Littérature scientifique sur le sujet « Central nervous system-associated macrophages »

Macrophages can be characterized as a very multifunctional cell type with a spectrum of phenotypes and functions being observed spatially and temporally in various disease states. Ample studies have now demonstrated a possible causal link between macrophage activation and the development of autoimmune disorders. How these cells may be contributing to the adaptive immune response and potentially perpetuating the progression of neurodegenerative diseases and neural injuries is not fully understood. Within this review, we hope to illustrate the role that macrophages and microglia play as initiators of adaptive immune response in various CNS diseases by offering evidence of: (1) the types of immune responses and the processes of antigen presentation in each disease, (2) receptors involved in macrophage/microglial phagocytosis of disease-related cell debris or molecules, and, finally, (3) the implications of macrophages/microglia on the pathogenesis of the diseases.

The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Abstract Mature myeloid cells (macrophages and CD11b+ dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b+CD62L+Ly6Chi monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6Chi monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6Chi monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor–driven release of Ly6Chi precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.

Cells of the macrophage lineage are ubiquitously distributed in the body, including the central nervous system. They represent an essential host defense system to protect from infections. However, recent evidence indicates that brain macrophages may also be responsible for tissue destruction, including loss of neurons and demyelination.

L’HIC est une pathologie grave pour laquelle il n’existe actuellement aucune stratégie thérapeutique efficace. Une meilleure compréhension des mécanismes sous-jacents à l’HIC et de ses conséquences est donc essentielle pour identifier de nouvelles cibles thérapeutiques potentielles. Parmi les axes de recherche émergents, le rôle des microglies dans la clairance de l’hématome suscite un intérêt croissant. Toutefois, les microglies ne représentent pas le seul type de macrophages résidents du SNC. En effet, les CAMs comprenant les macrophages résidents des plexus choroïdes, des méninges et les macrophages périvasculaire constituent les macrophages résidents des bordures du SNC. Des études réalisées sur l’HSA ont mis en évidence le rôle majeur des CAMs dans les processus inflammatoires et l’élimination des érythrocytes. Par ailleurs, les CAMs influencent certains facteurs de risque associés à l’HIC, tels que le vieillissement, l’hypertension, l’angiopathie amyloïde cérébrale, et pourraient ainsi moduler directement ou indirectement l’HIC. Sur la base de ces observations, nous avons émis l’hypothèse que les CAMs pourraient donc jouer un rôle central dans l’HIC. Pour vérifier cette hypothèse, nous avons mis en place un modèle expérimental d’HIC par injection intracorticale de collagénase chez des souris mâles et femelles, avec ou sans déplétions des CAMs. Nos résultats mettent en évidence le rôle essentiel des CAMs dans l’évolution des HIC, notamment en influençant l’homéostasie de l’unité neurovasculaire et en participant à la résorption endogène de l’hématome. À notre connaissance, cette étude est la première à explorer le rôle des CAMs dans l’HIC tout en incluant une analyse comparative entre les mâles et les femelles
ICH is a severe pathology for which there is currently no effective therapeutic strategy. A deeper understanding of the mechanisms underlying ICH and its consequences is therefore crucial for identifying new potential therapeutic targets. While the role of microglia in hematoma clearance has gained increasing attention, it is important to note that microglia are not the only resident macrophages in the CNS. CAMs, which include choroid plexus macrophages, meningeal macrophages, and perivascular macrophages, are the resident macrophages located at the borders of the CNS.Studies in the context of SAH have demonstrated that CAMs play a pivotal role in inflammatory processes and in clearance of erythrocytes. Additionally, CAMs influence key risk factors associated with ICH, including aging, hypertension, and cerebral amyloid angiopathy, thereby modulating ICH outcomes both directly and indirectly. Based on these findings, we hypothesized that CAMs could have a central role in the progression of ICH.To test this hypothesis, we conducted loss-of-function studies by establishing an experimental model of ICH through intracortical collagenase injection in both male and female mice, with or without CAM depletion. Our results highlight that CAMs play a critical in the progression of ICH, by maintaining the homeostasis of the neurovascular unit and contributing to the endogenous clearance of the hematoma. the best of our knowledge, this study is the first to investigate the role of CAMs in ICH while including a comparative analysis between males and females

Thesis advisor: Kenneth C. Williams
Thesis advisor: Welkin Johnson
Neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is likely instigated by chronic immune activation in response to residual infection in the central nervous system (CNS), where combined antiretroviral therapy (cART) has limited access. Monocyte/macrophages (Mo/Mϕ) constitute the predominant population of infected cells in the CNS and play a major role in HIV-induced neuropathogenesis. Emergence of compartmentalized HIV subpopulations in the brain corresponds with accumulation of HIV-infected Mo/Mϕ and is consistent with acquired immune deficiency syndrome (AIDS)-related neuropathology. We used a rhesus macaque model of neuroAIDS to elucidate the role of Mo/Mϕ in establishing CNS infection and the emergence of compartmentalized virus in the brain. To do this, we: 1) performed phylogenetic analysis of viral sequences from peripheral and CNS compartments and determined the incidence of Mo/Mϕ infection in CNS tissues to identify sources of CNS viral subpopulations that emerge with AIDS-related neuropathology; 2) optimized a method for obtaining single genome viral sequences from Mo/Mϕ populations extracted from tissues and 3) performed phylogenetic analysis of viral sequences from bone marrow (BM) and CNS Mo/Mϕ and determined the incidence of Mo/Mϕ infection in the BM to assess whether BM Mo/Mϕ are sources of infected Mo/Mϕ that accumulate in the CNS with AIDS-related neuropathology. We found that animals with AIDS-related neuropathology had a higher incidence of Mo/Mϕ infection and compartmentalized SIV subpopulations in CNS tissues compared to animals without neuropathology. Additionally, CSF virus, which is used to assess the presence of CNS virus compartmentalization in living patients, was not compartmentalized even with significant compartmentalization in the brain and severe AIDS-related neuropathology (Chapter 2). Relative to animals without CNS pathology, animals with AIDS-related neuropathology had a higher incidence of Mo/Mϕ infection in the BM and viral sequences from BM and CNS perivascular Mo/Mϕ clustered with sequences from trafficking monocytes and CNS tissues (Chapter 4). The results suggest that infected Mo/MΦ in CNS tissues are sources of compartmentalized virus and that infected Mo/Mϕ in the BM are sources of infected Mo/Mϕ that accumulate in the CNS with AIDS-related neuropathology. In summary, the data in this dissertation suggest that targeting Mo/Mϕ may prevent CNS infection and inflammation associated with HIV-induced neuropathogenesis
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology

Thesis (Ph. D.)--University of California, Riverside, 2010.
Includes abstract. Available via ProQuest Digital Dissertations. Title from first page of PDF file (viewed May 17, 2010). Includes bibliographical references. Also issued in print.

