Lawrence Steinman

• Stanford University

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which is linked to Epstein–Barr virus (EBV) infection, preceding the disease. The molecular mechanisms underlying this connection are only partially understood. We previously described molecular mimicry between the EBV transcription factor EBV nucle...

Epstein–Barr virus (EBV) is implicated as a necessary factor in the development of multiple sclerosis (MS) and may also be a driver of disease activity. Although it is not clear whether ongoing viral replication is the driver for MS pathology, MS researchers have considered the prospect of using drugs with potential efficacy against EBV in the trea...

Objective X‐linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1 , a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of...

Background Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as...

The Epstein-Barr virus (EBV) is epidemiologically associated with development of autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. Although there is well-established evidence for this association, the underlying mechanistic basis remains incompletely defined. In this Review,...

At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aqua...

Although FOXP3⁺ regulatory T cells (Treg) depend on IL-2 produced by other cells for their survival and function, the levels of IL-2 in inflamed tissue are low, making it unclear how Treg access this critical resource. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (E...

Objective To assess NEDA-3 and NEDA-4 in RMS patients treated with ozanimod. Methods Data are from a randomized phase 3 trial (RADIANCE-NCT02047734) of oral ozanimod 0.92 mg/d vs intramuscular interferon β-1a (IFN) 30 µg/wk and an open-label extension trial (DAYBREAK-NCT02576717) of ozanimod 0.92 mg/d. NEDA-3 (no gadolinium-enhancing lesions, new/...

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, in...

Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inf...

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to A...

Background and Objectives There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD. Methods In this ope...

FOXP3 ⁺ regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resource in vivo . Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed cent...

Here, we offer a roadmap for what might be studied next in understanding how EBV triggers MS. We focus on two areas: The first area concerns the molecular mechanisms underlying how clonal antibody in the CSF emanates in widespread molecular mimicry to key antigens in the nervous system including GlialCAM, a protein associated with chloride channels...

Vitamin D is a steroid hormone that has been widely studied as a potential therapy for multiple sclerosis and other inflammatory disorders. Pre-clinical studies have implicated vitamin D in the transcription of thousands of genes, but its influence may vary by cell type. A handful of clinical studies have failed to identify an in vivo gene expressi...

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with cli...

Background: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. Methods: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis w...

Background Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. Objective To characterize long-term safety and efficacy of ozanimod. Methods Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study...

Significance A target-agnostic approach that harnesses the human antitumor immune response to find potential anticancer lead antibodies and their targets was used to generate ATRC-101, an engineered version of a tumor-targeting antibody identified from a patient with non-small cell lung cancer experiencing an ongoing antitumor immune response. ATRC...

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epi...

Infection with Epstein-Barr virus is the trigger for the development of multiple sclerosis

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins. Epstein-Barr virus (EBV) infection has been linked to MS epidem...

Objectives Plasma neurofilament light chain concentration (pNfL-c) is increased in patients with multiple sclerosis (MS) and may serve as a biomarker for neurologic damage and disease activity in relapsing MS. We analyzed changes in pNfL-c and on-treatment risk of relapse with ozanimod vs interferon β-1a (IFN). Methods In this post hoc analysis of...

Background: We investigated plasma neurofilament light chain concentrations (pNfL) as a biomarker for neuroaxonal damage and disease activity using data from phase 3 trials of ozanimod in relapsing multiple sclerosis (RMS). Methods: pNfL were measured before and after ozanimod 0.46 mg or 0.92 mg daily or interferon β-1a 30 µg weekly in the rando...

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design...

Introduction Ozanimod est un modulateur oral des récepteurs de sphingosine 1-phosphate des sous-types 1 et 5, qui a obtenu l’AMM en Europe et aux États-unis dans la sclérose en plaques récurrente¹. Objectifs Caractériser la sécurité et l’efficacité à long terme de l’ozanimod chez les patients atteints de SEP-R dans l’étude d’extension en ouvert en...

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this i...

Objective To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19 ⁺ B cells approximates 40%–50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity. Methods In this hypothe...

