Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

Kemmerer, Constanze Louisa; Pernpeintner, Verena; Ruschil, Christoph; Abdelhak, Ahmed; Scholl, Matthias; Ziemann, Ulf; Krumbholz, Markus; Hemmer, Bernhard; Kowarik, Markus C.

doi:10.1371/journal.pone.0235449

Cited by 26 publications

(41 citation statements)

References 45 publications

(65 reference statements)

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“…When exploring the ability of these cells to predict secondary autoimmunity at baseline, we found that this was not the case in patients treated previously with natalizumab, who mostly presented a lower percentage of plasmablasts. This agrees with previous data showing that natalizumab and no other disease modifying drugs diminish the percentages of plasmablasts in blood (14,15,24).…”

Section: Discussionsupporting

confidence: 93%

“…Fourteen out of 22 patients presenting AIAEs but only eight of the 35 AIAEs-patients had a percentage of PB/PC higher than 0.10 [Odds ratio (OR) 5.91, 95% CI 1.83-19.10, p=0.004, Figure 4A]. To improve the sensitivity of the assay, we next explored if the heterogeneity found in AIAEs group could be related to previous treatment, since it has been described that natalizumab diminishes the concentration of blood plasmablasts (13,14). We found that five of the eight AIAEs patients who presented a percentages of PB/PC at baseline <0,1%, received natalizumab as the last treatment prior to alemtuzumab.…”

Section: Flow Cytometry Analysesmentioning

confidence: 99%

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Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

et al. 2021

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ObjectiveTo explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment.MethodsMulticenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases.ResultsTwenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058).ConclusionsA PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.

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Section: Discussionsupporting

confidence: 93%

Section: Flow Cytometry Analysesmentioning

confidence: 99%

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

et al. 2021

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“…As mentioned previously, MS has historically been considered a T-cell-mediated disease, but emerging evidence also supports a significant role for the B-cell compartment (Hauser et al, 2008;Hauser and Cree, 2020;Kemmerer et al, 2020). This is a very important distinction as a recent study evaluating the most commonly used DMTs, found that these drugs have differential effects on distinct B-cell subsets, with some inducing an expansion of potentially pathogenic subtypes (Kemmerer et al, 2020). A role for the B-cell compartment in MS pathogenesis has been increasingly supported by the recent studies demonstrating efficacy of anti-CD20 antibody-mediated B-cell depletion in patients with both RRMS and progressive disease (Florou et al, 2020).…”

Section: Autoimmune Neuroinflammatory Diseasementioning

confidence: 90%

“…With the rapid expansion of targeted immunotherapies, fully appreciating the contribution of distinct entities within the neuroinflammatory response to MS pathogenesis will be critical for the development of efficacious and individualized therapeutic strategies (Rotstein and Montalban, 2019). As mentioned previously, MS has historically been considered a T-cell-mediated disease, but emerging evidence also supports a significant role for the B-cell compartment (Hauser et al, 2008;Hauser and Cree, 2020;Kemmerer et al, 2020). This is a very important distinction as a recent study evaluating the most commonly used DMTs, found that these drugs have differential effects on distinct B-cell subsets, with some inducing an expansion of potentially pathogenic subtypes (Kemmerer et al, 2020).…”

Section: Autoimmune Neuroinflammatory Diseasementioning

confidence: 99%

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Mitchell

Shireman

Potchanant

et al. 2021

Front. Cell. Neurosci.

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According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

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“…Multiple sclerosis (MS) is a chronic, progressive, neuroinflammatory disease characterized by immune-mediated inflammation, demyelination, and axonal damage in the central nervous system (CNS) [1][2][3]. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the CNS, primarily affecting the optic nerves and the spinal cord, leading to blindness and paralysis [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor Homolog CD180 Expression Is Diminished on Natural Autoantibody-Producing B Cells of Patients with Autoimmune CNS Disorders

Hayden

Erdő-Bonyár

Bóné

et al. 2021

Journal of Immunology Research

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Purpose. Decreased expression of TLR homolog CD180 in peripheral blood B cells and its potential role in antibody production have been described in autoimmune diseases. Effectiveness of anti-CD20 therapy in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) strengthens the role of B cells in the pathogenesis. Therefore, we aimed to investigate the CD180 expression of peripheral blood B cell subsets in NMOSD and MS patients and analyze the levels of natural anti-citrate synthase (CS) IgG autoantibodies and IgG antibodies induced by bacterial infections reported to play a role in the pathogenesis of NMOSD or MS. Methods. We analyzed the distribution and CD180 expression of peripheral blood B cell subsets, defined by CD19/CD27/IgD staining, and measured anti-CS IgM/G natural autoantibody and antibacterial IgG serum levels in NMOSD, RRMS, and healthy controls (HC). Results. We found decreased naïve and increased memory B cells in NMOSD compared to MS. Among the investigated four B cell subsets, CD180 expression was exclusively decreased in CD19+CD27+IgD+ nonswitched (NS) memory B cells in both NMOSD and MS compared to HC. Furthermore, the anti-CS IgM natural autoantibody serum level was lower in both NMOSD and MS. In addition, we found a tendency of higher anti-CS IgG natural autoantibody levels only in anti-Chlamydia IgG antibody-positive NMOSD and MS patients. Conclusions. Our results suggest that reduced CD180 expression of NS B cells could contribute to the deficient natural IgM autoantibody production in NMOSD and MS, whereas natural IgG autoantibody levels show an association with antibacterial antibodies.

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Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

Cited by 26 publications

References 45 publications

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Toll-Like Receptor Homolog CD180 Expression Is Diminished on Natural Autoantibody-Producing B Cells of Patients with Autoimmune CNS Disorders

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