Keeping it in check: chronic viral infection and antiviral immunity in the brain.
Miller Katelyn D,Schnell Matthias J,Rall Glenn F
Nature reviews. Neuroscience
It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response - when combined with the unique anatomy and physiology of the CNS - provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.
Protective and Pathological Immunity during Central Nervous System Infections.
Klein Robyn S,Hunter Christopher A
The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege.
The role of infections in autoimmune encephalitides.
Joubert B,Dalmau J
Autoimmune encephalitides are autoimmune neurological disorders characterized by rapidly progressive central nervous system symptoms associated with specific auto-antibodies targeting neuronal cell-surface proteins. The clinical features of encephalitis are frequently preceded by symptoms suggesting an infectious process, and specific pathogens have been detected at the early phase of the disease in some patients, suggesting that it can be triggered by infections. Moreover, recent data have shown an association with specific HLA haplotypes, suggesting a genetic susceptibility to develop at least some subtypes of autoimmune encephalitis. Nonetheless, the immunological mechanisms leading from an adequate response to infection to autoimmunity against neuronal self-antigens remain highly hypothetical. Molecular mimicry, inborn errors of the host immune system, as well as epitope spreading and chronic activation of innate immunity actors, may be involved. Importantly, the frequency of prodromal infectious symptoms and association with HLA haplotypes differ among autoimmune encephalitides, suggesting that depending on the subtype distinct immunopathogenic mechanisms are involved. A direct link between infection and autoimmune encephalitis was recently provided by the demonstration that most of the so-called relapsing neurological symptoms post-herpes simplex virus encephalitis corresponded to viral-induced autoimmune encephalitis with antibodies against NMDA receptors or other, yet unknown, neuronal surface antigens. Although this association has also been demonstrated experimentally in mice, the underlying immunological mechanisms remain unknown. Overall, a body of clinical, epidemiological and experimental data suggests infections are involved in the pathogenesis of autoimmune encephalitides. Further studies, focusing on the interplays between pathogens, genetic determinants of the host immune response, and brain inflammation, are needed to clarify the immunological mechanisms that lead to autoimmune encephalitis after infection.
The mucosal immune system: master regulator of bidirectional gut-brain communications.
Powell Nick,Walker Marjorie M,Talley Nicholas J
Nature reviews. Gastroenterology & hepatology
Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.
T cell responses in the central nervous system.
Korn Thomas,Kallies Axel
Nature reviews. Immunology
T cells are required for immune surveillance of the central nervous system (CNS); however, they can also induce severe immunopathology in the context of both viral infections and autoimmunity. The mechanisms that are involved in the priming and recruitment of T cells to the CNS are only partially understood, but there has been renewed interest in this topic since the 'rediscovery' of lymphatic drainage from the CNS. Moreover, tissue-resident memory T cells have been detected in the CNS and are increasingly recognized as an autonomous line of host defence. In this Review, we highlight the main mechanisms that are involved in the priming and CNS recruitment of CD4 T cells, CD8 T cells and regulatory T cells. We also consider the plasticity of T cell responses in the CNS, with a focus on viral infection and autoimmunity.
Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System.
Dalmau Josep,Geis Christian,Graus Francesc
Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all characterized by autoantibodies against neuronal proteins involved in synaptic signaling and plasticity. In clinical practice these findings have changed the diagnostic and treatment approach to potentially lethal, but now treatable, neurological and psychiatric syndromes previously considered idiopathic or not even suspected to be immune-mediated. Studies show that patients' antibodies can impair the surface dynamics of the target receptors eliminating them from synapses (e.g., NMDA receptor), block the function of the antigens without changing their synaptic density (e.g., GABAb receptor), interfere with synaptic protein-protein interactions (LGI1, Caspr2), alter synapse formation (e.g., neurexin-3α), or by unclear mechanisms associate to a new form of tauopathy (IgLON5). Here we first trace the process of discovery of these diseases, describing the triggers and symptoms related to each autoantigen, and then review in detail the structural and functional alterations caused by the autoantibodies with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?
Pellegrini Carolina,Antonioli Luca,Colucci Rocchina,Blandizzi Corrado,Fornai Matteo
Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.
B cells in autoimmune and neurodegenerative central nervous system diseases.
Nature reviews. Neuroscience
B cells are essential components of the adaptive immune system and have important roles in the pathogenesis of several central nervous system (CNS) diseases. Besides producing antibodies, B cells perform other functions, including antigen presentation to T cells, production of proinflammatory cytokines and secretion of anti-inflammatory cytokines that limit immune responses. B cells can contribute to CNS disease either through their actions in the periphery (meaning that they have an 'outside-in' effect on CNS immunopathology) or following their compartmentalization within the CNS. The success of B cell-depleting therapy in patients with multiple sclerosis and CNS diseases with an autoantibody component, such as neuromyelitis optica spectrum disorder and autoimmune encephalitides, has underscored the role of B cells in both cellular and humoral-mediated CNS conditions. Emerging evidence suggests B cells also contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer disease and Parkinson disease. Advancing our understanding of the role of B cells in neuroinflammatory and neurodegenerative diseases could lead to novel therapeutic approaches.
Vascular, glial, and lymphatic immune gateways of the central nervous system.
Engelhardt Britta,Carare Roxana O,Bechmann Ingo,Flügel Alexander,Laman Jon D,Weller Roy O
Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood-brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer's disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system.
Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis.
Morfopoulou Sofia,Mee Edward T,Connaughton Sarah M,Brown Julianne R,Gilmour Kimberly,Chong W K 'Kling',Duprex W Paul,Ferguson Deborah,Hubank Mike,Hutchinson Ciaran,Kaliakatsos Marios,McQuaid Stephen,Paine Simon,Plagnol Vincent,Ruis Christopher,Virasami Alex,Zhan Hong,Jacques Thomas S,Schepelmann Silke,Qasim Waseem,Breuer Judith
Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuV) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuV associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuV isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections.
Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy.
Muftuoglu Muharrem,Olson Amanda,Marin David,Ahmed Sairah,Mulanovich Victor,Tummala Sudhakar,Chi T Linda,Ferrajoli Alessandra,Kaur Indreshpal,Li Li,Champlin Richard,Shpall Elizabeth J,Rezvani Katayoun
The New England journal of medicine
JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .).
Herpes-simplex-related antigen in human demyelinative disease and encephalitis.
Martin J R,Holt R K,Webster H D
Using immunohistochemical methods optimized to detect herpes simplex virus type 2 (HSV-2) antigen, paraffin sections from human central nervous system tissues from 31 cases pathologically diagnosed as multiple sclerosis (MS), 34 cases of other neurological diseases, 4 adult cases of HSV encephalitis, and mouse brains infected with various HSV strains were examined. Two distinct patterns of immunoreactivity with HSV antisera were seen. In typical acute human and experimental encephalitis, antigen was readily detected using high dilutions of antisera to both HSV types -1 and -2, and was found nonselectively in both neurons and glia. Lesions were destructive, with necrosis of all neural cell types, and inflammation was a mixture of polymorphonuclear and mononuclear cells. By contrast, immunoreactivity in lesions in each of three MS cases and in one case of brain stem encephalitis was found only with HSV-2 antisera, and relatively high antiserum concentrations were required to detect it. Reactivity appeared to be largely restricted to glial cell nuclei within and near lesions that were selectively demyelinated. Only mononuclear inflammation was present. These experiments suggest that HSV-related antigen may be found in a broader spectrum of human CNS lesions than has previously been recognized, and that HSV or a related agent may be associated with a selective infection of glial cells and with CNS demyelination.
Clinical categories of neurobrucellosis. A report on 19 cases.
Shakir R A,Al-Din A S,Araj G F,Lulu A R,Mousa A R,Saadah M A
Brain : a journal of neurology
Brucellosis rarely can present with involvement restricted to the nervous system. We describe a total of 19 cases of neurobrucellosis in whom the clinical presentation lay in three distinct categories. The first was an acute presentation with meningoencephalitis. The disease also presented in a chronic form where the brunt of the illness can either be in the peripheral or the central nervous system (CNS). The chronic peripheral form is that of a proximal polyradiculoneuropathy. The central form is that of diffuse CNS involvement, predominantly with myelitis or cerebellar involvement with or without cranial nerve palsies. Although the two chronic forms, 'peripheral' and 'central', are distinct, some overlap is possible. This was not observed for the acute form. The pathology of the three presentations may be different, being a direct effect of infection in the acute form, and an immune-related process, possibly demyelinating in nature, in the chronic forms. The response to treatment in the acute and chronic forms is also different, being much better in the acute form. Awareness of the condition and performance of the appropriate serological tests will differentiate neurobrucellosis from other chronic CNS infections, especially tuberculosis and neurosyphilis.
