The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

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Bruton's tyrosine kinase inhibition in the treatment of preclinical models and multiple sclerosis

Current Pharmaceutical Design ◽

10.2174/1381612827666210701152934 ◽

2021 ◽

Vol 27 ◽

Author(s):

Anja Steinmaurer ◽

Isabella Wimmer ◽

Thomas Berger ◽

Paulus Stefan Rommer ◽

Johann Sellner

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

Tyrosine Kinase ◽

B Cell ◽

Bruton’S Tyrosine Kinase ◽

Cumulative Number ◽

Phase 2 ◽

Bruton's Tyrosine Kinase ◽

Relapsing Remitting

: Significant progress has been made in understanding the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.

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The frequencies of peripheral blood CD5+CD19+ B cells, CD3−CD16+CD56+ NK, and CD3+CD56+ NKT cells and serum interleukin-10 in patients with multiple sclerosis and neuromyelitis optica spectrum disorder

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-021-00596-5 ◽

2022 ◽

Vol 18 (1) ◽

Author(s):

Leila Khani ◽

Mir Hadi Jazayeri ◽

Reza Nedaeinia ◽

Mahmood Bozorgmehr ◽

Seyed Masood Nabavi ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

Natural Killer ◽

Neuromyelitis Optica ◽

Peripheral Blood ◽

Inflammatory Diseases ◽

Study Groups ◽

Nkt Cells ◽

Interleukin 10 ◽

Enzyme Linked Immunosorbent Assay

Abstract Background Multiple sclerosis (MS) and neuromyelitis optica syndrome disease (NMOSD) are inflammatory diseases of the central nervous system. The pathogenesis and treatments for these two conditions are very different. Natural killer (NK) and natural killer T (NKT) cells are immune cells with an important role in shaping the immune response. B cells are involved in antigen presentation as well as antibody and cytokine production. There is conflicting evidence of the roles of NK, NKT, and B cells in the two conditions. We aimed to compare the frequency of CD3−CD16+CD56+NK, CD3+ CD56+ NKT, and CD5+CD19+ B cells in the peripheral blood and serum Interleukin-10 (IL-10) in patients with MS and NMOSD. Methods CD19+CD5+ B, CD3− CD16+CD56+ NK, and CD3+CD56+ NKT cells were quantitated by flow cytometry in 15 individuals with Interferon-Beta (IFN-β) treated relapsing–remitting MS (RRMS), 15 untreated RRMS, and 15 NMOSD patients as well as 30 healthy controls (HC). Serum IL-10 was measured using an enzyme-linked immunosorbent assay (ELISA). Results The percentage of CD3−CD56+CD16+ NK cells in the peripheral blood of IFN-treated MS (1.81 ± 0.87) was significantly lower than for untreated RRMS (4.74 ± 1.80), NMOSD (4.64 ± 1.26) and HC (5.83 ± 2.19) (p < 0.0001). There were also differences for the percentage of CD3−CD16+ and CD3−CD56+ cells (p < 0.001 and p < 0.0007; respectively). IFN-treated RRMS (2.89 ± 1.51) had the lowest proportion of CD3+CD56+ among the study groups (p < 0.002). Untreated RRMS (5.56 ± 3.04) and NMOSD (5.47 ± 1.24) had higher levels of CD3+CD56+ than the HC (3.16 ± 1.98). The mean percentage of CD19+CD5+ B cells in the peripheral blood of untreated RRMS patients (1.32 ± 0.67) was higher compared to the patients with NMOSD (0.30 ± 0.20), HC (0.5 ± 0.22) and IFN-treated RRMS (0.81 ± 0.17) (p < 0.0001). Serum interleukin-10 was significantly higher in the IFN-treated RRMS (8.06 ± 5.39) and in HC (8.38 ± 2.84) compared to untreated RRMS (5.07 ± 1.44) and the patients with NMOSD (5.33 ± 2.56) (p < 0.003). Conclusions The lower proportion of CD3−CD56+ CD16+ NK and CD3+CD56+ cells in peripheral blood of IFN-treated RRMS compared to other groups suggests the importance of immunomodulation in patients with RRMS disorder. Based on the differences in CD19+CD5+ B cells and serum IL-10 between patients and HC, supplementary assessments could be of value in clarifying their roles in autoimmunity.

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Role of B Cells in the Pathogenesis of Multiple Sclerosis

Multiple Sclerosis ◽

10.1016/b978-0-12-800763-1.00003-8 ◽

2016 ◽

pp. 23-39

Author(s):

Behrouz Nikbin ◽

Mandana Mohyeddin Bonab ◽

Fatemeh Talebian ◽

Yadollah Shakiba

Keyword(s):

Multiple Sclerosis ◽

B Cells

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Role of Diffusional Kurtosis Imaging in Differentiating Neuromyelitis Optica–Related and Multiple Sclerosis–Related Acute Optic Neuritis

Journal of Computer Assisted Tomography ◽

10.1097/rct.0000000000000974 ◽

2020 ◽

Vol 44 (1) ◽

pp. 47-52 ◽

Cited By ~ 1

Author(s):

Ping Lu ◽

Ting Yuan ◽

Xilan Liu ◽

Guohong Tian ◽

Jibin Zhang ◽

...

