In JoVE (1)

Other Publications (37)

Articles by Catharina C. Gross in JoVE

Other articles by Catharina C. Gross on PubMed

Use of Transfected Drosophila S2 Cells to Study NK Cell Activation

Methods in Molecular Biology (Clifton, N.J.). 2010  |  Pubmed ID: 20033635

Determining the contribution of individual receptors to natural killer (NK) cell function is complicated by the multiplicity of activating and inhibitory NK cell receptors. Mammalian target cells typically express a variety of ligands for NK cell receptors. Engagement of NK cell receptors by antibodies may not mimic activation by natural ligands. To define requirements for activation and dissect the contribution of receptors to NK cell function, we have generated Drosophila Schneider line 2 (S2) cell transfectants expressing ligands for NK cell receptors. The evolutionary distance between Drosophila and mammals greatly reduces the potential of recognition of insect cell molecules by mammalian NK cells. Here, we present methods for maintenance and transfection of S2 cells, as well as protocols for their use in NK cell assays.

Synergistic Signals for Natural Cytotoxicity Are Required to Overcome Inhibition by C-Cbl Ubiquitin Ligase

Immunity. Feb, 2010  |  Pubmed ID: 20189481

Natural killer (NK) cell cytotoxicity toward target cells depends on synergistic coactivation by NK cell receptors such as NKG2D and 2B4. How synergy occurs is not known. Synergistic phosphorylation of phospholipase PLC-gamma2, Ca(2+) mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 siRNA knockdown, but enhanced by knockdown of c-Cbl. c-Cbl inhibited Vav1-dependent signals, given that c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the necessity for synergy because NKG2D or 2B4 alone became sufficient for activation. Thus, synergy requires not strict complementation but, rather, strong Vav1 signals to overcome inhibition by c-Cbl. Inhibition of NK cell cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms.

Tethering of Intercellular Adhesion Molecule on Target Cells is Required for LFA-1-dependent NK Cell Adhesion and Granule Polarization

Journal of Immunology (Baltimore, Md. : 1950). Sep, 2010  |  Pubmed ID: 20675589

Alpha(L)beta(2) integrin (LFA-1) has an important role in the formation of T cell and NK cell cytotoxic immunological synapses and in target cell killing. Binding of LFA-1 to ICAM on target cells promotes not only adhesion but also polarization of cytolytic granules in NK cells. In this study, we tested whether LFA-1-dependent NK cell responses are regulated by the distribution and mobility of ICAM at the surface of target cells. We show that depolymerization of F-actin in NK-sensitive target cells abrogated LFA-1-dependent conjugate formation and granule polarization in primary NK cells. Degranulation, which is not controlled by LFA-1, was not impaired. Fluorescence recovery after photobleaching experiments and particle tracking by total internal reflection fluorescence microscopy revealed that ICAM-1 and ICAM-2 were distributed in largely immobile clusters. ICAM clusters were maintained and became highly mobile after actin depolymerization. Moreover, reducing ICAM-2 mobility on an NK-resistant target cell through expression of ezrin, an adaptor molecule that tethers proteins to the actin cytoskeleton, enhanced LFA-1-dependent adhesion and granule polarization. Finally, although NK cells kept moving over freely diffusible ICAM-1 on a lipid bilayer, they bound and spread over solid-phase ICAM-1. We conclude that tethering, rather than clustering of ICAM, promotes proper signaling by LFA-1 in NK cells. Our findings suggest that the lateral diffusion of integrin ligands on cells may be an important determinant of susceptibility to lysis by cytotoxic lymphocytes.

Cutting Edge: NKG2D-dependent Cytotoxicity is Controlled by Ligand Distribution in the Target Cell Membrane

Journal of Immunology (Baltimore, Md. : 1950). May, 2011  |  Pubmed ID: 21464092

Although the importance of membrane microdomains in receptor-mediated activation of lymphocytes has been established, much less is known about the role of receptor ligand distribution on APC and target cells. Detergent-resistant membrane domains, into which GPI-linked proteins partition, are enriched in cholesterol and glycosphingolipids. ULBP1 is a GPI-linked ligand for natural cytotoxicity receptor NKG2D. To investigate how ULBP1 distribution on target cells affects NKG2D-dependent NK cell activation, we fused the extracellular domain of ULBP1 to the transmembrane domain of CD45. Introduction of this transmembrane domain eliminated the association of ULBP1 with the detergent-resistant membrane fraction and caused a significant reduction of cytotoxicity and degranulation by NK cells. Clustering and lateral diffusion of ULBP1 was not affected by changes in the membrane anchor. These results show that the partitioning of receptor ligands in discrete membrane domains of target cells is an important determinant of NK cell activation.

