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In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrPd deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), oligodendroglial pathology has been rarely addressed. We assessed a series of sCJD cases with the aim to identify particular histotypes that could be more prone to harbor oligodendroglial PrPd. Particularly, the MM2C phenotype, in both its more “pure” and its mixed MM1+2C or MV2K+2C forms, showed more frequent oligodendroglial PrP pathology in the underlying white matter than the more common MM1/MV1 and VV2 histotypes, and was more abundant in patients with a longer disease duration. We concluded that the MM2C strain was particularly prone to accumulate PrPd in white matter oligodendrocytes.

Background The C9orf72 hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD‐ALS. Its underlying neuropathology combines TDP‐43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration‐associated protein aggregates. Herein we present a unique combination of C9orf72 mutation with sporadic Creutzfeldt−Jakob disease (CJD) in a 74‐year‐old patient with rapidly progressive dementia. Methods Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional C9orf72 mutation carriers for prion−protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies. Results Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months’ duration confirmed the diagnosis of CJD. She harbored valine homozygosity at PRNP codon 129. In addition, a frontotemporal lobar degeneration (FTLD)‐pattern with TDP‐43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer‐related pathology (A3B3C3) were identified. The suspected C9orf72 expansion mutation was confirmed by repeat‐primed PCR. Screening of 13 C9orf72 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other C9orf72 expansion mutation carriers. Conclusion A combination of a C9orf72 expansion mutation‐related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies., We describe clinicopathological features of a patient with co‐incident C9orf72 expansion mutation‐related FTLD‐pathology and sporadic Creutzfeldt−Jakob disease (sCJD). This combination has not been described to date.

Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.

The syndrome of sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO), defined genetically by mutations of the gene for the mitochondrial DNA polymerase-γ, POLG, was first described in 1997 (1). Since then, several case reports with various POLG, or more rarely PEO1, mutations have been published (2-4), some specifically addressing muscle and nerve pathology (1, 3), nerve electrophysiology (5), or radiological aspects (4, 6, 7). This article is protected by copyright. All rights reserved.

Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau-immunoreactive neuritic profiles. Fifty-two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains.

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define “definite”, “probable” and “possible” diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A “definite” diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a “probable” diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A “possible” diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1591-8) contains supplementary material, which is available to authorized users.

OBJECTIVE Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation. METHODS We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by delayed clinical improvement. RESULTS Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and clonal expansion of activated CD8(+) effector T cells with a CD4(dim) CD8(+) phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4(+) T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD8(+) T-cell responses after IRIS. INTERPRETATION Our findings suggest that efficient CD4(+) T-cell recognition of neurotropic JCV variants is crucial to support CD8(+) T cells in combating JCV infection of the CNS.

Creutzfeldt–Jakob disease (CJD) and Gerstmann–Straussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes of human prion diseases or transmissible spongiform encephalopathies (TSEs). TSEs arise either spontaneously (sporadic disease forms such as sporadic CJD/sCJD or sporadic fatal insomnia/sFI), by genetic aberration (genetic CJD/gCJD, GSS, fatal familial insomnia/FFI) or acquired by contact with infectious prions from bovine spongiform encephalopathy (BSE), causing variant CJD (vCJD), or – more or less historically – as iatrogenic CJD (iCJD) from invasive medical procedures such as dural or corneal transplantations, cadaveric pituitary hormone preparations or surgical instruments, or from blood and blood products with vCJD prions. Genetic forms constitute about 10–15% of human prion diseases and result from more than 30 mutations, insertions or rarely deletions in the prion protein (PrP) gene, PRNP. A polymorphism at PRNP codon 129 is an important susceptibility factor and relevant for phenotypic heterogeneity. Other genes have not convincingly been shown to be involved. Key Concepts: Prion diseases are invariably lethal and transmissible neurological disorders that affect humans and animals. In humans, they occur sporadically and can also be acquired or inherited. The infectious agent is considered to be solely an abnormal conformer of the host-encoded prion protein (PrP). Genetic disease forms constitute about 10–15%, result from aberrations in the PrP gene, PRNP, and are inherited as autosomal dominant trait with variable penetrance. There is a broad clinical and neuropathological phenotypic spectrum, which is modulated by molecular factors including PRNP polymorphisms and PrP strains. Creutzfeldt–Jakob disease (CJD) and Gerstmann–Straussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes. CJD occurs mostly sporadically (sCJD), more rarely by genetic aberration (gCJD), whereas GSS is always of genetic origin. There is no effective treatment yet.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a “serum antibody–consuming effect” during lesion formation.

