Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases.

The neurovascular unit, composed of vascular endothelium, vascular smooth muscle, extracellular matrix components, pericytes, astrocytes, microglia, and neurons, allows the highly regulated exchange of molecules and the limited trafficking of cells to the brain through coordinated signaling activity. The passage of peripheral immune cells to the brain parenchyma is observed when there is clear damage to the barriers of this neurovascular unit, as occurs in traumatic brain injury. The possibility of leukocyte infiltration to the brain in neurodegenerative conditions has been proposed. In this review, we focus on describing the evidence for peripheral immune cell infiltration to the brain in the two most frequent neurodegenerative diseases: Alzheimer's and Parkinson's diseases. In particular, we address the mechanisms that promote the passage of these cells into the brain under such pathological conditions. We also discuss the relevance of the resulting cellular interactions, which provide evidence that the presence of peripheral immune cells in the brain is a key point in these neurodegenerative diseases.

Encephalitis associated with anti-mGluR5 antibodies.

A 30-year-old woman had 5 days of visual hallucinations, nystagmus, memory impairment and mutism. On examination, she was disorientated with reduced attention span, gaze-evoked nystagmus, paratonia and abnormal frontal reflexes. Cerebrospinal fluid (CSF) showed 80 cells, protein 0.41 g/L and glucose 3.2 mmol/L (plasma glucose 5.0 mmol/L). MR scan of the brain showed involvement of limbic and extra-limbic regions and brainstem. Commercial cell-based assays were negative, but tissue-based assays showed neuropil staining, and cell-based assays for anti-metabotropic glutamate receptor 5 (mGluR5) antibodies were positive in serum and CSF. Six months later, she was diagnosed with Hodgkin's lymphoma. This case emphasises the broader clinical spectrum of anti-mGluR5 encephalitis, challenging its initial characterisation as Ophelia syndrome. It underscores the significance of interpreting commercial cell-based assays and advocates for tissue-based assay testing followed by cell-based assay testing in serum and CSF for diagnosing rare autoimmune encephalitis.

Neuroimmunology of rabies: New insights into an ancient disease.

Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family Rhabdoviridae) disease affecting approximately 59,000 people worldwide. The central nervous system (CNS) is targeted, and rabies has a case fatality rate of almost 100% in humans and animals. Rabies is entirely preventable through proper vaccination, and thus, the highest incidence is typically observed in developing countries, mainly in Africa and Asia. However, there are still cases in European countries and the United States. Recently, demographic, increasing income levels, and the coronavirus disease 2019 (COVID-19) pandemic have caused a massive raising in the animal population, enhancing the need for preventive measures (e.g., vaccination, surveillance, and animal control programs), postexposure prophylaxis, and a better understanding of rabies pathophysiology to identify therapeutic targets, since there is no effective treatment after the onset of clinical manifestations. Here, we review the neuroimmune biology and mechanisms of rabies. Its pathogenesis involves a complex and poorly understood modulation of immune and brain functions associated with metabolic, synaptic, and neuronal impairments, resulting in fatal outcomes without significant histopathological lesions in the CNS. In this context, the neuroimmunological and neurochemical aspects of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are likely related to the clinical manifestations of rabies infection. Uncovering new links between immunopathological mechanisms and neurochemical imbalance will be essential to identify novel potential therapeutic targets to reduce rabies morbidity and mortality.

Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage.

Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB´s) and blood-cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.

Neuroimmune interactions in atopic and allergic contact dermatitis.

The skin is a barrier organ populated by many types of skin-resident immune cells and sensory neurons. It has become increasingly appreciated that neuroimmune interactions are an important component of inflammatory diseases such as atopic dermatitis and allergic contact dermatitis. Neuropeptides secreted from nerve terminals play an important role in mediating cutaneous immune cell function, and soluble mediators derived from immune cells interact with neurons to induce itch. In this review article, we will explore emerging research describing neuronal effector functions on skin immune cells in mouse models of atopic and contact dermatitis. We will also discuss the contributions of both specific neuronal subsets and secreted immune factors to itch induction and the associated inflammatory processes. Finally, we will explore how treatment strategies have emerged around these findings and discuss the relationship between scratching and dermatitis.

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression.