Palmitoylation of MICA, a Ligand for NKG2D, Mediates Its Recruitment to Membrane Microdomains and Promotes Its Shedding

European Journal of Immunology. Dec, 2011  |  Pubmed ID: 21928280

MICA and MICB (MHC-class-I-related chain A/B) are transmembrane proteins expressed in pathological conditions that are ligands for NKG2D, an activating receptor found on cytotoxic lymphocytes. The recognition on target cells of NKG2D ligands leads to the activation of lysis and cytokine secretion by NK cells and T cells. Besides being expressed at the cell surface, MICA/B can be released as soluble proteins. Soluble NKG2D ligands downmodulate expression of the NKG2D receptor on lymphocytes, leading to a diminished cytotoxic response. Prior studies suggested that recruitment of MICA/B molecules to cholesterol-enriched microdomains was an important factor regulating the proteolytic release of these molecules. We now show that recruitment of MICA to these microdomains depends on palmitoylation of two cysteine residues that allow MICA molecules to reside in the membrane in the same domains as caveolin-1. Compared with WT molecules, nonpalmitoylated mutant MICA molecules were shed to the supernatant with low efficiency; however, both WT and mutant MICA were able to trigger NK cell cytotoxicity. These data suggest that the presence of NKG2D ligands at the plasma membrane is sufficient to activate cytotoxicity and reflect the need of different ligands to exploit different cellular pathways to reach the cell surface upon different stress situations.

CD4(+) T Cells Predominate in Cerebrospinal Fluid and Leptomeningeal and Parenchymal Infiltrates in Cerebral Amyloid β-related Angiitis

Archives of Neurology. Jun, 2012  |  Pubmed ID: 22351850

In amyloid (Aβ)-related angiitis (ABRA)of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. It has been suggested that ABRA is triggered by vascular deposition of A followed by an Aβ-directed (auto)immune response.

Fulfilling the Dream: Tolerogenic Dendritic Cells to Treat Multiple Sclerosis

European Journal of Immunology. Mar, 2012  |  Pubmed ID: 22488360

Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs = tolDCs) and are potential targets for the treatment of MS. While the immunogenic potential of DCs in fighting infection and cancer has been well established, approaches that exploit their tolerogenic features to promote transplantation tolerance and autoimmunity have emerged only more recently. TolDCs usually maintain antigen-specific T-cell tolerance either directly by inducing anergy, apoptosis, or phenotype skewing or indirectly by induction of regulatory T (Treg) cells. The use of ex vivo-generated tolDCs is an experimental approach to achieve tolerance towards myelin-antigen-specific CD4(+) T cells. In the article by Raϊch-Regué and colleagues (Eur. J. Immunol. 2011. 42:772-783) in this issue of the European Journal of Immunology, advances in human tolDC preparation and promise for autologous therapy are described. These findings raise hopes of achieving the "ideal" of a highly-specific, causally-oriented immune intervention for central nervous system (CNS) autoimmunity in MS. However, recent experience with antigen-specific immune interventions in MS and some general caveats associated with cell-based-therapies highlight the challenges for clinical translation of the "immunologist's dream" of treating autoimmunity as discussed in this Commentary.

Cytotoxic CD8+ T Cells and CD138+ Plasma Cells Prevail in Cerebrospinal Fluid in Non-paraneoplastic Cerebellar Ataxia with Contactin-associated Protein-2 Antibodies

Journal of Neuroinflammation. 2012  |  Pubmed ID: 22759321

The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2) and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF) compared to the peripheral blood (PB). CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy.

Dendritic Cell Vaccination in Autoimmune Disease

Current Opinion in Rheumatology. Mar, 2013  |  Pubmed ID: 23370378

Autoimmune diseases are the result of an imbalanced immune regulatory network. Tolerogenic dendritic cells (tolDCs) are key players of this network by inducing and maintaining both central and peripheral tolerance. Therefore, ex vivo generated tolDCs are considered as therapeutic vaccines to re-establish (antigen-specific) tolerance in autoimmune disorders.

