Nicholas Schwab

University of Münster | WWU · Department of Neurology

To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatme...

Significance Our analysis shows that sex can be associated with the degree to which HLA molecules propagate selection and expansion of T cells as characterized by their T cell receptor variable beta chain (TCRBV). Furthermore, CD8 T cells, especially in men with autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, are capable of...

Multiple sclerosis (MS) disease risk is associated with reduced sunexposure. 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 (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivityassocia...

Epstein–Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discor...

Peripheral central nervous system (CNS)–infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (T RM ) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible f...

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a...

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general stat...

One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection bas...

Background Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, s...

Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing ver...

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including pr...

Background and Objectives Follicular helper T (Tfh) cells play a critical role in protective immunity helping B cells produce antibodies against foreign pathogens and are likely implicated in the pathogenesis of various autoimmune diseases. The purpose of this study was to investigate the role of Tfh cells in the pathogenesis of multiple sclerosis...

Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity a...

High-throughput sequencingHigh-throughput sequencing of adaptive immune receptor repertoiresAdaptive immune receptor repertoires (AIRR, i.e., IGImmunoglobulin (IG) and TRT cell receptor (TR)) has revolutionized the ability to study the adaptive immune response via large-scale experiments. Since 2009, AIRR sequencing (AIRR-seq) has been widely appli...

Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing int...

Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis...

It is increasingly clear that an extraordinarily diverse range of clinically important conditions—including infections, vaccinations, autoimmune diseases, transplants, transfusion reactions, aging, and cancers—leave telltale signatures in the millions of V(D)J-rearranged antibody and T cell receptor [TR per the Human Genome Organization (HUGO) nome...

Multiple sclerosis is a chronic auto-inflammatory disease of the central nervous system affecting patients worldwide. Neuroinflammation in multiple sclerosis is mainly driven by peripheral immune cells which invade the central nervous system and cause neurodegenerative inflammation. To enter the target tissue, immune cells have to overcome the endo...

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...

In “Prospective validation of the PML risk biomarkerL-selectin and influence ofnatalizumab extended intervals, ”Schwab et al. reported that natalizumab is associated withreduction inL-selectin (CD62L) values and an increase in risk of PML but that cessation of natalizumab or extension of treatment intervals leads to recovery of CD62L values, whichc...

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 applie...

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...

Progressive multifocal leukoencephalopathy (PML) is a rare pathologic CNS condition caused by JC polyomavirus (JCPyV) in immunodeficient patients. Immune checkpoint inhibition was previously reported to potentially facilitate the antiviral response. Here, we present an ultimately fatal case, where a patient with PML was treated with the anti-progr...

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...

Introduction: Low L-selectin (CD62L) on CD4+ T cells after cryopreservation has been introduced in 2013 as a risk biomarker for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment1 or HIV infection2. The biomarker has been reproduced retrospectively in some international cohorts3,4, but not in others5, p...

Background: Progressive multifocal leukoencephalopathy (PML) is a rare complication of patients treated with fingolimod. Case presentation: Routine MRI eventually led to diagnosis of asymptomatic early PML that remained stable after discontinuation of fingolimod. As blood lymphocyte counts normalized, signs of immune reconstitution inflammatory syn...

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 a...

Objective: To evaluate characteristics relevant to diagnosis of JC polyomavirus-associated progressive multifocal leukoencephalopathy (PML), and PML risk stratification in a large national cohort of patients with multiple sclerosis during therapy with natalizumab. Methods: Analysis of 292 adverse drug reaction forms on suspected cases of PML rep...

In recent years, there has been a paradigm shift in the treatment of multiple sclerosis (MS) owing to the approval of a number of new drugs with very distinct mechanisms of action. All approved disease-modifying drugs primarily work directly on the immune system. However, the identification of an ‘optimal choice’ for individual patients with regard...

Integrin α2β1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collage...

Sodium chloride promotes vascular fibrosis, arterial hypertension, pro-inflammatory immune cell polarization and endothelial dysfunction, all of which might influence outcomes following stroke. But despite enormous translational relevance, the functional importance of sodium chloride in the pathophysiology of acute ischemic stroke is still unclear....