Keyword(s):

Multiple Sclerosis ◽

Optic Neuritis ◽

Neuromyelitis Optica ◽

Diffusional Kurtosis Imaging ◽

Acute Optic Neuritis

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A Tolerogenic Role of Cathepsin G in a Primate Model of Multiple Sclerosis: Abrogation by Epstein–Barr Virus Infection

Archivum Immunologiae et Therapiae Experimentalis ◽

10.1007/s00005-020-00587-1 ◽

2020 ◽

Vol 68 (4) ◽

Author(s):

Bert A. ‘t Hart

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

Epstein Barr Virus ◽

Cathepsin G ◽

Epstein Barr Virus Infection ◽

Primate Model ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

Abstract Using a non-human primate model of the autoimmune neuroinflammatory disease multiple sclerosis (MS), we have unraveled the role of B cells in the making and breaking of immune tolerance against central nervous system myelin. It is discussed here that B cells prevent the activation of strongly pathogenic T cells present in the naïve repertoire, which are directed against the immunodominant myelin antigen MOG (myelin oligodendrocyte glycoprotein). Prevention occurs via destructive processing of a critical epitope (MOG34-56) through the lysosomal serine protease cathepsin G. This effective tolerance mechanism is abrogated when the B cells are infected with Epstein–Barr virus, a ubiquitous γ1-herpesvirus that entails the strongest non-genetic risk factor for MS.

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CYT-0853, a Novel RAD51 Inhibitor, Modulates Immunoregulatory B-Lymphocytes

Blood ◽

10.1182/blood-2019-131311 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2330-2330

Author(s):

Tamar Aprahamian ◽

ED Keniston ◽

Jane Branca ◽

Muneer G Hasham ◽

Melinda Day ◽

...

Keyword(s):

Multiple Sclerosis ◽

Bone Marrow ◽

B Cells ◽

B Cell ◽

Antibody Production ◽

Cytidine Deaminase ◽

Autoreactive B Cells ◽

Freund’S Adjuvant ◽

Freund's Adjuvant

Activation Induced Cytidine Deaminase (AICDA/AID) is a DNA-directed cytidine deaminase that is normally only expressed in activated B-cells to promote somatic hypermutations and immunoglobulin class switching. In cancer cells, AID causes significant genotoxic stress through DNA replication fork damage, creating a dependency upon the homologous recombination repair factor, RAD51, for survival. We have demonstrated anti-cancer activity through disruption of this axis in multiple preclinical lymphoid cancer models. Autoreactive B cells depend on RAD51 for survival and are chronically auto-stimulated and therefore continually re-express AID. It has been shown that ectopic expression of AID in autoreactive B-cells causes genome-wide DNA damage (similar to cancers). Given the role of autoreactive B cells and autoantibodies in autoimmune disorders, we hypothesize that immunomodulation of B cells via the RAD51/AID axis will remediate inflammatory disease processes. Our previous data suggests that RAD51 modulation enhances the CD73+ B cell population and reduces antibody diversity in T1D mice, indicating precise effects on AID-mediated antibody diversification. CYT-0853 is a novel RAD51 inhibitor that sensitizes cells to AID activity. Here, we assessed the in vivo effect of CYT-0853 on primary B cells and antibody production. Wild-type C57BL/6 mice were treated with 40mg/kg CYT-0853 or vehicle for five weeks. One-week post-treatment start, mice were immunized with DNP-KLH antigen mixed with Complete Freund's Adjuvant. A second booster with DNP-KLH antigen mixed with Incomplete Freund's Adjuvant was administered two weeks later. At termination, blood, spleen, and bone marrow was collected for analysis by flow cytometry. Surface expression of CD45, CD19, IgM, and IgG1 was assessed to determine white blood cell count, B cells, and pre- and post-class switch recombination (CSR), respectively. While no significant changes to B cell populations were observed in bone marrow or spleen, we demonstrate that CYT-0853 significantly decreases the median number of circulating CD45+ and IgG1 (post-CSR) B cells (61.8% vs. 31.6% and 8.7% vs. 4.4%, respectively). In addition, we observed a modest, significant increase in the amount of IgM+ (pre-CSR) B cells. These results were complemented by an associated overall significant decrease in circulating IgM levels. Of note, no adverse effects were observed in these mice over this treatment period. Based on these data and the role of B cells not only in antibody production, but also as antigen-presenting cells in multiple sclerosis, we tested our molecule in the myelin oligodendrocyte glycoprotein35-55-experimental autoimmune encephalomyelitis model of multiple sclerosis. Prophylactic treatment using 40mg/kg CYT-0853 did not affect disease activity or circulating cytokine production, however we observed a significant decrease in the spleen. Based on these results, further exploration is warranted to harness the power of CYT-0853 on the AID/RAD51 axis. This specific targeting may elicit beneficial therapeutic changes to B-lymphocyte populations and provide a novel immunomodulatory target to treat immunity and inflammation. Taken together, these data provide a foundation for continued preclinical development of CYT-0853 with applicability towards autoimmune diseases. Disclosures Aprahamian: Cyteir Therapeutics: Consultancy. Day:Cyteir Therapeutics: Employment. Mills:Cyteir Therapeutics: Employment, Equity Ownership.

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Continued dysregulation of the B cell lineage promotes multiple sclerosis activity despite disease modifying therapies

F1000Research ◽

10.12688/f1000research.74506.1 ◽

2021 ◽

Vol 10 ◽

pp. 1305

Author(s):

Ana C. Londoño ◽

Carlos A. Mora

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Cell Lineage ◽

Clear Understanding ◽

Cellular Activity ◽

Regulatory B Cells ◽

Disease Modifying Therapies

A clear understanding of the origin and role of the different subtypes of the B cell lineage involved in the activity or remission of multiple sclerosis (MS) is important for the treatment and follow-up of patients living with this disease. B cells, however, are dynamic and can play an anti-inflammatory or pro-inflammatory role, depending on their milieu. Depletion of B cells has been effective in controlling the progression of MS, but it can have adverse side effects. A better understanding of the role of the B cell subtypes, through the use of surface biomarkers of cellular activity with special attention to the function of memory and regulatory B cells (Bregs), will be necessary in order to offer specific treatments without inducing undesirable effects.

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