Modulation of IL-2Rα with Daclizumab for Treatment of Multiple Sclerosis

Nature Reviews. Neurology. Jul, 2013  |  Pubmed ID: 23732529

Multiple sclerosis (MS) is a debilitating neurological disorder involving autoimmune destruction of myelin. Although the pathogenic mechanisms underlying MS are not fully understood, T cells are thought to have a key role in orchestrating the aberrant CNS-directed adaptive immune response in the early and relapsing-remitting phase of disease. New therapeutic interventions with improved efficacy over existing drugs and good tolerability are needed. A promising therapy under investigation is daclizumab--a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25). Clinical trials have shown that daclizumab strongly inhibits disease activity and slows disease progression in MS. Novel and intriguing mechanisms of action of daclizumab have been identified that might explain its clinical efficacy--namely, expansion and enhancement of the immune regulatory function of CD56bright natural killer cells, reduction of early T-cell activation through blockade of IL-2 cross-presentation by dendritic cells, and reduction of lymphoid tissue inducer cells--thereby enhancing endogenous mechanisms of immune tolerance. This Review discusses the efficacy and safety of daclizumab in patients with MS and provides a detailed insight into the multifunctional mechanisms of action of this drug.

CD4+NKG2D+ T Cells Exhibit Enhanced Migratory and Encephalitogenic Properties in Neuroinflammation

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.

Ultraviolet B Light Attenuates the Systemic Immune Response in Central Nervous System Autoimmunity

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.

Effects of Blood Transportation on Human Peripheral Mononuclear Cell Yield, Phenotype and Function: Implications for Immune Cell Biobanking

PloS One. 2014  |  Pubmed ID: 25541968

Human biospecimen collection, processing and preservation are rapidly emerging subjects providing essential support to clinical as well as basic researchers. Unlike collection of other biospecimens (e.g. DNA and serum), biobanking of viable immune cells, such as peripheral blood mononuclear cells (PBMC) and/or isolated immune cell subsets is still in its infancy. While certain aspects of processing and freezing conditions have been studied in the past years, little is known about the effect of blood transportation on immune cell survival, phenotype and specific functions. However, especially for multicentric and cooperative projects it is vital to precisely know those effects. In this study we investigated the effect of blood shipping and pre-processing delay on immune cell phenotype and function both on cellular and subcellular levels. Peripheral blood was collected from healthy volunteers (n = 9): at a distal location (shipped overnight) and in the central laboratory (processed immediately). PBMC were processed in the central laboratory and analyzed post-cryopreservation. We analyzed yield, major immune subset distribution, proliferative capacity of T cells, cytokine pattern and T-cell receptor signal transduction. Results show that overnight transportation of blood samples does not globally compromise T- cell subsets as they largely retain their phenotype and proliferative capacity. However, NK and B cell frequencies, the production of certain PBMC-derived cytokines and IL-6 mediated cytokine signaling pathway are altered due to transportation. Various control experiments have been carried out to compare issues related to shipping versus pre-processing delay on site. Our results suggest the implementation of appropriate controls when using multicenter logistics for blood transportation aiming at subsequent isolation of viable immune cells, e.g. in multicenter clinical trials or studies analyzing immune cells/subsets. One important conclusion might be that despite changes due to overnight shipment, highly standardized central processing (and analysis) could be superior to multicentric de-central processing with more difficult standardization.

Clinical Relevance of Specific T-cell Activation in the Blood and Cerebrospinal Fluid of Patients with Mild Alzheimer's Disease

Neurobiology of Aging. Jan, 2015  |  Pubmed ID: 25277040

In Alzheimer's disease, the contribution of inflammation is still controversially discussed. The aim of this study was to identify a particular immune profile in the peripheral blood (PB) and cerebrospinal fluid (CSF) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and its potential functional relevance and association with neurodegeneration. A total of 88 patients with cognitive decline (54 mAD, 19 MCI, and 15 other dementias) were included in this study and compared with a group of younger (mean age, 31.3 years) and older (mean age, 68.9 years) healthy volunteers. Patients underwent detailed neurologic and neuropsychological examination, magnetic resonance imaging including voxel-based morphometry of gray matter, voxel-based diffusion tensor imaging, and white matter lesion volumetry, and PB and CSF analysis including multiparameter flow cytometry. Multiparameter flow cytometry revealed that proportions of activated HLA-DR positive CD4(+) and CD8(+) T-cells were slightly and significantly increased in the PB of MCI and mAD patients, respectively, when compared with healthy elderly controls but not in patients with other dementias. Although only a slight enhancement of the proportion of activated CD4(+) T-cells was observed in the CSF of both MCI and mAD patients, the proportion of activated CD8(+) T-cells was significantly increased in the CSF of mAD patients when compared with healthy elderly individuals. A slight increase in the proportion of activated CD8(+) T-cells was also observed in the intrathecal compartment of MCI patients. Activation of cytotoxic CD8(+) T-cells was considerably related to AD-typical neuropsychological deficits. Voxel-based regression analysis revealed a significant correlation between CD8(+) T-cell activation and microstructural tissue damage within parahippocampal areas as assessed by diffusion tensor imaging. Taken together, peripheral and intrathecal CD8(+) T-cell activation in mAD was significantly different from other dementias, suggesting a specific adaptive immune response. Lymphocyte activation seems to have a clinical impact because levels of activated CD8(+) T-cells were correlated with clinical and structural markers of AD pathology.

