Publications by authors named "Catharina C Gross"

80 Publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Department of Neurology with Institute of Translational Neurology, University of Muenster, 48149 Muenster, Germany;

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

Signatures of immune reprogramming in anti-CD52 therapy of MS: markers for risk stratification and treatment response.

Neurol Res Pract 2019 13;1:40. Epub 2019 Dec 13.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.

Background: Multiple sclerosis is one of the most prevalent neurological diseases in young adults affecting over 2 million people worldwide. Alemtuzumab is a highly effective therapy in relapsing remitting MS. Alemtuzumab is a monoclonal CD52 antibody that proved its efficacy against an active comparator (interferon [IFN]-β1a) in a phase II trial and two phase III trials regarding clinical and MRI outcomes. Nevertheless, the exact mode of action is still unknown. Alemtuzumab is commonly associated with secondary autoimmune disorders significantly affecting the risk-benefit ratio. Therefore, new biomarkers predicting treatment response and adverse events are urgently needed. This study aims to further elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS).

Methods/design: This is a 3-year multicentre, explorative study including overall 150 patients comprising three different groups: (i) de novo patients prior and after alemtuzumab treatment initiation, (ii) patients under alemtuzumab treatment and (iii) patients requiring more than two alemtuzumab infusions. Peripheral blood and serum samples will be collected semi-annually for several in vitro/ex vivo assays to detect and characterize immune cells including their functional activity. Furthermore, data of MRI scans and disease-related impairment (using EDSS and MSFC), as well as the number and time of relapses, will be assessed. The clinical study is registered at clinicaltrials.gov (NCT04082260).

Perspective: Our study will provide deep insights into the underlying immunological changes in a longitudinal analysis of alemtuzumab treated RRMS patients. By combining clinical, radiological and functional immune-phenotype data, we will be able to identify biomarkers and/or immune signatures predicting treatment response and adverse events. Thereby, the understanding of the mechanisms of action of alemtuzumab will improve its efficacy and safety for present and future patients.
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http://dx.doi.org/10.1186/s42466-019-0045-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650051PMC
December 2019

High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients.

Mult Scler 2020 Nov 5:1352458520970103. Epub 2020 Nov 5.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration.

Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk.

Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts.

Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before ( = 2) or at diagnosis ( = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange ( = 4).

Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.
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http://dx.doi.org/10.1177/1352458520970103DOI Listing
November 2020

Cerebrospinal fluid analysis in 108 patients with progressive multifocal leukoencephalopathy.

Fluids Barriers CNS 2020 Oct 27;17(1):65. Epub 2020 Oct 27.

Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically.

Methods: We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups.

Results: The PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function.

Conclusions: This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.
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http://dx.doi.org/10.1186/s12987-020-00227-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590675PMC
October 2020

Pro-inflammatory Vδ1T-cells infiltrates are present in and around the hair bulbs of non-lesional and lesional alopecia areata hair follicles.

J Dermatol Sci 2020 Nov 18;100(2):129-138. Epub 2020 Sep 18.

Monasterium Laboratory, Skin and Hair Research Solutions GmbH, Münster, Germany; Dr. Phillip Frost Dept. of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA; Centre for Dermatology Research, University of Manchester, MAHSC, and Manchester NIHR Biomedical Research Centre, Manchester, UK. Electronic address:

Background: It is widely accepted that NKG2Dcells are critically involved in alopecia areata (AA) pathogenesis. However, besides being expressed in CD8T-cells and NK cells, NKG2D is also found in human γδT-cells. AA lesional hair follicles (HFs) overexpress NKG2D and γδTCR activating ligands, e.g. MICA and CD1d, and chemoattractants for γδT-cells, such as CXCL10.

Objective: To investigate whether abnormal activities of γδT-cells may be involved in AA pathogenesis.

Methods: We analyzed the number and activation status of γδT-cells in human healthy, lesional and non-lesional AA scalp biopsies by FACS and/or quantitative (immuno-)histomorphometry.

