- Email: [email protected]
Editorial commentary: “What does immunology have to do with brain development and neuropsychiatric disorders?”
brain research ] (]]]]) ]]]–]]]
Available online at www.sciencedirect.com
www.elsevier.com/locate/brainres
Editorial
Editorial commentary: “What does immunology have to do with brain development and neuropsychiatric disorders?” The most important thing to understand is that the brain is “context bound.” Gerald M. Edelman (2004) In the not too distant past, the ‘immune system’ was viewed as a complex set of cellular and molecular processes that protect us against pathogens—from viruses and bacteria to parasitic worms. It is now clear that the cellular and molecular processes that make up our ‘immune system’ are also crucial to normal brain development and the formation of neural circuits. It is also becoming increasingly evident that the immune system plays a key role in the pathobiology of a number of neuropsychiatric and neurodegenerative disorders. This special issue of Brain Research features eleven articles from authoritative leaders in the field on how a deeper understanding of neuroimmunology is transforming the field of neuropsychiatry. These articles illustrate how far this field has come over the past two decades, as well as how much further effort is needed to complete the picture (Schwartz et al., 2013). A hallmark of many of these reviews is the vast complexity of the neural and immune systems and how interconnected they are with one another and with our environment, internal and external. We are honored to dedicate this special issue to two distinguished colleagues, Francis H. Ruddle (1929–2013) and Gerald M. Edelman (1929–2014). Frank Ruddle was a renowned geneticist at Yale who gained international acclaim for his work on homeobox genes and how clusters of homeobox genes have been maintained within our genomes over the course of evolution (Murtha et al., 1991). It was our connection with the Ruddle lab that provided the initial foundation of our work together over the past two decades (Vaccarino et al., 1995; Robel et al., 1995; Lin et al., 1996; Lennington et al., 2014). It is also fascinating to note that at least one homeobox gene, Hoxb8, plays an important role in the emerging field of neuroimmunology. Specifically, when Hoxb8 is knocked out, mice show unexpected behavior characterized by compulsive grooming and hair removal, similar to behavior in humans with the obsessive–compulsive disorder (OCD) spectrum trichotillomania (Greer and Capecchi, 2002). Initially the cause of this behavioral deficit was unclear, but eventually they discovered that the Hoxb8 cell lineage exclusively labels bone marrow-derived microglia
and that mutant microglia were indeed responsible for this abnormal behavioral phenotype (Chen et al., 2010). This finding is just one of many that point to the crucial importance of the microglia at the interface of the immune and neural systems. Initially described nearly 100 years ago by Río Hortega, a student of Ramón y Cajal, it has only been during the last decade that the microglia, which constitute approximately 15% of the glial cells in the brain, have been a focus of investigation by neuroscientists. Bilimoria and Stevens (2014) review the role of the microglia in regulating programmed cell death as well as their constant surveillance of synaptic activity and their resulting impact on circuit formation. As emphasized by other authors in this special issue, activated microglia have also been implicated in the pathobiology of a number of neuropsychiatric and neurodegenerative disorders including autism, schizophrenia, Tourette syndrome, OCD, pediatric neuropsychiatric disorders associated with streptococcal infections (PANDAS), Alzheimer’s and Parkinson’s diseases, and amyotrophic lateral sclerosis (ALS). Clearly, a deeper understanding of the function of the microglia in health and disease has a high priority. The next article by Filiano et al. (this issue) extends this discussion beyond the microglia and other elements of the innate immune system and considers how the adaptive immune system interacts with the developing nervous system. Remarkably, as long as the activity of the innate and adaptive components of the immune system is well regulated, they are active players in maintaining key cognitive functions (Irwin and Cole, 2011). For example, at least within animal models systems, certain T cell populations, along with the microglia, are essential for hippocampal neurogenesis, spatial learning and memory to occur (Ziv et al., 2006; Radjavi et al., 2014). This review also provides an initial glimpse of some of the emerging data concerning neuroinflammation and the role it may play early in neural development leading to conditions including autism and schizophrenia. While this topic is considered in much greater detail elsewhere in this special issue (McDougle et al., 2014; Anders and Kinney, 2014), it is clear that maternal immune activation (MIA) during gestation may have deleterious consequences for the fetus. How exactly inflammatory processes affect fetal brain development in utero is an area of active research using animal models,
2
Editorial / brain research ] (]]]]) ]]]–]]]
including primates (Bauman et al., 2014). Despite the controversy concerning MIA, findings such as these provide a compelling rationale to invest in this area of research. Marques et al., (2014) continue this theme and masterfully examine the available evidence linking other aspects of the maternal environment and their impact on fetal brain development. In particular, they focus on the mother’s nutritional status, her level of physical activity and her experience of psychosocial stress. This review expands our scientific perspective by considering the impact on brain development of core neural and metabolic pathways that are part of evolutionarily conserved bio-behavioral systems, including our hypothalamic–pituitary–adrenal stress response axis as well as others, e.g., threat detection, salience, reward, and attachment. In a similar fashion, a deeper understanding of these many interactive parts may provide guidance for early interventions to enhance early child development and prevent the emergence of neurodevelopmental and psychopathological outcomes in vulnerable children. A consideration of our evolutionarily conserved biobehavioral systems recalls an opportunity one of us had to spend a sabbatical leave with Gerald Edelman and his team at the Neuroscience Institute some years ago. This visit provided a group of investigators the opportunity to consider the potential value of evolutionary accounts to understand developmental psychopathology (Leckman and Mayes, 1998). Although Edelman began his career as an immunologist, our discussions at the Neuroscience Institute in the late 1990s did not directly touch on neuroimmunology per se. What we did discuss was his interest in the molecular basis of how cells interact and interconnect and how this eventually led him into the field of neuroscience. He postulated that neural connectivity in the brain occurs via selective “mechano-chemical” events that take place epigenetically over the course of development. He also was convinced that once some degree of structural diversity was established, a second set of selective processes occurs that enhances or diminishes the strength of synaptic connections between neuronal groups depending on experience. In a final step he postulated that what he called “re-entrant” signaling between neuronal groups was essential for adaptive spatiotemporal responses to real-world events and interactions. Although a full exploration Edelman’s conceptualization of Neural Darwinism is well beyond the scope of this commentary (Edelman, 1987, 2004, 2006), his emphasis on the importance of interconnections within the embodied brain, and the formative role that context plays vis a vis brain structure and function resonates with many of the articles in this special issue. This extends from the important contributory role of the microglia in establishing neural circuits and monitoring synapses to a consideration of the importance of early life events and their epigenetic consequences as well as our growing appreciation of the importance of our microbiomes and exosomes. Rook et al., (2014) introduce us to the reality that we coevolved with a vast array of symbiotic species including viruses, archaea, bacteria, fungi, protozoa, and even multicellular mites that reside in our hair follicles and sebaceous glands. They also remind us that less than 10% of the cells in our body are human and that our symbionts collectively
