Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity

Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation.     

Primary anaplastic large cell lymphoma of central nervous system--a case report

Central nervous system (CNS) involvement is extremely rare in anaplastic large cell lymphoma (ALCL). Primary ALCL of CNS on radiology is often misdiagnosed as tuberculosis. We report a fatal case of primary ALCL of CNS in a 17 year old male. He came with history of headache and left partial seizures. MRI showed a well- circumscribed lesion in the right fronto-parietal lobe eroding the skull bone. Biopsy showed large pleomorphic cells. Immunohistochemical stains showed positivity for CD30, CD43, EMA and ALK-1. In spite of radiotherapy and steroids, patient expired. Hence a high level of suspicion is essential for early diagnosis and for instituting appropriate treatment.     

Inflammatory cell migration into the central nervous system: a few new twists on an old tale

Understanding the mechanisms of leukocyte trafficking into the brain might provide insights into how to modulate pathologic immune responses or enhance host protective mechanisms in neuroinflammatory diseases such as multiple sclerosis. This review summarized our knowledge about the sites for leukocyte entry into the central nervous system, highlighting the routes from blood into the perivascular space and brain parenchyma through the blood-brain barrier. We further discussed the multistep paradigm of leukocyte-endothelial interactions at the blood-brain barrier, focusing on the adhesion molecules and chemokines involved in leukocyte transmigration. Luminal chemokines, which are immobilized on endothelial surfaces, initiate leukocyte integrin clustering and conformational change, leading to leukocyte arrest. Some leukocytes undergo post-arrest locomotion across the endothelial surface until interendothelial junctions are identified. Leukocytes then extend protrusions through the interendothelial junctions, in search of abluminal chemokines, which will serve as guidance cues for transmigration. Extravasating cells first accumulate in the perivascular space between the endothelial basement membrane and the basement membrane of the glia limitans. Matrix metalloproteases may be involved in leukocyte transverse across glia limitans into the brain parenchyma. The adhesion molecules and chemokine receptors provide attractive targets for neuroinflammatory diseases because of their important role in mediating central nervous system inflammation.     

The role of T cell apoptosis in nervous system autoimmunity

Fas is a transmembrane receptor involved in the death program of several cell lines, including T lymphocytes. Deleterious mutations hitting genes involved in the Fas pathway cause the autoimmune lymphoprolipherative syndrome (ALPS). Moreover, defective Fas function is involved in the development of common autoimmune diseases, including autoimmune syndromes hitting the nervous system, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). In this review, we first explore some peculiar aspects of Fas mediated apoptosis in the central versus peripheral nervous system (CNS, PNS); thereafter, we analyze what is currently known on the role of T cell apoptosis in both MS and CIDP, which, in this regard, may be seen as two faces of the same coin. In fact, we show that, in both diseases, defective Fas mediated apoptosis plays a crucial role favoring disease development and its chronic evolution.     

Immune checkpoints in central nervous system autoimmunity

A number of autoimmune diseases, including multiple sclerosis, are mediated by self-reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self-reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programed death-1), Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule 3), and TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non-redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.     

Heterochromatin assembly: A new twist on an old model

The organization of eukaryotic genomes requires a harmony between efficient compaction and accessibility. This is achieved through its packaging into chromatin. Chromatin can be subdivided into two general structural and functional compartments: euchromatin and heterochromatin. Euchromatin comprises most of the expressed genome, while heterochromatin participates intimately in the production of structures such as centromeres and telomeres essential for chromosome function. Studies in the fission yeast Schizosaccharomyces pombe have begun to highlight the genetic pathways critical for the assembly and epigenetic maintenance of heterochromatin, including key roles played by the RNAi machinery, H3 lysine 9 methylation and heterochromatin protein 1 (HP1). Recent studies have also identified a novel E3 ubiquitin ligase universally required for H3 K9 methylation. Here we outline these studies and propose several models for the role of this E3 ligase in heterochromatin assembly.     

Senescence and serration: a new twist to an old tale

Interest in the role of oncogene-induced senescence in tumorigenesis is mounting. Raf-associated senescence in cutaneous nevi has been advanced as an example of this process occurring in the context of a human tumour. In this model, conversion from a senescent nevus to a malignant melanoma is accompanied by loss of expression of p16. Serrated polyps of the colorectum may provide a further example of oncogene-induced senescence. BRAF and KRAS mutation may initiate different pathways of senescence-associated serrated neoplasia in the colorectum, the former linked to CpG island methylator phenotype (CIMP)-high (CIMP1) and microsatellite instability (MSI)-high status and the latter with CIMP-low (CIMP2) and MSI-low status. The role of methylation in both Raf- and Ras-associated pathways is to drive tumorigenesis by silencing pro-apoptotic and cell cycle inhibitory genes. Both pathways are associated with mutation of Ras-induced senescence 1 (RIS1), but the biological role of RIS1 requires further elucidation.     

