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In JoVE (1)
Other Publications (34)
- Journal of Neuroimmunology
- Personality & Social Psychology Bulletin
- Neurobiology of Disease
- Brain : a Journal of Neurology
- PloS One
- Journal of Neuroimmunology
- Journal of Leukocyte Biology
- The American Journal of Pathology
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Neuroimmunology
- PloS One
- European Journal of Immunology
- Cellular and Molecular Life Sciences : CMLS
- Multiple Sclerosis (Houndmills, Basingstoke, England)
- PloS One
- AIDS (London, England)
- Annals of Neurology
- The Journal of Experimental Medicine
- International Immunology
- BMC Neurology
- Multiple Sclerosis (Houndmills, Basingstoke, England)
- The Journal of Social Psychology
- Neurology(R) Neuroimmunology & Neuroinflammation
- Nature Communications
- Proceedings of the National Academy of Sciences of the United States of America
- Multiple Sclerosis (Houndmills, Basingstoke, England)
- Proceedings of the National Academy of Sciences of the United States of America
- Science Translational Medicine
Articles by Nicholas Schwab in JoVE
Analysis of Lymphocyte Extravasation Using an In Vitro Model of the Human Blood-brain Barrier
Andreas Schulte-Mecklenbeck1, Urvashi Bhatia1, Tilman Schneider-Hohendorf1, Nicholas Schwab1, Heinz Wiendl*1, Catharina C. Gross*1
1Department of Neurology with Institute of Translational Neurology, University Hospital Münster
Other articles by Nicholas Schwab on PubMed
Journal of Neuroimmunology. Aug, 2008 | Pubmed ID: 18644633
Muscle biopsy specimens of myositis patients were analyzed for the presence of dendritic cells (DC) and macrophages (MPh) by immunohistochemistry. The interaction of DC and myoblasts (MB) was studied by coculture and effects on DC phenotype and function were assessed by flow cytometry and T-cell proliferation assays. Effects of MB-lysates on the phagocytic capacity of MPh were analyzed in bead-incorporation assays. Myositis specimens revealed a tendency towards more immature DC. MB modulated the maturation state of DC and DC recovered from MB-coculture had an inhibitory effect on T-cell proliferation. MB-lysates strongly stimulated MPh phagocytosis. Hypothetically, MB might modulate APC, counterbalancing immune-mediated damage.
The Cognitive and Affective Dimensions of Moral Conviction: Implications for Attitudinal and Behavioral Measures of Interpersonal Tolerance
Personality & Social Psychology Bulletin. Nov, 2008 | Pubmed ID: 18685130
The present studies investigate the role of both cognitive and affective dimensions of moral conviction in contributing to negative interpersonal responses. After demonstrating that the cognitive and affective dimensions of moral conviction are distinct constructs, the studies show that the cognitive dimension is sufficient to produce many forms of interpersonal intolerance. Simply believing an issue to be moral (i.e., objectively grounded, non-negotiable) results in greater intolerance for (Study 1), less sharing with (Study 2), and greater distancing from (Study 3) people with divergent attitudes. The emotional intensity with which beliefs are experienced is not alone explanatory. Nonetheless, it interacts with moral beliefs to produce the highest levels of interpersonal intolerance, distancing from dissimilar others, and context insensitivity. This interaction pattern between moral beliefs and affect was specific to emotional intensity and not other measures of attitude strength (Study 3).
The Co-inhibitory Molecule PD-1 Modulates Disease Severity in a Model for an Inherited, Demyelinating Neuropathy
Neurobiology of Disease. Jan, 2009 | Pubmed ID: 18996482
We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule "programmed death" (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phenotype of CD8+ T-lymphocytes in the P0 myelin mutants. PD-1 deficiency in P0+/- mice leads to a stronger increase of CD8+ T-lymphocytes and a substantially aggravated histological phenotype in the PNS compared to P0+/- mice expressing PD-1. Correspondingly, functional down-stream features, such as electrophysiological parameters, walking coordination and mechano-sensation are more affected than in PD-1-expressing myelin mutants. Our study demonstrates that a monogenic nerve disorder can be substantially modified by immune-controlling mechanisms. Thus, understanding the implication of disease-modifiers in inherited demyelination could be of pivotal interest for limiting the detrimental impact of primarily genetically-mediated myelin disorders by fostering immuno-regulatory pathways.