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as a significant contributing factor. It involves the activation of microglia and astrocytes, leading to the release of pro-inflammatory cytokines and chemokines and the infiltration of peripheral leukocytes into the central nervous system (CNS). These instances result in neuronal damage and neurodegeneration through activated nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain containing protein 3 (NLRP3) and nuclear factor kappa B (NF-kB) pathways and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Due to limited effectiveness regarding the inhibition of neuroinflammatory targets using conventional drugs, there is challenging growth in the search for innovative therapies for alleviating neuroinflammation in CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling and Expression, Cold Exposure, and Fibrin-Targeted strategies significantly promise to mitigate neuroinflammatory processes. These approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such as Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson's Disease, and Alzheimer's Disease. While the findings are promising, immunomodulatory therapies often face limitations due to Immune-Related Adverse Events. Therefore, the conduction of randomized clinical trials in this matter is mandatory, and will pave the way for a promising future in the development of new medicines with specific therapeutic targets.

Characteristics and management of Susac syndrome in an emergent country: a multi-center case series from Brazil.

BACKGROUND: Susac syndrome (SS) is a rare endotheliopathy with an estimated prevalence of 0.14-0.024 per 100,000. It is an important differential diagnosis in demyelinating disorders. There are few case series and no large randomized controlled trials, and most reports come from developed countries. We report six cases of SS in three centers in Brazil and discuss management challenges in emergent countries. METHODS: This is a retrospective case series of patients diagnosed with SS in three medical centers in Brazil between April 2018 and July 2021. The European Susac consortium (EuSaC) criteria were used for diagnosis of SS. Demographic data and clinical interventions were described and outcomes were assessed subjectively and by applying the modified Rankin Scale (mRS) on last follow-up. RESULTS: Six patients were diagnosed with SS (3 males, 3 females). Mean age at presentation was 36 years (range 17 to 54). The most common initial symptom was confusion, followed by visual impairment and hearing loss. Characteristic snowball lesions on magnetic resonance imaging (MRI) were present in four patients (66%). Retinal artery abnormalities were present in half (3/6) of patients, and sensorineural hearing loss was present in four patients (66%). Outcome was favorable (mRS ≤ 2) in five patients (86%). Patients treated early had a more favorable outcome. CONCLUSION: Emergent countries face challenges in the diagnosis and management of patients with SS, such as access to advanced tests (fluorescein angiography, serial MRI) and treatment drugs (rituximab, mycophenolate). Further research should consider particularities of patients with SS in emergent countries.

Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively.

Dr. C. Alberto Juan Dorta Contreras: heraldo de la ciencia abierta y la neuroinmunología en Cuba / Dr. Alberto Juan Dorta Contreras: herald of open science and neuroimmunology in Cuba

RESUMEN Esta Semblanza resume la trayectoria del Dr. Alberto Juan Dorta Contreras, eminente científico, quien dedicara su vida a la Neuroinmunología y difusión de los principios de Ciencia Abierta en Cuba. Su labor profesional se centró principalmente en la investigación básica y clínica, sobre todo, de la Inmunología con énfasis en la repercusión de las enfermedades infecciosas y el papel del sistema del complemento en el Sistema Nervioso Central. Importante ha sido, además, su función como docente en pregrado y posgrado a través de las Becas Quincke, un espacio creado por el Dr. Dorta para acercarse al mundo de la experimentación. Se desempeñó en los últimos años como director de la Revista Cubana de Investigaciones Biomédicas, la que impulsó a categorías superiores con su esfuerzo y rigor de trabajo, con lo que llegó a ocupar en este momento el primer lugar de las revistas cubanas según el ranking de Scimago. Su vida, obra y destacada trayectoria hacen que el Dr. Dorta Contreras sea un ejemplo de sacrificio, consagración, valor, honestidad, sencillez, altruismo y entrega a la ciencia y la humanidad. Por tales razones, el objetivo de esta Semblanza es destacar los aspectos más relevantes de su obra como científico y docente, apoyados en testimonios, búsqueda en bases de datos, entrevistas a estudiantes y colegas de trabajo para resumir la prolífera vida laboral del Dr.C Alberto Juan Dorta Contreras.