CD30 ligand is a new therapeutic target for central nervous system autoimmunity

The CD30 ligand (CD30L)/CD30 axis plays a critical role in Th1 and Th17 cell differentiation. However, the role in the pathogenesis of central nervous system autoimmunity remains unknown. Here we show the resistance for experimental autoimmune encephalomyelitis (EAE) with markedly reduced induction of antigen-specific Th1 and Th17 cells in CD30L knockout mice. Bone marrow chimera experiments indicated that CD30L on bone marrow-derived cells were critical for the development of EAE and that CD30L reverse signaling in CD4 T cells was dispensable for the pathogenic Th17 cell differentiation at the induction phase. Adoptive transfer experiment revealed an additional role for CD30L in the environment at the effector phase. In vivo neutralization of CD30L by soluble murine CD30-Immunoglobulin fusion protein before disease onset or even after disease onset significantly ameliorated the clinical symptoms. These results indicate that CD30L/CD30 signaling is critically involved in antigen-specific CD4 T cell responses at both the induction and effector phase, thus could be a new target molecule for the treatment of central nervous system autoimmunity.     

Nature versus nurture revisited: an old idea with a new twist

The nature versus nurture debate has recently resurfaced with the emergence of the field of developmental molecular neurobiology. The questions associated with "nature" have crystallized into testable hypotheses regarding patterns of gene expression during development, and those associated with "nurture" have given over to activity-dependent cellular mechanisms that give rise to variable phenotypes in developing nervous systems. This review focuses on some of the features associated with complex brains and discusses the evolutionary and activity-dependent mechanisms that generate these features. These include increases in the size of the cortical sheet, changes in cortical domain and cortical field specification, and the activity-dependent intracellular mechanisms that regulate the structure and function of neurons during development. We discuss which features are likely to be genetically mediated, which features are likely to be regulated by activity, and how these two mechanisms act in concert to produce the wide variety of phenotypes observed for the mammalian neocortex. For example, the size of the cortical sheet is likely to be under genetic control, and regulation of cell-cycle kinetics through upregulation of genes such as beta-catenin can account for increases in the size of the cortical sheet. Similarly, intrinsic signaling genes or gene products such as Wnt, Shh, Fgf2, Fgf8 and BMP may set up a combinatorial coordinate system that guides thalamic afferents. Changes in peripheral morphology that regulate patterned activity are also likely to be under genetic control. Finally, the intracellular machinery that allows for activity-dependent plasticity in the developing CNS may be genetically regulated, although the specific phenotype they generate are not. On the other hand, aspects of neocortical organization such as sensory domain assignment, the size and shape of cortical fields, some aspects of connectivity, and details of functional organization are likely to be activity-dependent. Furthermore, the role of genes versus activity, and their interactions, may be different for primary fields versus non-primary fields.     

T lymphocyte autoimmunity in peripheral nervous system autoimmune disease

Conclusion Autoaggressive T cells specific for the PNS myelin P2 protein play a central role in the initiation of EAN in the Lewis rat, although there is as yet no direct experimental evidence that the T cells can themselves mediate demyelination in vivo. However, the striking similarities in the pathogenesis of EAN and the Guillain-Barré syndrome suggest that T cell mediated EAN provides an excellent model to study the immunological mechanisms of inflammation and demyelination that are relevant to human PNS disease.     

The roles of the new negative T cell costimulatory pathways in regulating autoimmunity

The B7 family of T cell costimulatory molecules has recently acquired several new members. Some of these are activating while others are inhibitory. In this review, we will focus on the novel inhibitory pathways with particular emphasis on the PD-1:PD-L pathway. Understanding the mechanisms of these pathways has implications for development of novel treatment strategies for autoimmune disease, transplantation, tumor immunotherapy, and vaccine development.     

Neoplasms involving the central nervous system in the older old

Geriatric cancer patients present special challenges for clinicians. Few large series have been published in the last 20 years on the types of neoplasms that involve the central nervous system (CNS) in older individuals. To review types of neoplasms involving the central CNS that are currently being encountered by pathologists and neurosurgeons, we identified from our databases for the years 1992-2002, inclusive, patients 75 years or older who had symptomatic lesions requiring neurosurgical interventions. Retrospective characterization of tumors by immunohistochemistry, in situ hybridization, and fluorescence in situ hybridization was performed whenever possible and relevant to tumor type. Neurosurgical procedures (n=125) on 119 patients were identified; 90 patients were diagnosed as having neoplasms, with clot evacuation or infections being the most frequent non-neoplastic conditions necessitating surgery. Tumor types included glioblastomas (36 patients), meningiomas (16), pituitary adenomas (12), lymphomas or other hematological malignancies (8), anaplastic gliomas (5), metastases (6), head and neck malignancies with direct intracranial extension (3), and other miscellaneous tumor types (4). Compared with older literature series, we encountered a larger number of elderly patients with CNS lymphomas and fewer who came to surgery for CNS metastatic disease. In the "older old", glioblastomas are the most frequent symptomatic tumors necessitating surgical intervention. Glioblastomas in this aged cohort display the signature features of the small cell phenotype (62%), high cell cycle labeling indices (mean MIB-1-labeling index=25.1%), and either amplification of epidermal growth factor receptor or gain of chromosome 7 by fluorescence in situ hybridization (93% of assessable cases).     