Clinical diagnosis and treatment recommendations for immune checkpoint inhibitor-related adverse reactions in the nervous system.
Shi Jiayu,Niu Jingwen,Shen Dongchao,Liu Mingsheng,Tan Ying,Li Yi,Huang Yangyu,Cui Liying,Guan Yuzhou,Zhang Li
Immune checkpoint inhibitors (ICIs) can cause adverse reactions in the nervous system. The incidence rate is 0.1%-12% and 80% of nervous system adverse reactions occur within the first four months of application. ICIs can cause diseases of various parts of the nervous system including central nervous system diseases such as aseptic meningitis, meningeal encephalitis, necrotizing encephalitis, brainstem encephalitis, transverse myelitis, etc., and peripheral neuropathy such as cranial nerve peripheral neuropathy, multifocal nerve root neuropathy, Guillain-Barré syndrome, spinal nerve root neuropathy, myasthenia gravis, myopathy, etc. For these complications of the nervous system, diagnosis could be difficult. Physicians require a specific collection of nervous system symptoms and signs, combined with supplementary examinations including imaging, cerebrospinal fluid cytology, EEG or electromyography in order to exclude infection or malignant tumor before reaching a final diagnosis. With regard to treatment, ICIs should be discontinued in severe cases, and large doses of glucocorticoid or gamma globulin administered, and supportive treatment may be necessary. If severe adverse reactions of the nervous system occur, the prognosis could be poor.
Central Nervous System Fungal Infection-Related Stroke: A Descriptive Study of Mold and Yeast-Associated Ischemic Stroke.
George Pravin,Ramiro Joanna I,Gomes Joao A,Newey Christopher R,Bhimraj Adarsh
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
OBJECTIVE:Central nervous system (CNS) ischemic events caused by fungal infections are rare, and clinical characteristics of these ischemic events are largely unknown. The objective of this manuscript is to highlight characteristics of fungal-related strokes and describe possible mechanistic differences between CNS mold and yeast infection-related strokes. METHODS:We report a single-center retrospective case series of all adult patients who presented with concurrent CNS fungal infection and stroke between 2010 and 2018. Patients believed to have a stroke etiology due to cardioembolic, atheroembolic, or strokes nontemporally associated with a CNS fungal infection and those with incomplete stroke workups were excluded from analysis. RESULTS:Fourteen patients were identified with ischemic stroke and concurrent CNS fungal infection without other known ischemic stroke etiology. Eight patients had a CNS yeast infection, and 6 had a CNS mold infection. All patients presented with recurrent or progressive stroke symptoms. Six patients were immune-compromised. Four patients admitted to intravenous drug use. All yeast infections were identified by cerebrospinal fluid culture or immunologic studies while all but one of the mold infections required identification by tissue biopsy. Leptomeningeal enhancement was only associated with CNS yeast infections, while basal ganglia stroke was only associated with CNS mold infections. CONCLUSION:Ischemic stroke secondary to CNS fungal infections should be considered in patients with recurrent or progressive cryptogenic stroke, regardless of immune status and cerebrospinal fluid profile. CNS yeast and mold infections have slightly different stroke and laboratory characteristics and should have a distinct diagnostic method. Depending on clinical suspicion, a thorough diagnostic approach including spinal fluid analysis and biopsy should be considered.
Pregnancy-Related Immune Changes and Demyelinating Diseases of the Central Nervous System.
Qiu Ke,He Qiang,Chen Xiqian,Liu Hui,Deng Shuwen,Lu Wei
Frontiers in neurology
Demyelinating diseases of the central nervous system comprise a heterogeneous group of autoimmune disorders characterized by myelin loss with relative sparing of axons occurring on a background of inflammation. Some of the most common demyelinating diseases are multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Besides showing clinical, radiological, and histopathological features that complicate their diagnosis, demyelinating diseases often involve different immunological processes that produce distinct inflammatory patterns. Evidence of demyelination diseases derives mostly from animal studies of experimental autoimmune encephalomyelitis (EAE), a model that relies on direct antibody-antigen interactions induced by encephalitogenic T cells. Pregnancy is characterized by non-self-recognition, immunomodulatory changes and an altered Th1/Th2 balance, generally considered a Th2-type immunological state that protects the mother from infections. During pregnancy, the immune response of patients with autoimmune disease complicated with pregnancy is different. Immune tolerance in pregnancy may affect the course of some diseases, which may reach remission or be exacerbated. In this review, we summarize current knowledge on the immune status during pregnancy and discuss the relationship between pregnancy-related immune changes and demyelinating diseases of the central nervous system.
Guillain-Barré Syndrome Associated with Zika Virus Infection in Colombia.
Parra Beatriz,Lizarazo Jairo,Jiménez-Arango Jorge A,Zea-Vera Andrés F,González-Manrique Guillermo,Vargas José,Angarita Jorge A,Zuñiga Gonzalo,Lopez-Gonzalez Reydmar,Beltran Cindy L,Rizcala Karen H,Morales Maria T,Pacheco Oscar,Ospina Martha L,Kumar Anupama,Cornblath David R,Muñoz Laura S,Osorio Lyda,Barreras Paula,Pardo Carlos A
The New England journal of medicine
BACKGROUND:Zika virus (ZIKV) infection has been linked to the Guillain-Barré syndrome. From November 2015 through March 2016, clusters of cases of the Guillain-Barré syndrome were observed during the outbreak of ZIKV infection in Colombia. We characterized the clinical features of cases of Guillain-Barré syndrome in the context of this ZIKV infection outbreak and investigated their relationship with ZIKV infection. METHODS:A total of 68 patients with the Guillain-Barré syndrome at six Colombian hospitals were evaluated clinically, and virologic studies were completed for 42 of the patients. We performed reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays for ZIKV in blood, cerebrospinal fluid, and urine, as well as antiflavivirus antibody assays. RESULTS:A total of 66 patients (97%) had symptoms compatible with ZIKV infection before the onset of the Guillain-Barré syndrome. The median period between the onset of symptoms of ZIKV infection and symptoms of the Guillain-Barré syndrome was 7 days (interquartile range, 3 to 10). Among the 68 patients with the Guillain-Barré syndrome, 50% were found to have bilateral facial paralysis on examination. Among 46 patients in whom nerve-conduction studies and electromyography were performed, the results in 36 patients (78%) were consistent with the acute inflammatory demyelinating polyneuropathy subtype of the Guillain-Barré syndrome. Among the 42 patients who had samples tested for ZIKV by RT-PCR, the results were positive in 17 patients (40%). Most of the positive RT-PCR results were in urine samples (in 16 of the 17 patients with positive RT-PCR results), although 3 samples of cerebrospinal fluid were also positive. In 18 of 42 patients (43%) with the Guillain-Barré syndrome who underwent laboratory testing, the presence of ZIKV infection was supported by clinical and immunologic findings. In 20 of these 42 patients (48%), the Guillain-Barré syndrome had a parainfectious onset. All patients tested were negative for dengue virus infection as assessed by RT-PCR. CONCLUSIONS:The evidence of ZIKV infection documented by RT-PCR among patients with the Guillain-Barré syndrome during the outbreak of ZIKV infection in Colombia lends support to the role of the infection in the development of the Guillain-Barré syndrome. (Funded by the Bart McLean Fund for Neuroimmunology Research and others.).
[Specific antibody activity as a marker of pathogen-stimulated immune response in the central nervous system. Exemplified by syphilis and zoster diseases].