Mental disorders, such as Attention deficit hyperactivity disorder (ADHD), and 22q11 deletion syndrome (22q11DS) are both related to a dopaminergic system dysfunction. Several studies have shown that dopamine (DA) not only mediates interactions into the nervous system, but can also contribute to the modulation of immunity via receptors expressed in the immune cells (Nagakome et al., 2011; Nakano et al., 2011). Autoimmunity in the central nervous system has been suggested to play a pivotal role in the pathogenesis of neurodevelopmental disorders (ND) (Schwartz. 2013), but how an immune system alteration might lead to ADHD and participate to the psychiatric features of the 22q11DS is still unclear. The importance of immune system for life-long maintenance of the brain is demonstrated by its role in the formation of new neurons, support to normal cognitive performance and neurogenesis regulation. These evidences have broken the theory of the central nervous system (CNS) as immune privileged organ, indicating that peripheral immune cells can contribute to brain homeostasis and repair. In particular, it was demonstrated that circulating blood macrophages recruitment in brain parenchyma is needed for CNS health and homeostasis. The immune cells access to the CNS is regulated by choroid plexus (CP) activation, promoted by pro-inflammatory signals from both brain parenchyma or peripheral T cells accumulated in CP (Baruch et al., 2015). Importantly, a possible role of the neuropeptide adrenomedullin (ADM) in ND has been suggested, since several studies reported a role of this peptide as a biomarker of different psychiatric disorders, such as Alzheimer (Fernandez et al., 2016), autism (Zoroglu et al., 2003), bipolar disorder (Akpinar et al., 2013), schizophrenia (Chia-Hsing Huang et al., 2004) and ADHD (Fernandez et al., 2008). ADM is a regulatory peptide involved in thymic immune tolerance mechanisms (Rulle et al., 2012; Castellani et al., 2016), which are suggested to be altered in ND. On the basis of these considerations, in this study we investigated the involvement of immunological mechanisms and their dependence to ADM both in the periphery and in CNS in mouse models of ADHD and 22q11DS, in order to define whether an immunomodulatory approach can be useful in the management of these diseases.
I disturbi mentali, come il disturbo da deficit di attenzione e iperattività (ADHD) e la sindrome da delezione 22q11 (22q11DS) sono entrambi correlati a una disfunzione del sistema dopaminergico. Diversi studi hanno dimostrato che la dopamina (DA) non solo media diverse interazioni nel sistema nervoso, ma può anche contribuire alla modulazione dell'immunità attraverso dei recettori espressi nelle cellule immunitarie (Nagakome et al., 2011; Nakano et al., 2011). È stato suggerito che l'autoimmunità nel sistema nervoso centrale svolga un ruolo fondamentale nella patogenesi di disturbi del neurosviluppo (ND) (Schwartz, 2013), ma come una alterazione del sistema immunitario possa portare all'ADHD e indurre alterazioni psichiatriche caratteristiche del 22q11DS rimane tuttora poco chiaro. L'importanza del sistema immunitario per il supporto del sistema nervoso centrale (SNC) a lungo termine è dimostrata dal suo ruolo nella formazione di nuovi neuroni, nel supporto alle normali prestazioni cognitive e nella regolazione della neurogenesi. Queste evidenze hanno rivelato i limiti della precedente teoria del SNC come organo immuno-privilegiato, indicando che le cellule immunitarie periferiche possano contribuire all'omeostasi e alla riparazione del cervello. In particolare, è stato dimostrato che il reclutamento dei macrofagi circolanti, nel parenchima cerebrale, è necessario per la salute e l'omeostasi del SNC. L'accesso delle cellule immunitarie al SNC è regolato dall'attivazione del plesso coroideo (CP), promossa da segnali pro-infiammatori provenienti sia dal parenchima cerebrale che dalle cellule T periferiche accumulate in CP (Baruch et al., 2015). Inoltre, è stato suggerito un possibile ruolo del neuropeptide adrenomedullina (ADM) in ND. Diversi studi hanno infatti riportato un ruolo di questo peptide come biomarcatore in diversi disturbi psichiatrici, come Alzheimer (Fernandez et al., 2016), autismo (Zoroglu et al., 2003), disturbo bipolare (Akpinar et al., 2013), schizofrenia (Chia-Hsing Huang et al., 2004) e ADHD (Fernandez et al., 2008). ADM è un peptide regolatorio coinvolto in meccanismi di tolleranza immunitaria che hanno luogo nel timo (Rulle et al., 2012; Castellani et al., 2016), che sembra essere modificato in ND. Sulla base di queste considerazioni, in questo studio abbiamo studiato il coinvolgimento di meccanismi immunologici e la loro dipendenza dall'ADM, sia in periferia che nel SNC di modelli murini di ADHD e 22q11DS, al fine di definire se un approccio immunomodulatorio possa essere utile nel trattamento di queste malattie.