contain at least 150-fold more genes than does the human genome. While it comes as no surprise that our immune system “farms” our microbiota, especially in the gastrointestinal track, the emerging reality that our microbiota influences brain development and function via multiple pathways is amazing and reminds us again just how “context bound” we are as a species. This article also directly connects with the other reviews in this special issue including how perinatal stress and other events including Caesarean delivery, breast feeding, over use of antibiotics and immigration can affect our microbiome, which in turn can affect brain development and our long term mental and physical wellbeing via this complex multidirectional gut-microbe-brainimmune axis. While we are just learning about the importance of the microbiome in health and disease, it is now clear that one set of important players in this multidirectional gut-microbebrain-immune axis are exosomes. As briefly described by Kawikova and Askenase (this issue), exosomes are membraneenveloped nanovesicles that often contain small non-coding microRNA (miRNA). In addition, antigen specific antibodies are present on their surfaces that in some instances allow them to target specific cell types. During the past decade, exosomes have been detected in all kingdoms and phyla of life. Although much remains to be determined in order to characterize fully their scope of biological action, they are clearly an important part of our interconnected world. For example, abundant amounts of plant miRNAs appear to be present in mammal breast milk exosomes (Lukasik and Zielenkiewicz, 2014). Perhaps exosomes play an important role in farming our microbiota as well as being one mechanism by which our microbiota interact directly with brain cells. As Kawikova and Askenase emphasize, the engineering of exosomes may provide a novel therapeutic approach in the treatment to neuropsychiatric and neurodegenerative disorders. The final six reviews examine the role of immune mechanisms across a broad range of disorders, summarizing evidence from epidemiological studies, biomarker assays, postmortem analyses as well as a number of animal models. As comprehensively reviewed by Christopher McDougle and colleagues (this issue), self-report and registry studies suggest an association between autism spectrum disorder (ASD) and familial autoimmunity. In addition, postmortem studies (Morgan et al., 2010; Voineagu et al., 2011) and one in vivo TSPO PET neuroimaging study (Suzuki et al., 2013) uncovered signs of astrocyte and microglial activation in the brains of some ASD individuals. The McDougle et al. review also explores in detail the evidence supporting MIA as a potential etiological factor in ASD. Here, we also note the passing of Paul H. Patterson (1944-2014) a distinguished neuroscientist who was a pioneer in the exploration of the interactions between the nervous and immune systems during CNS development. Indeed, his laboratory at the California Institute of Technology was the first to develop the MIA animal model system (Shi et al., 2003). It is now increasingly clear that genetic and environmental risk factors for ASD impact the early developing CNS, both at pre- and perinatal stages (Willsey et al., 2013). The McDougle et al. review ends with an extensive consideration of the promise and pitfalls of immunomodulators as possible treatment options for some
Editorial / brain research ] (]]]]) ]]]–]]]
individuals with ASD where aberrant immune processes may be involved. Next Sherry Anders and Dennis McKinney (this issue) provide a recounting of the empirical data that support the hypothesis that some cases of schizophrenia are the result of an “abnormal” development of the immune system triggered by pre- and perinatal adversities in combination with peripubertal stress. Their wide ranging review focuses on the available data concerning the importance of pre-natal exposures to stressful environmental factors (ranging from malnutrition to maternal infections and high levels of psychosocial stress), an increased personal and familial predisposition to autoimmune disorders, an increased vulnerability to infections, altered peripheral immune responses, as well as microglia activation as documented in both in vivo brain imaging studies and in studies of post-mortem brain tissue. Although their focus is largely on human studies, translational animal model systems also provide clear support for their hypothesis (Giovanoli et al., 2013). Lotrich (2014) in his comprehensive review of immune mechanisms in mood disorders (with more than 280 citations) begins with the well-established clinical observation that inflammatory cytokines can induce depressive symptoms in some individuals. For example, there is a doseresponse relationship between depressive symptoms and the administration of interferon-alpha, which is used to treat a range of medical conditions from chronic hepatitis C to hairy cell leukemia and malignant melanoma. While this association is robust, it is also clear that not everyone, indeed less than 5% of individuals receiving therapeutic doses of interferon-alpha, become clinically depressed. For other cytokines, including IL-6, the association with major depression and depressive symptomatology is robust coming both from meta-analyses (Howren et al., 2009) and from prospective longitudinal studies (Khandaker et al., 2014). Once again, translational studies also provide evidence that proinflammatory cytokines can affect CNS monoaminergic and glutamatergic systems and elicit behaviors that are homologous to depressive symptoms in humans. These observations have led Lotrich and his team to propose that there is a subclass of mood disorders that are cytokine-related, i.e., inflammatory cytokine associated depression (ICAD). As with many other neuropsychiatric disorders, the host factors (genetic, environmental, etc) leading to an increased vulnerability have yet to be determined. Likewise, studies are just beginning to explore possible differences in phenomenology, natural history, and treatment response. Moving on to Tourette’s syndrome (TS), Martino et al., (2014) review studies again describing an intriguing temporal correlation. This time the correlation is between newly acquired infections, particularly group A streptococcal (GAS) infections, and tic symptoms in some cases, as well as the documented alterations in molecules of the innate and adaptive immune system in the peripheral blood in some patients with TS. It is unclear whether a hyperimmune state triggered by an environmental event (such as an infection) causes CNS alterations, perhaps by antibody mimicry or by a direct effect of cytokines on the nervous system, or whether the immune dysregulation is part of a primary genetic predisposition to the disorder. Indeed, it seems likely that a genetic risk for
3
immune dysregulation may be an important component of several neuropsychiatric disorders. Unfortunately, familial history of autoimmune disorders has not been systematically investigated in adult Tourette’s patients and, as yet, direct evidence for a genetic risk has not been established. This is an area of active investigation. Perhaps the most compelling evidence comes from postmortem studies, where both microarrays (Hong et al., 2004; Morer et al., 2010) and RNA sequencing (Lennington et al., 2014) suggest increased expression of several cytokines and other markers of inflammation in the absence of an infiltrate of immune cells from the periphery. In addition a recent in vivo 11C-[R]–PK11195 PET neuroimaging study also uncovered signs of microglial activation in the caudate nucleus of 12 children with Tourette’s syndrome (Kumar et al., 2014). The recent report by Kumar et al. cited above also provides a clear point of transition to the review prepared by Williams and Swedo (2014) on Sydenham’s chorea and PANDAS. As detailed by Williams and Swedo, children with Sydenham’s often display in addition to chorea a board range of neuropsychiatric symptoms including OCD, tic disorders as well as mood and anxiety disorders. In contrast, PANDAS cases are characterized by the sudden overnight onset of OCD in prepubertal children. These children also experience the sudden onset of other neuropsychiatric symptoms ranging from severe separation anxiety, emotional lability, and behavioral regression to a deterioration in