Prange H W,Ritter G
Under normal conditions the portion of any antigen specific IgG of total IgG is identical in serum and CSF. This thesis was investigated in 51 patients who were found to have seropositive syphilis without CNS involvement. For this purpose a special index (ITpA-index) was used, based on the ratio of specific IgG per total IgG of CSF to specific IgG per total IgG of serum. This index has a value of 1 (0.5-2), if there is no antibody synthesis in the CNS, as confirmed on the 51 seropositive control patients. In patients with syphilitic CNS involvement the index rose above 2 (3-430), due to local antibody synthesis in the CNS. When there is an ITpA-index below 2.0 in patients with seropositive syphilis who show any CNS symptoms whatsoever, it can be presumed that the actual CNS disease is not a consequence of the former syphilitic infection, but is caused by a condition other than syphilis. In 6 patients with reactive syphilis tests, moderate CSF pleocytosis and increased CSF total IgG, the ITpA-index was below 0.5. Among these 6 patients the inflammatory CNS process was non-syphilitic. The principle of the ITpA-index is applicable to other bacterial or viral CNS diseases insofar as a local humoral immune response takes place. This could be demonstrated in cases of herpes zoster.
The virology of demyelinating diseases.
Johnson R T
Annals of neurology
Infectious agents have been postulated as causes of multiple sclerosis for over a century. The possible role of a virus or viruses is supported by data that (1) a childhood exposure is involved and "viral" infections may precipitate exacerbations of disease, (2) experimental infections in animals and natural infections in humans can cause diseases with long incubation periods, remitting and relapsing courses, and demyelination, and (3) patients with multiple sclerosis have abnormal immune responses to viruses. The pathogenesis of three human demyelinating diseases of known viral etiology is discussed. In progressive multifocal leukoencephalopathy, a papovavirus selectively infects oligodendrocytes and causes focal areas of demyelination. In postmeasles encephalomyelitis, the virus is lymphotrophic and disrupts immune regulation that can result in an autoimmune perivenular demyelinating illness without evidence of infection of the central nervous system. In human immunodeficiency virus-encephalopathy and myelopathy virus is present in macrophages and microglia and the myelin abnormalities apparently are caused by soluble factors such as viral proteins, cytokines, or neurotoxins. These findings may have implications on how, when, and where to seek viruses in multiple sclerosis.
An encephalitic episode in a multiple sclerosis patient with human herpesvirus 6 latent infection.
Merelli E,Sola P,Barozzi P,Torelli G
Journal of the neurological sciences
All the human herpesviruses may cause central nervous system (CNS) diseases, including benign aseptic meningitis or fatal encephalitis. It has recently been stated that human herpesvirus 6 (HHV-6) may also be neuropathogenic in children after primary infection, while in the adult, cases of fatal encephalitis have been reported only in immune-compromised hosts such as AIDS patients, and in one case of an immunosuppressed bone marrow transplant patient. We describe a multiple sclerosis (MS) patient, carrier of HHV-6 latent infection, who experienced an acute inflammation of the CNS diagnosed as encephalitis. HHV-6 specific genomic sequences have been detected by PCR in the patient's PBMCs DNA collected before and during the encephalitis. The PCR performed in the CSF in course of the acute episode was positive, while the CSF collected before the encephalitis was negative. This finding is consistent with an acute encephalopathy caused by the reactivation of a HHV-6 latent infection within the CNS, in a patient with altered immune response due to MS.
Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia.
Yao J,Wigdahl B
Frontiers in bioscience : a journal and virtual library
HTLV-I has been identified as the etiologic agent of neoplasia within the human peripheral blood T lymphocyte population, and a progressive neurologic disorder based primarily within the central nervous system. We have examined the role of HTLV-I in these two distinctly different clinical syndromes by examining the life cycle of the virus, with emphasis on the regulation of viral gene expression within relevant target cell populations. In particular, we have examined the impact of specific viral gene products, particularly Tax, on cellular metabolic function. Tax is a highly promiscuous and pleiotropic viral oncoprotein, and is the most important factor contributing to the initial stages of viral-mediated transformation of T cells after HTLV-I infection. Tax, which weakly binds to Tax response element 1 (TRE-1) in the viral long terminal repeat (LTR), can dramatically trans-activate viral gene expression by interacting with cellular transcription factors, such as activated transcription factors and cyclic AMP response element binding proteins (ATF/CREB), CREB binding protein (CBP/p300), and factors involved with the basic transcription apparatus. At the same time, Tax alters cellular gene expression by directly or indirectly interacting with a variety of cellular transcription factors, cell cycle control elements, and cellular signal transduction molecules ultimately resulting in dysregulated cell proliferation. The mechanisms associated with HTLV-I infection, leading to tropical spastic paraparesis (TSP) are not as clearly resolved. Possible explanations of viral-induced neurologic disease range from central nervous system (CNS) damage caused by direct viral invasion of the CNS to bystander CNS damage caused by the immune response to HTLV-I infection. It is interesting to note that it is very rare for an HTLV-I infected individual to develop both adult T cell leukemia (ATL) and TSP in his/her life time, suggesting that the mechanisms governing development of these two diseases are mutually exclusive.
Interleukin-1beta, interleukin-1 receptor antagonist levels in patients with subacute sclerosing panencephalitis and the effects of different treatment protocols.
Haspolat S,Anlar B,Köse G,Coskun M,Yegin O
Journal of child neurology
Subacute sclerosing panencephalitis is a rare progressive inflammatory disease of the central nervous system caused by a persistent aberrant measles virus infection. Cytokines are polypeptides that regulate immune responses and inflammatory reactions. Interleukin-1beta has been implicated as a central mediator of tissue damage and destruction in a number of central nervous system diseases. Interleukin-1 receptor antagonist could function as an important anti-inflammatory cytokine. We studied interleukin-1beta and interleukin-1 receptor antagonist levels in the cerebrospinal fluids of patients with subacute sclerosing panencephalitis and evaluated the effects of different treatment protocols on these cytokines. Interleukin-1beta and interleukin-1 receptor antagonist levels were measured in 15 patients who had a recent diagnosis of subacute sclerosing panencephalitis (group 1), 6 patients who had been treated with isoprinosine (group 2), 5 patients with intraventricular interferon-alpha (group 3), and 6 patients with interferon-beta (group 4). The results were compared within the groups and also with the results of 10 patients with other neurologic disease (group 5). The interleukin-1beta concentrations in cerebrospinal fluid and sera were all below the detection limits (3.9 pg/mL). Interleukin-1 receptor antagonist levels were not statistically different, except for the group treated with intraventricular interferon-alpha. Interleukin-1 receptor antagonist levels were 170 +/- 52, 175 +/- 58, 1605 +/- 518, 77.5 +/- 24, and 108 +/- 18 pg/mL in groups 1 to 5, respectively. Interleukin-1 receptor antagonist levels and cerebrospinal fluid serum ratios were significantly increased during interferon-alpha treatment. In conclusion, interleukin-1 and interleukin-1 receptor antagonist levels were not elevated in the patients with subacute sclerosing panencephalitis. The only treatment protocol that affects interleukin-1 receptor antagonist levels in cerebrospinal fluid was intraventricular interferon-alpha. Further studies on higher numbers of patients may better document the immunologic status of patients with subacute sclerosing panencephalitis and the effects of different treatment modes.
Central nervous system infections in the compromised host: a diagnostic approach.
