Joseph J. Sabatino

University of California, San Francisco

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Scott S. Zamvil

University of California, San Francisco

Michael R. Wilson

University of California, San Francisco

Riley Bove

University of California, San Francisco

Kristen Mittl

University of California, San Francisco

Stephen L. Hauser

University of California, San Francisco

William Rowles

University of California, San Francisco

Jill A. Hollenbach

University of California, San Francisco

Bruce Cree

University of California, San Francisco

Ari Green

University of California, San Francisco

Chloe Gerungan

University of California, San Francisco

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Washington University in St. Louis

Stanford University

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B-Cell Therapies in Multiple Sclerosis

Cold Spring Harbor Perspectives in Medicine (2018)

Joseph J. Sabatino Scott S. Zamvil Stephen L. Hauser

Joseph J. Sabatino Jr., Scott S. Zamvil and Stephen L. Hauser Multiple Sclerosis Center, Department of Neurology, University of California, San Francisco, California 94158 Correspondence: jsabatino{at}ucsf.neuroimmunol.org

Center (category theory)

10.1101/cshperspect.a032037

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Citations (71)

Publisher Correction: B cells in autoimmune and neurodegenerative central nervous system diseases

Nature reviews. Neuroscience (2019)

Joseph J. Sabatino Anne‐Katrin Pröbstel Scott S. Zamvil

10.1038/s41583-019-0251-0

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Citations (6)

Characterization of Myelin-reactive CD8+ T cells in Multiple Sclerosis (P2.2-065)

Neurology (2019)

Joseph J. Sabatino Michael R. Wilson Peter A. Calabresi Stephen L. Hauser Jonathan P. Schneck

Characterization

10.1212/wnl.92.15_supplement.p2.2-065

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Impact of MS disease-modifying therapies on antibody and T cell responses following COVID-19 vaccination

Multiple Sclerosis Journal (2021)

Joseph J. Sabatino William Rowles Kristen Mittl Kira McPolin Jency R. Rajan

Introduction: MS disease-modifying therapies (DMTs) lead to distinct effects on humoral and cellular immunity. Effective vaccine- elicited immunity to severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), the causative agent of the ongoing COVID-19 pandemic, requires robust antibody and CD4+ and CD8+ T cell responses against the SARS-CoV-2 spike protein. Understanding how different MS DMTs affect COVID-19 vaccine immunity is a vital clinical gap that needs to be urgently addressed. Objectives: The goal of this study is to assess COVID-19 vaccine- elicited antibody and T cell responses in MS patients on different of DMTs. Aims: To measure SARS-CoV-2 spike antigen-specific antibody and CD4+ and CD8+ T cell responses before and after COVID- 19 vaccination of MS patients on different DMTs. Methods: Enrolment included MS patients on no therapy, or treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NAT), sphingosine-1-phosphate receptor (S1P) modulator, or anti-CD20 monoclonal antibody (mAb). Serum and peripheral blood mononuclear cells (PBMCs) were collected from all patients before and 2-4 weeks following final COVID-19 vaccination. Patient serum was tested on a Luminex bead-based assay to quantitatively measure IgG levels against the whole SARSCoV- 2 spike protein and the spike receptor binding domain (RBD). PBMCs were stimulated with pools of SARS-CoV-2 spike peptides to measure the frequencies of spike-specific CD4+ and CD8+ T cells by activation-induced marker expression. Results: Following COVID-19 vaccination, all untreated MS patients and patients on GA, DMF, and NAT were seropositive with similar high IgG titres to total spike and spike RBD. MS patients on S1P modulators and anti-CD20 mAb exhibited significantly reduced IgG titres to total spike and spike RBD antigens, with only a fraction of patients reaching seropositivity. Spike antigen-specific CD4+ and CD8+ T cell responses were present at similar levels across all DMT categories following COVID-19 vaccination. Conclusions: MS DMTs exhibited differential effects on COVID- 19 vaccine-elicited humoral, but not T cell immunity. Whereas IgG responses were unaffected in MS patients on GA, DMF, and NAT, IgG levels were reduced in MS patients on S1P modulators and anti-CD20 mAb. The findings of this study have important clinical implications for assessing potential risk of COVID-19 infection in vaccinated MS patients on specific DMTs.

Natalizumab

Glatiramer acetate

Cellular immunity

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Stiff person syndrome masquerading as multiple sclerosis

Journal of the Neurological Sciences (2016)

Joseph J. Sabatino Scott D. Newsome

Stiff person syndrome

10.1016/j.jns.2016.11.066

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Citations (9)

Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

Proceedings of the National Academy of Sciences (2021)

Qin Ma Stacy J. Caillier Shaun Ivan Muzic Michael R. Wilson Roland G. Henry

Significance Cellular and molecular mediators driving multiple sclerosis (MS) pathology have been discovered to a great extent. However, the early molecular events leading to aberrant immune responses remain largely unknown. In this study, we combined bisulfite sequencing with transcriptome profiling to characterize the epigenetic landscape of four peripheral immune cell populations isolated from newly diagnosed, untreated MS patients and healthy individuals. We demonstrate widespread hypomethylation in CD19 + B cells at clinical disease onset. Notably, this epigenetic signature is functionally linked with the overactivation of B cells. Altogether, our results pinpoint the role of aberrant DNA methylation in connecting defects in the periphery with central nervous system autoimmunity and corroborate the key role of B cells in the initial stages of MS.

