B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies

Cencioni, Maria Teresa; Mattoscio, Miriam; Magliozzi, Roberta; Bar‐Or, Amit; Muraro, Paolo A.

doi:10.1038/s41582-021-00498-5

Cited by 158 publications

(114 citation statements)

References 184 publications

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“…EBV infection and altered immune responses during IM have now been strongly associated with an increased risk of developing MS [55,[80][81][82]. It is less clear, however, if this results from an uncontrolled reservoir of B cells, activated by EBV infection, that stimulates autoreactive T cells, possibly even in the CNS, or if the infection primes crossreactive T cell responses that recognize both EBV and myelin antigens.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains unclear why preferentially EBV infection and no other pathogens would explore genetic susceptibility for MS development. One possibility is that EBV converts B cells into potent APCs that then could stimulate autoreactive, possibly EBV cross-reactive CD4 + T cells [55]. Along these lines EBNA2 has been shown to augment transcription of MS risk loci, resulting in increased LCL proliferation [56,57].…”

Section: Role Of B Cells and Their Antigen Presentation During Msmentioning

confidence: 99%

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Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

Läderach

Münz

2021

Microorganisms

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Role Of B Cells and Their Antigen Presentation During Msmentioning

confidence: 99%

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

Läderach

Münz

2021

Microorganisms

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“…After anti-CD20 therapies, B-cell repopulation starts in bone marrow and spleen, followed by blood, with a different rate between memory B cells and CD19 + cells [ 35 ].…”

Section: Mechanisms Of Action Of Anti-cd20 Therapiesmentioning

confidence: 99%

“…Of note, B-cell counts are usually determined using CD19, which largely overlaps with CD20 during B-cell differentiation, because it is less prone to potential interference in presence of anti-CD20 monoclonal antibodies [ 35 ].…”

Section: Mechanisms Of Action Of Anti-cd20 Therapiesmentioning

confidence: 99%

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

et al. 2021

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Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being ‘T-cell mediated’ to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.

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“…However, not all PMS patients present with inflammatory follicles, which suggests the presence of factors other than CNS B cells contributing to the persistent inflammation observed behind the intact BBB (Magliozzi et al, 2007). A number of studies have identified the presence of meningeal follicles only in SPMS and absent in PPMS (Magliozzi et al, 2007;Choi et al, 2012), yet a few others have identified follicular structures in PPMS cases associated with a rapid disease progression (Kutzelnigg et al, 2005;Haider et al, 2016;Cencioni et al, 2021).…”

Section: The Role Of Lymphocytesmentioning

confidence: 99%

Stem Cell Therapies for Progressive Multiple Sclerosis

Smith¹,

Nicaise

Ionescu

et al. 2021

Front. Cell Dev. Biol.

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.

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B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies

Cited by 158 publications

References 184 publications

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

Anti-CD20 therapies for multiple sclerosis: current status and future perspectives

Stem Cell Therapies for Progressive Multiple Sclerosis

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