The concept of antibody–associated central nervous system (CNS) disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T-cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Accordingly it was thought that antibodies rarely, if ever, caused CNS disease. Recently, however, it has become increasingly clear that there are CNS syndromes associated with antibodies that bind to cell surface determinants on neuronal cells and are likely to be pathogenic. Over the last ten years identification of autoimmune forms of encephalitis with antibodies against neuronal surface (NS) antigens, particularly the VGKC-complex proteins or the glutamate NMDA receptor, have shown that CNS disorders, often without associated tumours, can be antibody-mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered, and some types of more common disorders, as epilepsy or psychosis, may prove to have an autoimmune basis. Here, we call these antibodies neuronal surface antibodies (NSAbs), and the diseases associated with them NSAb syndromes or NSAS. The aim of the research performed in the three years of PhD study has been to characterize NSAS from both a laboratory and a clinical point of view. The first year of the PhD was spent at the Oxford laboratory under the supervision of Prof. Angela Vincent. During this period I contributed to the laboratory characterization of the two most important groups of NSAS: encephalitis associated with VGKC-complex-Abs and NMDAR-Abs. The results of these studies have been published (Irani et al., Brain 2010a; Irani et al., 2010b). My personal contribution in these studies included the development and optimization of immunofluorescence techniques for the detection of autoantibodies against neuronal surface antigens (NSAbs) using both primary cultures of rat hippocampal neurons and mammalian cells transfected with the antigen of interest. In addition, during my time at Oxford I investigated a possible novel proteomics approach to identify new NSAb by means of immunoprecipitation and mass spectrometry. These experiments have subsequently been applied to screen samples of patients with autoimmune cerebellar syndromes. The results of this study are described in the third part of the thesis. The doctoral thesis is divided into three parts. In the first part I have reviewed the state of the art of syndromes associated with neuronal surface antibodies, starting with a comparison of the conditions associated with antibodies to intracellular antigens and those associated with antibodies to cell surface antigens. I have then summarised the main clinical and paraclinical features of the syndromes that have already been identified. On the basis of these observations, I have designed guidelines for recognizing these and other immune-mediated conditions in the future. The guidelines work has been supervised by Prof. Angela Vincent (Oxford, UK) and critically reviewed by Prof. Francesc Graus (Barcelona, Spain), Prof. Christian Bien (Bielefeld, Germany) and Dr. Bruno Giometto (Treviso, Italy). The second part of the thesis describes the clinical and immunological characterization of a cohort of patients with suspected autoimmune encephalitis and VGKC-complex-Abs that I collected and reviewed in Padua during the 3-year period of the PhD. Recently the Oxford group showed that most antibodies previously attributed to VGKC (by radioimmunoprecipitation) target two proteins complexed with the channels Lgi1 and Caspr2, which also tend to associate with LE and Morvan’s syndrome phenotypes, respectively (see (Irani et al., Brain 2010b)). I therefore decided to focus my research on patients with autoimmune encephalitis associated with ‘VGKC’-complex-Abs in order to report their clinical and immunological profile, with a view to showing a possible antigen-phenotype correlation. During the 3-year period of my PhD, I screened 503 samples for NSAbs from 366 patients with suspected autoimmune encephalitis sent to our laboratory between January 2005 and December 2011: 279 serum (and cerebrospinal fluid) samples from 232 patients were tested for VGKC-complex-Abs; in addition 226 samples were tested for NMDAR-Abs, 59 for AMPAR1,2- and GABAbR-Abs, 91 for GAD-Abs; 21 samples were also tested on live hippocampal neurons. Screening methods included: radioimmunoprecipitation (RIA) assay for VGKC-Abs and GAD65-Abs; cell-based assay for antibodies binding human NMDAR, AMPAR1, AMPAR2, GABAbR, Lgi1 and Caspr2; indirect immunofluorescence on live hippocampal cell cultures. Thirty-two of the 232 patients tested for VGKC-complex-Abs were positive. Clinical data were available for 18 patients: 10 patients harboured Lgi1-Abs in their sera, 3 Caspr2-Abs, 5 patients were positive on RIA but not on IIF. Two patients had Morvan’s syndrome, one associated with Lgi1-ab and the other with Caspr2-Ab and a thymoma. Response to immune modulation was reported in all patients with the exception of a patient who died from lung cancer. A consistently high VGKC-complex-Abs titre despite clinical remission prompted the discovery and subsequent removal of an enlarged hyperplastic thymus in a patient with Lgi1-Abs associated LE; one Caspr2-Abs positive patient had mild encephalitis overlapping with an anti-phospholipid syndrome; another patient with an immunotherapy-responsive encephalomyelitis tested negative on IIF but had high-titre VGKC-complex-Abs on RIA. Striatal hypermetabolism was found in 4 patients with Lgi1-Abs in one case associated with faciobrachial dystonic seizures. In conclusion, these results have expanded the clinical spectrum of autoimmune encephalopathy associated with VGKC-complex antibody. It has been shown that VGKC-LE can associate not only with thymomas, but also with a hyperplastic thymus, similarly to the well-known finding in myasthenia gravis and therefore that the persistence of high VGKC-Abs titres should prompt the search for an enlarged thymus. The third part of the thesis describes a study whose aim was to identify new autoantibodies in cerebellar syndromes of possible autoimmune origin. Dr. Esther Becker from Oxford University contributed equally to me in this work. Relatively few studies have searched for potentially pathogenic antibodies in non-paraneoplastic patients with cerebellar ataxia. We first screened sera from more 52 idiopathic ataxia patients for the binding of serum IgG antibodies to cerebellar neurons. One strong-binding serum was selected for immunoprecipitation and mass spectrometry, which resulted in the identification of contactin-associated protein 2 (Caspr2) as a major antigen. Caspr2 antibodies were then found by a cell-based assay in 9/88 (10%) ataxia patients, compared to 3/144 (2%) multiple sclerosis or dementia controls. Caspr2 is strongly expressed in the cerebellum, only partly in association with voltage-gated potassium channels. Prospective studies are needed to see whether identification of Caspr2-antibodies has relevance for the diagnosis and treatment of idiopathic cerebellar ataxia.