their school performance. Some of the most distinctive symptoms include the sudden onset of dysgraphia, fine piano-playing choreiform movements and pollakiuria (a frequent urge to urinate). Both Sydenham’s chorea and PANDAS are considered to be postinfectious autoimmune disorders associated with GAS. The link to the Kumar et al. study is that 17 children with PANDAS also had PET scans and the PANDAS subgroup of patients showed even more robust evidence of microglia-mediated neuroinflammation bilaterally within the basal ganglia. While PANDAS and PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) remain controversial topics (Singer et al., 2012; Swedo et al., 2012), a number of studies are presently underway that seek to clarify the role that the immune system may play in CNS dysfunction leading to Sydenham’s chorea, OCD, TS and related conditions. While the pathoetiological mechanisms have yet to be established, translational animal models of PANDAS provide a clear proof of concept. Indeed, a growing literature suggests that both active immunization with GAS antigens, or passive infusion of cytokines, commercial anti-GAS monoclonal antibodies or infusion of antibodies from patient’s sera can result in increased stereotypic behavior and cellular deposition of immune complexes within the CNS (Lotan et al., 2014). Molecular mimicry between the GAS and brain are thought to be important in directing immune responses (Cunningham, 2014). Some of the antineuronal antibodies which have been found in Sydenham’s chorea include antilysoganglioside, antitubulin, antidopamine D1 and D2 receptors. In the final contribution to this special issue, Doty et al. (2014) also point to the importance of microglia-mediated neuroinflammation in nearly all neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and ALS. Indeed, in many respects, the role of the immune system in neurodegenerative disorders has led the way in
4
Editorial / brain research ] (]]]]) ]]]–]]]
characterizing the interactions of the immune system and the CNS. The availability of postmortem tissue and the identification of risk genes, especially for Parkinson’s disease and ALS have clearly facilitated efforts to understand the pathobiology of these catastrophic conditions. It is also becoming clear that not all aspects of neuroinflammation are pathological and that, at least in some instances, inhibition of anti-inflammatory molecules can actually improve clinically relevant outcomes in animal model systems. Despite recent progress, and in contrast to neurodegenerative disorders, much of the evidence pointing to the involvement of the adaptive and innate immune systems in neuropsychiatric disorders is simply correlational in nature. However, given the reality that many of these disorders, e.g., ASD, schizophrenia, mood disorders, and Tourette’s, are heritable, but genetically heterogeneous, one area that needs to be more thoroughly explored is what components of the host genome affect immune response. To date, direct evidence from genetic association studies supporting a role of immune system-related genes in neuropsychiatric disorders has been obtained only in schizophrenia. Specifically, the Schizophrenia Working Group of the Psychiatric Genomics (2014) recently reported that among the 108 genetic loci found to be associated with schizophrenia several were active in tissues with important immune functions, particularly B-lymphocyte lineages involved in acquired immunity. The use of patient-specific induced pluripotent stem cells (iPSCs) may provide another way forward in this area of research. By engineering specific risk-conferring alleles in this model, we may have the opportunity to test the relative importance of a person’s genetic background and its interaction with environmental stimuli as well as the potential occurrence of enduring epigenetic changes during specific phases of in vitro neurodevelopment (Vaccarino et al., 2011). This approach may also reveal useful biomarkers for specific disorders and lead to novel therapeutic strategies. For example, the demonstration of a risk allele is not enough to conceive a therapeutic strategy. But understanding how this risk allele is played out during neurodevelopment, i.e., what neurodevelopmental cellular processes are affected and what transcripts are secondarily perturbed, can lead to a concrete way of antagonizing or preventing these alterations. iPSC has been successfully used to model embryonic brain development (Mariani et al., 2012). As a result gene-environment interactions should be able to be explored by transplanting the cells in a mouse model and exposing the mice to known environmental perturbations. Although inducing appropriate “aging” iPSC-derived neurons remains challenging, the ability of iPSCs to recapitulate aspects of the phenotypes of several late-onset neurodegenerative diseases also marks a new era in in vitro modeling (Cao et al., 2014). Furthermore, stem cellbased therapeutic approaches continue to be actively pursued particularly for neurodegenerative disorders (CanetAviles et al., 2014). As highlighted above, other emerging areas of study that in our estimation have great potential include genotyping an individual’s microbiome over the course of development as well as characterizing the exosome populations found in the serum and CSF. In conclusion, it is now clear that the cellular and molecular processes that make up our ‘immune system’ are also
crucial to normal brain development and likely play an important role in the pathoetiology of many, but not all, neurodegenerative, neurodevelopmental and psychiatric disorders. While the complexities of the interactions within the immune system and between the immune and neural systems during CNS development are staggering, we are convinced that the area of neuroimmunology will emerge as one of the most important areas of discovery in the years to come. A crucial question to be answered is whether there is a common pathophysiological role for the immune system in several neuropsychiatric disorders, or rather whether there are separate mechanisms whereby aberrant neuroimmune factors play a separate role for each disorder, perhaps rooted in different genes or in response to exposure to other specific risk factors at different stages of development While work in developmental psychoneuroimmunology engenders a good deal of excitement, the ‘promise’ of the field clearly remains greater than the ‘deliverables’, in terms of any direct effect benefits on patient care. Time will tell whether valid biomarkers emerge and whether or not novel interventions to control unwanted immune responses, will make a difference in the care of our patients. We will also be intrigued to see whether fecal transplants or engineered exosomes can make a difference. We are also hopeful that a deeper understanding of the complexity and dynamics of the interactions between the immune systems and the development of the CNS will lead to interventions that will prevent the emergence of one or more of these devastating disorders.
r e f e r e n c e s
Anders, S., Kinney, D., 2014. Abnormal immune system development in schizophrenia: a unifying hypothesis helps explain diverse findings and suggests new approaches to treatment and prevention. Brain Res. (This issue). Bauman, M.D., Iosif, A.M., Smith, S.E., Bregere, C., Amaral, D.G., Patterson, P.H., 2014. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol. Psychiatry. 75 (4), 332–341. Bilimoria P.M., Stevens B., Microglia function during brain development: new insights from animal models. Brain Res. 2014, This issue. Canet-Aviles, R., Lomax, G.P., Feigal, E.G., Priest, C., 2014. Proceedings: cell therapies for Parkinson’s disease from discovery to clinic. Stem Cells Transl. Med. 3 (9), 979–991. Cao, L., Tan, L., Jiang, T., Zhu, X.C., Yu, J.T., 2014. Induced pluripotent stem cells for disease modeling and drug discovery in neurodegenerative diseases. Mol. Neurobiol. (Aug 23. [Epub ahead of print]). Chen, S.K., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., Capecchi, M.R., 2010. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141 (5), 775–785. Cunningham, M.W., 2014. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection. Int. Rev. Immunol. 33 (4), 314–329. Doty K.R., Guillot-Sestier M.-V., Town T. The role of the immune system in neurodegenerative disorders: adaptive or maladaptive? Brain Res. 2014, This issue. Edelman, G.M., 1987. Neural Darwinism: The Theory of Neuronal Group Selection. Basic Books, New York, NY.