CD8+ T-cell Clones Dominate Brain Infiltrates in Rasmussen Encephalitis and Persist in the Periphery
Brain : a Journal of Neurology. May, 2009 | Pubmed ID: 19179379
Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. Destruction of neurons and astrocytes by cytotoxic CD8 T cells has been proposed as a pathogenic mechanism underlying this enigmatic disorder. We tested this hypothesis by analysing the clonal composition and T-cell receptor (TCR) repertoire of CD4+ and CD8+ T cells using complementarity determining region 3 (CDR3) spectratyping from peripheral blood and corresponding CNS specimens. Severe perturbations of the TCR repertoire were found in brain infiltrates from all specimens (n = 5). Clonal expansions, as evidenced by peripheral blood analysis (n = 14), belonged to the CD8+ T-cell subset, while CD4+ cells showed normal distributions. Some of those expansions were analysed in the respective CNS specimens by histochemistry. The stainings showed Vbeta specific T cells containing the cytotoxic molecule granzyme B and lying in close appositions to NeuN+ neurons and GFAP+ astrocytes. Analysis of corresponding CNS/blood specimens revealed overlapping but also CNS-restricted expansions of certain TCR clonotypes suggesting expansions of T cells within the target organ itself. Longitudinal analysis of peripheral blood samples (n = 5) demonstrated dominance but also longitudinal persistence of specific CD8 T-cell clones over time. The Vbeta/Jbeta usage, length of the CDR3, and biochemical characteristics of the CDR3 amino acids suggested high similarities putatively related to common driving antigen(s) without shared clones. Taken together, our data strongly support the hypothesis of an antigen-driven MHC class-I restricted, CD8+ T cell-mediated attack against neurons and astrocytes in the CNS dominating the pathogenesis in RE.
PloS One. 2009 | Pubmed ID: 19197390
We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.
Intercellular Exchanges of Membrane Fragments (trogocytosis) Between Human Muscle Cells and Immune Cells: a Potential Mechanism for the Modulation of Muscular Immune Responses
Journal of Neuroimmunology. Apr, 2009 | Pubmed ID: 19269695
Trogocytosis is a cell-contact dependent intercellular transfer of membrane fragments and associated molecules. We studied trogocytosis in the interaction of T cells with human skeletal muscle cells modeling muscle-immune cell interactions under pathophysiological conditions i.e. myositis. Human myoblasts donate membrane fragments to T cells. Acquisition of muscle-derived membrane molecules depended on T-cell activation, was independent of T-cell receptor engagement, sensitive to inhibition of actin polymerization and amplified by protein kinase C activation. Single-cell patch clamping was used to demonstrate the change in membrane capacitance upon incorporation of membrane fragments in T cells. Membrane uptake was fast and temporarily, but had clear functional consequences: T cells after intimate contact with myoblasts stimulated the proliferation of autologous T cells. Our observations raise the hypothesis that trogocytosis may modulate the outcome of T-T interactions within the micromilieu of skeletal muscle.
T Cell Suppression by Naturally Occurring HLA-G-expressing Regulatory CD4+ T Cells is IL-10-dependent and Reversible
Journal of Leukocyte Biology. Aug, 2009 | Pubmed ID: 19401389
CD4(+) T cells constitutively expressing the immune-tolerogenic HLA-G have been described recently as a new type of nT(reg) (HLA-G(pos) T(reg)) in humans. HLA-G(pos) T(reg) accumulate at sites of inflammation and are potent suppressors of T cell proliferation in vitro, suggesting their role in immune regulation. We here characterize the mechanism of how CD4(+) HLA-G(pos) T(reg) influence autologous HLA-G(neg) T(resp) function. Using a suppression system free of APC, we demonstrate a T-T cell interaction, resulting in suppression of HLA-G(neg) T(resp), which is facilitated by TCR engagement on HLA-G(pos) T(reg). Suppression is independent of cell-cell contact and is reversible, as the removal of HLA-G(pos) T(reg) from the established coculture restored the proliferative capability of responder cells. Further, HLA-G(pos) T(reg)-mediated suppression critically depends on the secretion of IL-10 but not TGF-beta.
Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-deficient Central Nervous System Myelin Mutants
The American Journal of Pathology. Jun, 2009 | Pubmed ID: 19443704
It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.