Results: In healthy human scalp skin, the few skin-resident γδT-cells were found to be mostly Vδ1, non-activated (CD69NKG2D) and positive for CXCL10, and CXCL12 receptors. These Vδ1T-cells predominantly localized in/around the HF infundibulum. In striking contrast, the number of Vδ1T-cells was significantly higher around and even inside the proximal (suprabulbar and bulbar) epithelium of lesional AA HFs. These cells also showed a pro-inflammatory phenotype, i.e. higher NKG2D, and IFN-γ and lower CD200R expression. Importantly, more pro-inflammatory Vδ1T-cells were seen also around non-lesional AA HFs. Lesional AA HFs also showed significantly higher expression of CXCL12.

Conclusion: Our pilot study introduces skin-resident γδT-cells as a previously overlooked, but potentially important, mostly (auto-)antigen-independent, new innate immunity protagonist in AA pathobiology. The HF infiltration of these activated, IFN-γ-releasing cells already around non-lesional AA HFs suggest that Vδ1T-cells are involved in the early stages of human AA pathobiology, and may thus deserve therapeutic targeting for optimal AA management.
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http://dx.doi.org/10.1016/j.jdermsci.2020.09.001DOI Listing
November 2020

Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.

Epilepsia 2020 10 7;61(10):e153-e158. Epub 2020 Sep 7.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Inflammation plays a role in the pathogenesis of immune-mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age-matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65-LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen-DR isotype (HLA-DR)-expressing CD4 T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14 CD16 cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8 T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.
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http://dx.doi.org/10.1111/epi.16688DOI Listing
October 2020

Immune signatures of prodromal multiple sclerosis in monozygotic twins.

Proc Natl Acad Sci U S A 2020 09 17;117(35):21546-21556. Epub 2020 Aug 17.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer Campus 1, 48149 Münster, Germany;

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4 effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.
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http://dx.doi.org/10.1073/pnas.2003339117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474627PMC
September 2020

Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions.

Int J Mol Sci 2020 Mar 17;21(6). Epub 2020 Mar 17.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A01, D-48149 Münster, Germany.

The central nervous system (CNS) is an immune-privileged compartment that is separated from the circulating blood and the peripheral organs by the blood-brain and the blood-cerebrospinal fluid (CSF) barriers. Transmigration of lymphocyte subsets across these barriers and their activation/differentiation within the periphery and intrathecal compartments in health and autoinflammatory CNS disease are complex. Mathematical models are warranted that qualitatively and quantitatively predict the distribution and differentiation stages of lymphocyte subsets in the blood and CSF. Here, we propose a probabilistic mathematical model that (i) correctly reproduces acquired data on location and differentiation states of distinct lymphocyte subsets under homeostatic and neuroinflammatory conditions, (ii) provides a quantitative assessment of differentiation and transmigration rates under these conditions, (iii) correctly predicts the qualitative behavior of immune-modulating therapies, (iv) and enables simulation-based prediction of distribution and differentiation stages of lymphocyte subsets in the case of limited access to biomaterial. Taken together, this model might reduce future measurements in the CSF compartment and allows for the assessment of the effectiveness of different immune-modulating therapies.
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http://dx.doi.org/10.3390/ijms21062046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139518PMC
March 2020

Next-Generation Neuroimmunology: New Technologies to Understand Central Nervous System Autoimmunity.

Trends Immunol 2020 04 5;41(4):341-354. Epub 2020 Mar 5.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, University of Münster, Münster, Germany. Electronic address:

Understanding neuroimmunological disorders is essential for developing new diagnostic and therapeutic strategies. Rodent models have provided valuable insights, but are sometimes equated with their human counterparts. Here, we summarize how novel technologies may enable an improved human-focused view of immune mechanisms. Recent studies have applied these new technologies to the brain parenchyma, its surrounding cerebrospinal fluid, and peripheral immune compartments. Therapeutic interventions have also facilitated translational understanding in a reverse way. However, with improved technology, access to patient samples remains a rate-limiting step in translational research. We anticipate that next-generation neuroimmunology is likely to integrate, in the immediate future, diverse technical tools for optimal diagnosis, prognosis, and treatment of neuroimmunological disorders.
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http://dx.doi.org/10.1016/j.it.2020.02.005DOI Listing
April 2020

Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis.

