to as the „handicap principle‟ [4]. Another example is bipedalism, which putatively evolved to enable our hominin ancestors to travel long distances at relatively low energy consumption [5], but renders humans vulnerable to develop instability of the vertebral column (slipping discs). Walking upright also produced a discrepancy between the growing newborn skull and the narrowing maternal birth canal, which forced our ancestors to deliver birth to immature and helpless babies (“the obstetrical dilemma”, [6]) – a design compromise that radically changed the way we care for our infants, with far-reaching consequences for our human psyche, including attachment, trust and cooperation [7]. Thus, the human body (like all other living organisms) comprises a set of design trade-offs of often conflicting adaptive mechanisms [2]. Evolutionary medicine emphasizes the mismatch of humans‟ slowly evolving bodies with rapidly changing modern environments [8], providing access to new toxins, such as tobacco, alcohol and other psychotropic substances, as well as to highcalorie, high-fat diets along with an increasingly sedentary and physically less active lifestyle [9]. In addition, environmental pollution, excessive population growth producing social stress, the introduction of effective methods of birth control, and the changing patterns of exposure to infectious agents [10] have all left their marks on our bodies and continue to do so. The catalogue of conditions that may arise from such mismatch is long, including obesity, metabolic syndrome and Type 2 diabetes, coronary heart disease, Crohn‟s disease, renal failure, osteoporosis, stroke, depression, Alzheimer‟s disease, atherosclerosis, asthma, cancer, chronic liver disease or cirrhosis, chronic obstructive pulmonary disease, and sexually transmitted infections, to mention just those ranking high on the WHO „hit-list‟ of diseases causing disability. One of the most important lessons from evolution for an aging society is to learn why we must age and why so many get cancer. Cancer and aging are not adaptive, so why do they exist? A trade-off conveyed by antagonistic pleiotropy is one of the key concepts that answers this question. It concerns the action of genes that have beneficial effects at early stages of development (particularly when one‟s reproductive potential peaks), whereas the same genes exert deleterious effects as the organism ages [11,12]. Now that evolutionary medicine has been around for almost 20 years, we strongly believe the time is ripe for the field to engage in translational research. This encompasses research into evolutionary developmental biology (“evo -devo”), which studies the developmental mechanisms that control body growth, shape and form [13], the alterations in gene expression and function that lead to such phylogeny [14], and issues pertaining to the role of gene-environment interaction in health and disease [15]. In the forthcoming series to be published in BMC Medicine, distinguished scholars from various medical backgrounds will demonstrate how insights from evolutionary theory not only improve our understanding of disease, but offer new ways to diagnose, manage and prevent human ailment. As a par excellence illustration for trade-offs of early-life advantage against later disease, Al-Daghri et al. report on positive selection of the NPC1 gene that has been associated with type-2 diabetes, yet also conveys some protection against virus infection [16]. Brüne has published on genetic polymorphisms of the oxytocin receptor as possible candidates for conveying “differential susceptibility” to developing psychiatric disorders [17]. Hochberg and Belsky examine adolescence as an evolutionary life-history stage in its developmental context. They show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence, and maturation toward youth and adulthood. Using the evolutionary theory of socialization, they demonstrate that familial psychosocial stress fosters a fast life-history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency [18]. In a similar vein, yet from a translational research perspective, Crispel et al. describe in a rat model how the age at weaning from lactation regulates life history, growth, body composition and maturational tempo [19]. Rühli and Henneberg highlight the fact that humans continue to evolve and that microevolutionary changes can be observed over a few generations, including changes that are brought about by improved medical care [20]. This new article collection on Evolutionary Medicine is intended to encourage clinicians to acknowledge the fruitfulness of adding an evolutionary dimension to the “standard” approach of understanding the causes of disease, to advance treatment of disease, and to bolster the search for improved prevention [15,21].

Competing interests
The authors declare that they have no competing interests.

Authors’ information
MB is Professor of Cognitive Neuropsychiatry and Psychiatric Preventive Medicine and the author of the Textbook of Evolutionary Psychiatry. The Origins of Psychopathology, Oxford University Press, 2008. ZH is Professor of Pediatrics and Endocrinology and the author of Evo-Devo of Child Growth, Wiley, 2012. Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of several autoantibodies, including anti-double-stranded DNA. Neuropsychiatric (NP)LE contributes to the prognosis of SLE, and is divided into 19 NPLE syndromes. Its mechanisms are mediated through autoantibodies, complement components, and cytokines. The pathophysiology and diagnosis of NPLE are diverse and complicated. Recent studies have shown that several autoantibodies crossreact with human brain tissue and cause NPLE symptoms in SLE. It is known that in mice, depression and hippocampus-related memory impairment are induced by anti-ribosomal P antibody and anti-NR2 antibody, respectively. In a BMC Medicine research article, Kivity et al. demonstrated novel work showed that the 16/6 Id antibody impaired visual memory and spatial memory by causing hippocampal injury in mice. Given differences in the cross-reactivity of each autoantibody with the nervous system, the clinical features might be different and diverse in NPLE. Identification of autoantibody targets could lead to the development of novel therapies. Investigators and clinicians should consider not only the inhibition of autoantibody synthesis but also the protection of neuronal cells in the treatment strategy for NPLE. See related Research article: http://www.biomedcentral.com/1741-7015/11/90 webcite