Fingolimod Treatment Promotes Regulatory Phenotype and Function of B Cells

Annals of Clinical and Translational Neurology. Feb, 2015  |  Pubmed ID: 25750917

To evaluate the influence of Fingolimod treatment on B-cell subset composition and function in multiple sclerosis patients and its potential clinical relevance.

A Case Report on Juvenile Neuromyelitis Optica: Early Onset, Long Remission Period, and Atypical Treatment Response

Neuropediatrics. Aug, 2015  |  Pubmed ID: 26058738

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system and preferentially targets the optic nerves and spinal cord. NMO is rare in children and clinical course of the disease is highly variable as described in studies. Here, we present a case report of a young girl presenting with a rare course of pediatric NMO with an early disease onset at the age of 12 years, a relapse free interval of 4 years, evidence of NMO immunoglobulin G (IgG) and an unusual response against immunosuppressive therapy. The aim of this report is to highlight the potentially long remission period between relapses complicating proper diagnosis despite well defined diagnostic criteria. In addition, we want to encourage the use of rituximab in pediatric NMO, although larger cohorts are warranted to establish B cell depleting therapies in juvenile NMO.

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.

The Two-pore Domain K2 P Channel TASK2 Drives Human NK-cell Proliferation and Cytolytic Function

European Journal of Immunology. Sep, 2015  |  Pubmed ID: 26140335

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor- and virus-infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage-gated KV 1.3 and the calcium-activated KCa 3.1 channels, human NK cells also express the two-pore domain K2 P channel TASK2 (TWIK-related acid-sensitive potassium channel). Expression of Task2 varies among NK-cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2(high) CD56(bright) CD16(-) and TASK2(low) CD56(dim) CD16(+) NK cells, TASK2 is involved in cytokine-induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA-1) mediated adhesion of both resting and cytokine-activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL-15-induced NK cells. Taken together, our data exhibit two-pore potassium channels as important players in NK-cell activation and effector function.

Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells

International Journal of Molecular Sciences. Jul, 2015  |  Pubmed ID: 26193267

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by imbalanced immune regulatory networks, and MS patient-derived T effector cells are inefficiently suppressed through regulatory T cells (Treg), a phenomenon known as Treg resistance. In the current study we investigated T cell function in MS patients before and after interferon-beta therapy. We compared cytokine profile, responsiveness for Treg-mediated suppression ex vivo and evaluated reactivity of T cells in vivo using a humanized mouse model. We found that CD4+ and CD8+ T cells of therapy-naive MS patients were resistant to Treg-mediated suppression. Treg resistance is associated with an augmented IL-6 production, enhanced IL-6 receptor expression, and increased PKB/c-Akt phosphorylation. These parameters as well as responsiveness of T cells to Treg-mediated suppression were restored after interferon-beta therapy of MS patients. Following transfer into immunodeficient mice, MS T cells induced a lethal graft versus host disease (GvHD) and in contrast to T cells of healthy volunteers, this aggressive T cell response could not be controlled by Treg, but was abolished by anti-IL-6 receptor antibodies. However, magnitude and lethality of GvHD induced by MS T cells was significantly decreased after interferon-beta therapy and the reaction was prevented by Treg activation in vivo. Our data reveals that interferon-beta therapy improves the immunoregulation of autoaggressive T effector cells in MS patients by changing the IL-6 signal transduction pathway, thus restoring their sensitivity to Treg-mediated suppression.

Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study

Frontiers in Neurology. 2015  |  Pubmed ID: 26284025

Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab.

Neurocognitive Decline in HIV Patients is Associated with Ongoing T-cell Activation in the Cerebrospinal Fluid

Annals of Clinical and Translational Neurology. Sep, 2015  |  Pubmed ID: 26401512

HIV-associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND.