J Neuroimmunol 2020 04 27;341:577171. Epub 2020 Jan 27.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany. Electronic address:

Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577171DOI Listing
April 2020

Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis.

Nat Commun 2020 01 14;11(1):247. Epub 2020 Jan 14.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) - an autoimmune disease of the CNS - increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.
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http://dx.doi.org/10.1038/s41467-019-14118-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959356PMC
January 2020

CD8 T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Nat Commun 2019 12 18;10(1):5779. Epub 2019 Dec 18.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, CHU Purpan - BP 3028 - 31024, Toulouse Cedex 3, Toulouse, France.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
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http://dx.doi.org/10.1038/s41467-019-13593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920411PMC
December 2019

Alemtuzumab therapy changes immunoglobulin levels in peripheral blood and CSF.

Neurol Neuroimmunol Neuroinflamm 2020 03 11;7(2). Epub 2019 Dec 11.

From the Department of Neurology and Clinical Neuroimmunology and Neurochemistry (N.M., T.S., M.S.), Hannover Medical School, Hannover, Germany; and Neurology Clinic with Institute of Translational Neurology (S.P., T.R., C.C.G., L.K., H.W., S.G.M.), University of Münster, Münster, Germany.

Objective: The use of alemtuzumab, a humanized monoclonal anti-CD52 antibody has changed the therapy of highly active relapsing-remitting MS (RRMS). Alemtuzumab infusion depletes most lymphocytes in peripheral blood, whereas differential recovery of immune cells, probably those with a less CNS-autoreactive phenotype, is supposed to underlie its long-lasting effects. To determine whether alemtuzumab significantly reduces immunoglobulin levels in blood and CSF of treated patients, we analyzed blood and CSF samples of 38 patients with MS treated with alemtuzumab regarding changes in immunoglobulin levels.

Methods: Blood and CSF samples of patients were collected at the beginning of alemtuzumab treatment and at 12, 24, and 36 months after the first administration of the drug. Specimens were analyzed regarding immunoglobulin concentrations in blood and CSF.

Results: We observed significant and dose-dependent reductions of immunoglobulin levels (IgG, IgM, and IgA) in serum and CSF 12 and 24 months following 2 courses of alemtuzumab. Patients with persistent or returning disease activity who were treated with a third course of alemtuzumab exhibited even further decrease in IgG levels compared with matched controls treated twice. Here, alemtuzumab-treated patients with IgG levels below the lower limits of normal were more susceptible to pneumonia, sinusitis, and otitis, whereas upper respiratory tract and urinary tract infections were not associated therewith.

Conclusions: Our results suggest to monitor IgG levels for safety reasons in patients treated with alemtuzumab-in particular when additional treatment courses are required-and to consider preventive action in critical cases.

Classification Of Evidence: This study provides Class IV evidence that for patients with RRMS alemtuzumab reduces immunoglobulin levels.
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http://dx.doi.org/10.1212/NXI.0000000000000654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007635PMC
March 2020

Fulminant MS Reactivation Following Combined Fingolimod Cessation and Yellow Fever Vaccination.

Int J Mol Sci 2019 Nov 28;20(23). Epub 2019 Nov 28.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, D-48149 Muenster, Germany.

A major concern caused by the discontinuation of disease modifying treatment for multiple sclerosis (MS) is a rebound of disease activity. Hypotheses about the underlying mechanism of fingolimod (FTY) induced exaggerated inflammatory responses are diverse. So far, vaccinations as a trigger for rebound activity following FTY suspension have not been described. However, several reports have highlighted the occurrence of neurological and autoimmune side effects after single or combined multi-vaccination procedures. Here, we describe the case of a highly active female MS patient demonstrating recurrent, severe MS relapses accompanied by extensive MRI activity, subsequent to yellow fever vaccination two months following FTY withdrawal. Blood and cerebrospinal fluid immunophenotyping indicated a B cell/plasma cell autoreactivity. Following a therapy with natalizumab the clinical, laboratory, MRI, and disease course improved significantly. This case hints towards a combined immunological mechanism characterized by molecular mimicry, bystander activation, and lymphocyte re-egress, resulting in extensive neurological impairment and shows that natalizumab represents a therapeutic option to counteract B cell mediated autoreactivity. Especially, the diagnostic and therapeutic management of this complex scenario might be instructive for clinical practice.
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http://dx.doi.org/10.3390/ijms20235985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929059PMC
November 2019

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis.