Editorial / brain research ] (]]]]) ]]]–]]]
Edelman, G.M., 2004. Wider Than the Sky: The Phenomenal Gift of Consciousness. Yale University Press, New Haven, CT. Edelman, G.M., 2006. Second Nature: Brain Science and Human Knowledge. Yale University Press, New Haven, CT. Filiano A.J., Gadani S.P., Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res. This issue. Greer, J.M., Capecchi, M.R., 2002. Hoxb8 is required for normal grooming behavior in mice. Neuron 33 (1), 23–34. Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R., Winter, C., Riva, M.A., Mortensen, P.B., Feldon, J., Schedlowski, M., Meyer, U., 2013. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339 (6123), 1095–1099. Hong, J.J., Loiselle, C.R., Yoon, D.Y., Lee, O., Becker, KG, Singer, H.S., 2004. Microarray analysis in Tourette syndrome postmortem putamen. J. Neurol. Sci. 225 (1-2), 57–64. Howren, M.B., Lamkin, D.M., Suls, J., 2009. Associations of depression with C-reactive protein, IL-1, and IL-6: a metaanalysis. Psychosom. Med. 71 (2), 171–186. Irwin, M.R., Cole, S.W., 2011. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11 (9), 625–632. Kawikova I, Askenase P.W. Therapeutic potential of exosomes in CNS diseases. Brain Res. This issue. Khandaker, G.M., Pearson, R.M., Zammit, S., Lewis, G., Jones, P.B., 2014. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 71 (10), 1121–1128. Kumar A., Williams M.T., Chugani H.T. Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric Disorders associated with streptococcal infection and Tourette syndrome: a positron emission tomographic (PET) study using 11C-[R]-PK11195. J. Child. Neurol. 2014 Aug 12 Aug 12. pii: 0883073814543303. [Epub ahead of print]. Leckman, J.F., Mayes, L..C., 1998. Understanding developmental psychopathology: how useful are evolutionary accounts? J. Am. Acad. Child Adolesc. Psychiatry 37 (10), 1011–1021. Lennington, J.B., Coppola, G., Kataoka-Sasaki, Y., Fernandez, T.V., Palejev, D., Li, Y., Huttner, A., Pletikos, M., Sestan, N., Leckman, J.F., Vaccarino, F.M., 2014. Transcriptome analysis of the human striatum in Tourette syndrome. Biol. Psychiatry (Jul 24 [Epub ahead of print]). Lin, X., Swaroop, A., Vaccarino, F.M., Murtha, M.T., Haas, M., Ji, X., Ruddle, F.H., Leckman, J.F., 1996. Characterization and sequence analysis of the human homeobox-containing gene GBX2. Genomics 31 (3), 335–342. Lotan, D., Benhar, I., Alvarez, K., Mascaro-Blanco, A., Brimberg, L., Frenkel, D., Cunningham, M.W., Joel, D., 2014. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav. Immun. 38, 249–262. Lotrich F.E. Inflammatory cytokine-associated depression. Brain Res. 2014, This issue. Lukasik, A., Zielenkiewicz, P., 2014. In silico identification of plant miRNAs in mammalian breast milk exosomes—a small step forward?. PLoS One 9 (6), e99963. Mariani, J., Simonini, M.V., Palejev, D., Tomasini, L., Coppola, G., Szekely, A.M., Horvath, T.L., Vaccarino, F.M., 2012. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 109, 12770–12775. Marques A.H., Bjørke-Monsen A.-L., Teixeira A., Silverman M. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology. Brain Res., 2014, This issue. Martino D., Zis P., Buttiglione M. The role of immune mechanisms in Tourette syndrome. Brain Res. 2014, This volume.
5
McDougle C.J., Landino S.M., Vahabzadeh A., O’Rourke J., Zurcher N.R., Finger B.C., Palumbo M.L., Helt J., Mullett J.E., Hooker J.M., Carlezon W.A. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. 2014, This volume. Morer, A., Chae, W., Henegariu, O., Bothwell, A.L., Leckman, J.F., Kawikova, I., 2010. Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases. Brain Behav. Immun. 24 (7), 1069–1073. Morgan, J.T., Chana, G., Pardo, C.A., Achim, C., Semendeferi, K., Buckwalter, J., Courchesne, E., Everall, I.P., 2010. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68 (4), 368–376. Murtha, M.T., Leckman, J.F., Ruddle, F.H., 1991. Detection of homeobox genes in development and evolution. Detection of homeobox genes in development and evolution. Proc. Natl. Acad. Sci. U.S.A. 88 (23), 10711–10715. Radjavi, A., Smirnov, I., Kipnis, J., 2014. Brain antigen-reactive CD4þ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav. Immun. 35, 58–63. Robel, L., Ding, M., James, A.J., Lin, X., Simeone, A., Leckman, J.F., Vaccarino, F.M., 1995. Fibroblast growth factor 2 increases Otx2 expression in precursor cells from mammalian telencephalon. J. Neurosci. 15 (12), 7879–7891. Rook G.A., Lowry C.A., Raison C.L. Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res. 2014 Apr 13 [Epub ahead of print]. Schizophrenia Working Group of the Psychiatric Genomics, 2014. Consortium. Biological insights from 108 schizophreniaassociated genetic loci. Nature 511 (7510), 421–427. Schwartz, M., Kipnis, J., Rivest, S., Prat, A., 2013. How do immune cells support and shape the brain in health, disease, and aging? J. Neurosci. 33 (45), 17587–17596. Shi, L., Fatemi, S.H., Sidwell, R.W., Patterson, P.H., 2003. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23 (1), 297–302. Singer, H.S., Gilbert, D.L., Wolf, D.S., Mink, J.W., Kurlan, R., 2012. Moving from PANDAS to CANS. J. Pediatr. 160 (5), 725–731. Suzuki, K., Sugihara, G., Ouchi, Y., Nakamura, K., Futatsubashi, M., Takebayashi, K., Yoshihara, Y., Omata, K., Matsumoto, K., Tsuchiya, K.J., Iwata, Y., Tsujii, M., Sugiyama, T., Mori, N., 2013. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70 (1), 49–58. Swedo, S.E., Leckman, J.F., Rose, N.R., 2012. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr. Therapeut. 2, 113, http://dx.doi.org/ 10.4172/2161-0665.1000113. Vaccarino, F.M., Schwartz, M.L., Hartigan, D., Leckman, J.F., 1995. Basic fibroblast growth factor increases the number of excitatory neurons containing glutamate in the cerebral cortex. Cereb. Cortex. 5 (1), 64–78. Vaccarino, F.M., Urban, A.E., Stevens, H.E., Szekely, A., Abyzov, A., Grigorenko, E.L., Gerstein, M., Weissman, S., 2011. The promise of stem cell research for neuropsychiatric disorders. J. Child. Psychol. Psychiatry 52 (4), 504–516. Voineagu, I., Wang, X., Johnston, P., Lowe, J.K., Tian, Y., Horvath, S., Mill, J., Cantor, R.M., Blencowe, B.J., Geschwind, D.H., 2011. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474 (7351), 380–384. Williams K.A., Swedo S.E. Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond. Brain Res. 2014, This issue.
6
Editorial / brain research ] (]]]]) ]]]–]]]
Willsey, A.J., Sanders, S.J., Li, M., Dong, S., Tebbenkamp, A.T., Muhle, R.A., Reilly, S.K., Lin, L., Fertuzinhos, S., Miller, J.A., Murtha, M.T., Bichsel, C., Niu, W., Cotney, J, Ercan-Sencicek, A.G., Gockley, J., Gupta, A.R., Han, W., He, X., Hoffman, E.J., Klei, L., Lei, J., Liu, W., Liu, L., Lu, C., Xu, X., Zhu, Y., Mane, S.M., Lein, E.S., Wei, L., Noonan, J.P., Roeder, K., Devlin, B., Sestan, N., 2013. State MW. Co-expression networks implicate human mid-fetal deep cortical projection neurons in the pathogenesis of autism. Cell 155 (5), 997–1007. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J., Schwartz, M., 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9 (2), 268–275.