A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Sträussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.

To identify the disease-causing gene responsible for an autosomal dominantly inherited Charcot–Marie–Tooth neuropathy subtype in a family excluded for mutations in the common Charcot–Marie–Tooth genes, we used array-based sequence capture to simultaneously analyse the disease-linked protein coding exome at chromosome 14q32. A missense mutation in fibulin-5 , encoding a widely expressed constituent of the extracellular matrix that has an essential role in elastic fibre assembly and has been shown to cause cutis laxa, was detected as the only novel non-synonymous sequence variant within the disease interval. Screening of 112 index probands with unclassified Charcot–Marie–Tooth neuropathies detected two further fibulin-5 missense mutations in two families with Charcot–Marie–Tooth disease and hyperextensible skin. Since fibulin-5 mutations have been described in patients with age-related macular degeneration, an additional 300 probands with exudative age-related macular degeneration were included in this study. Two further fibulin-5 missense mutations were identified in six patients. A mild to severe peripheral neuropathy was detected in the majority of patients with age-related macular degeneration carrying mutations in fibulin-5 . This study identifies fibulin-5 as a gene involved in Charcot–Marie–Tooth neuropathies and reveals heterozygous fibulin-5 mutations in 2% of our patients with age-related macular degeneration. Furthermore, it adumbrates a new syndrome by linking concurrent pathologic alterations affecting peripheral nerves, eyes and skin to mutations in the fibulin-5 gene. * Abbreviation : FBLN5 : fibulin-5

[This corrects the article DOI: 10.1371/journal.ppat.1002350.].

Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.

QUESTIONS UNDER STUDY: Alzheimer-type amyloid-β (Aβ) pathology was reported in brains of individuals developing iatrogenic Creutzfeldt-Jakob disease (iCJD) after treatment with human cadaveric growth hormone, and interpreted as evidence of human transmission of Aβ by the treatment. Here we investigated the prevalence of Aβ pathology in other instances of iCJD related to dura mater grafts. METHODS: By use of immunohistochemistry for Aβ, we investigated seven brains of patients (age range 28–63) who succumbed to iCJD after dural grafting, which had been applied by means of neurosurgery between 11 and 25 years before death. For control, we examined a series of 21 brains of age-matched (40–63 years) patients with sporadic CJD (sCJD) and an additional series of 81 sCJD cases (55–85 years) with the same methods. RESULTS: In five of seven iCJD brains, Aβ was deposited in meningeal vessels as congophilic amyloid angiopathy and brain parenchymal plaques. This was significantly (p

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology.

Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrP(Sc), a misfolded and aggregated form of the cellular prion protein (PrP(C)). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.

Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naïve patient. Based on recent data from genomic studies, we propose that a sequential evolution of molecular pathology lead to the co-occurrence of multiple myeloma and primary central nervous system B cell lymphoma in this patient, and interpret the development of the temporal lobe leukoencephalopathy as a likely paraneoplastic complication of smoldering myeloma.

Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation.We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted 21 months after IRIS accompanied by delayed clinical improvement.Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and clonal expansion of activated CD8(+) effector T cells with a CD4(dim) CD8(+) phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4(+) T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD8(+) T-cell responses after IRIS.Our findings suggest that efficient CD4(+) T-cell recognition of neurotropic JCV variants is crucial to support CD8(+) T cells in combating JCV infection of the CNS.

Objective:To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile.Methods:The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4+ and CD8+ T cells and high-throughput TCR Vβ-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized.Results:We found that CD4+, CD8+, and also γδ T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8+ but also CD4+ T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-γ and TNF. Broad cytokine profiling at the clonal level showed strong production of IFN-γ and TNF and also secretion of interleukin (IL)-5, IL-13, and granzyme B, both in CD4+ and CD8+ T cells.Conclusions:CD8+ T cells were until now considered the central players in the immunopathogenesis of RE. Our study adds to previous findings and highlights that CD4+ TCCs and γδ T cells that secrete IFN-γ and TNF are also involved. These findings underline the complexity of T-cell immunity in RE and suggest a specific role for CD4+ T cells in orchestrating the CD8+ T-cell effector immune response.