Cunha B A
Infectious disease clinics of North America
The diagnostic approach to the compromised host with CNS infection depends on an analysis of the patient's clinical manifestations of CNS disease, the acuteness or subacuteness of the clinical presentation, and an analysis of the type of immune defect compromising the patient's host defenses. Most patients with CNS infections may be grouped into those with meningeal signs, or those with mass lesions. Other common manifestations of CNS infection include encephalopathy, seizures, or a stroke-like presentation. Most pathogens have a predictable clinical presentation that differs from that of the normal host. CNS Aspergillus infections present either as mass lesions (e.g., brain abscess), or as cerebral infarcts, but rarely as meningitis. Cryptococcus neoformans, in contrast, usually presents as a meningitis but not as a cerebral mass lesion even when cryptococcal elements are present. Aspergillus and Cryptococcus CNS infections are manifestations of impaired host defenses, and rarely occur in immunocompetent hosts. In contrast, the clinical presentation of Nocardia infections in the CNS is the same in normal and compromised hosts, although more frequent in compromised hosts. The acuteness of the clinical presentation coupled with the CNS symptomatology further adds to limit differential diagnostic possibilities. Excluding stroke-like presentations, CNS mass lesions tend to present subacutely or chronically. Meningitis and encephalitis tend to present more acutely, which is of some assistance in limiting differential diagnostic possibilities. The analysis of the type of immune defect predicts the range of possible pathogens likely to be responsible for the patient's CNS signs and symptoms. Patients with diseases and disorders that decrease B-lymphocyte function are particularly susceptible to meningitis caused by encapsulated bacterial pathogens. The presentation of bacterial meningitis is essentially the same in normal and compromised hosts with impaired B-lymphocyte immunity. Compromised hosts with impaired T-lymphocyte or macrophage function are prone to develop CNS infections caused by intracellular pathogens. The most common intracellular pathogens are the fungi, particularly Aspergillus, other bacteria (e.g., Nocardia), viruses (i.e., HSV, JC, CMV, HHV-6), and parasites (e.g., T. gondii). The clinical syndromic approach is most accurate when combining the rapidity of clinical presentation and the expression of CNS infection with the defect in host defenses. The presence of extra-CNS sites of involvement also may be helpful in the diagnosis. A patient with impaired cellular immunity with mass lesions in the lungs and brain that have appeared subacutely or chronically should suggest Nocardia or Aspergillus rather than cryptococcosis or toxoplasmosis. Patients with T-lymphocyte defects presenting with meningitis generally have meningitis caused by Listeria or Cryptococcus rather than toxoplasmosis or CMV infection. The disorders that impair host defenses, and the therapeutic modalities used to treat these disorders, may have CNS manifestations that mimic infections of the CNS clinically. Clinicians must be ever vigilant to rule out the mimics of CNS infections caused by noninfectious etiologies. Although the syndromic approach is useful in limiting diagnostic possibilities, a specific diagnosis still is essential in compromised hosts in order to describe effective therapy. Bacterial meningitis, cryptococcal meningitis, and tuberculosis easily are diagnosed accurately from stain, culture, or serology of the CSF. In contrast, patients with CNS mass lesions usually require a tissue biopsy to arrive at a specific etiologic diagnosis. In a compromised host with impaired cellular immunity in which the differential diagnosis of a CNS mass lesion is between TB, lymphoma, and toxoplasmosis, a trial of empiric therapy is warranted. Antitoxoplasmosis therapy may be initiated empirically and usually results in clinical improvement after 2 to 3 weeks of therapy. The nonresponse to antitoxoplasmosis therapy in such a patient would warrant an empiric trial of antituberculous therapy. Lack of response to anti-Toxoplasma and antituberculous therapy should suggest a noninfectious etiology (e.g., CNS lymphoma). Fortunately, most infections in compromised hosts are similar in their clinical presentation to those in the normal host, particularly in the case of meningitis. The compromised host is different than the normal host in the distribution of pathogens, which is determined by the nature of the host defense defect. In compromised hosts, differential diagnostic possibilities are more extensive and the likelihood of noninfectious explanations for CNS symptomatology is greater. (ABSTRACT TRUNCATED)
Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogeneses?
Acta odontologica Scandinavica
Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities Crohn disease (CD) and ulcerative colitis (UC) both apparently caused by immunological overreaction (hypersensitivity) to commensal gut bacteria. Under normal conditions the intestinal immune system shows a down-regulating tone ('oral tolerance') against dietary antigens and the indigenous microbiota. This local homeostasis is disturbed in IBD, leading to hyperactivation of T helper 1 (Th1) cells with abundant secretion of interferon-gamma and tumor necrosis factor (TNF) and production of IgG antibodies against commensal bacteria. In addition, UC includes genetically determined autoimmunity, particularly IgG1-mediated cytotoxic epithelial attack. Breaching of the epithelium is the best-defined event underlying abrogation of oral tolerance, but immune deviation caused by cytokines fiom irritated epithelial cells or subepithelial elements (for example, mast cells, natural killer cells, macrophages) may also be involved. Endogenous infection with local hypersensitivity likewise causes periodontal disease, reflecting 'frustrated' immune elimination mechanisms entertained by antigens from dental plaque. Altogether, perturbation of a tightly controlled cytokine network, with abnormal crosstalk between several cell types, apparently explains the progressive immunopathology of chronic inflammatory mucosal diseases in general. This adverse development will be influenced by numerous immunity genes, the dosage and potential pathogeniciy of commensal bacteria, general health, nutritional status, and psychological factors. Several targets for new therapy have tentatively been identified to block immunopathological mechanisms in IBD, and inhibition of TNF has a striking beneficial effect in CD, supporting a central role of this cytokine.
Fazakerley John K,Walker Robert
Journal of neurovirology
A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.
Human T-cell lymphotropic virus type I and neurological diseases.
Nagai Masahiro,Osame Mitsuhiro
Journal of neurovirology
Human T-cell lymphotropic virus type I (HTLV-I) infection is associated with a variety of human diseases. In particular, there are two major diseases caused by HTLV-I infection. One is an aggressive neoplastic disease called adult T-cell leukemia (ATL), and another is a chronic progressive inflammatory neurological disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is still unknown why one virus causes these different diseases. With regard to HAM/TSP, virus-host immunological interactions are an considered to be important cause of this disease. Coexisting high HTLV-I proviral load and HTLV-I-specific T cells (CD4+ T cells and CD8+ T cells) is an important feature of HAM/TSP. Histopathological studies indicate the existence of an inflammatory reaction and HTLV-I-infected cells in the affected lesions of HAM/TSP. Therefore, the immune response to HTLV-I probably contributes to the inflammatory process of the central nervous system lesions in HAM/TSP patients.
[Neurological complications of inflammatory intestinal diseases].
Dietrich W,Erbguth F
Fortschritte der Neurologie-Psychiatrie
A number of neurological symptoms have been described as complications of inflammatory bowel disorders such as coeliac disease, Whipple's disease, Crohn's disease and ulcerative colitis. The neurology of coeliac disease includes disorders of the central nervous system encompassing cerebellar ataxia, epilepsy, myoclonus, dementia and multifocal leukoencephalopathy. Peripheral neuropathies, of axonal and demyelinating types, and myopathies have also been reported. The pathomechanisms are more related to immunological-inflammatory processes than to a malresorptive vitamin deficiencies. While CNS symptoms of coeliac disease show a poor response to gluten restriction, peripheral symptoms may respond to elimination of gluten from the diet. There are few reports of a successful corticosteroid treatment in patients showing inflammatory findings in the CSF or bioptic material. Whipple's disease is caused by the gram-positive bacillus Tropheryma whipplei. Patients with a central nervous system manifestation of Whipple's disease may develop a variety of symptoms including dementia, supranuclear gaze palsy, movement disorders, hypothalamic dysfunction and myorhythmia. The CNS-infection is diagnosed by PCR of the CSF. Long-term antibiotic treatment is required, and relapses may occur after withdrawal of antimicrobial therapy. Crohn's disease and ulcerative colitis are complicated by various forms of polyneuropathies, and arterial and venous cerebrovascular diseases. In most cases with neurological complications of inflammatory gastrointestinal diseases an immune mediated inflammatory process is suspected to be the underlying pathomechanism.
Regulation by innate immune T lymphocytes in the host defense against pulmonary infection with Cryptococcus neoformans.
Japanese journal of infectious diseases
Recently, innate immune lymphocytes, such as natural killer (NK) T cells and gamma/delta antigen receptor-bearing T (gamma delta T) cells, have garnered much attention, and their biological significance in the tumor immunity, allergic diseases and infectious diseases is extensively exploited. We have addressed the role of these cells in the host defense using a mouse model of pulmonary infection with Cryptococcus neoformans, which frequently causes fatal meningoencephalitis in AIDS patients. Host defense to this fungal pathogen is largely mediated by cellular immunity, and type-1 helper T (Th1) cells play a central role in this process. This infection causes a prompt accumulation of both NKT and gamma delta T cells in the lung tissues in a monocyte chemoattractant protein (MCP)-1-dependent or -independent manner, respectively. Genetic deletion of V alpha 14+ NKT cells ameliorates the Th1 response and clearance of microorganisms in the lungs, whereas these host protective responses are rather enhanced in mice lacking gamma delta T cells. Thus, in some aspect, these innate immune lymphocytes may co-regulate the Th1-mediated response for induction of the moderate host defense. gamma delta T cells may act to keep the balance of Th1-Th2 responses in a proper manner by suppressing the exaggerated Th1 response caused by NKT cells. In this review, I describe the recent research development in the innate immune host defense against cryptococcal infection in respiratory organs with emphasis on our data in the regulatory role of NKT cells and gamma/delta T cells.
A specific viral cause of multiple sclerosis: one virus, one disease.