Dimethyl Fumarate Treatment Alters Circulating T Helper Cell Subsets in Multiple Sclerosis

Neurology(R) Neuroimmunology & Neuroinflammation. Feb, 2016  |  Pubmed ID: 26767188

To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4(+) and CD8(+) T cell subsets in patients with multiple sclerosis (MS).

Therapy with Natalizumab is Associated with High JCV Seroconversion and Rising JCV Index Values

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.

ALAIN01--Alemtuzumab in Autoimmune Inflammatory Neurodegeneration: Mechanisms of Action and Neuroprotective Potential

BMC Neurology. Mar, 2016  |  Pubmed ID: 26966029

Alemtuzumab (Lemtrada®) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers.

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.

Blood Coagulation Factor XII Drives Adaptive Immunity During Neuroinflammation Via CD87-mediated Modulation of Dendritic Cells

Nature Communications. May, 2016  |  Pubmed ID: 27188843

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.

Evidence of a Pathogenic Role for CD8(+) T Cells in Anti-GABAB Receptor Limbic Encephalitis

Neurology(R) Neuroimmunology & Neuroinflammation. Jun, 2016  |  Pubmed ID: 27213174

To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE).

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).

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.

Alemtuzumab Treatment Alters Circulating Innate Immune Cells in Multiple Sclerosis

Neurology(R) Neuroimmunology & Neuroinflammation. Dec, 2016  |  Pubmed ID: 27766281

To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.

Prothrombin and Factor X Are Elevated in Multiple Sclerosis Patients

Annals of Neurology. Oct, 2016  |  Pubmed ID: 27774643

Animal models have implicated an integral role for coagulation factors in neuroinflammatory diseases such as multiple sclerosis (MS) beyond their role in hemostasis. However, their relevance in humans requires further elucidation. This study aimed to determine whether levels of coagulation factors differ between patients with neuroimmunological disorders and respective controls. Individuals suffering from relapsing-remitting and secondary progressive MS had significantly higher prothrombin and factor X levels than healthy donors, whereas levels were unchanged in primary progressive MS and neuromyelitis optica patients. Our study demonstrates that coagulation factors may be key mediators in neuroinflammation and may therefore provide future targets for therapeutic strategies. Ann Neurol 2016.

Imaging Matrix Metalloproteinase Activity in Multiple Sclerosis As a Specific Marker of Leukocyte Penetration of the Blood-brain Barrier

Science Translational Medicine. Nov, 2016  |  Pubmed ID: 27831901

The enzymes gelatinase A/matrix metalloproteinase-2 (MMP-2) and gelatinase B/MMP-9 are essential for induction of neuroinflammatory symptoms in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS); in the absence of these enzymes, the disease does not develop. We therefore investigated the cellular sources and relative contributions of MMP-2 and MMP-9 to disease at early stages of EAE induction. We demonstrated that MMP-9 from an immune cell source is required in EAE for initial infiltration of leukocytes into the central nervous system and that MMP-9 activity is a reliable marker of leukocyte penetration of the blood-brain barrier. We then developed a molecular imaging method to visualize MMP activity in the brain using fluorescent- and radioactive-labeled MMP inhibitors (MMPis) in EAE animals and used the radioactive MMP ligand for positron emission tomography (PET) imaging of MMP activity in patients with MS. In contrast to traditional T1-gadolinium contrast-enhanced MRI, MMPi-PET enabled tracking of MMP activity as a unique feature of early lesions and ongoing leukocyte infiltration. MMPi-PET therefore allows monitoring of the early steps of MS development and provides a sensitive, noninvasive means of following lesion formation and resolution in murine EAE and human MS.

Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

Frontiers in Immunology. 2016  |  Pubmed ID: 28066417

There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56(bright) NK cells have been suggested to play a major role in controlling T cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immunoprotective role of NK cells in MS. Here, we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK cell/T cell interactions in MS and discuss how disease-modifying treatments for MS affect NK cells.

Diagnostic Criteria for Susac Syndrome

Journal of Neurology, Neurosurgery, and Psychiatry. Dec, 2016  |  Pubmed ID: 28103199

Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome.

Neurochondrin is a Neuronal Target Antigen in Autoimmune Cerebellar Degeneration

Neurology(R) Neuroimmunology & Neuroinflammation. Jan, 2017  |  Pubmed ID: 27957508

To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.

Reply to Liu Et Al.: Haplotype Matters: CD226 Polymorphism As a Potential Trigger for Impaired Immune Regulation in Multiple Sclerosis

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2017  |  Pubmed ID: 28137888

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