Il concetto di sindromi del sistema nervoso centrale (SNC) associate ad anticorpi è relativamente recente. Si ritiene che le classiche sindromi paraneoplastiche neurologiche abbiano una patogenesi immunitaria prevalentemente cellulo-mediata e che gli anticorpi onconeurali costituiscano semplicemente dei biomarker. Sulla base di questo assunto si è ritenuto a lungo improbabile che autoanticorpi potessero determinare malattie del SNC. Recentemente si è resa sempre più evidente l’esistenza di sindromi del SNC associate ad anticorpi diretti contro antigeni presenti sulla superficie neuronale e pertanto potenzialmente patogenetici. L’identificazione negli ultimi dieci anni di forme di encefaliti autoimmuni con anticorpi diretti contro antigeni della superficie neuronale, ed in particolare le proteine del complesso dei canali del potassio voltaggio-dipendenti (VGKC-complex) e i recettori del glutammato di tipo NMDA, ha dimostrato l’esistenza di sindromi del SNC, generalmente non associate alla presenza di neoplasie, che possono essere anticorpo-mediate e pertanto potenzialmente trattabili. Lo spettro clinico di queste malattie non è stato ancora pienamente esplorato, vi potrebbero essere altre malattie che devono ancora essere scoperte, e vi sono forme di epilessia o sindromi psichiatriche che potrebbero avere una base autoimmune. Definiamo questi anticorpi neuronal surface antibodies (NSAbs) e le malattie ad essi associate NSAS (Neuronal Surface Antibody Syndrome). Lo scopo della ricerca effettuata in questo percorso di tre anni di dottorato è stato la caratterizzazione clinica e laboratoristica di alcune NSAS. Il primo anno di dottorato è stato effettuato presso l’Università di Oxford sotto la supervisione della Prof. Angela Vincent. Durante questo periodo ho contribuito alla caratterizzazione delle due più importanti forme di NSAS, le encefaliti associate ad anticorpi anti-VGKC-complex e ad anti-NMDAR. I risultati di questi studi sono stati pubblicati (Irani et al., Brain 2010 a e b). Il mio personale contributo è consistito nello sviluppo e ottimizzazione di tecniche di immunofluorescenza per l’identificazione di NSAbs, utilizzando sia colture primarie di neuroni ippocampali che cellule di mammifero transfettate con l’antigene di interesse. Inoltre durante il soggiorno presso il laboratorio di Oxford ho cercato di mettere a punto un approccio di proteomica per l’identificazione di nuovi NSAbs mediante immunoprecipitazione e spettrometria di massa. Tale approccio è stato successivamente applicato nello screening di pazienti con sindromi cerebellari autoimmuni. I risultati di questo studio sono descritti nella terza parte della tesi. La tesi di dottorato è divisa in tre parti. Nella prima parte ho esaminato lo stato dell’arte delle sindromi associate ad anticorpi contro antigeni di superficie iniziando con un confronto tra disordini associati ad anticorpi contro antigeni intracellulari e antigeni di superficie. Ho quindi riassunto i maggiori aspetti clinici e paraclinici delle sindromi che sono state già identificate, e da queste osservazioni ho disegnato delle linee guida per il futuro riconoscimento di queste e altre condizioni potenzialmente mediate da NSAbs. Il lavoro di stesura di queste linee guida è stato supervisionato dalla Prof. Angela Vincent e riesaminato criticamente dai Prof. Francesc Graus (Barcelona, Spain) e Prof. Christian Bien (Bielefeld, Germany) e dal Dr. Bruno Giometto (Treviso, Italy). La seconda parte della tesi descrive la caratterizzazione clinica e immunologica di una coorte di pazienti con sospetta encefalite autoimmune e anticorpi anti-VGKC-complex che ho raccolto ed esaminato a Padova nei 3 anni di dottorato. Recentemente è stato dimostrato dal gruppo di lavoro di Oxford che la maggior parte degli anticorpi precedentemente attribuiti ai canali del potassio VGKC (mediante immunoprecipitazione) in realtà hanno come bersaglio due proteine canale complessate con i VGKC, Lgi1 e Caspr2; anticorpi diretti contro queste due proteine tendono ad associarsi rispettivamente con encefalite limbica (EL) e sindrome di Morvan (vedi Irani et al. Brain 2010b). Ho quindi deciso di focalizzare la mia indagine su pazienti con encefaliti autoimmuni associate ad anticorpi anti-VGKC-complex con l’obiettivo di riportare il profilo clinico e immunologico di questi pazienti e possibilmente dimostrare una correlazione tra antigene e fenotipo. Durante i tre anni di dottorato ho analizzato 503 campioni da 366 pazienti con sospetta encefalite autoimmune inviati al nostro laboratorio tra gennaio 2005 e dicembre 2011: 279 campioni di siero (e/o di liquido cerebrospinale) da 232 pazienti sono stati testati per anti-VGKC-complex; inoltre 226 campioni sono stati testati per anticorpi anti-NMDAR, 59 per anti-AMPAR1 e 2 e GABAbR, 91 per anti-GAD; 21 campioni inoltre sono stati testati su neuroni ippocampali. Le metodiche di screening hanno incluso: radioimmunoprecipitazione (RIA) per anti-VGKC e -GAD65; immunofluorescenza indiretta (IFI) su cellule transfettate con NMDAR, AMPAR1, AMPAR2, GABAbR, Lgi1 and Caspr2; IFI su neuroni ippocampali. I dati raccolti dai pazienti risultati positivi per anti-VGKC-complex sono quindi stati analizzati. Trentadue pazienti su 232 testati sono risultati positivi per anti-VGKC-complex. Informazioni cliniche sono risultate disponibili per 18 pazienti: 10 positivi per anti-Lgi1, 3 per anti-Caspr2 mentre 5 sono risultati positivi su RIA ma non su IFI. Due pazienti hanno presentato un quadro sindromico compatibile con la sindrome di Morvan, in un caso in associazione ad anti-Lgi1 e nell’altro ad anti-Caspr2 e timoma. In tutti i pazienti in cui è stato somministrato un trattamento immunomodulante si è assistito ad un miglioramento clinico con l’eccezione di una paziente deceduta a causa di un microcitoma polmonare. Un titolo anticorpale persistentemente elevato nonostante la remissione clinica in una paziente con EL e anticorpi anti-Lgi1 ha condotto all’individuazione e alla successiva rimozione di un timo iperplastico; un paziente con anti-Caspr2 ha manifestato un’encefalite di grado lieve in concomitanza di una sindrome da anticorpi anti-fosfolipidi; un altro paziente con una forma di encefalomielite responsiva al trattamento è risultato negativo in IFI ma ha presentato un alto titolo anticorpale per anti-VGKC su RIA. Un ipermetabolismo dei gangli della base è stato individuato in 4 pazienti con anti-Lgi1, in un caso associato alla presenza di crisi epilettiche distoniche facio-brachiali. In conclusione i risultati di questo studio hanno esteso lo spettro delle manifestazioni cliniche note associate ad anticorpi anti-VGKC-complex. E’ stato dimostrato che le EL con anti-VGKC possono associare non solo a timomi ma anche ad iperplasia del timo, in maniera analoga a quanto avviene nella miastenia gravis. La persistenza di un alto titolo anticorpale dovrebbe pertanto indurre un accurato imaging del timo. La terza parte della tesi descrive uno studio sperimentale che ha avuto lo scopo di identificare nuovi autoanticorpi nelle sindromi cerebellari di possibile origine autoimmune. La Dr.ssa Esther Becker dell’Università di Oxford ha contribuito in egual misura al sottoscritto in questo studio. Pochi studi in precedenza avevano ricercato anticorpi potenzialmente patogenetici in pazienti non paraneoplastici con atassia cerebellare. Inizialmente 52 pazienti con atassia cerebellare idiopatica sono stati sottoposti a screening mediante immunofluorescenza su neuroni cerebellari. Un siero che ha dimostrato un intensa reattività sui neuroni è stato selezionato per gli esperimenti di immunoprecipitazione e spettrometria di massa. Tale approccio ha portato all’identificazione di Caspr2 (contactin-associated protein 2) come maggiore antigene. Anticorpi anti-Caspr2 sono stati poi identificati mediante immunofluorescenza su cellule transfettate in 9 pazienti su 88 con atassia (10%), in confronto a 3 pazienti su 144 di controllo affetti da sclerosi multipla o demenza. Caspr2 è altamente espresso nel cervelletto, e solo in parte in associazione ai canali del potassio voltaggio-dipendenti. Studi prospettici saranno necessari per valutare se l’identificazione di anticorpi anti-Caspr2 abbia valore nella diagnosi e trattamento delle sindromi cerebellari.

