Faiez Al Nimer

Karolinska Institutet | KI · Department of Clinical Neuroscience

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral...

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing–remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural n...

Background: Rituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity are limited. The objective here was therefore to determine the rate and cause of RTX treatment...

B-cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to SARS-CoV-2 has raised concerns with the COVID-19 pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participa...

Background: Recent findings document a blunted humoral response to SARS-CoV-2 vaccination in patients on anti-CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion in order to optimize vaccine responses. Methods: We determined antibody responses after SARS-CoV-2 vaccina...

Background and Objectives B cell–depleting therapies are highly effective in relapsing-remitting multiple sclerosis (RRMS) but are associated with increased infection risk and blunted humoral vaccination responses. Extension of dosing intervals may mitigate such negative effects, but its consequences on MS disease activity are yet to be ascertained...

Background B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multip...

Objective: Multiple sclerosis (MS) is a neuroinflammatory disease where immune cells cross the blood-brain barrier (BBB) into the central nervous system (CNS). What predisposes these immune cells to cross the BBB is still unknown. Here, we examine the possibility that genomic rearrangements could predisposespecific immune cells in the peripheral b...

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screen...

Background Severe traumatic brain injury (TBI) is associated with blood–brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-ter...

Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom prote...

Significance Dysregulation of microRNAs (miRNAs), a type of small noncoding RNAs (sncRNAs), has frequently been associated with multiple sclerosis (MS). However, most studies have focused on peripheral blood, and few investigated other classes of sncRNAs. To address this, we analyzed all classes of sncRNAs in matching peripheral blood mononuclear c...

Background Altered levels of two extracellular matrix (ECM) proteoglycans, brevican and neurocan, have been found in brain injury models; however, their proteolytic processing in traumatic brain injury (TBI) remains unexplored. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a possible contributor to ECM remodelling follo...

Matrix metalloproteinases (MMPs) are extracellular enzymes involved in the degradation of extracellular matrix (ECM) proteins. Increased expression of MMPs have been described in traumatic brain injury (TBI) and may contribute to additional tissue injury and blood–brain barrier damage. The objectives of this study were to determine longitudinal cha...

Background: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-te...

Background Rituximab (RTX) and ocrelizumab (OCR) are two anti-CD20 biologics used in MS; however, comparisons on safety and efficacy are rare. Objective To compare treatment outcomes over the first year with RTX and OCR. Methods Retrospective cohort study comprising MS patients initiating RTX at the Karolinska University Hospital (Sweden; n = 311...

The majority of variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognised prognostic factors, suggesting a contribution from unaccounted variables. One key candidate variable is neuroinflammation, including the generation of autoantibodies against brain specific antigens which have been described...

Objective To determine what kappa free light chain (KFLC) metric has the highest capacity to separate healthy patients from patients with MS, we evaluated the sensitivity, specificity, and the overall diagnostic accuracy of 4 different KFLC metrics. To assess the usefulness of KFLC in the diagnostics of MS, we compared the different KFLC metrics wi...

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is associated with dysregulation of microRNAs (miRNA). We here analyzed all classes of small non-coding RNAs (sncRNAs) in matching peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells and cell-free CSF from relapsing-remitting...

The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous syst...

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS pat...

Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neuro-cr...

Background Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI)....

We describe a woman with both central and peripheral nervous system symptoms consistent with Morvan’s syndrome who was successfully treated with immunosuppression including rituximab and the new antiepileptic drug lacosamide against peripheral nerve hyperexcitability. Despite being over 8 months in hospital and 4 months in an intensive care unit sh...

Table S6. Identified Peptide Sequences of RASGRPs in Brain and Peripheral B Cells of HDs and REM Using Mass-Spectrometry-Based Proteome Analysis, Results from B Cells (Excel Sheet 1), and Brain Tissue (Excel Sheet 2), Related to Figures 6 and 7

Table S1. Demographic Characteristics of the Study Population, Related to Figures 1, 2, 3, 4, 7, S1, S2, S3, S4, and S7 and Tables S2 and S3

Table S3. Association between Individual MS Non-HLA Risk SNPs and AP in HDs and REM (Excel Sheet 1) and Raw Data of MS Risk SNP Genotyping (Excel Sheet 2), Related to Figure 1 and Tables S1 and S2