Epigenesis

10.1073/pnas.2111920118

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Citations (22)

Unique invariant CD8 ⁺ T cell population persists in MS

Neurology Neuroimmunology & Neuroinflammation (2015)

Joseph J. Sabatino Scott S. Zamvil

Although historically overshadowed by CD4+ T cells, and more recently by B cells, a number of lines of evidence point toward a potentially vital role of CD8+ T cells in multiple sclerosis (MS) pathogenesis. CD8+ T cells outnumber CD4+ in the parenchyma of MS lesions1 and are abundant at the leading edge in chronic active lesions.2 Some studies have detected increased frequencies of myelin-specific CD8+ T cells in patients with MS.3,4 Human leukocyte antigen (HLA)-A3 (A*0301), which encodes one of the major histocompatibility complex (MHC) class I proteins used for antigen recognition by CD8+ T cells, doubles the risk of MS even in the absence of HLA-DR2 (DRB*1501, DQB*0602) genes that encode MHC II proteins used for antigen presentation to CD4+ T cells.5 Furthermore, it has been demonstrated that myelin-specific CD8+ T cells can induce an MS-like disease in HLA-A3 transgenic6 and wild-type mice.7 If antigen-specific CD8+ T cells participate in MS pathogenesis, one might ask whether certain ones expand selectively and whether they persist.

CD1

10.1212/nxi.0000000000000140

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A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations

Journal of Clinical Investigation (2025)

Claudia Cantoni Margarita Smirnov Maria Firulyova Prabhakar S. Andhey Tara R. Bradstreet

Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization of CSF immune cells. CSF derives from and borders central nervous system (CNS) tissue, allowing for comprehensive accounting of cell types along with their relative abundance and immunologic profiles relevant to CNS diseases. Using integration techniques applied to publicly available datasets in combination with our own studies, we generated a compendium with 139 subjects encompassing 135 CSF and 58 blood samples. Healthy subjects and individuals across a wide range of diseases, such as multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, COVID-19, and autoimmune encephalitis, were included. We found differences in lymphocyte and myeloid subset frequencies across different diseases as well as in their distribution between blood and CSF. We identified what we believe to be a new subset of AREG+ dendritic cells exclusive to the CSF that was more abundant in subjects with MS compared with healthy controls. Finally, transcriptional cell states in CSF microglia-like cells and lymphoid subsets were elucidated. Altogether, we have created a reference compendium for single-cell transcriptional profiling encompassing CSF immune cells useful to the scientific community for future studies on neurologic diseases.

Compendium

10.1172/jci177793

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Humoral immune response following SARS-CoV-2 mRNA vaccination concomitant to anti-CD20 therapy in multiple sclerosis

Multiple Sclerosis and Related Disorders (2021)

Frederik Novak Anna Christine Nilsson Christian Nielsen Dorte Kinggaard Holm Kamilla Østergaard

10.1016/j.msard.2021.103251

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Citations (40)

Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis

European Journal of Immunology (2005)

Gregory D. Gregory Michaela Robbie‐Ryan Virginia H. Secor Joseph J. Sabatino Melissa A. Brown

Once considered to be of sole importance in allergy and parasitic infections, the role of mast cells in other pathologic and protective immune responses is becoming increasingly evident. We previously demonstrated that mast cells contribute to the severity of EAE, the rodent model of multiple sclerosis. Here we show that one mode of mast cell action is through effects on the autoreactive T cell response. Early indices of both peripheral CD4 and CD8 T cell activation, including IFN-gamma production and increases in CD44 and CD11a expression, are attenuated in mast cell-deficient (W/Wv) mice after myelin oligodendrocyte glycoprotein(35-55) priming when compared to WT animals. Reduced infiltrates of activated T cells in the central nervous system are also observed. Importantly, selective repletion of the mast cell compartment restores most T cell responses in the lymph nodes and the central nervous system, correlating with reconstitution of severe disease. The adoptive transfer of WT-derived encephalitogenic T cells results in significantly less severe disease in W/Wv recipients, indicating that mast cells also exert potent effects after the initial T cell response is generated. Our data provide the first in vivo evidence that mast cells can significantly influence T cell responses and suggest that mast cells exacerbate disease during both the inductive and effector phases.

Myelin oligodendrocyte glycoprotein

Adoptive Cell Transfer

Priming (agriculture)

10.1002/eji.200535271

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Citations (81)