Significance Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). B cells play a key role in MS immunopathology, as demonstrated by the success of B cell-directed therapies; however, the target antigen of MS remains unknown. Using a combination of ELISpot-based prescreening of peripheral blood mononuclear cells foll...

In a rare neurologic disease known as IgM monoclonal gammopathy the immune system targets a sulfated trisaccharide known as the Human Natural Killer‐1 (HNK‐1) epitope that comprises a constituent of the myelin sheath known as MAG (myelin‐associated glycoprotein). This Editorial highlights a study by Aliu and colleagues in the current issue of the J...

The COVID-19 pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constraining our freedom of movement. This respiratory tract infection is unprecedented in that it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the alveoli that are responsible for the...

Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial t...

Introduction: Immunotherapies for multiple sclerosis (MS) significantly decrease the risk of new relapses. However, the chronic compartmentalized inflammation and neurodegeneration that define progressive MS are not prevented by these therapies and so significant damage to the brain and spinal cord and resulting disability ensues. Hence, the possib...

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long his...

Background: Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to asse...

Background: Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The...

Trials of antigen-specific tolerance have been undertaken in the clinic for over fifty years and the results of these antigen-specific clinical trials are described in this review. Antigen-specific tolerization of the immune system in protein replacement therapy for hemophilia A is an accepted treatment. Clinical trials are ongoing for autoimmune c...

Successful anti-tumor therapy using antibody-drug conjugates (ADCs) depends, in part, on antibodies that bind tumor selective targets that are subsequently internalized at a high rate into tumor cells. Only a select number of tumor-selective internalizing antibodies have been identified, and this has limited the scope of ADC therapeutic strategies...

Significance A growing body of literature has shown that, aside from carrying genetic information, both nuclear and mitochondrial DNA can be released by innate immune cells and promote inflammatory responses. Here we show that when CD4 ⁺ T lymphocytes, key orchestrators of adaptive immunity, are activated, they form a complex extracellular architec...

The α7 nicotinic acetylcholine receptor (α7nAChR) is central to the anti-inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological ro...

Significance Duchenne muscular dystrophy is a genetic disorder in which mutations in the dystrophin gene causes severe muscle wasting. A proposed treatment method involves systemic gene replacement therapy to introduce a functional dystrophin gene to the skeletal and cardiac muscles of the patient via rAAV6. A potentially serious problem may arise...

Background Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-...

Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin...

Raw data files for amylin study. Enclosed are the raw data used to generate Figs 1 to 5 using Prism 7 for Mac OS X (version 7.0b) software. (ZIP)

Objective We sought to confirm the presence and frequency of B cells and Epstein-Barr virus (EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by immunohistochemistry. Methods We quantified the type and location of B-cell subsets within active and chronic MS brain lesions in relation to viral antigen expression. The pre...

Background: The role of B cells and antibodies in anticancer immune responses may correlate with improved prognosis in several types of cancer. Indeed, tumor-reactive antibodies are detected in the blood of cancer patients, tumor-infiltrating B cells have been shown to produce tumor-reactive antibodies, and tumor-reactive antibodies can cause tumor...

Significance The identification of α7 nicotinic acetylcholine receptor (α7 NAChR) as the principal receptor for amyloid fibrils and small heat shock proteins clarifies their mechanism of immune suppression. The discovery of the receptor allows previous experiments using amyloid fibrils to be interpreted based on the extensive body of literature det...

Objective To evaluate cerebrospinal fluid (CSF) cytokine profiles in myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) disease in adult and paediatric patients. Methods In this cross-sectional study, we measured 27 cytokines in the CSF of MOG-IgG+ disease in acute phase before treatment (n=29). The data were directly compared with those...

Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloidforming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin h...

Rasmussen's encephalitis (RE) is a neuroinflammatory disease that typically affects only one hemisphere of the brain, resulting in severe seizures. Sixty years after the disease was first described, the preferred and best treatment option for RE is grotesque and involves removing a hemisphere of the brain (hemispherectomy); therefore, a better unde...