Table S4. Overview of TCRVβ Sequencing Results in Brain and Peripheral Blood Compartment, Related to Figures 5, 6, S5, and S6 and Table S5

Table S7. Overlapping RASGRP2 Peptides and Organization of Peptide Pools, Related to Figures 7 and S7

Table S2. Association of Polygenic MS Risk Score (non-HLA risk SNPs) or HLA-DR15 on AP in HD and REM, Related to Figure 1 and Tables S1 and S3

Table S5. Shared Unique TCRVβ (CDR3) Sequences in Brain and Peripheral Blood Compartment in MS Patient 1 (Excel Sheet 1) and MS Patient 2 (Excel Sheet 2), Related to Figures 5, 6, S5, and S6 and Table S4

Traumatic brain injury (TBI) leads to a deleterious and multifactorial secondary inflammatory response in the brain. Oxidative stress from the inflammation likely contributes to the brain damage although it is unclear to which extent. A largely unexplored approach is to consider phenotypic regulation of oxidative stress levels. Genetic polymorphism...

Objective To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. Methods The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-c...

Besides its vital role in immunity, the complement system also contributes to the shaping of the synaptic circuitry of the brain. We recently described that soluble Complement Receptor 2 (sCR2) is part of the nerve injury response in rodents. We here study CR2 in context of multiple sclerosis (MS) and explore the molecular effects of CR2 on C3 acti...

Objective: We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration. Methods: We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n =...

Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expressi...

Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (sand nd cereb...

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetyl-ch...

Neuropathic pain is believed to be influenced in part by inflammatory processes. In this study we examined the effect of variability in the C-type lectin gene cluster (Aplec) on the development of neuropathic pain-like behavior after ligation of the L5 spinal nerve in the inbred DA and the congenic Aplec strains, which carries seven C-type lectin g...

The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in...

Background C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat...

Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations be...

Further details of the prediction set cases (Set 2 and Set 4): Numbers of cases with individual ELISA data available. (DOC)

OPLS model summaries. (DOC)

Increasing evidence suggests that genetic background affects outcome of traumatic brain injuries (TBI). Still, there is limited detailed knowledge on what pathways/processes are affected by genetic heterogeneity. The inbred rat strains DA and PVG differ in neuronal survival following TBI. We here carried out global expressional profiling to identif...

Aim: Genetic factors are important for outcome after traumatic brain injury (TBI), although exact knowledge of relevant genes/pathways is still lacking. We here used an unbiased approach to define differentially activated pathways between the inbred DA and PVG rat strains. The results prompted us to study further if a naturally occurring genetic v...

Nitric oxide is a key mediator of post-traumatic inflammation in the brain. We examined the expressions of iNOS, nNOS, and eNOS in inbred DA and PVGa rat strains where DA is susceptible to autoimmune neuroinflammation and PVGa-resistant. Parietal contusions using a weight drop model were produced in five rats per genotype. After 24 h, the brains we...

A large number of molecular pathways have been implicated in the degeneration of axotomized motoneurons. We previously have demonstrated substantial differences in the survival rate of axotomized motoneurons across different rat strains. Identification of genetic differences underlying such naturally occurring strain differences is a powerful appro...

Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II...

Local CNS inflammation takes place in many neurological disorders and is important for autoimmune neuroinflammation. Microglial activation is strain-dependent in rats and differential MHC class II expression is influenced by variations in the Mhc2ta gene. Despite sharing Mhc2ta and MHC class II alleles, BN and LEW.1N rats differ in MHC class II exp...

Neural stem cells have emerged as a promising therapeutic tool in CNS disease and injuries. In the clinical setting, cultured human neural stem/progenitor cells (hNSC) are an attractive possibility for transplantation to the damaged brain. However, transplantation of hNSC requires toxic immunosuppressive treatment to avoid rejection. The aim of the...

Brain trauma is a risk factor for delayed CNS degeneration which may be attenuated by anti-inflammatory treatment. CNS injuries may cause anti-brain reactivity. This study was undertaken to analyze the pattern of delayed post-traumatic anti-brain immunity in experimental brain contusion. Adult Sprague-Dawley and Lewis rats were subjected to experim...

Human neural stem cells survive and improve motor function after transplantation to the contused brain. However, the transplants might be rejected and that depends on the graft immunogenicity, the host immunological status and the immunosuppression strategy. We transplanted human neural stem cells to rats with brain contusion and analyzed the donor...