Ann Clin Transl Neurol 2019 12 4;6(12):2586-2594. Epub 2019 Nov 4.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell-depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high-affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing-remitting multiple sclerosis. No differences in clinical and MRI-based efficacy parameters, the development of severe infusion-associated reactions and secondary autoimmune diseases during a 2 year follow-up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.
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http://dx.doi.org/10.1002/acn3.50935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917309PMC
December 2019

Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis.

Brain 2019 11;142(11):3411-3427

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, University of Münster, Münster, Germany.

Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, we identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. These cells used their high levels of VLA-4 to arrest on scattered VCAM1, their open-conformation LFA-1 to crawl preferentially against the flow in search for sites permissive for extravasation, and their stored granzyme K (GZMK) to induce local ICAM1 aggregation and perform trans-, rather than paracellular diapedesis through unstimulated primary brain microvascular endothelial cells. This study included peripheral blood mononuclear cell samples from 175 healthy donors, 29 patients infected with HIV, with neurological symptoms in terms of cognitive impairment, 73 patients with relapsing-remitting multiple sclerosis in remission, either 1-4 weeks before (n = 29), or 18-60 months after the initiation of natalizumab therapy (n = 44), as well as white matter brain tissue of three patients suffering from epilepsy. We here provide ex vivo evidence that CCR5highGZMK+CD4+ effector memory T cells are involved in CNS immune surveillance during homeostasis, but could also play a role in CNS pathology. Among CD4+ T cells, this subset was found to dominate the CNS of patients without neurological inflammation ex vivo. The reduction in peripheral blood of HIV-positive patients with neurological symptoms correlated to their CD4 count as a measure of disease progression. Their peripheral enrichment in multiple sclerosis patients and specific peripheral entrapment through the CNS infiltration inhibiting drug natalizumab additionally suggests a contribution to CNS autoimmune pathology. Our transcriptome analysis revealed a migratory phenotype sharing many features with tissue-resident memory and Th17.1 cells, most notably the transcription factor eomesodermin. Knowledge on this cell subset should enable future studies to find ways to strengthen the host defence against CNS-resident pathogens and brain tumours or to prevent CNS autoimmunity.
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http://dx.doi.org/10.1093/brain/awz301DOI Listing
November 2019

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

BMJ Open 2019 09 9;9(9):e030309. Epub 2019 Sep 9.

Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.

Methods And Analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.

Ethics And Dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.

Trial Registration Numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.
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http://dx.doi.org/10.1136/bmjopen-2019-030309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738722PMC
September 2019

Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals.

Neurology 2019 09 22;93(12):550-554. Epub 2019 Aug 22.

From the Department of Neurology with Institute of Translational Neurology (N.S., T.S.-H., P.O., L.K., C.C.G., S.G.M., H.W.), University of Münster, Münster, Germany; CRC-SEP-Neurosciences Department (B.P., F.B., L.S., J.C., D. Biotti, D. Brassat), CHU Toulouse, Toulouse, France; CPTP-INSERM U1043-CNRS U5282-Université Toulouse III (B.P., F.B., L.S., D. Brassat), Toulouse, France; APHM (C.L.-F.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France; CHU of Nice (G.M.), Nice, France; CHU Montpied, Neurology, Clermont-Ferrand, France (P.C.); APHM (J.P.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, CRCSEP Marseille, France; Institute of Clinical Neuroimmunology (I.M.), Ludwig-Maximilians University, Munich, Germany; Department of Neurology (S.W.), Clinics Osnabrück, Osnabrück, Germany; and Department of Neurology (F.G.), Innsbruck Medical University, Innsbruck, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000008135DOI Listing
September 2019

Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: A prospective cohort study.