James F. Leckman, Flora M. Vaccarino The Child Study Center and the Departments of Psychiatry, Pediatrics, Psychology, and Neurobiology, Yale University, New Haven, CT, USA 23 September 2014
0006-8993/$ - see front matter & 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.brainres.2014.09.052
Available online at www.sciencedirect.com
www.elsevier.com/locate/brainres
Editorial
Editorial commentary: “What does immunology have to do with brain development and neuropsychiatric disorders?” The most important thing to understand is that the brain is “context bound.” Gerald M. Edelman (2004) In the not too distant past, the ‘immune system’ was viewed as a complex set of cellular and molecular processes that protect us against pathogens—from viruses and bacteria to parasitic worms. It is now clear that the cellular and molecular processes that make up our ‘immune system’ are also crucial to normal brain development and the formation of neural circuits. It is also becoming increasingly evident that the immune system plays a key role in the pathobiology of a number of neuropsychiatric and neurodegenerative disorders. This special issue of Brain Research features eleven articles from authoritative leaders in the field on how a deeper understanding of neuroimmunology is transforming the field of neuropsychiatry. These articles illustrate how far this field has come over the past two decades, as well as how much further effort is needed to complete the picture (Schwartz et al., 2013). A hallmark of many of these reviews is the vast complexity of the neural and immune systems and how interconnected they are with one another and with our environment, internal and external. We are honored to dedicate this special issue to two distinguished colleagues, Francis H. Ruddle (1929–2013) and Gerald M. Edelman (1929–2014). Frank Ruddle was a renowned geneticist at Yale who gained international acclaim for his work on homeobox genes and how clusters of homeobox genes have been maintained within our genomes over the course of evolution (Murtha et al., 1991). It was our connection with the Ruddle lab that provided the initial foundation of our work together over the past two decades (Vaccarino et al., 1995; Robel et al., 1995; Lin et al., 1996; Lennington et al., 2014). It is also fascinating to note that at least one homeobox gene, Hoxb8, plays an important role in the emerging field of neuroimmunology. Specifically, when Hoxb8 is knocked out, mice show unexpected behavior characterized by compulsive grooming and hair removal, similar to behavior in humans with the obsessive–compulsive disorder (OCD) spectrum trichotillomania (Greer and Capecchi, 2002). Initially the cause of this behavioral deficit was unclear, but eventually they discovered that the Hoxb8 cell lineage exclusively labels bone marrow-derived microglia
and that mutant microglia were indeed responsible for this abnormal behavioral phenotype (Chen et al., 2010). This finding is just one of many that point to the crucial importance of the microglia at the interface of the immune and neural systems. Initially described nearly 100 years ago by Río Hortega, a student of Ramón y Cajal, it has only been during the last decade that the microglia, which constitute approximately 15% of the glial cells in the brain, have been a focus of investigation by neuroscientists. Bilimoria and Stevens (2014) review the role of the microglia in regulating programmed cell death as well as their constant surveillance of synaptic activity and their resulting impact on circuit formation. As emphasized by other authors in this special issue, activated microglia have also been implicated in the pathobiology of a number of neuropsychiatric and neurodegenerative disorders including autism, schizophrenia, Tourette syndrome, OCD, pediatric neuropsychiatric disorders associated with streptococcal infections (PANDAS), Alzheimer’s and Parkinson’s diseases, and amyotrophic lateral sclerosis (ALS). Clearly, a deeper understanding of the function of the microglia in health and disease has a high priority. The next article by Filiano et al. (this issue) extends this discussion beyond the microglia and other elements of the innate immune system and considers how the adaptive immune system interacts with the developing nervous system. Remarkably, as long as the activity of the innate and adaptive components of the immune system is well regulated, they are active players in maintaining key cognitive functions (Irwin and Cole, 2011). For example, at least within animal models systems, certain T cell populations, along with the microglia, are essential for hippocampal neurogenesis, spatial learning and memory to occur (Ziv et al., 2006; Radjavi et al., 2014). This review also provides an initial glimpse of some of the emerging data concerning neuroinflammation and the role it may play early in neural development leading to conditions including autism and schizophrenia. While this topic is considered in much greater detail elsewhere in this special issue (McDougle et al., 2014; Anders and Kinney, 2014), it is clear that maternal immune activation (MIA) during gestation may have deleterious consequences for the fetus. How exactly inflammatory processes affect fetal brain development in utero is an area of active research using animal models,
2
Editorial / brain research ] (]]]]) ]]]–]]]
including primates (Bauman et al., 2014). Despite the controversy concerning MIA, findings such as these provide a compelling rationale to invest in this area of research. Marques et al., (2014) continue this theme and masterfully examine the available evidence linking other aspects of the maternal environment and their impact on fetal brain development. In particular, they focus on the mother’s nutritional status, her level of physical activity and her experience of psychosocial stress. This review expands our scientific perspective by considering the impact on brain development of core neural and metabolic pathways that are part of evolutionarily conserved bio-behavioral systems, including our hypothalamic–pituitary–adrenal stress response axis as well as others, e.g., threat detection, salience, reward, and attachment. In a similar fashion, a deeper understanding of these many interactive parts may provide guidance for early interventions to enhance early child development and prevent the emergence of neurodevelopmental and psychopathological outcomes in vulnerable children. A consideration of our evolutionarily conserved biobehavioral systems recalls an opportunity one of us had to spend a sabbatical leave with Gerald Edelman and his team at the Neuroscience Institute some years ago. This visit provided a group of investigators the opportunity to consider the potential value of evolutionary accounts to understand developmental psychopathology (Leckman and Mayes, 1998). Although Edelman began his career as an immunologist, our discussions at the Neuroscience Institute in the late 1990s did not directly touch on neuroimmunology per se. What we did discuss was his interest in the molecular basis of how cells interact and interconnect and how this eventually led him into the field of neuroscience. He postulated that neural connectivity in the brain occurs via selective “mechano-chemical” events that take place epigenetically over the course of development. He also was convinced that once some degree of structural diversity was established, a second set of selective processes occurs that enhances or diminishes the strength of synaptic connections between neuronal groups depending on experience. In a final step he postulated that what he called “re-entrant” signaling between neuronal groups was essential for adaptive spatiotemporal responses to real-world events and interactions. Although a full exploration Edelman’s conceptualization of Neural Darwinism is well beyond the scope of this commentary (Edelman, 1987, 2004, 2006), his emphasis on the importance of interconnections within the embodied brain, and the formative role that context plays vis a vis brain structure and function resonates with many of the articles in this special issue. This extends from the important contributory role of the microglia in establishing neural circuits and monitoring synapses to a consideration of the importance of early life events and their epigenetic consequences as well as our growing appreciation of the importance of our microbiomes and exosomes. Rook et al., (2014) introduce us to the reality that we coevolved with a vast array of symbiotic species including viruses, archaea, bacteria, fungi, protozoa, and even multicellular mites that reside in our hair follicles and sebaceous glands. They also remind us that less than 10% of the cells in our body are human and that our symbionts collectively