Early Detrimental T-cell Effects in Experimental Cerebral Ischemia Are Neither Related to Adaptive Immunity nor Thrombus Formation
Blood. May, 2010 | Pubmed ID: 20215643
T cells contribute to the pathophysiology of ischemic stroke by yet unknown mechanisms. Mice with transgenic T-cell receptors (TCRs) and mutations in costimulatory molecules were used to define the minimal immunologic requirements for T cell-mediated ischemic brain damage. Stroke was induced in recombination activating gene 1-deficient (RAG1(-/-)) mice devoid of T and B cells, RAG1(-/-) mice reconstituted with B cells or T cells, TCR-transgenic mice bearing 1 single CD8(+) (2C/RAG2, OTI/RAG1 mice) or CD4(+) (OTII/RAG1, 2D2/RAG1 mice) TCR, mice lacking accessory molecules of TCR stimulation (CD28(-/-), PD1(-/-), B7-H1(-/-) mice), or mice deficient in nonclassical T cells (natural killer T [NKT] and gammadelta T cells) by transient middle cerebral artery occlusion (tMCAO). Stroke outcome was assessed at day 1. RAG1(-/-) mice and RAG1(-/-) mice reconstituted with B cells developed significantly smaller brain infarctions compared with controls, but thrombus formation after FeCl(3)-induced vessel injury was unimpaired. In contrast, TCR-transgenic mice and mice lacking costimulatory TCR signals were fully susceptible to tMCAO similar to mice lacking NKT and gammadelta T cells. These findings were corroborated by adoptive transfer experiments. Our data demonstrate that T cells critically contribute to cerebral ischemia, but their detrimental effect neither depends on antigen recognition nor TCR costimulation or thrombus formation.
An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis
Journal of Immunology (Baltimore, Md. : 1950). May, 2010 | Pubmed ID: 20357264
Plasmacytoid dendritic cells (pDCs) are instrumental in peripheral T cell tolerance and innate immunity. How pDCs control peripheral immunetolerance and local parenchymal immune response and contribute to the altered immunoregulation in autoimmune disorders in humans is poorly understood. Based on their surface markers, cytokine production, and ability to prime naive allogenic T cells, we found that purified BDCA-2(+)BDCA-4(+) pDCs consist of at least two separate populations, which differed in their response to oligodeoxynucleotides and IFNs (IFN-beta), and differently induced IL-17- or IL-10-producing T cells. To evaluate the potential immunoregulatory role of these two types of pDCs in multiple sclerosis (MS) and other human autoimmune disorders (myasthenia gravis), we studied the phenotype and regulatory function of pDCs isolated from clinically stable, untreated patients with MS (n = 16). Patients with MS showed a reversed ratio of pDC1/pDC2 in peripheral blood (4.4:1 in healthy controls, 0.69:1 in MS), a phenomenon not observed in the other autoimmune disorders. As a consequence, MS pDCs had an overall propensity to prime IL-17-secreting cells over IL-10-secreting CD4+ T cells. Immunomodulatory therapy with IFN-beta induced an increase of the pDC1 population in vivo (n = 5). Our data offer a plausible explanation for the disturbed immune tolerance in MS patients and provide evidence that immunomodulatory therapy acts at the level of reconstituting homeostasis of pDC, thus reconstituting the disturbed balance.
Journal of Neuroimmunology. Aug, 2010 | Pubmed ID: 20537411
FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3 expression in dermatomyositis, polymyositis and inclusion body myositis was assessed by immunohistochemistry and real-time PCR. FOXP3+ Tregs were found in close proximity to effector cells and their numbers correlated with the degree of inflammation. Despite divergent pathogenetic concepts, we observed no differences in the frequency of FOXP3 immunoreactive cells or FOXP3 mRNA expression between different myositis entities. Functional assays using human myoblasts as targets of CD8+ cells demonstrate that Tregs are capable to inhibit the lytic activity of cytotoxic cells. Our data suggest that FOXP3 Tregs serve to counterbalance muscle destruction by cytotoxic T cells in myositis.
Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis
PloS One. 2010 | Pubmed ID: 21085578
Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.
Regulatory T Cells Exhibit Enhanced Migratory Characteristics, a Feature Impaired in Patients with Multiple Sclerosis
European Journal of Immunology. Dec, 2010 | Pubmed ID: 21108477
Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.
Cellular and Molecular Life Sciences : CMLS. Feb, 2011 | Pubmed ID: 21086150
The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.
Multiple Sclerosis (Houndmills, Basingstoke, England). Mar, 2012 | Pubmed ID: 21908480
Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML).
Neurology. Aug, 2013 | Pubmed ID: 23925765
To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.
PloS One. 2013 | Pubmed ID: 24282598
Migration of encephalitogenic CD4(+) T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4(+) T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4(+)NKG2D(+) cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4(+)NKG2D(+) cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4(+)NKG2D(+) T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4(+) T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4(+)NKG2D(+) T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4(+) T cells. Taken together, we identify CD4(+)NKG2D(+) cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.
Specific Loss of Cellular L-selectin on CD4+ T Cells is Associated with PML Development During HIV Infection
AIDS (London, England). Jan, 2014 | Pubmed ID: 24445368
HIV progressive multifocal leukoencephalopathy (PML) patients had a significantly lower expression of CD62L on CD4 T cells (P < 0.001) when compared with HIV patients who did not develop PML. CD62L expression on CD4 T cells did not correlate with parameters such as CDC stage, CD4 cell percentage (of total CD3 T cells), CD4 cell counts, virus count, or clinical parameters. Measurement of CD62L might provide a biomarker for PML risk and could prompt a treatment change and/or close monitoring.