Neuroinflammation and neurodegeneration may represent two poles of brain pathology. Brain myeloid cells, particularly microglia, play key roles in these conditions. We employed single-cell mass cytometry (CyTOF) to compare myeloid cell populations in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, the R6/2 model of...

See also: Original Article by Gjelstrup et al.

Background Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in...

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their...

In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced cli...

Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin...

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunizat...

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunizat...

The entry of immune cells into the central nervous system (CNS) for immune surveillance occurs during normal physiological conditions, although it is difficult to detect. However, during CNS autoimmune diseases, such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis, immune cells extensively invade the CNS. Unders...

Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glu...

We all learn from adversity. In pharmaceutical development, this adage is manifest in helping to define the risk part of the risk-benefit profile for a potential therapeutic agent. We refer to serious adverse events (SAEs) in the standard vocabulary of those engaged in clinical trials. Serious adverse events are described in detail in the package i...

Objective To determine the average age of MS onset vs the age at which Epstein-Barr infection has previously occurred and stratify this analysis by sex and the blood level of Epstein-Barr nuclear antigen 1 (EBNA1) antibody. Methods Using infectious mononucleosis (IM) as a temporal marker in data from the Swedish epidemiologic investigation of MS,...

Objective To investigate the effects of targeting the high-affinity receptor for immunoglobulin E (FcεRI), that plays a central role in allergic responses and is constitutively expressed on mast cells and basophils, in clinical disease and autoimmune T-cell response in experimental MS. Methods Experimental autoimmune encephalomyelitis (EAE) was in...

Figure S1: Western Blot Analysis of Anti‐rMuPH20 Antibodies. Lane M: molecular weight marker. Lanes 1–4: increasing amounts (25, 50, 100, and 200 ng) of the rMuPH20‐FLAG protein. Panel A) blot probed with Ab1637 and B) blot probed with Ab2678.

Figure S7: HA fragments generated by PH20 did not inhibit OPC differentiation. (A) Rat OPCs were incubated with T3 hormone (200 ng/mL, Sigma‐Aldrich) and 40 μg/mL of bovine testicular hyaluronidase BTH IV‐S (Hyal type IV‐S (SLBC1033V), Sigma‐Aldrich), BTH IV‐S (Hyal type IV‐S (SLBD1402V), Sigma‐Aldrich), recombinant human PH20 (rHuPH20), and recomb...

Significance αB-crystallin (CRYAB) is a protein involved in the protection of cells from stress and cell death, and is very highly produced in brain lesions in multiple sclerosis (MS). Astrocytes are the main non-neuronal cell type in the central nervous system. Although they are involved in many processes in health and injury, their precise role i...

Objective Expression of Spam1/PH20 and its modulation of high/low molecular weight hyaluronan substrate have been proposed to play an important role in murine oligodendrocyte precursor cell (OPC) maturation in vitro and in normal and demyelinated central nervous system (CNS). We reexamined this using highly purified PH20. Methods Steady‐state expr...

The accumulation of amyloidogenic proteins in conditions like multiple sclerosis is considered pathologic. However, in a murine model of multiple sclerosis, amyloidogenic hexapeptides derived from major prion protein and amylin were antiinflammatory. Whether these molecules can modulate inflammation in sepsis is unknown. We hypothesized that amylin...

Background: The objective of this study was to evaluate monthly intramuscular adrenocorticotropic hormone (ACTH) gel versus intravenous methylprednisolone (IVMP) add-on therapy to interferon β for breakthrough disease in patients with relapsing forms of multiple sclerosis. Methods: This was a prospective, open-label, examiner-blinded, 15-month p...

We read with great interest the editorial from Nellore and Randall (1) regarding narcolepsy and influenza vaccination and our recent publication (2). Their conclusions become even more important in light of a recent publication demonstrating an increased risk of narcolepsy in adults in England after receipt of Pandemrix vaccination (3).

New therapeutic approaches for progressive forms of multiple sclerosis (MS) will be the challenge for the future. While we now have 10 approved medicines for relapsing-remitting MS (RRMS), the major unmet need for RRMS is for predictive biomarkers to enable us to decide for a given individual which of the 10 drugs we should use in a given patient....