Lipton Howard L,Liang Zhiguo,Hertzler Shannon,Son Kyung-No
Annals of neurology
"Multiple sclerosis is an autoimmune disease," is heard so often that it is widely accepted as fact by the current generation of students and physicians. Yet, although it is undisputed that multiple sclerosis (MS) is immune mediated, an autoimmune mechanism remains unproven. Immune-mediated tissue damage can also result from viral infections in which the host immune response is directed to viral rather than self proteins, or as a consequence of nonspecific or bystander immune responses that change the local cytokine environment. Increasing evidence suggests that poorly controlled host immune responses account for much of the tissue damage in chronic infections, and it has been postulated that a similar mechanism may underlie many chronic diseases with features suggestive of an infectious causative factor, including MS. A recent study suggesting that oligodendrocyte death accompanied by microglial activation is the primary event in new MS lesion formation, rather than lymphocyte infiltration, could change the current mindset almost exclusively focused on autoimmunity. This review presents the rationale for considering MS a single disease caused by one virus, as well as the anticipated pattern of a persistent central nervous system infection, the application of Koch's postulates to viral discovery in MS as the causative agent, and tissue culture-independent genotypic approaches to viral discovery in MS.
Parasites and autoimmunity: the case of fungi.
Infectious agents can induce autoimmune diseases in several experimental settings, some of which have clinical counterparts. A variety of mechanisms have been invoked to explain these observations, including molecular mimicry and an increase in the immunogenicity of autoantigens caused by inflammation in the target organ. Paradoxically, infectious agents can also suppress allergic and autoimmune disorders. A central question is to determine whether immune dysregulation precedes, if not promotes, infection or alternatively, but not mutually exclusive, the extent to which microbial exposure/colonization contributes to the burst of pathogenic autoimmunity. Here we discussed recent evidence with fungi that help to accommodate microbes, either commensals or ubiquitous, within the immune homeostasis and its dysregulation.
Cellular and molecular biology of Neisseria meningitidis colonization and invasive disease.
Hill Darryl J,Griffiths Natalie J,Borodina Elena,Virji Mumtaz
Clinical science (London, England : 1979)
The human species is the only natural host of Neisseria meningitidis, an important cause of bacterial meningitis globally, and, despite its association with devastating diseases, N. meningitidis is a commensal organism found frequently in the respiratory tract of healthy individuals. To date, antibiotic resistance is relatively uncommon in N. meningitidis isolates but, due to the rapid onset of disease in susceptible hosts, the mortality rate remains approx. 10%. Additionally, patients who survive meningococcal disease often endure numerous debilitating sequelae. N. meningitidis strains are classified primarily into serogroups based on the type of polysaccharide capsule expressed. In total, 13 serogroups have been described; however, the majority of disease is caused by strains belonging to one of only five serogroups. Although vaccines have been developed against some of these, a universal meningococcal vaccine remains a challenge due to successful immune evasion strategies of the organism, including mimicry of host structures as well as frequent antigenic variation. N. meningitidis express a range of virulence factors including capsular polysaccharide, lipopolysaccharide and a number of surface-expressed adhesive proteins. Variation of these surface structures is necessary for meningococci to evade killing by host defence mechanisms. Nonetheless, adhesion to host cells and tissues needs to be maintained to enable colonization and ensure bacterial survival in the niche. The aims of the present review are to provide a brief outline of meningococcal carriage, disease and burden to society. With this background, we discuss several bacterial strategies that may enable its survival in the human respiratory tract during colonization and in the blood during infection. We also examine several known meningococcal adhesion mechanisms and conclude with a section on the potential processes that may operate in vivo as meningococci progress from the respiratory niche through the blood to reach the central nervous system.
Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome.
Aly Lilian,Yousef Sara,Schippling Sven,Jelcic Ilijas,Breiden Petra,Matschke Jakob,Schulz Robert,Bofill-Mas Silvia,Jones Louise,Demina Viktorya,Linnebank Michael,Ogg Graham,Girones Rosina,Weber Thomas,Sospedra Mireia,Martin Roland
Brain : a journal of neurology
Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4(+)> CD8(+) T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4(+) T cells were studied regarding antigen specificity and function. CD4(+) T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4(+) Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-γ and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4(+) T cells was confirmed and extended by examining brain-derived JC virus-specific CD4(+) T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4(+) T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcome.
CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.
Matullo Christine M,O'Regan Kevin J,Curtis Mark,Rall Glenn F
Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.
Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies.
Bellizzi A,Nardis C,Anzivino E,Rodìo D M,Fioriti D,Mischitelli M,Chiarini F,Pietropaolo V
Journal of neurovirology
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus JC (JCV) lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of human immunodeficiency virus (HIV) infection in the 1980s. Despite the ubiquity of this virus, PML is rare and always seen in association with underlying immunosuppressive condition, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys, where it displays a stable archetypal non-coding control region (NCCR). Conversely, rearranged JCV NCCR, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific site and mechanism of JCV NCCR transformation is unknown. According to one model, during the course of immunosuppression, JCV departs from its latent state and after entering the brain, productively infects and destroys oligodendrocytes. Although the majority of PML cases occur in severely immunesuppressed individuals, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies (mAbs) that modulate immune system functions: in fact, CD4+ and CD8+ T lymphopenia, resulting from this immunomodulatory therapy, are the primary risk factor. Furthermore, JCV reactivation in nonpermissive cells after treatment with mAbs, such as intestinal epithelial cells in Crohn's disease patients, in association with other host tumor-inducing factors, could provide valid information on the role of JCV in several malignancies, such as colorectal cancer.
Population Dynamics of Borrelia burgdorferi in Lyme Disease.
Binder Sebastian C,Telschow Arndt,Meyer-Hermann Michael
Frontiers in microbiology
Many chronic inflammatory diseases are known to be caused by persistent bacterial or viral infections. A well-studied example is the tick-borne infection by the gram-negative spirochaetes of the genus Borrelia in humans and other mammals, causing severe symptoms of chronic inflammation and subsequent tissue damage (Lyme Disease), particularly in large joints and the central nervous system, but also in the heart and other tissues of untreated patients. Although killed efficiently by human phagocytic cells in vitro, Borrelia exhibits a remarkably high infectivity in mice and men. In experimentally infected mice, the first immune response almost clears the infection. However, approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase. We developed a mathematical model describing the bacterial growth and the immune response against Borrelia burgdorferi in the C3H mouse strain that has been established as an experimental model for Lyme disease. The peculiar dynamics of the infection exclude two possible mechanistic explanations for the regrowth of the almost cleared bacteria. Neither the hypothesis of bacterial dissemination to different tissues nor a limitation of phagocytic capacity were compatible with experiment. The mathematical model predicts that Borrelia recovers from the strong initial immune response by the regrowth of an immune-resistant sub-population of the bacteria. The chronic phase appears as an equilibration of bacterial growth and adaptive immunity. This result has major implications for the development of the chronic phase of Borrelia infections as well as on potential protective clinical interventions.
The adaptive immune system in diseases of the central nervous system.
Wraith David C,Nicholson Lindsay B
The Journal of clinical investigation
Tissues of the CNS, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. The immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. It is clearly vital that cells of the immune system patrol the CNS and protect against infection. However, in contrast to other tissues, damage caused by immune pathology in the CNS can be irreparable. The nervous and immune systems have, therefore, coevolved to permit effective immune surveillance while limiting immune pathology. Here we will consider aspects of adaptive immunity in the CNS and the retina, both in the context of protection from infection as well as cancer and autoimmunity, while focusing on immune responses that compromise health and lead to significant morbidity.
Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation.
Livraghi-Butrico A,Kelly E J,Klem E R,Dang H,Wolfgang M C,Boucher R C,Randell S H,O'Neal W K
It has been postulated that mucus stasis is central to the pathogenesis of obstructive lung diseases. In Scnn1b-transgenic (Scnn1b-Tg⁺ mice, airway-targeted overexpression of the epithelial Na⁺ channel β subunit causes airway surface dehydration, which results in mucus stasis and inflammation. Bronchoalveolar lavage from neonatal Scnn1b-Tg⁺ mice, but not wild-type littermates, contained increased mucus, bacteria, and neutrophils, which declined with age. Scnn1b-Tg⁺ mice lung bacterial flora included environmental and oropharyngeal species, suggesting inhalation and/or aspiration as routes of entry. Genetic deletion of the Toll-interleukin-1 receptor adapter molecule MyD88 in Scnn1b-Tg⁺ mice did not modify airway mucus obstruction, but caused defective neutrophil recruitment and increased bacterial infection, which persisted into adulthood. Scnn1b-Tg⁺ mice derived into germ-free conditions exhibited mucus obstruction similar to conventional Scnn1b-Tg⁺ mice and sterile inflammation. Collectively, these data suggest that dehydration-induced mucus stasis promotes infection, compounds defects in other immune mechanisms, and alone is sufficient to trigger airway inflammation.
Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.
Ferenczy Michael W,Marshall Leslie J,Nelson Christian D S,Atwood Walter J,Nath Avindra,Khalili Kamel,Major Eugene O
Clinical microbiology reviews
Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.
Rapidly progressive cerebellar ataxia in West Wales.
Ali Khalid,Amin Reem,Yoganathan Kathir G,Powell Rob
BMJ case reports
Progressive multifocal leucoencephalopathy (PML) is a severe demyelinating disease of the central nervous system that is caused by the JC virus infection. It is often fatal or severely disabling. PML exclusively happens in the context of cell-mediated immunosuppression. Prior to the era of HIV, PML was mainly confined to patients with haematological malignancies and rheumatological diseases. The HIV epidemic in the early eighties led to massive expansion in the incidence and prevalence of the disease. PML has also been recognised to happen due to treatment with monoclonal antibodies such as natalizumab, which is used as a disease-modifying agent for relapsing remitting multiple sclerosis and other monoclonal antibodies used in dermatological and haematological conditions. The clinical picture is that of cognitive decline, visual disturbance and hemiparesis. The correct clinicoradiological picture combined with demonstrating the JC virus DNA in the cerebrospinal fluid (CSF) using PCR (PMR) is enough to establish the diagnosis. Brain biopsy is rarely needed. Immune reconstitution represents the mainstay in the treatment of PML. We present a case of a 47-year-old man who presented with progressive cerebellar ataxia. Investigations confirmed PML. He was found to be HIV positive. We also review the literature.
The risk of progressive multifocal leukoencephalopathy under biological agents used in the treatment of chronic inflammatory diseases.
Toussirot Éric,Bereau Matthieu
Inflammation & allergy drug targets
Biological agents such as monoclonal antibodies and soluble cytokine receptors have taken on an expanding role in the treatment of chronic immune mediated diseases. Progressive multifocal leukoencephalopathy (PML) is a rare central neurological disease caused by JC virus infection that has been described in the setting of conditions with severe impairment of immune surveillance, such as haematological malignancies, stem cell or solid organ transplantation and AIDS. This serious demyelinating disease has recently been described in patients receiving monoclonal antibodies for chronic inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus or psoriasis. We review here the disease of PML, the different biological agents used in chronic inflammatory diseases that are associated with an increased risk of PML (natalizumab, rituximab, efalizumab and alemtuzumab), and the potential mechanisms that may explain the development of PML. Based on current knowledge of the biology of the JC virus and on the mechanisms of action of these biological agents, we discuss currently available tools that may be helpful in evaluating the risk of PML in this patient population.
The role of viruses in neurodegenerative and neurobehavioral diseases.
Karim Sajjad,Mirza Zeenat,Kamal Mohammad A,Abuzenadah Adel M,Azhar Esam I,Al-Qahtani Mohammed H,Damanhouri Ghazi A,Ahmad Fahim,Gan Siew H,Sohrab Sayed S
CNS & neurological disorders drug targets
Neurodegenerative and neurobehavioral diseases may be caused by chronic and neuropathic viral infections and may result in a loss of neurons and axons in the central nervous system that increases with age. To date, there is evidence of systemic viral infections that occur with some neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, and HIV-associated neurocognitive disorders. With increasing lifespan, the incidence of neurodegenerative diseases increases consistently. Neurodegenerative diseases affect approximately 37 million people worldwide and are an important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and viruses associated with neurodegenerative diseases have been proposed. Neuronal degeneration can be either directly or indirectly affected by viral infection. Viruses that attack the human immune system can also affect the nervous system and interfere with classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism cannot be understood well. Various studies have supported viral- and non-viral-mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to illustrate the association between viral infections and both neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases can be better explained. This information will strengthen new concepts and ideas for neurodegenerative and neurobehavioral disease treatment.
Alterations in immune cells and mediators in the brain: it's not always neuroinflammation!
Estes Myka L,McAllister A Kimberley
Brain pathology (Zurich, Switzerland)
Neuroinflammation was once a clearly defined term denoting pathological immune processes within the central nervous system (CNS). Historically, this term was used to indicate the four hallmarks of peripheral inflammaton that occur following severe CNS injuries, such as stroke, injury or infection. Recently, however, the definition of neuroinflammation has relaxed to the point that it is often now assumed to be present when even only a single classical hallmark of inflammation is measured. As a result, a wide range of disorders, from psychiatric to degenerative diseases, are now assumed to have an integral inflammatory component. Ironically, at the same time, research has revealed unexpected nonclassical immune actions of immune mediators and cells in the CNS in the absence of pathology, increasing the likelihood that homeostatic and adaptive immune processes in the CNS will be mistaken for neuroinflammation. Thus, we suggest reserving the term neuroinflammation for contexts where multiple signs of inflammation are present to avoid erroneously classifying disorders as inflammatory when they may instead be caused by nonimmune etiologies or secondary immune processes that serve adaptive roles.
Persistence and pathogenesis of the neurotropic polyomavirus JC.
Wollebo Hassen S,White Martyn K,Gordon Jennifer,Berger Joseph R,Khalili Kamel
Annals of neurology
Many neurological diseases of the central nervous system (CNS) are underpinned by malfunctions of the immune system, including disorders involving opportunistic infections. Progressive multifocal leukoencephalopathy (PML) is a lethal CNS demyelinating disease caused by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with immune disruption, including patients with human immunodeficiency virus/acquired immunodeficiency syndrome, patients receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients. Thus, the public health significance of this disease is high, because of the number of individuals constituting the at-risk population. The incidence of PML is very low, whereas seroprevalence for the virus is high, suggesting infection by the virus is very common, and so it is thought that the virus is restrained but it persists in an asymptomatic state that can only occasionally be disrupted to lead to viral reactivation and PML. When JCV actively replicates in oligodendrocytes and astrocytes of the CNS, it produces cytolysis, leading to formation of demyelinated lesions with devastating consequences. Defining the molecular nature of persistence and events leading to reactivation of the virus to cause PML has proved to be elusive. In this review, we examine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis. We will discuss the normal course of the JCV life cycle including transmission, primary infection, viremia, and establishment of asymptomatic persistence as well as pathogenic events including migration of the virus to the brain, reactivation from persistence, viral infection, and replication in the glial cells of the CNS and escape from immunosurveillance.
Targeting T Cell Bioenergetics by Modulating P-Glycoprotein Selectively Depletes Alloreactive T Cells To Prevent Graft-versus-Host Disease.
McIver Zachariah A,Grayson Jason M,Coe Benjamin N,Hill Jacqueline E,Schamerhorn Gregory A,Ohulchanskyy Tymish Y,Linder Michelle K,Davies Kellie S,Weiner Roy S,Detty Michael R
Journal of immunology (Baltimore, Md. : 1950)
T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. Selectively depleting GVHD-causing cells prior to transplant may prevent GVHD. In this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive T lymphocytes and identified the photosensitizer 2-Se-Cl, which accumulates in stimulated T cells in proportion to oxidative phosphorylation. The photosensitizer is also a potent stimulator of P-glycoprotein (P-gp). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 d with irradiated BALB/c splenocytes and then photodepleted (PD). PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 d without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD-treated splenocytes died of lethal GVHD. To evaluate the preservation of antiviral immune responses, acute lymphocytic choriomeningitis virus infection was used. After photodepletion, expansion of Ag-specific naive CD8(+) T cells and viral clearance remained fully intact. The high selectivity of this novel photosensitizer may have broad applications and provide alternative treatment options for patients with T lymphocyte-mediated diseases.
CCL2, but not its receptor, is essential to restrict immune privileged central nervous system-invasion of Japanese encephalitis virus via regulating accumulation of CD11b(+) Ly-6C(hi) monocytes.