Whipple disease (WD) is a multisystemic infection caused by the bacillus Tropheryma whipplei. Although the organism is ubiquitous in the environment, WD is rare. In affected individuals, the organism resides intracellularly within macrophages and can manipulate host immune responses to avoid clearance. Central nervous system (CNS) involvement can occur as a manifestation of classic WD, in the setting of a relapse of previously treated WD, or rarely as isolated nervous system infection. Diagnosis of CNS WD rests on polymerase chain reaction (PCR) and demonstration of periodic acid-Schiff (PAS) positive macrophages in tissue, and ef

The human immunodeficiency virus (HIV) enters the central nervous system soon after infection; can infect glia and tissue macrophages in the brain; and can injure neurons, resulting in loss of dendrites. These and other processes underpin a syndrome of cognitive and motor impairment termed HIV-associated neurocognitive disorder (HAND). This chapter principally focuses on HAND, although delirium and other neurocognitive disorders are also discussed and should remain in the differential diagnosis of cognitive impairment in persons with HIV. A differential diagnosis of cognitive impairment in HIV also includes multimorbid conditions that can influence neurocognitive performance, such as metabolic syndrome, vascular disease, medication toxicity, and substance use disorders. When developing treatment recommendations for HAND, initiation of ART and treatment of multimorbid conditions and other neurocognitive disorders should be prioritized. It is important for clinicians to regularly monitor HIV patients for HAND and other neurocognitive disorders since cognitive impairment can affect activities of daily living; quality of life; adherence to risk reduction, medical care, and medication; and survival.