EBioMedicine 2019 Aug 29;46:381-386. Epub 2019 Jul 29.

Clinic of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Background: Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions.

Methods: We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti-thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months.

Findings: Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73-31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity.

Interpretation: Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation. FUND: German Ministry of Education, Science, Research and Technology and the German Research foundation.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711888PMC
August 2019

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.

Sci Transl Med 2019 05;11(490)

University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany.

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.
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http://dx.doi.org/10.1126/scitranslmed.aao5563DOI Listing
May 2019

Immune Cell Profiling of the Cerebrospinal Fluid Provides Pathogenetic Insights Into Inflammatory Neuropathies.

Front Immunol 2019 21;10:515. Epub 2019 Mar 21.

Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany.

Utilize immune cell profiles in the cerebrospinal fluid (CSF) to advance the understanding and potentially support the diagnosis of inflammatory neuropathies. We analyzed CSF cell flow cytometry data of patients with definite Guillain-Barré syndrome (GBS, = 26) and chronic inflammatory demyelinating polyneuropathy (CIDP, = 32) based on established diagnostic criteria in comparison to controls with relapsing-remitting multiple sclerosis (RRMS, = 49) and idiopathic intracranial hypertension (IIH, = 63). Flow cytometry revealed disease-specific changes of CSF cell composition with a significant increase of NKT cells and CD8+ T cells in CIDP, NK cells in GBS, and B cells and plasma cells in MS in comparison to IIH controls. Principal component analysis demonstrated distinct CSF immune cells pattern in inflammatory neuropathies vs. RRMS. Systematic receiver operator curve (ROC) analysis identified NKT cells as the best parameter to distinguish GBS from CIDP. Composite scores combing several of the CSF parameters differentiated inflammatory neuropathies from IIH and GBS from CIDP with high confidence. Applying a novel dimension reduction technique, we observed an intra-disease heterogeneity of inflammatory neuropathies. Inflammatory neuropathies display disease- and subtype-specific alterations of CSF cell composition. The increase of NKT cells and CD8+ T cells in CIDP and NK cells in GBS, suggests a central role of cytotoxic cell types in inflammatory neuropathies varying between acute and chronic subtypes. Composite scores constructed from multi-dimensional CSF parameters establish potential novel diagnostic tools. Intra-disease heterogeneity suggests distinct disease mechanisms in subgroups of inflammatory neuropathies.
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http://dx.doi.org/10.3389/fimmu.2019.00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448021PMC
August 2020

A fatal case of daclizumab-induced liver failure in a patient with MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 21;6(2):e539. Epub 2019 Jan 21.

Department of Neurology (M.S., A.K.M., R.P., C.K.), University Hospital Essen; Clinic of Neurology with Institute of Translational Neurology (C.C.G., A.S.-M., H.W., S.G.M.), University Hospital Münster, University Münster; Institute of Neuropathology (A.J.), University Hospital Essen; and Institute of Pathology (H.A.B.), University Hospital Essen, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369971PMC
March 2019

Immune Cell Activation in the Cerebrospinal Fluid of Patients With Parkinson's Disease.

Front Neurol 2018 18;9:1081. Epub 2018 Dec 18.

Department of Neurology, University Hospital Münster, Münster, Germany.

Parkinson's disease (PD) is a common neurodegenerative disorder. The contribution of the immune system to its pathogenesis remains incompletely understood. In this study, we performed comprehensive immune cell profiling in the cerebrospinal fluid (CSF) and peripheral blood (PB) of PD patients. Ten PD patients were diagnosed according to brain bank criteria and underwent detailed clinical examination, magnetic resonance imaging, PB and CSF immune cell profiling by multiparameter flow cytometry, and cytokine and chemokine measurements by bead-based arrays. Thirteen healthy elderly volunteers served as control population. The proportions of activated T-lymphocytes and non-classical monocytes in the CSF were increased in patients with PD compared to the control group. In accordance, we found increased levels of the pro-inflammatory cytokines IL-2, IL-6 and TNFα and of the monocyte chemoattractant protein 1 (MCP-1) in the CSF of the included PD patients. Our data provide novel evidence for a response of the innate and adaptive immune system in the central nervous system of patients with PD.
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http://dx.doi.org/10.3389/fneur.2018.01081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305582PMC
December 2018

Plasma kallikrein modulates immune cell trafficking during neuroinflammation via PAR2 and bradykinin release.