Burkholderia cenocepacia sp. nov.--a new twist to an old story

DNA-DNA hybridisation experiments between isolates representing Burkholderia cepacia genomovar III recA lineages IIIA and IIIB reinforced the classification of both phylogenetic subgroups as a single genospecies, distinct from B. cepacia (genomovar I). A formal classification of B. cepacia genomovar III encompassing the recA lineages IIIA and IIIB, and the new recA lineages IIIC and IIID, as B. cenocepacia sp. nov., with LMG 16656 as the type strain, is proposed.     

Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity

MS is an inflammatory CNS disorder, which typically occurs in early adulthood and rarely in children. Here we tested whether functional maturation of innate immune cells may determine susceptibility to CNS autoimmune disease in EAE. Two‐week‐old mice were resistant to active EAE, which causes fulminant paralysis in adult mice; this resistance was associated with an impaired development of Th1 and Th17 cells. Resistant, young mice had higher frequencies of myeloid‐derived suppressor cells and plasma‐cytoid DCs. Furthermore, myeloid APCs and B cells from young mice expressed lower levels of MHC class II and CD40, produced decreased amounts of proinflammatory cytokines, and released enhanced levels of anti‐inflammatory IL‐10. When used as APCs, splenocytes from 2‐week‐old mice failed to differentiate naive T cells into Th1 and Th17 cells irrespective of the T‐cell donor's age, and promoted development of Treg cells and Th2 cells instead. Adoptive transfer of adult APCs restored the ability of 2‐week‐old mice to generate encephalitogenic T cells and develop EAE. Collectively, these findings indicate that the innate immune compartment functionally matures during development, which may be a prerequisite for development of T‐cell‐mediated CNS autoimmune disease.     

Adapting to inversion of the visual field: a new twist on an old problem

While sensorimotor adaptation to prisms that displace the visual field takes minutes, adapting to an inversion of the visual field takes weeks. In spite of a long history of the study, the basis of this profound difference remains poorly understood. Here, we describe the computational issue that underpins this phenomenon and presents experiments designed to explore the mechanisms involved. We show that displacements can be mastered without altering the updated rule used to adjust the motor commands. In contrast, inversions flip the sign of crucial variables called sensitivity derivatives—variables that capture how changes in motor commands affect task error and therefore require an update of the feedback learning rule itself. Models of sensorimotor learning that assume internal estimates of these variables are known and fixed predicted that when the sign of a sensitivity derivative is flipped, adaptations should become increasingly counterproductive. In contrast, models that relearn these derivatives predict that performance should initially worsen, but then improve smoothly and remain stable once the estimate of the new sensitivity derivative has been corrected. Here, we evaluated these predictions by looking at human performance on a set of pointing tasks with vision perturbed by displacing and inverting prisms. Our experimental data corroborate the classic observation that subjects reduce their motor errors under inverted vision. Subjects’ accuracy initially worsened and then improved. However, improvement was jagged rather than smooth and performance remained unstable even after 8 days of continually inverted vision, suggesting that subjects improve via an unknown mechanism, perhaps a combination of cognitive and implicit strategies. These results offer a new perspective on classic work with inverted vision.     

Regulatory T cells in the central nervous system

Regulatory T cells (Tregs) are critical to the human immune system, providing appropriately scaled immune responses and mediating peripheral tolerance. A central role for forkhead box protein 3 (FoxP3)(+) Tregs has been shown in the pathogenesis of mechanistically diverse central nervous system (CNS) diseases from autoimmune diseases such as multiple sclerosis to glioblastomas. Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases, where there is loss of Treg function, will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases.     

Role of complementary proteins in autoimmunity: an old idea re-emerges with new twists

It has been suggested that complementary proteins are involved in autoimmunity through a network involving idiotype-anti-idiotype reactions termed 'autoantigen complementarity'. We propose that complementary proteins, which occur naturally or result from cellular dysfunction, might be more common than recognized currently. This implies that the role of complementary proteins in autoimmunity merits increasing investigation. The concept of complementary proteins is reviewed here and, also, new ideas are presented that underscore the role of open-reading frames in frame -1 of recognized genes in the production of complementary proteins (frame -1 is the reverse complement sequence of a gene that uses the antisense of the codons of frame +1). Furthermore, a novel role for palindromic sequences in autoimmunity and a new model explaining how abzymes and autoantigen complementarity might be related are proposed.     

T cell metabolism in metabolic disease-associated autoimmunity

This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro-environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease-associated autoimmunity.