Kim Jin Hyoung,Patil Ajit Mahadev,Choi Jin Young,Kim Seong Bum,Uyangaa Erdenebileg,Hossain Ferdaus Mohd Altaf,Park Sang-Youel,Lee John Hwa,Kim Koanhoi,Eo Seong Kug
Japanese encephalitis virus (JEV) is a re-emerging zoonotic flavivirus that poses an increasing threat to global health and welfare due to rapid changes in climate and demography. Although the CCR2-CCL2 axis plays an important role in trafficking CD11b(+) Ly-6C(hi) monocytes to regulate immunopathological diseases, little is known about their role in monocyte trafficking during viral encephalitis caused by JEV infection. Here, we explored the role of CCR2 and its ligand CCL2 in JE caused by JEV infection using CCR2- and CCL2-ablated murine models. Somewhat surprisingly, the ablation of CCR2 and CCL2 resulted in starkly contrasting susceptibility to JE. CCR2 ablation induced enhanced resistance to JE, whereas CCL2 ablation highly increased susceptibility to JE. This contrasting regulation of JE progression by CCR2 and CCL2 was coupled to central nervous system (CNS) infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. There was also enhanced expression of CC and CXC chemokines in the CNS of CCL2-ablated mice, which appeared to induce CNS infiltration of these cell populations. However, our data revealed that contrasting regulation of JE in CCR2- and CCL2-ablated mice was unlikely to be mediated by innate natural killer and adaptive T-cell responses. Furthermore, CCL2 produced by haematopoietic stem cell-derived leucocytes played a dominant role in CNS accumulation of Ly-6C(hi) monocytes in infected bone marrow chimeric models, thereby exacerbating JE progression. Collectively, our data indicate that CCL2 plays an essential role in conferring protection against JE caused by JEV infection. In addition, blockage of CCR2, but not CCL2, will aid in the development of strategies for prophylactics and therapeutics of JE.
Infectious immunity in the central nervous system and brain function.
Klein Robyn S,Garber Charise,Howard Nicole
Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.
Involvement of chronic epipharyngitis in autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA).
Hotta Osamu,Tanaka Ayaki,Torigoe Akira,Imai Kazuaki,Ieiri Norio,
The epipharynx is an immunologically active site even under normal conditions, and enhanced immunologic activation is prone to occur in response to an upper respiratory infection, air pollution, and possibly to vaccine adjuvants. Due to the potential link between the central nervous system and immune function, a relationship between epipharyngitis and autonomic nervous disturbance as well as autoimmune disease has been suggested. Various functional somatic symptoms have been described after human papillomavirus (HPV) vaccination, although a causal relationship has not been established. We examined the epipharynx in young women showing functional somatic symptoms following HPV vaccination. Surprisingly, despite having minimal symptoms involving the pharynx, all patients were found to have severe epipharyngitis. In addition, significant improvement in symptoms was seen in most patients who underwent epipharyngeal treatment. Thus, we speculate that the chronic epipharyngitis potentially caused by the vaccine adjuvant may be involved in the pathogenesis of functional somatic syndrome (FSS) post-HPV vaccination. Further, we suggest that epipharyngeal treatment may be effective for various types of FSS regardless of the initial cause, as well as for some autoimmune diseases, and that this may be an important direction in future research.
The Risk of Progressive Multifocal Leukoencephalopathy in the Biologic Era: Prevention and Management.
Molloy Eamonn S,Calabrese Cassandra M,Calabrese Leonard H
Rheumatic diseases clinics of North America
Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, demyelinating central nervous system infection caused by reactivation of the John Cunningham virus that generally occurs in immunosuppressed patients. With an evolving understanding of a greater clinical heterogeneity of PML and significant implications for therapy, PML should be considered in the differential diagnosis of neurologic presentations of rheumatic diseases. Increased awareness of PML among rheumatologists is required, as earlier diagnosis and restoration of immune function may improve the otherwise grim prognosis associated with PML.
Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit.
Tohidpour Abolghasem,Morgun Andrey V,Boitsova Elizaveta B,Malinovskaya Natalia A,Martynova Galina P,Khilazheva Elena D,Kopylevich Natalia V,Gertsog Galina E,Salmina Alla B
Frontiers in cellular and infection microbiology
Neuroinflammation is a complex inflammatory process in the central nervous system, which is sought to play an important defensive role against various pathogens, toxins or factors that induce neurodegeneration. The onset of neurodegenerative diseases and various microbial infections are counted as stimuli that can challenge the host immune system and trigger the development of neuroinflammation. The homeostatic nature of neuroinflammation is essential to maintain the neuroplasticity. Neuroinflammation is regulated by the activity of neuronal, glial, and endothelial cells within the neurovascular unit, which serves as a "platform" for the coordinated action of pro- and anti-inflammatory mechanisms. Production of inflammatory mediators (cytokines, chemokines, reactive oxygen species) by brain resident cells or cells migrating from the peripheral blood, results in the impairment of blood-brain barrier integrity, thereby further affecting the course of local inflammation. In this review, we analyzed the most recent data on the central nervous system inflammation and focused on major mechanisms of neurovascular unit dysfunction caused by neuroinflammation and infections.
Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy.
DePaula-Silva Ana Beatriz,Hanak Tyler J,Libbey Jane E,Fujinami Robert S
Journal of neuroimmunology
Mouse models are great tools to study the mechanisms of disease development. Theiler's murine encephalomyelitis virus is used in two distinct viral infection mouse models to study the human diseases multiple sclerosis (MS) and epilepsy. Intracerebral (i.c.) infection of the SJL/J mouse strain results in persistent viral infection of the central nervous system and a MS-like disease, while i.c. infection of the C57BL/6J mouse strain results in acute seizures and epilepsy. Our understanding of how the immune system contributes to the development of two disparate diseases caused by the same virus is presented.
Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis.
Blackmore Stephen,Hernandez Jessica,Juda Michal,Ryder Emily,Freund Gregory G,Johnson Rodney W,Steelman Andrew J
Proceedings of the National Academy of Sciences of the United States of America
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.
CD8 T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection.
Huang Huarong,Li Shihua,Zhang Yongli,Han Xiaojuan,Jia Baoqian,Liu Hongtao,Liu Dandan,Tan Shuguang,Wang Qihui,Bi Yuhai,Liu William J,Hou Baidong,Gao George Fu,Zhang Fuping
Journal of virology
Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8 T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8 T cell response was elicited, major histocompatibility complex class I-restricted CD8 T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8 T cells was developed, and virus-specific memory CD8 T cells were generated in these mice. The CD8 T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8 T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection. ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8 T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8 T cells , which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8 T cell responses were generated and that CD8 T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.
Molecular Neuro-Pathomechanism of Neurocysticercosis: How Host Genetic Factors Influence Disease Susceptibility.
Arora Naina,Tripathi Shweta,Sao Reshma,Mondal Prosenjit,Mishra Amit,Prasad Amit
Neurocysticercosis (NCC) is one of the most neglected tropical diseases among widely endemic neurological diseases. It is caused by cysticerci of Taenia solium. The clinical symptom for the outcome of infection and progression of disease is pleomorphic and its neuro-pathomechanism is still illusive. Identification of host genetic factors and their association with disease susceptibility is one of the most important areas of research towards personalized medicine in the era of omics. Several genes and their allelic variations had been identified to be associated with various neurological disorders; however, the information for parasitic diseases affecting the central nervous system is very limited. Both Th1 and Th2 arms of the immune system are reported to be active at different stages of T. solium infection in the brain. Recently, several papers had been published, where the role of host genetic makeup with NCC had been explored. Increased frequency of HLA-A28, HLA-B63, HLA-B58, TLR 4 Asp299Gly, sICAM-1 gene K469E, GSTM1, and GSTT1 were found to be associated with increased risk of NCC occurrence, while HLA-DQW2 and HLA-A11 were shown to be providing protection from disease. In this review, we have summarized these findings and analyzed the influence of host genetic polymorphism on the susceptibility/resistance of host to NCC.
Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System.
Uyangaa Erdenebileg,Choi Jin Young,Patil Ajit Mahadev,Hossain Ferdaus Mohd Altaf,Park Sung Ok,Kim Bumseok,Kim Koanhoi,Eo Seong Kug
Frontiers in immunology
The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4 and CD8 T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV.
Neuroinflammation, Microglia, and Cell-Association during Prion Disease.