contain at least 150-fold more genes than does the human genome. While it comes as no surprise that our immune system “farms” our microbiota, especially in the gastrointestinal track, the emerging reality that our microbiota influences brain development and function via multiple pathways is amazing and reminds us again just how “context bound” we are as a species. This article also directly connects with the other reviews in this special issue including how perinatal stress and other events including Caesarean delivery, breast feeding, over use of antibiotics and immigration can affect our microbiome, which in turn can affect brain development and our long term mental and physical wellbeing via this complex multidirectional gut-microbe-brainimmune axis. While we are just learning about the importance of the microbiome in health and disease, it is now clear that one set of important players in this multidirectional gut-microbebrain-immune axis are exosomes. As briefly described by Kawikova and Askenase (this issue), exosomes are membraneenveloped nanovesicles that often contain small non-coding microRNA (miRNA). In addition, antigen specific antibodies are present on their surfaces that in some instances allow them to target specific cell types. During the past decade, exosomes have been detected in all kingdoms and phyla of life. Although much remains to be determined in order to characterize fully their scope of biological action, they are clearly an important part of our interconnected world. For example, abundant amounts of plant miRNAs appear to be present in mammal breast milk exosomes (Lukasik and Zielenkiewicz, 2014). Perhaps exosomes play an important role in farming our microbiota as well as being one mechanism by which our microbiota interact directly with brain cells. As Kawikova and Askenase emphasize, the engineering of exosomes may provide a novel therapeutic approach in the treatment to neuropsychiatric and neurodegenerative disorders. The final six reviews examine the role of immune mechanisms across a broad range of disorders, summarizing evidence from epidemiological studies, biomarker assays, postmortem analyses as well as a number of animal models. As comprehensively reviewed by Christopher McDougle and colleagues (this issue), self-report and registry studies suggest an association between autism spectrum disorder (ASD) and familial autoimmunity. In addition, postmortem studies (Morgan et al., 2010; Voineagu et al., 2011) and one in vivo TSPO PET neuroimaging study (Suzuki et al., 2013) uncovered signs of astrocyte and microglial activation in the brains of some ASD individuals. The McDougle et al. review also explores in detail the evidence supporting MIA as a potential etiological factor in ASD. Here, we also note the passing of Paul H. Patterson (1944-2014) a distinguished neuroscientist who was a pioneer in the exploration of the interactions between the nervous and immune systems during CNS development. Indeed, his laboratory at the California Institute of Technology was the first to develop the MIA animal model system (Shi et al., 2003). It is now increasingly clear that genetic and environmental risk factors for ASD impact the early developing CNS, both at pre- and perinatal stages (Willsey et al., 2013). The McDougle et al. review ends with an extensive consideration of the promise and pitfalls of immunomodulators as possible treatment options for some
Editorial / brain research ] (]]]]) ]]]–]]]
individuals with ASD where aberrant immune processes may be involved. Next Sherry Anders and Dennis McKinney (this issue) provide a recounting of the empirical data that support the hypothesis that some cases of schizophrenia are the result of an “abnormal” development of the immune system triggered by pre- and perinatal adversities in combination with peripubertal stress. Their wide ranging review focuses on the available data concerning the importance of pre-natal exposures to stressful environmental factors (ranging from malnutrition to maternal infections and high levels of psychosocial stress), an increased personal and familial predisposition to autoimmune disorders, an increased vulnerability to infections, altered peripheral immune responses, as well as microglia activation as documented in both in vivo brain imaging studies and in studies of post-mortem brain tissue. Although their focus is largely on human studies, translational animal model systems also provide clear support for their hypothesis (Giovanoli et al., 2013). Lotrich (2014) in his comprehensive review of immune mechanisms in mood disorders (with more than 280 citations) begins with the well-established clinical observation that inflammatory cytokines can induce depressive symptoms in some individuals. For example, there is a doseresponse relationship between depressive symptoms and the administration of interferon-alpha, which is used to treat a range of medical conditions from chronic hepatitis C to hairy cell leukemia and malignant melanoma. While this association is robust, it is also clear that not everyone, indeed less than 5% of individuals receiving therapeutic doses of interferon-alpha, become clinically depressed. For other cytokines, including IL-6, the association with major depression and depressive symptomatology is robust coming both from meta-analyses (Howren et al., 2009) and from prospective longitudinal studies (Khandaker et al., 2014). Once again, translational studies also provide evidence that proinflammatory cytokines can affect CNS monoaminergic and glutamatergic systems and elicit behaviors that are homologous to depressive symptoms in humans. These observations have led Lotrich and his team to propose that there is a subclass of mood disorders that are cytokine-related, i.e., inflammatory cytokine associated depression (ICAD). As with many other neuropsychiatric disorders, the host factors (genetic, environmental, etc) leading to an increased vulnerability have yet to be determined. Likewise, studies are just beginning to explore possible differences in phenomenology, natural history, and treatment response. Moving on to Tourette’s syndrome (TS), Martino et al., (2014) review studies again describing an intriguing temporal correlation. This time the correlation is between newly acquired infections, particularly group A streptococcal (GAS) infections, and tic symptoms in some cases, as well as the documented alterations in molecules of the innate and adaptive immune system in the peripheral blood in some patients with TS. It is unclear whether a hyperimmune state triggered by an environmental event (such as an infection) causes CNS alterations, perhaps by antibody mimicry or by a direct effect of cytokines on the nervous system, or whether the immune dysregulation is part of a primary genetic predisposition to the disorder. Indeed, it seems likely that a genetic risk for
3
immune dysregulation may be an important component of several neuropsychiatric disorders. Unfortunately, familial history of autoimmune disorders has not been systematically investigated in adult Tourette’s patients and, as yet, direct evidence for a genetic risk has not been established. This is an area of active investigation. Perhaps the most compelling evidence comes from postmortem studies, where both microarrays (Hong et al., 2004; Morer et al., 2010) and RNA sequencing (Lennington et al., 2014) suggest increased expression of several cytokines and other markers of inflammation in the absence of an infiltrate of immune cells from the periphery. In addition a recent in vivo 11C-[R]–PK11195 PET neuroimaging study also uncovered signs of microglial activation in the caudate nucleus of 12 children with Tourette’s syndrome (Kumar et al., 2014). The recent report by Kumar et al. cited above also provides a clear point of transition to the review prepared by Williams and Swedo (2014) on Sydenham’s chorea and PANDAS. As detailed by Williams and Swedo, children with Sydenham’s often display in addition to chorea a board range of neuropsychiatric symptoms including OCD, tic disorders as well as mood and anxiety disorders. In contrast, PANDAS cases are characterized by the sudden overnight onset of OCD in prepubertal children. These children also experience the sudden onset of other neuropsychiatric symptoms ranging from severe separation anxiety, emotional lability, and behavioral