ABSTRACT This Semblance summarizes the career of Dr. Alberto Juan Dorta Contreras, an eminent scientist who dedicated his life to Neuroimmunology and the dissemination of open science principles in Cuba. His professional work was mainly focused on basic and clinical research, especially Immunology, with an emphasis on the impact of infectious diseases and the role of the complement system in the Central Nervous System. Also important has been his role as an undergraduate and graduate teacher in the Quincke Scholarships, a space created by Dr. Dorta to get closer to the world of experimentation. In recent years, he served as director of the Cuban Journal of Biomedical Research, which he promoted to higher categories with the effort and rigor of his work, currently occupying the first place among Cuban journals according to the Scimago ranking. His life, work and outstanding career make Dr. Dorta Contreras an example of sacrifice, dedication, value, honesty, simplicity, altruism and dedication to science and humanity. For these reasons, the objective of this article is to highlight the most relevant aspects of his work as a scientist and teacher, supported by testimonies, database searches, interviews with students and work colleagues to summarize the prolific working life of Dr C. Alberto Juan Dorta Contreras.

Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome - a case report.

BACKGROUND: The term "Tolosa-Hunt syndrome" (THS) has been used to refer to painful ophthalmoplegia associated with nonspecific inflammation of the cavernous sinus and many processes can result in a similar clinical picture, including infectious, inflammatory and neoplastic diseases. Rosai-Dorfman disease (RDD) is a lymphoproliferative disorder that rarely affects the central nervous system. We report a case of isolated CNS Rosai-Dorfman disease involving the cavernous sinus and presenting as "Tolosa-Hunt syndrome". CASE PRESENTATION: Our patient presented with horizontal diplopia due to impairment of cranial nerves III, IV and VI and a stabbing/throbbing headache predominantly in the left temporal and periorbitary regions. There was a nonspecific enlargement of the left cavernous sinus on MRI and the patient had a dramatic response to steroids. Biopsy of a frontal meningeal lesion was compatible with RDD. CONCLUSIONS: We highlight the importance of including Rosai-Dorfman disease as a differential diagnosis in cavernous sinus syndrome and demonstrate a satisfactory long-term response to steroid treatment in this disease.

Intracranial mass lesions and skin discoloration in the armpits as unusual clues to Erdheim-Chester disease: a case report.

BACKGROUND: Erdheim-Chester disease (ECD) is a non-Langerhans histiocytosis that results in multi-organ disease involving the skin, bones, lungs and kidneys. Central nervous system (CNS) involvement occurs in about 50 % of patients, and diabetes insipidus, visual disturbances, and cerebellar ataxia are the most frequent neurological signs. We report a case of Erdheim-Chester disease with central nervous system involvement in the form of enhancing intracranial mass lesions with massive edema. CASE PRESENTATION: The patient presented with vertigo, ataxia, encephalopathy and pyramidal signs. Diagnosis was suggested by xanthomatous skin lesions and a biopsy was compatible with Erdheim-Chester disease demonstrating xanthogranulomas CD68 positive (clone KP1) and CD1a and S100 negative. Testing for BRAF mutation was negative, which precluded treatment with Vemurafenib. Treatment with steroids and interferon resulted in improvement of neurological signs and regression of edema on MRI. CONCLUSIONS: The diagnosis of Erdheim-Chester disease should be considered in intracranial mass lesions. Xanthomatous skin lesions are a clue to the diagnosis.

Equine herpesvirus 1 elicits a strong pro-inflammatory response in the brain of mice.

Equine herpesvirus type 1 (EHV-1) is an emerging pathogen that causes encephalomyelitis in horses and non-equid species. Several aspects of the immune response in the central nervous system (CNS), mainly regarding the role of inflammatory mediators during EHV-1 encephalitis, remain unknown. Moreover, understanding the mechanisms underlying extensive neuropathology induced by viruses would be helpful to establish therapeutic strategies. Therefore, we aimed to evaluate some aspects of the innate immune response during highly neurovirulent EHV-1 infection. C57BL/6 mice infected intranasally with A4/72 and A9/92 EHV-1 strains developed a fulminant neurological disease at 3 days post-inoculation with high viral titres in the brain. These mice developed severe encephalitis with infiltration of monocytes and CD8+ T cells to the brain. The inflammatory infiltrate followed the detection of the chemokines CCL2, CCL3, CCL4, CCL5, CXCL2, CXCL9 and CXCL-10 in the brain. Notably, the levels of CCL3, CCL4, CCL5 and CXCL9 were higher in A4/72-infected mice, which presented higher numbers of inflammatory cells within the CNS. Pro-inflammatory cytokines, such as interleukins (ILs) IL-1α, IL-1ß, IL-6, IL-12ß, and tumour necrosis factor (TNF), were also detected in the CNS, and Toll-like receptor (TLR) TLR2, TLR3 and TLR9 genes were also upregulated within the brain of EHV-1-infected mice. However, no expression of interferon-γ (IFN-γ) and IL-12α, which are important for controlling the replication of other herpesviruses, was detected in EHV-1-infected mice. The results show that the activated innate immune mechanisms could not prevent EHV-1 replication within the CNS, but most likely contributed to the extensive neuropathology. The mouse model of viral encephalitis proposed here will also be useful to study the mechanisms underlying extensive neuropathology.