Carroll James A,Chesebro Bruce
Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated. Microglia are important first responders to foreign agents and damaged cells in the CNS, but these immune-like cells also serve many essential functions in the healthy CNS. Our current understanding is that microglia are beneficial during prion infection and critical to host defense against prion disease. Studies indicate that reduction of the microglial population accelerates disease and increases PrPSc burden in the CNS. Thus, microglia are unlikely to be a foci of prion propagation in the brain. In contrast, neurons and astrocytes are known to be involved in prion replication and spread. Moreover, certain astrocytes, such as A1 reactive astrocytes, have proven neurotoxic in other neurodegenerative diseases, and thus might also influence the progression of prion-associated neurodegeneration.
Innate Immunity Acts as the Major Regulator in Coinfected AIDS Patients: Cytokine Profile Surveillance During Initial 6-Month Antifungal Therapy.
Open forum infectious diseases
BACKGROUND:Talaromycosis caused by infection is a fatal systemic mycosis in immunosuppressed individuals, such as patients with AIDS. Cytokines and immunocytes play a central role against fungus infection. However, how the host immune system responds to infection and treatment has not been reported to date. METHODS:Forty-one coinfected AIDS patients were followed up, their immunocytes and cytokine profiles were obtained at different antifungal treatment stages, and data on clinical features and laboratory examinations were collected. Correlation analysis was used to identify factors associated with host immunity against infection in AIDS patients. RESULTS:Common diseases and conditions of these 41 patients were lymphadenopathy, hepatomegaly, and splenomegaly. CD4 T cells were extremely low in all of them. Moreover, significant increases of proinflammatory cytokines (IL-12, IL-17A, TNF-α, IFN-γ, IL-18, and IL-1β), anti-inflammatory cytokines (IL-10), and chemokines (IP-10) were observed in talaromycosis before treatment ( < .05), comparing to both AIDS patients and healthy controls. The cytokines IL-6, IL-8, TNF-α, IL-18, IL-17A, IL-7, IP-10, and IL-1β reached peak levels 3 days after initial antifungal therapy, and then gradually decreased. The symptoms of the patients gradually decreased. Furthermore, patients who died showed the highest levels of IL-6, TNF-α, IL-8, IL-1β, and IP-10, which were 1.4- to 164-fold higher than in surviving patients. CONCLUSIONS:Our findings indicate that innate immune-cell-derived cytokines are critical for host defense against AIDS-associated infection; furthermore, excessive inflammatory cytokines are associated with poor outcomes.
Severe Progressive Multifocal Leukoencephalopathy (PML) and Spontaneous Immune Reconstitution Inflammatory Syndrome (IRIS) in an Immunocompetent Patient.
Krey Lea,Raab Peter,Sherzay Romilda,Berding Georg,Stoll Matthias,Stangel Martin,Wegner Florian
Frontiers in immunology
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection with JC-virus (JCV), a papova-virus, affecting mostly oligodendrocytes and the white matter of the central nervous system. Progressive Multifocal Leukoencephalopathy (PML) almost exclusively occurs in immunocompromised patients based on different underlying conditions of severe cellular immunodeficiency such as HIV/AIDS, secondary to neoplastic and autoimmune diseases, or during immunosuppressive therapy. We present the case of an otherwise healthy and immunocompetent patient without immunosuppressive therapy who was admitted with hemianopsia to the right side, sensory aphasia and changes of behavior. Magnet resonance imaging (MRI) and laboratory testing confirmed the diagnosis of PML, although functional tests did not show any evidence for cellular immunodeficiency. Extensive immunological tests did not reveal an apparent immunodeficiency. During symptomatic therapy the patient developed seizures which were assumed to be caused by a spontaneous immune reconstitution inflammatory syndrome (IRIS) demonstrated by MRI. We added a high dose of intravenous corticosteroids to the antiepileptic treatment and seizures ended shortly thereafter. However, the impairments of vision, behavior and language persisted. Our case report highlights that an apparently immunocompetent patient can develop PML and IRIS spontaneously. Therefore, MRI should be applied immediately whenever a rapid progression of PML symptoms occurs as treatment of IRIS with corticosteroids can result in a marked clinical improvement.
The role of herpesvirus 6A and 6B in multiple sclerosis and epilepsy.
Dunn Nicky,Kharlamova Nastya,Fogdell-Hahn Anna
Scandinavian journal of immunology
Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two closely related viruses that can infect cells of the central nervous system (CNS). The similarities between these viruses have made it difficult to separate them on serological level. The broad term HHV-6 remains when referring to studies where the two species were not distinguished, and as such, the seroprevalence is over 90% in the adult population. HHV-6B has been detected in up to 100% of infants with the primary infection roseola infantum, but less is known about the primary infection of HHV-6A. Both viruses are neurotropic and have capacity to establish lifelong latency in cells of the central nervous system, with potential to reactivate and cause complications later in life. HHV-6A infection has been associated with an increased risk of multiple sclerosis (MS), whereas HHV-6B is indicated to be involved in pathogenesis of epilepsy. These two associations show how neurological diseases might be caused by viral infections, but as suggested here, through completely different molecular mechanisms, in an autoimmune disease, such as MS, by triggering an overreaction of the immune system and in epilepsy by hampering internal cellular functions when the immune system fails to eliminate the virus. Understanding the viral mechanisms of primary infection and reactivation and their spectrum of associated symptoms will aid our ability to diagnose, treat and prevent these severe and chronic diseases. This review explores the role of HHV-6A and HHV-6B specifically in MS and epilepsy, the evidence to date and the future directions of this field.
Toxoplasmosis of the central nervous system: Manifestations vary with immune responses.
Graham Alice K,Fong Crystal,Naqvi Asghar,Lu Jian-Qiang
Journal of the neurological sciences
Toxoplasmosis is an opportunistic infection caused by Toxoplasma gondii (TG), which affects one third of the global human population and commonly involves the central nervous system (CNS)/brain despite the so-called CNS immune privilege. Symptomatic clinical disease of TG infection is much more commonly associated with immunodeficiency; clinicopathological manifestations of CNS toxoplasmosis are linked to individual immune responses including the CNS infiltration of T-cells that are thought to prevent the disease. In patients with autoimmune diseases, immune status is complicated mainly byimmunosuppressant and/or immunomodulatory treatment but typically accompanied by infiltration of T-cells that supposedly fight against toxoplasmosis. In this article, we review characteristics of CNS toxoplasmosis comparatively in immunocompromised patients, immunocompetent patients, and patients with coexisting autoimmune diseases, as well as CNS immune responses to toxoplasmosis with a representative case to demonstrate brain lesions at different stages. In addition to general understanding of CNS toxoplasmosis, our review reveals that clinical manifestations of CNS toxoplasmosis are commonly nonspecific, and incidental pathological findings of TG infection are relatively common in immunocompetent patients and patients with autoimmune diseases (compared to immunocompromised patients); CNS immune responses such as T-cell infiltrates vary in acute and chronic lesions of brain toxoplasmosis.
Use of intravenous gamma globulins in neuroimmunologic diseases.
Latov N,Chaudhry V,Koski C L,Lisak R P,Apatoff B R,Hahn A F,Howard J F
The Journal of allergy and clinical immunology
Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.
Microglia in neuropathology caused by protozoan parasites.
Figarella Katherine,Wolburg Hartwig,Garaschuk Olga,Duszenko Michael
Biological reviews of the Cambridge Philosophical Society
Involvement of the central nervous system (CNS) is the most severe consequence of some parasitic infections. Protozoal infections comprise a group of diseases that together affect billions of people worldwide and, according to the World Health Organization, are responsible for more than 500000 deaths annually. They include African and American trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, and amoebiasis. Mechanisms underlying invasion of the brain parenchyma by protozoa are not well understood and may depend on parasite nature: a vascular invasion route is most common. Immunosuppression favors parasite invasion into the CNS and therefore the host immune response plays a pivotal role in the development of a neuropathology in these infectious diseases. In the brain, microglia are the resident immune cells active in defense against pathogens that target the CNS. Beside their direct role in innate immunity, they also play a principal role in coordinating the trafficking and recruitment of other immune cells from the periphery to the CNS. Despite their evident involvement in the neuropathology of protozoan infections, little attention has given to microglia-parasite interactions. This review describes the most prominent features of microglial cells and protozoan parasites and summarizes the most recent information regarding the reaction of microglial cells to parasitic infections. We highlight the involvement of the periphery-brain axis and emphasize possible scenarios for microglia-parasite interactions.