regression to a deterioration in their school performance. Some of the most distinctive symptoms include the sudden onset of dysgraphia, fine piano-playing choreiform movements and pollakiuria (a frequent urge to urinate). Both Sydenham’s chorea and PANDAS are considered to be postinfectious autoimmune disorders associated with GAS. The link to the Kumar et al. study is that 17 children with PANDAS also had PET scans and the PANDAS subgroup of patients showed even more robust evidence of microglia-mediated neuroinflammation bilaterally within the basal ganglia. While PANDAS and PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome) remain controversial topics (Singer et al., 2012; Swedo et al., 2012), a number of studies are presently underway that seek to clarify the role that the immune system may play in CNS dysfunction leading to Sydenham’s chorea, OCD, TS and related conditions. While the pathoetiological mechanisms have yet to be established, translational animal models of PANDAS provide a clear proof of concept. Indeed, a growing literature suggests that both active immunization with GAS antigens, or passive infusion of cytokines, commercial anti-GAS monoclonal antibodies or infusion of antibodies from patient’s sera can result in increased stereotypic behavior and cellular deposition of immune complexes within the CNS (Lotan et al., 2014). Molecular mimicry between the GAS and brain are thought to be important in directing immune responses (Cunningham, 2014). Some of the antineuronal antibodies which have been found in Sydenham’s chorea include antilysoganglioside, antitubulin, antidopamine D1 and D2 receptors. In the final contribution to this special issue, Doty et al. (2014) also point to the importance of microglia-mediated neuroinflammation in nearly all neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and ALS. Indeed, in many respects, the role of the immune system in neurodegenerative disorders has led the way in
4
Editorial / brain research ] (]]]]) ]]]–]]]
characterizing the interactions of the immune system and the CNS. The availability of postmortem tissue and the identification of risk genes, especially for Parkinson’s disease and ALS have clearly facilitated efforts to understand the pathobiology of these catastrophic conditions. It is also becoming clear that not all aspects of neuroinflammation are pathological and that, at least in some instances, inhibition of anti-inflammatory molecules can actually improve clinically relevant outcomes in animal model systems. Despite recent progress, and in contrast to neurodegenerative disorders, much of the evidence pointing to the involvement of the adaptive and innate immune systems in neuropsychiatric disorders is simply correlational in nature. However, given the reality that many of these disorders, e.g., ASD, schizophrenia, mood disorders, and Tourette’s, are heritable, but genetically heterogeneous, one area that needs to be more thoroughly explored is what components of the host genome affect immune response. To date, direct evidence from genetic association studies supporting a role of immune system-related genes in neuropsychiatric disorders has been obtained only in schizophrenia. Specifically, the Schizophrenia Working Group of the Psychiatric Genomics (2014) recently reported that among the 108 genetic loci found to be associated with schizophrenia several were active in tissues with important immune functions, particularly B-lymphocyte lineages involved in acquired immunity. The use of patient-specific induced pluripotent stem cells (iPSCs) may provide another way forward in this area of research. By engineering specific risk-conferring alleles in this model, we may have the opportunity to test the relative importance of a person’s genetic background and its interaction with environmental stimuli as well as the potential occurrence of enduring epigenetic changes during specific phases of in vitro neurodevelopment (Vaccarino et al., 2011). This approach may also reveal useful biomarkers for specific disorders and lead to novel therapeutic strategies. For example, the demonstration of a risk allele is not enough to conceive a therapeutic strategy. But understanding how this risk allele is played out during neurodevelopment, i.e., what neurodevelopmental cellular processes are affected and what transcripts are secondarily perturbed, can lead to a concrete way of antagonizing or preventing these alterations. iPSC has been successfully used to model embryonic brain development (Mariani et al., 2012). As a result gene-environment interactions should be able to be explored by transplanting the cells in a mouse model and exposing the mice to known environmental perturbations. Although inducing appropriate “aging” iPSC-derived neurons remains challenging, the ability of iPSCs to recapitulate aspects of the phenotypes of several late-onset neurodegenerative diseases also marks a new era in in vitro modeling (Cao et al., 2014). Furthermore, stem cellbased therapeutic approaches continue to be actively pursued particularly for neurodegenerative disorders (CanetAviles et al., 2014). As highlighted above, other emerging areas of study that in our estimation have great potential include genotyping an individual’s microbiome over the course of development as well as characterizing the exosome populations found in the serum and CSF. In conclusion, it is now clear that the cellular and molecular processes that make up our ‘immune system’ are also
crucial to normal brain development and likely play an important role in the pathoetiology of many, but not all, neurodegenerative, neurodevelopmental and psychiatric disorders. While the complexities of the interactions within the immune system and between the immune and neural systems during CNS development are staggering, we are convinced that the area of neuroimmunology will emerge as one of the most important areas of discovery in the years to come. A crucial question to be answered is whether there is a common pathophysiological role for the immune system in several neuropsychiatric disorders, or rather whether there are separate mechanisms whereby aberrant neuroimmune factors play a separate role for each disorder, perhaps rooted in different genes or in response to exposure to other specific risk factors at different stages of development While work in developmental psychoneuroimmunology engenders a good deal of excitement, the ‘promise’ of the field clearly remains greater than the ‘deliverables’, in terms of any direct effect benefits on patient care. Time will tell whether valid biomarkers emerge and whether or not novel interventions to control unwanted immune responses, will make a difference in the care of our patients. We will also be intrigued to see whether fecal transplants or engineered exosomes can make a difference. We are also hopeful that a deeper understanding of the complexity and dynamics of the interactions between the immune systems and the development of the CNS will lead to interventions that will prevent the emergence of one or more of these devastating disorders.
r e f e r e n c e s
Anders, S., Kinney, D., 2014. Abnormal immune system development in schizophrenia: a unifying hypothesis helps explain diverse findings and suggests new approaches to treatment and prevention. Brain Res. (This issue). Bauman, M.D., Iosif, A.M., Smith, S.E., Bregere, C., Amaral, D.G., Patterson, P.H., 2014. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol. Psychiatry. 75 (4), 332–341. Bilimoria P.M., Stevens B., Microglia function during brain development: new insights from animal models. Brain Res. 2014, This issue. Canet-Aviles, R., Lomax, G.P., Feigal, E.G., Priest, C., 2014. Proceedings: cell therapies for Parkinson’s disease from discovery to clinic. Stem Cells Transl. Med. 3 (9), 979–991. Cao, L., Tan, L., Jiang, T., Zhu, X.C., Yu, J.T., 2014. Induced pluripotent stem cells for disease modeling and drug discovery in neurodegenerative diseases. Mol. Neurobiol. (Aug 23. [Epub ahead of print]). Chen, S.K., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., Capecchi, M.R., 2010. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141 (5), 775–785. Cunningham, M.W., 2014. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection. Int. Rev. Immunol. 33 (4), 314–329. Doty K.R., Guillot-Sestier M.-V., Town T. The role of the immune system in neurodegenerative disorders: adaptive or maladaptive? Brain Res. 2014, This issue. Edelman, G.M., 1987. Neural Darwinism: The Theory of Neuronal Group Selection. Basic Books, New York, NY.