Integrin-directed antibody-based immunotherapy: focus on VLA-4.

One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing in vitro transendothial and fibronectin-driven migration of CD4+ and CD8+ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.

Protection induced by estradiol benzoate in the MPP+ rat model of Parkinson's disease is associated with the regulation of the inflammatory cytokine profile in the nigro striatum.

Previously, we have demonstrated that ß-estradiol-3-benzoate (EB) has a protective effect on the neurodegenerative experimental model of Parkinson's disease. The protective effect is through the induction of the expression of paraoxonase-2 (PON2) in the striatum. PON2 has proven to have antioxidant and anti-inflammatory activity, this protein has a beneficial effect in MPP+ model in rats decreasing the lipid peroxidation and the oxidative stress. Furthermore, the molecular effect and the pathway by which EB induces protection were not further pursued. This study shows the regulation by EB of the anti-inflammatory effect through the modulation of cytokines, antioxidant enzymes and PON2 in the rat striatum. Rats were gonadectomized and 30 days after were randomly assigned into four experimental groups; only vehicles (Control group); EB treatment (EB group); MPP+ injury (M group); EB plus MPP+ injured (EB/M group). EB treatment consisted of 100 µg of the drug administered every 48 h for 11 days. Results showed that EB (group EB/M) treatment decrease significantly (40%) the number of ipsilateral turns respect to the M group and prevents significantly the dopamine (DA) decreased induced by MPP+ (~75%). This results are correlate with a significant decrease in the level of lipid peroxidation (60%) of the EB/M group respect to the M group. The EB treatment showed protection against neurotoxicity induced with MPP+, this could be due to EB capacity to prevent the increase in the expression level of proinflammatory cytokines TNF-α, IL-1 and IL-6 induced by MPP+. While, TGF-ß1 and TGF-ß3 expression was reduced in the rats treated only with MPP+, in the rats of EB/M group the expression of both cytokines was increased. EB protective effect against MPP+ neurotoxicity is related to antioxidant effect of PON2, pro-inflammatory cytokines and GSHR but not to SOD2, catalase, GPX1 or GPX4.

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia.

Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.

Autoimmune Encephalitis in Latin America: A Critical Review.

Autoimmune encephalitis is an increasingly recognized cause of encephalitis. The majority of case series report patients residing in developed countries in the northern hemisphere. The epidemiologic features of autoimmune encephalitis in Latin America are still unclear. The aim of the study was to perform a review of the clinical presentation of autoimmune encephalitis in Latin America and compare to world literature. References were identified by an in-depth literature search and selected on the basis of relevance to the topic and authors' judgment. We selected clinical studies and case reports published from 2007 to July, 2020 including patients from Latin American countries. Of the 379 patients included, the majority were cases of anti-NMDA receptor encephalitis (93.14%), followed by anti-VGKC-complex encephalitis (N = 17; 4.48%), anti-GAD encephalitis (N = 9; 2.37%), anti-AMPA receptor encephalitis (N = 1; 0.26%), anti-GABA receptor encephalitis (N = 1; 0. 26%), anti-mGluR5 encephalitis (N = 1; 0. 26%), and anti-mGluR1 encephalitis (N = 1; 0. 26%). Reported cases of Anti-NMDA encephalitis in Latin-America had a very slight female predominance, lower prevalence of associated tumors and a lower incidence of extreme delta brush on electroencephalogram. Autoimmune encephalitis is possibly underdiagnosed in underdeveloped countries. Its outcome after treatment, however, appears to be similarly favorable in Latin American patients as has been reported in developed countries based on available case reports and case series. Regional specificities in the manifestation of autoimmune encephalitis could be related to epidemiologic factors, such as the presence of different triggers and different genetic and immunologic background, that need to be studied by future research.