Keywords:
Systemic lupus erythematosus; Autoantibody; Cross-reactivity; Neuropsychiatric symptoms

Introduction
Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder characterized by the presence of autoantibodies directed against double-stranded (ds) DNA. The prevalence ranges from 20 to 150 cases per 100,000 population, and it seems to be increasing, partly because the disease is recognized more readily and partly because of longer survival [1]. Specifically, lupus nephritis, which is a kidney disorder that is a complication of SLE, and neuropsychiatric (NP)LE contribute to the prognosis of SLE. NPLE is classified by the American College of Rheumatology (ACR) into 19 neuropsychiatric syndromes [2]. The diffuse central nervous system (CNS) form, focal CNS form, and peripheral nervous system (PNS) form were defined as diffuse psychiatric/neuropsychological syndromes, neurologic syndromes, and PNS syndromes, respectively, by the ACR. The pathophysiology of NPLE is mediated by several factors, including vasculitis, thromboembolism, and inflammation and apoptosis of neuronal and glial cells. Its mechanisms are mediated through autoantibodies, complement components, cytokines, chemical mediators, and inflammatory cells, including neutrophils, lymphocytes, and plasma cells. Thus, the pathophysiology and diagnosis of NPLE are diverse and complicated, which makes therapy difficult. The diagnosis of NPLE is based on the results of several investigations, including neurological examination, brain/spinal cord magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, nerve-conduction studies, psychiatric interview, and a short battery of neuropsychological tests recommended by the ACR committee [2]. Recent novel studies have identified some aspects of the pathophysiology of NPLE. Some anti-dsDNA antibodies cross-react with the N-methyl-D-aspartate (NMDA) receptor subunit 2 (NR2) in SLE [3]. NMDA receptors are ligand-gated ion channels that play crucial roles in synaptic transmission and CNS plasticity. NMDA receptor dysfunction has been implicated in multiple brain disorders, including stroke, chronic neurodegeneration, epilepsy, and schizophrenia. Anti-NR2 antibodies breaching the blood–brain barrier (BBB) can cause neuronal damage via an apoptotic pathway [4,5]. The 16/6 idiotype (Id) antibody, which was the focus of a recent study by Kivity et al. [6], is considered to be an anti-dsDNA Id antibody in SLE. Immunization of naive mice with the human 16/6 Id monoclonal antibody induced an SLE-like disease characterized by serological, clinical, and pathological features. This antibody cross-reacts with cytoskeletal proteins, glycoproteins, and brain glycolipids, as well as with pathogens such as Mycobacterium tuberculosis[7]. Deposition of 16/6 Id antibodies has been found in human tissues, such as the skin, kidney, and brain [8], and levels are high in patients with active SLE or NPLE [9]. These findings indicate that the 16/6 Id antibody is potentially one of the factors that cause NPLE. However, the way in which these neuropsychiatric symptoms are induced by the 16/6 Id antibody reaching the CNS and the underlying mechanisms of this induction are unknown. In their study, Kivity et al. showed for the first time the effect of the 16/6 Id antibody on the CNS by injecting naive

mice intracerebroventricularly with the 16/6 Id antibody [6]. In this commentary, we discuss their results and the pathophysiology and treatment strategy for NPLE.

Neurological effects of the 16/6 Id antibody
To understand if the 16/6 Id IgG antibody is able to induce neurological effects, Kivity et al. compared the cognitive and behavioral performance of C3H female mice that had been injected with the human 16/6 Id IgG antibody (16/6 Id mice subset) and those injected with a commercial human IgG (control mice subset) [6]. Visual-recognition memory was assessed by using the novel-object recognition test. The authors found that there was a significant preference for attention to the new object compared with the old object by the control mice, but no difference in preference was found between the new and the old objects by the 16/6 Id mice. This result indicates impairment of visual-recognition memory in the 16/6 Id mice. In the Y-maze test, which assesses spatial memory, the 16/6 Id mice were also found to have impairment of spatial memory. In addition, the brain pathology of these mice was examined to establish the potential mechanism by which the 16/6 Id IgG antibody is able to exert its neurological effects. In the brain tissue, increased microglial activation was seen in the hippocampus and amygdala, but not in the neurocortex or piriform cortex. In addition, the number of astrocytes in the hippocampus was found to be increased. Taken together, these results show that in mice, the 16/6 Id antibody causes impairment of both visual and spatial memory through hippocampal injury, and might selectively cross-react with some antigens in the hippocampus.