Editorial / brain research ] (]]]]) ]]]–]]]
Edelman, G.M., 2004. Wider Than the Sky: The Phenomenal Gift of Consciousness. Yale University Press, New Haven, CT. Edelman, G.M., 2006. Second Nature: Brain Science and Human Knowledge. Yale University Press, New Haven, CT. Filiano A.J., Gadani S.P., Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res. This issue. Greer, J.M., Capecchi, M.R., 2002. Hoxb8 is required for normal grooming behavior in mice. Neuron 33 (1), 23–34. Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R., Winter, C., Riva, M.A., Mortensen, P.B., Feldon, J., Schedlowski, M., Meyer, U., 2013. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339 (6123), 1095–1099. Hong, J.J., Loiselle, C.R., Yoon, D.Y., Lee, O., Becker, KG, Singer, H.S., 2004. Microarray analysis in Tourette syndrome postmortem putamen. J. Neurol. Sci. 225 (1-2), 57–64. Howren, M.B., Lamkin, D.M., Suls, J., 2009. Associations of depression with C-reactive protein, IL-1, and IL-6: a metaanalysis. Psychosom. Med. 71 (2), 171–186. Irwin, M.R., Cole, S.W., 2011. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11 (9), 625–632. Kawikova I, Askenase P.W. Therapeutic potential of exosomes in CNS diseases. Brain Res. This issue. Khandaker, G.M., Pearson, R.M., Zammit, S., Lewis, G., Jones, P.B., 2014. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 71 (10), 1121–1128. Kumar A., Williams M.T., Chugani H.T. Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric Disorders associated with streptococcal infection and Tourette syndrome: a positron emission tomographic (PET) study using 11C-[R]-PK11195. J. Child. Neurol. 2014 Aug 12 Aug 12. pii: 0883073814543303. [Epub ahead of print]. Leckman, J.F., Mayes, L..C., 1998. Understanding developmental psychopathology: how useful are evolutionary accounts? J. Am. Acad. Child Adolesc. Psychiatry 37 (10), 1011–1021. Lennington, J.B., Coppola, G., Kataoka-Sasaki, Y., Fernandez, T.V., Palejev, D., Li, Y., Huttner, A., Pletikos, M., Sestan, N., Leckman, J.F., Vaccarino, F.M., 2014. Transcriptome analysis of the human striatum in Tourette syndrome. Biol. Psychiatry (Jul 24 [Epub ahead of print]). Lin, X., Swaroop, A., Vaccarino, F.M., Murtha, M.T., Haas, M., Ji, X., Ruddle, F.H., Leckman, J.F., 1996. Characterization and sequence analysis of the human homeobox-containing gene GBX2. Genomics 31 (3), 335–342. Lotan, D., Benhar, I., Alvarez, K., Mascaro-Blanco, A., Brimberg, L., Frenkel, D., Cunningham, M.W., Joel, D., 2014. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav. Immun. 38, 249–262. Lotrich F.E. Inflammatory cytokine-associated depression. Brain Res. 2014, This issue. Lukasik, A., Zielenkiewicz, P., 2014. In silico identification of plant miRNAs in mammalian breast milk exosomes—a small step forward?. PLoS One 9 (6), e99963. Mariani, J., Simonini, M.V., Palejev, D., Tomasini, L., Coppola, G., Szekely, A.M., Horvath, T.L., Vaccarino, F.M., 2012. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 109, 12770–12775. Marques A.H., Bjørke-Monsen A.-L., Teixeira A., Silverman M. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology. Brain Res., 2014, This issue. Martino D., Zis P., Buttiglione M. The role of immune mechanisms in Tourette syndrome. Brain Res. 2014, This volume.
5
McDougle C.J., Landino S.M., Vahabzadeh A., O’Rourke J., Zurcher N.R., Finger B.C., Palumbo M.L., Helt J., Mullett J.E., Hooker J.M., Carlezon W.A. Toward an immune-mediated subtype of autism spectrum disorder. Brain Res. 2014, This volume. Morer, A., Chae, W., Henegariu, O., Bothwell, A.L., Leckman, J.F., Kawikova, I., 2010. Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases. Brain Behav. Immun. 24 (7), 1069–1073. Morgan, J.T., Chana, G., Pardo, C.A., Achim, C., Semendeferi, K., Buckwalter, J., Courchesne, E., Everall, I.P., 2010. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68 (4), 368–376. Murtha, M.T., Leckman, J.F., Ruddle, F.H., 1991. Detection of homeobox genes in development and evolution. Detection of homeobox genes in development and evolution. Proc. Natl. Acad. Sci. U.S.A. 88 (23), 10711–10715. Radjavi, A., Smirnov, I., Kipnis, J., 2014. Brain antigen-reactive CD4þ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav. Immun. 35, 58–63. Robel, L., Ding, M., James, A.J., Lin, X., Simeone, A., Leckman, J.F., Vaccarino, F.M., 1995. Fibroblast growth factor 2 increases Otx2 expression in precursor cells from mammalian telencephalon. J. Neurosci. 15 (12), 7879–7891. Rook G.A., Lowry C.A., Raison C.L. Hygiene and other early childhood influences on the subsequent function of the immune system. Brain Res. 2014 Apr 13 [Epub ahead of print]. Schizophrenia Working Group of the Psychiatric Genomics, 2014. Consortium. Biological insights from 108 schizophreniaassociated genetic loci. Nature 511 (7510), 421–427. Schwartz, M., Kipnis, J., Rivest, S., Prat, A., 2013. How do immune cells support and shape the brain in health, disease, and aging? J. Neurosci. 33 (45), 17587–17596. Shi, L., Fatemi, S.H., Sidwell, R.W., Patterson, P.H., 2003. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23 (1), 297–302. Singer, H.S., Gilbert, D.L., Wolf, D.S., Mink, J.W., Kurlan, R., 2012. Moving from PANDAS to CANS. J. Pediatr. 160 (5), 725–731. Suzuki, K., Sugihara, G., Ouchi, Y., Nakamura, K., Futatsubashi, M., Takebayashi, K., Yoshihara, Y., Omata, K., Matsumoto, K., Tsuchiya, K.J., Iwata, Y., Tsujii, M., Sugiyama, T., Mori, N., 2013. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70 (1), 49–58. Swedo, S.E., Leckman, J.F., Rose, N.R., 2012. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr. Therapeut. 2, 113, http://dx.doi.org/ 10.4172/2161-0665.1000113. Vaccarino, F.M., Schwartz, M.L., Hartigan, D., Leckman, J.F., 1995. Basic fibroblast growth factor increases the number of excitatory neurons containing glutamate in the cerebral cortex. Cereb. Cortex. 5 (1), 64–78. Vaccarino, F.M., Urban, A.E., Stevens, H.E., Szekely, A., Abyzov, A., Grigorenko, E.L., Gerstein, M., Weissman, S., 2011. The promise of stem cell research for neuropsychiatric disorders. J. Child. Psychol. Psychiatry 52 (4), 504–516. Voineagu, I., Wang, X., Johnston, P., Lowe, J.K., Tian, Y., Horvath, S., Mill, J., Cantor, R.M., Blencowe, B.J., Geschwind, D.H., 2011. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474 (7351), 380–384. Williams K.A., Swedo S.E. Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond. Brain Res. 2014, This issue.
6
Editorial / brain research ] (]]]]) ]]]–]]]
Willsey, A.J., Sanders, S.J., Li, M., Dong, S., Tebbenkamp, A.T., Muhle, R.A., Reilly, S.K., Lin, L., Fertuzinhos, S., Miller, J.A., Murtha, M.T., Bichsel, C., Niu, W., Cotney, J, Ercan-Sencicek, A.G., Gockley, J., Gupta, A.R., Han, W., He, X., Hoffman, E.J., Klei, L., Lei, J., Liu, W., Liu, L., Lu, C., Xu, X., Zhu, Y., Mane, S.M., Lein, E.S., Wei, L., Noonan, J.P., Roeder, K., Devlin, B., Sestan, N., 2013. State MW. Co-expression networks implicate human mid-fetal deep cortical projection neurons in the pathogenesis of autism. Cell 155 (5), 997–1007. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J., Schwartz, M., 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9 (2), 268–275.
James F. Leckman, Flora M. Vaccarino The Child Study Center and the Departments of Psychiatry, Pediatrics, Psychology, and Neurobiology, Yale University, New Haven, CT, USA 23 September 2014
0006-8993/$ - see front matter & 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.brainres.2014.09.052