Nitrogen monoxide is a gas transmitter that is an important intermediary in many organ systems, especially in the central nervous system. Nitrogen monoxide is involved in the relaxation of smooth vascular muscles, activation of neurons and responsible for the cytotoxicity of macrophages. The study of change nitrogen oxide metabolite concentration helps to determine its effects on human and animal organs. The study was carried out on laboratory animals of different ages. We used a spectrophotometric method to determine the level of metabolites based on the reaction of nitrites to the Griss reagent. We noted that the maximum level of metabolites NO was observed in newborn animals at the age of 4 days. In addition, metabolite concentrations decreased gradually by 14-15 days of life, reaching a minimum of 30 days Key words: nitrogen monoxide, rats, age, metabolites of nitrogen monoxide, spectrophotometry.

Stroke is the second leading cause of death and the primary cause of disability in Brazil. Ischemia resulting from a stroke triggers an inflammatory response in the central nervous system, primarily mediated by neutrophils, lymphocytes, and macrophages. Recent research suggests that the neutrophil/lymphocyte ratio (NLR) in peripheral blood can serve as a reliable marker of systemic inflammation in various diseases. The present study aims to quantify the NLR in patients diagnosed with ischemic stroke, who received treatment at a specialized clinic of a university hospital situated in the central region of São Paulo. Additionally, the study aims to investigate if any correlation exists between NLR values and risk factors associated with ischemic stroke and its severity — assessed using the National Institutes of Health Stroke Scale (NIHSS). This retrospective study is based on medical records of patients aged over 18 years, who had ischemic stroke between 2017 and 2022. The collection of clinical data includes information on the type of ischemic stroke and the presence of risk factors. The quantification of NLR is performed by analyzing blood count data from the patients’ medical records. Of the 194 stroke patients whose data were collected, 80.5% had NLR values exceeding 2, a value considered non-physiological by literature and preliminary data obtained from healthy individuals at the same university hospital. It was also observed that patients with a more severe condition, according to the NIHSS scale, had a higher NLR. However, no statistically significant correlation was found between NLR, types of stroke, and the presence of risk factors. In conclusion, stroke patients exhibit a higher neutrophil-lymphocyte ratio, which is associated with the severity of the condition but not with risk factors. NLR can be a prognostic marker of stroke.