Annals of Neurology. May, 2014 | Pubmed ID: 24771567
Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity.
VLA-4 Blockade Promotes Differential Routes into Human CNS Involving PSGL-1 Rolling of T Cells and MCAM-adhesion of TH17 Cells
The Journal of Experimental Medicine. Aug, 2014 | Pubmed ID: 25135296
The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.
International Immunology. Jan, 2015 | Pubmed ID: 25326459
Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood-brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen encephalitis and neuromyelitis optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets' migration through the BBB in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-John Cunningham virus (JCV) antibody seropositivity, but also experimental factors such as anti-JCV antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential PML.
Assessment of Immune Functions and MRI Disease Activity in Relapsing-remitting Multiple Sclerosis Patients Switching from Natalizumab to Fingolimod (ToFingo-Successor)
BMC Neurology. Jun, 2015 | Pubmed ID: 26099927
In light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated.
Multiple Sclerosis (Houndmills, Basingstoke, England). Jul, 2016 | Pubmed ID: 26432858
Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.
The Journal of Social Psychology. Jul-Aug, 2016 | Pubmed ID: 26541710
The present study investigated the potential clustering of worry appraisals within college social networks. Participants living in campus residence buildings responded to online surveys across the course of several months. Worry appraisals were measured 10 weeks into the fall semester and again approximately 6 months later. Analysis of sociometric data suggests that the majority of participants' social interactions occurred within their respective residence building floors, indicating that proximity strongly influenced the development of social network ties and sources of social influence. Further, significant clustering of worry appraisals occurred across time, and more importantly, within residence building floors. The present findings compliment previous work suggesting that several physical and psychological states appear to spread and cluster within social networks. Implications for the study of emotional appraisals and future research are discussed.
Neurology(R) Neuroimmunology & Neuroinflammation. Feb, 2016 | Pubmed ID: 26848486
The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.
CD8(+) T-cell Pathogenicity in Rasmussen Encephalitis Elucidated by Large-scale T-cell Receptor Sequencing
Nature Communications. Apr, 2016 | Pubmed ID: 27040081
Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.
Impaired NK-mediated Regulation of T-cell Activity in Multiple Sclerosis is Reconstituted by IL-2 Receptor Modulation
Proceedings of the National Academy of Sciences of the United States of America. May, 2016 | Pubmed ID: 27162345
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.
Distinct Pattern of Lesion Distribution in Multiple Sclerosis is Associated with Different Circulating T-helper and Helper-like Innate Lymphoid Cell Subsets
Multiple Sclerosis (Houndmills, Basingstoke, England). Aug, 2016 | Pubmed ID: 27481205
Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS).
Neurology. Aug, 2016 | Pubmed ID: 27572431
B7-H1 Shapes T-cell-mediated Brain Endothelial Cell Dysfunction and Regional Encephalitogenicity in Spontaneous CNS Autoimmunity
Proceedings of the National Academy of Sciences of the United States of America. Oct, 2016 | Pubmed ID: 27671636
Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.
Science Translational Medicine. Oct, 2016 | Pubmed ID: 27797962
In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Treg function is impaired. We show that a recently approved drug, Nle(4)-d-Phe(7)-α-melanocyte-stimulating hormone (NDP-MSH), induced functional Treg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders.
Neurology. Nov, 2016 | Pubmed ID: 27815407
Neurology. Mar, 2017 | Pubmed ID: 28228564
Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today's clinical practice are potentially outdated and the risk for patients with prior immunosuppression might have been underestimated. (2) Risk stratification according to treatment duration epochs likely suggests lower risk due to patients stopping treatment within a given epoch. PML incidence within the complete treatment epoch is statistically lowered due to the fact that patients at the beginning of an epoch presumably have a lower PML risk than the patients at the end. Periodic risk is not accurate in assessing risk for long treatment durations. (3) The JC virus (JCV) serostatus risk factor has low specificity concerning PML prediction and anti-JCV seroconversion during treatment with natalizumab further lowers its specificity over time. Specificity of the risk factor treatment duration varies depending on the average treatment duration and the number of short-term patients. These short-term patients reduce overall average treatment duration and thus enhance the specificity of the risk factor and reduce overall PML incidence. It is also suggested that short-term natalizumab patients are exclusively non-PML, even though they might still develop PML. Clinicians have to consider the cumulative risk of patients to stratify efficiently.