Proc Natl Acad Sci U S A 2019 01 17;116(1):271-276. Epub 2018 Dec 17.

Clinic of Neurology, Institute of Translational Neurology, University of Münster, 48149 Münster, Germany.

Blood-brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2-dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.
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http://dx.doi.org/10.1073/pnas.1810020116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320546PMC
January 2019

Vitiligo after alemtuzumab treatment: Secondary autoimmunity is not all about B cells.

Neurology 2018 12 7;91(24):e2233-e2237. Epub 2018 Nov 7.

From the Clinic of Neurology with Institute of Translational Neurology (T.R., S.P., A.S.-M., C.C.G., M.L., H.W., S.G.M., L.K.) and Department of Dermatology (D.M., J.E.), University of Münster; and Departments of Dermatology, Venereology, and Allergology (W.S.) and Neurology (R.P., C.K.), University School of Medicine Essen-Duisburg, Essen, Germany.

Objective: To report 3 patients with relapsing-remitting multiple sclerosis (RRMS) showing vitiligo after treatment with alemtuzumab.

Methods: Retrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.

Results: We describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8 T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8 T cells with an activated (human leukocyte antigen-DR), memory (CD45RO), and type 1 cytokine (interferon-γ + tumor necrosis factor-α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.

Conclusion: The 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.
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http://dx.doi.org/10.1212/WNL.0000000000006648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329330PMC
December 2018

Primary B Cell Lymphoma of the CNS Mimicking Anti-LGI1 Limbic Encephalitis.

Front Neurol 2018 10;9:658. Epub 2018 Aug 10.

Clinic of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Limbic encephalitis is a potentially paraneoplastic type of encephalitis mainly involving the limbic system. Recently, diagnostic criteria comprising clinical presentation as well as imaging, laboratory and electrophysiological findings have been established. Here, we show that incipient primary central nervous system lymphoma can closely resemble limbic encephalitis including positive testing for anti-LGI1 antibodies illustrating the need for thorough interpretation of initial laboratory and radiologic findings and tight follow-up examinations.
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http://dx.doi.org/10.3389/fneur.2018.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095976PMC
August 2018

Immune Cell Profiling During Switching from Natalizumab to Fingolimod Reveals Differential Effects on Systemic Immune-Regulatory Networks and on Trafficking of Non-T Cell Populations into the Cerebrospinal Fluid-Results from the ToFingo Successor Study.

Front Immunol 2018 9;9:1560. Epub 2018 Jul 9.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Muenster, Germany.

Leukocyte sequestration is an established therapeutic concept in multiple sclerosis (MS) as represented by the trafficking drugs natalizumab (NAT) and fingolimod (FTY). However, the precise consequences of targeting immune cell trafficking for immunoregulatory network functions are only incompletely understood. In the present study, we performed an in-depth longitudinal characterization of functional and phenotypic immune signatures in peripheral blood (PB) and cerebrospinal fluid (CSF) of 15 MS patients during switching from long-term NAT to FTY treatment after a defined 8-week washout period within a clinical trial (ToFingo successor study; ClinicalTrials.gov: NCT02325440). Unbiased visualization and analysis of high-dimensional single cell flow-cytometry data revealed that switching resulted in a profound alteration of more than 80% of investigated innate and adaptive immune cell subpopulations in the PB, revealing an unexpectedly broad effect of trafficking drugs on peripheral immune signatures. Longitudinal CSF analysis demonstrated that NAT and FTY both reduced T cell subset counts and proportions in the CSF of MS patients with equal potency; NAT however was superior with regard to sequestering non-T cell populations out of the CSF, including B cells, natural killer cells and inflammatory monocytes, suggesting that disease exacerbation in the context of switching might be driven by non-T cell populations. Finally, correlation of our immunological data with signs of disease exacerbation in this small cohort suggested that both (i) CD49d expression levels under NAT at the time of treatment cessation and (ii) swiftness of FTY-mediated effects on immune cell subsets in the PB together may predict stability during switching later on.
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http://dx.doi.org/10.3389/fimmu.2018.01560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052886PMC
July 2018

Onconeural antigen spreading in paraneoplastic neurological disease due to small cell lung cancer.