Context: COVID-19 is well-known to increase the risk of developing thromboembolism; thus, patients may present with diverse neurovascular manifestations. Case report: A 56-year-old man presented with sudden onset of incoordination of his left arm and leg. He also had a history of recurrent episodes of transient left hemithoracic pain radiating to his left arm, along with right visual hemi-field positive phenomena. Additionally, he reported self-limited fever and anosmia three weeks earlier. Examination revealed left hemiataxia (NIHSS score: 2). Initial assessment with brain CT, intracranial and cervical CT angiography was normal. Shortly after admission, the patient developed acute weakness of his four limbs and urinary retention. Neurological exam showed left homonimous hemianopia, asymmetric tetraparesis and a superficial sensory level at C4. Neuraxis MRI was performed and diffusion-weighted imaging revealed acute ischemic lesions in the occiptal lobes, cerebellum and cervicalthoracic spine. A thorough diagnostic work-up was conducted. Laboratory tests were unremarkable, including inflammatory markers, viral hepatitis, HIV and syphilis serologies, as well as rheumatologic tests and a thrombophilia panel, except for SARS-COV-2 serology, with detection of IgM antibodies. RT-PCR nasopharyngeal swab was negative. Further investigation with CSF analysis, CT angiography of the aorta, transthoracic echocardiogram, 24-hour holter monitoring and transcranial Doppler didn’t show any abnormalities. Transesophageal echocardiogram revelead a minor patent foramen ovale. Conclusion: This is a case of acute cerebral, cerebellar and spinal embolic infarction, probably related to Covid-19, illustrating the infection’s associated coagulopathy¹.

Background: The most prevalent autoimmune diseases (AID) of the Central Nervous System (CNS) are Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder (NMOSD), both being demyelinating diseases. Recent studies show that patients with CNS demyelinating diseases have a higher risk of presenting associated diagnosis of another AIDs. Objectives: The present study aimed to evaluate the frequency of autoimmune comorbidities and autoantibodies in patients with MS and NMOSD. Design and setting: Were analyzed the medical records of 126 patients with MS or NMOSD, from the Demyelinating Diseases Outpatient Clinic in the Neurological and Psychiatric Unit in the Complexo Hospital de Clinicas da Universidade Federal do Parana (CHC-UFPR), taking in consideration the presence of AIDs and autoantibodies. Methods: The variables were organized in a Microsoft® Office Excel spreadsheet for statistical analysis. Results: Of the 126 analyzed cases, 111 (88%) corresponded to MS and 15 (12%) to NMOSD. From the total, at least one AID was associated in 11 patients (8.7%), six of which were diagnosed with MS and five with NMOSD (p<0.05). Regarding autoantibodies, there were 21 cases (16.7%) in which antinuclear antibodies (ANA) were present, and 12 cases (9.5%) in which autoantibodies other than ANA were present (p<0.05). Conclusions: The results of the study showed a higher frequency of AIDs in patients with CNS demyelinating diseases compared to the normal population. The results found in this study may contribute to improve the treatment and follow-up of patients with CNS demyelinating diseases, so that the concomitance of other AIDs is considered by the clinician.

Is the perineuronal net structure within emotional processing brain regions associated with changes in affective state? The objective of this scoping review is to bring together the literature on human and animal studies which have measured perineuronal net structure in brain regions associated with emotional processing (such as but not limited to amygdala, hippocampus and prefrontal cortex). Perineuronal nets are a specialised form of condensed extracellular matrix that enwrap and protect neurons (Suttkus et al., 2016), regulate synaptic plasticity (Celio and Blumcke, 1994) and ion homeostasis (Morawski et al., 2015). Perineuronal nets are dynamic structures that are influenced by external and internal environmental shifts – for example, increasing in intensity and number in response to stressors (Blanco and Conant, 2021) and pharmacological agents (Riga et al., 2017). This review’s objective is to generate a compilation of existing knowledge regarding the structural changes of perineuronal nets in experimental studies that manipulate affective state, including those that alter environmental stressors. The outcomes will inform future research directions by elucidating non-cellular central nervous system mechanisms that underpin positive and negative emotional states. These methods may also be targets for manipulation to manage conditions of depression or promote wellbeing. Population: human and animal Condition: affective state as determined through validated behavioural assessment methods or established biomarkers. This includes both positive and negative affective states. Context: PNN structure, measuringPNNs.