The 16/6 Id antibody is a novel antibody contributing to the pathophysiology of NPLE
Kivity et al. also showed that, in addition to the anti-ribosomal P and anti-NR2 antibodies, another autoantibody, anti-16/6 Id antibody, can cross-react with human brain tissue and cause NPLE symptoms in SLE [6]. Brain tissue-reactive antibodies in NPLE are thought to be synthesized in the CNS or peripheral organs, such as the lymph nodes and bone marrow [10]. Therefore, if NPLE is associated with antibodies reaching the CNS through the BBB, treatments that not only eliminate brain-tissue-reactive antibodies but also protect the integrity of the BBB should be considered. Therapy of NPLE is currently difficult. Although corticosteroids and immunosuppressive agents, such as cyclophosphamide, are broadly effective for NPLE, the condition is occasionally refractory to these treatments. Moreover, brain-tissue-reactive autoantibodies might cause irreversible neuronal degeneration via apoptosis. For instance, anti-ribosomal P antibody targets a neuronal surface protein, causing calcium influx and apoptosis [11]. These antibodies specifically bind to neurons in the hippocampus, cingulate cortex, and the primary olfactory piriform cortex, and, in mice, resulted in the induction of depression. These results implicate the olfactory and limbic areas in the pathogenesis of depression in SLE [12]. The anti-NR2 antibody also causes neuronal cell apoptosis, impairs the hippocampus-dependent memory function in mice, stimulates NMDA receptor-mediated synaptic responses and excitotoxicity through enhanced mitochondrial permeability [13]. and decreases cell viability through increased Ca2+ influx [5]. Kivity et al. showed that the anti-16/6 Id antibody hampers visual-recognition and spatial memory. Their hypothesis about the pathophysiology of anti-16/6 Id antibody-induced brain involvement was that brain inflammation induces modification of neuronal function and neuronal degeneration [6]. The authors also found increases in astrocyte number and microglial activation in the hippocampus of anti-16/6 Id antibody-injected mice. They suggested that increased astrocytes and activated microglial cells were involved in brain inflammation and therefore, an inflammatory process may affect cognitive impairment in mice injected with anti-16/6 Id antibody. By contrast, there was minimal local activation of astrocytes and microglial cells, and no lymphocytic inflammation in the brains of anti-NR2 antibody-injected mice [3]. It is plausible, therefore, that the wide variety of NPLE syndromes might be caused by differences in the recognition of brain tissue by lupus autoantibodies, such as anti-ribosomal P, anti-NR2, and anti-16/6 Id antibodies. Identification and evaluation of such differences would perhaps be useful in developing therapies for NPLE.

Future directions and conclusions
In the future, it is hoped that new agents will be developed to improve the prognosis for NPLE. The efficacy of such new agents should be determined through their ability to protect neuronal cells, modulate intracellular Ca 2+, or regulate the deposition of autoantibodies in NPLE. Memantine is a drug used to treat Alzheimer‟s disease, which modulates intracellular Ca 2+ by blocking NMDA receptors. In addition, the DWEYS pentapeptide, which the anti-NR2 antibody recognizes as an antigen, prevents the antiNR2 antibody from being deposited in tissues and mediating neuronal excitotoxicity in mice [14]. As Kivity et al. have shown, several autoantibodies against brain tissue are involved in NPLE. Given the differences in the crossreactivity of each autoantibody with the nervous system, this may explain the difference and diversity of the clinical features in NPLE. Investigators and clinicians should consider not only inhibition of autoantibody synthesis but also protection of neuronal cells when investigating treatment strategies for NPLE.

Abbreviations

ACR: American college of rheumatology; BBB: Blood–brain barrier; CNS: Central nervous system; ds: Double-stranded; NMDA: N-methyl-D-aspartate; NPLE: Neuropsychiatric lupus erythematosus; PNS: Peripheral nervous system; SLE: Systemic lupus erythematosus

Competing interests
The authors declared that they have no competing interest.

Authors’ contributions
TG drafted the manuscript, and YK and HY read and revised it. All authors have given final approval of the final manuscript to be published.

Authors’ information
TG is an assistant professor in the Institute of Rheumatology (IOR), Tokyo Women‟s Medical University (TWMU), and is interested in the neurological complications associated with connective tissue disease. YK is an associate professor of Medicine and Rheumatology in TWMU. HY is a professor of Medicine and Rheumatology, and a director of the IOR, TWMU. All authors are board-certified members of the Japan College of Rheumatology.

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