Oxf Med Case Reports 2018 Jul 9;2018(7):omy034. Epub 2018 Jul 9.

Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, Münster, Germany.

Cellular and humoral immunity towards distinct onconeural antigens is the hallmark of paraneoplastic neurological diseases (PNDs). Stable formation of immunoglobulin (Ig) G antibodies to particular onconeural antigens occurs in the majority of cases, whereas persistent coexistence of antibodies specific for multiple onconeural antigens is a relatively rare phenomenon of certain malignant tumors like small cell lung cancer (SCLC). We here describe onconeural antigen spreading in a 70-year-old Caucasian male with PND due to SCLC. Onconeural antigen spreading may be promoted by two mutually non-exclusive mechanisms: (i) a switch of antigen expression pattern of the underlying tumor tissue as a result of a mutagenic process caused by the cancer itself and (ii) a self-propagated paraneoplastic immune response with persistent neuronal destruction, liberation, processing and presentation of intracellular neural antigens. This illustrates a potential dissociation between peripheral anti-tumoral immunity and central anti-neural immunity during the course of PND.
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http://dx.doi.org/10.1093/omcr/omy034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037119PMC
July 2018

Immune cell profiling in the cerebrospinal fluid of patients with primary angiitis of the central nervous system reflects the heterogeneity of the disease.

J Neuroimmunol 2018 08 7;321:109-116. Epub 2018 Jun 7.

Clinic of Neurology with Institute of Translational Neurology, University Hospital Münster, University Münster, 48149 Münster, Germany. Electronic address:

Primary angiitis of the central nervous system (PACNS) is a rare and heterogeneous inflammatory disease of the CNS vasculature with poorly understood pathophysiology. Comprehensive immune-cell phenotyping revealed increased frequencies of leukocytes in the cerebrospinal fluid (CSF) of PACNS patients compared to patients with multiple sclerosis, ischemic stroke, and somatoform disorders (n = 18 per group). Changes in the intrathecal immune-cell profile were heterogeneous in PACNS. While proportions of T-cell subsets remained unaltered, some PACNS patients showed a shift toward NK- or B cells. Intrathecal immunoglobulin synthesis was observed in a subgroup of PACNS patients with an increased frequency of antibody producing plasma cells.
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http://dx.doi.org/10.1016/j.jneuroim.2018.06.004DOI Listing
August 2018

Cerebrospinal Fluid Concentrations of Neuronal Proteins Are Reduced in Primary Angiitis of the Central Nervous System.

Front Neurol 2018 5;9:407. Epub 2018 Jun 5.

Department of Neurology, University of Münster, Münster, Germany.

Primary angiitis of the central nervous system (PACNS) is a rare autoimmune vasculitis limited to the CNS often causing substantial disability. Understanding of this disease is impaired by the lack of available biomaterial. Here, we collected cerebrospinal fluid (CSF) from patients with PACNS and matched controls and performed unbiased proteomics profiling using ion mobility mass spectrometry to identify novel disease mechanisms and candidate biomarkers. We identified 14 candidate proteins, including amyloid-beta A4 protein (APP), with reduced abundance in the CSF of PACNS patients and validated APP by Enzyme-linked Immunosorbent Assay (ELISA) in an extended cohort of patients with PACNS. Subsequent functional annotation surprisingly suggested neuronal pathology rather than immune activation in PACNS. Our study is the first to employ mass spectrometry to local immune reactions in PACNS and it identifies candidates such as APP with pathogenic relevance in PACNS to improve patient care in the future.
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http://dx.doi.org/10.3389/fneur.2018.00407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996103PMC
June 2018