Background: Very late antigen 4 (VLA-4; integrinα4β1) is critical for transmigration of T helper (TH) 1 cells into thecentral nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previouslyshown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migrationof human TH17 cel...

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...

Multiple sclerosis (MS) is a disease of presumed auto-immune origin. Long-standing observations such as the correlation between MS incidence and geographical latitude or the levels of Vitamin D (Vit D) in the serum have implicated the environmental factors UVB radiation and diet in the etiology of the disease. Clinical trials have been conducted an...

In summary, the patient developed a mild hemiparesis and slurred speech before interferon-α treatment. During peginterferon-alfa-2a therapy, a slow progression in her neurological symptoms was observed. A similar interfer- on treatment attempt against JCV PML was also ineffec- tive in a previously reported PID case [1]. However, it seems likely tha...

Objective: Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood-brain barrier (BBB). Methods: Effects of fumaric acid esters were analyzed using primary human brain-derived microvascular en...

The nuclear receptor Liver X Receptor (LXR) is a ligand-activated transcription factor that has been implicated in control of chronic inflammation by downregulating pro-inflammatory T cell responses. An impaired function of regulatory T cells, a subset of CD4+ T cells with a crucial role in maintaining lymphocytes homeostasis and immune regulation,...

GPCR expression was intensively studied in bulk cDNA of leukocyte populations, but limited data are available with respect to expression in individual cells. Here, we show a microfluidic-based single-cell GPCR expression analysis in primary T cells, myeloid cells, and endothelial cells under naive conditions and during experimental autoimmune encep...

Background: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. Objectives and methods: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499...

The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of TH17 cells, and regulatory T cell (Treg) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Usin...

Lymphocyte extravasation into the central nervous system (CNS) is critical for immune surveillance. Disease-related alterations of lymphocyte extravasation might result in pathophysiological changes in the CNS. Thus, investigation of lymphocyte migration into the CNS is important to understand inflammatory CNS diseases and to develop new therapy ap...

Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today&apos...

Natalizumab (NTZ)-related progressive multifocal leukoencephalopathy (PML) risk varies between 3 and 100 in 10,000 NTZ-treated patients (based on the presence of anti–JC virus (JCV) antibodies, treatment duration, and prior immunosuppressant [IS] drugs). Recently, we proposed that L-selectin (CD62L) expression in peripheral blood mononuclear cells...

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS...

Significance A crucial step in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS), is transmigration of pathogenic T cells across the blood–brain barrier. These T cells mediate inflammation and subsequent lesion formation in the CNS. However, molecular mechanisms underlying lesion distribution and formation are not well unders...

Background: 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). Objective: To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of di...

Significance The importance of natural killer (NK) cells in the control of autoimmunity has recently attracted considerable attention. The current study revealed NK cells as additional players in controlling T-cell activity in CNS autoimmunity. NK-mediated control of T-cell activity in multiple sclerosis (MS) is dysregulated and caused by impaired...

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripher...

Objective: 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. Methods: German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy wit...

Background: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratif...

Immune cell migration over the blood-brain barrier into the central nervous system has been a topic of research for the last century, but it has gained significant momentum 20 years ago with the possibility of blocking adhesion molecules with monoclonal antibodies and use these as a therapeutic avenue for immune-mediated tissue damage (Yednock et a...

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. O...

Multiple Sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very-late-antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approva...

Objective: 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 ne...

The focus of this study is the characterization of human T cell blood–brain barrier migra- tion and corresponding molecular traf cking signatures. We examined peripheral blood and cerebrospinal uid immune cells from patients under long-term anti–very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients’ cerebrospi...

HIV+ progressive multifocal leukoencephalopathy (PML) patients had a significantly lower expression of CD62L on CD4(+) T cells (P<0.001) when compared with HIV+ patients who did not develop PML. CD62L expression on CD4(+) T cells did not correlate with parameters such as CDC stage, CD4(+) cell percentage (of total CD3(+) T cells), CD4(+) cell count...

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 es...

Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted...