Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis

Yeseul Kim, Gayoung Kim, Hyun June Shin, Jae Won Hyun, Su Hyun Kim, Eunjig Lee, Ho Jin Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19 + CD24 hi CD38 hi cells and CD19 + PD-L1 hi cells, with disparate regulatory mechanisms have been defined. Alemtuzumab provides a long-lasting suppression of disease activity in MS. In contrast to its documented efficacy, alemtuzumab's mechanism of action is not fully understood and information about the composition of repopulating B cell pool is scarce. Aim: To characterize repopulated B cell subsets and elucidate alemtuzumab's mechanism of action in B cell perspective. Methods: The frequency and the absolute number of Bregs were studied in peripheral blood mononuclear cells (PBMC) of 37 MS patients and 11 healthy controls (HC). Longitudinal analysis of the frequency and the absolute number of Bregs in PBMC of 11 MS patients was evaluated, before and at 6, 9, and 12 months post alemtuzumab. Results: We found deficiency of CD19 + CD24 hi CD38 hi cells during relapse compared to remission and HC (relapse vs remission: p = 0.0006, relapse vs HC: p = 0.0004). CD19 + PD-L1 hi cells were deficient during relapse than remission and HC (relapse vs remission: p = 0.0113, relapse vs HC: p = 0.0007). Following alemtuzumab, the distribution of B cells shifts towards naïve phenotype and Breg deficiency is restored. The frequency of CD19 + CD24 hi CD38 hi cells was significantly increased at 6 M and 9 M compared to 0 M (6 M vs 0 M: p = 0.0004, 9 M vs 0 M: p = 0.0079). At 9 M, the frequency of CD19 + CD24 hi CD38 hi cells started to decrease and by 12 M the frequency was reduced compared to 6 M, although it was significantly higher than baseline level (12 M vs 0 M: p = 0.0257). The absolute number was significantly increased at 6 M and 9 M post-alemtuzumab (6 M vs 0 M: p = 0.0063, 9 M vs 0 M: p = 0.02). The frequency of CD19 + PD-L1 hi cells significantly increased until 12 M (6 M vs 0 M: p = 0.0004, 12 M vs 0 M: p = 0.0036). The frequency of CD19 + PD-L1 hi cells at 12 M was significantly higher than 9 M (p = 0.0311). We further pinpoint that CD19 + CD24 hi CD38 hi cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery. Conclusions: Our results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19 + CD24 hi CD38 hi cells as a potential biomarker for disease activity.

Original languageEnglish
Article number300
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
Publication statusPublished - 2018 Oct 30

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Regulatory B-Lymphocytes
Multiple Sclerosis
Recurrence
B-Lymphocyte Subsets
Therapeutics
B-Lymphocytes
Blood Cells
alemtuzumab
Autoimmunity

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Kim, Yeseul ; Kim, Gayoung ; Shin, Hyun June ; Hyun, Jae Won ; Kim, Su Hyun ; Lee, Eunjig ; Kim, Ho Jin. / Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. In: Journal of Neuroinflammation. 2018 ; Vol. 15, No. 1.
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title = "Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis",
abstract = "Background: Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19 + CD24 hi CD38 hi cells and CD19 + PD-L1 hi cells, with disparate regulatory mechanisms have been defined. Alemtuzumab provides a long-lasting suppression of disease activity in MS. In contrast to its documented efficacy, alemtuzumab's mechanism of action is not fully understood and information about the composition of repopulating B cell pool is scarce. Aim: To characterize repopulated B cell subsets and elucidate alemtuzumab's mechanism of action in B cell perspective. Methods: The frequency and the absolute number of Bregs were studied in peripheral blood mononuclear cells (PBMC) of 37 MS patients and 11 healthy controls (HC). Longitudinal analysis of the frequency and the absolute number of Bregs in PBMC of 11 MS patients was evaluated, before and at 6, 9, and 12 months post alemtuzumab. Results: We found deficiency of CD19 + CD24 hi CD38 hi cells during relapse compared to remission and HC (relapse vs remission: p = 0.0006, relapse vs HC: p = 0.0004). CD19 + PD-L1 hi cells were deficient during relapse than remission and HC (relapse vs remission: p = 0.0113, relapse vs HC: p = 0.0007). Following alemtuzumab, the distribution of B cells shifts towards na{\"i}ve phenotype and Breg deficiency is restored. The frequency of CD19 + CD24 hi CD38 hi cells was significantly increased at 6 M and 9 M compared to 0 M (6 M vs 0 M: p = 0.0004, 9 M vs 0 M: p = 0.0079). At 9 M, the frequency of CD19 + CD24 hi CD38 hi cells started to decrease and by 12 M the frequency was reduced compared to 6 M, although it was significantly higher than baseline level (12 M vs 0 M: p = 0.0257). The absolute number was significantly increased at 6 M and 9 M post-alemtuzumab (6 M vs 0 M: p = 0.0063, 9 M vs 0 M: p = 0.02). The frequency of CD19 + PD-L1 hi cells significantly increased until 12 M (6 M vs 0 M: p = 0.0004, 12 M vs 0 M: p = 0.0036). The frequency of CD19 + PD-L1 hi cells at 12 M was significantly higher than 9 M (p = 0.0311). We further pinpoint that CD19 + CD24 hi CD38 hi cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery. Conclusions: Our results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19 + CD24 hi CD38 hi cells as a potential biomarker for disease activity.",
author = "Yeseul Kim and Gayoung Kim and Shin, {Hyun June} and Hyun, {Jae Won} and Kim, {Su Hyun} and Eunjig Lee and Kim, {Ho Jin}",
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doi = "10.1186/s12974-018-1334-y",
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Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. / Kim, Yeseul; Kim, Gayoung; Shin, Hyun June; Hyun, Jae Won; Kim, Su Hyun; Lee, Eunjig; Kim, Ho Jin.

In: Journal of Neuroinflammation, Vol. 15, No. 1, 300, 30.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis

AU - Kim, Yeseul

AU - Kim, Gayoung

AU - Shin, Hyun June

AU - Hyun, Jae Won

AU - Kim, Su Hyun

AU - Lee, Eunjig

AU - Kim, Ho Jin

PY - 2018/10/30

Y1 - 2018/10/30

N2 - Background: Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19 + CD24 hi CD38 hi cells and CD19 + PD-L1 hi cells, with disparate regulatory mechanisms have been defined. Alemtuzumab provides a long-lasting suppression of disease activity in MS. In contrast to its documented efficacy, alemtuzumab's mechanism of action is not fully understood and information about the composition of repopulating B cell pool is scarce. Aim: To characterize repopulated B cell subsets and elucidate alemtuzumab's mechanism of action in B cell perspective. Methods: The frequency and the absolute number of Bregs were studied in peripheral blood mononuclear cells (PBMC) of 37 MS patients and 11 healthy controls (HC). Longitudinal analysis of the frequency and the absolute number of Bregs in PBMC of 11 MS patients was evaluated, before and at 6, 9, and 12 months post alemtuzumab. Results: We found deficiency of CD19 + CD24 hi CD38 hi cells during relapse compared to remission and HC (relapse vs remission: p = 0.0006, relapse vs HC: p = 0.0004). CD19 + PD-L1 hi cells were deficient during relapse than remission and HC (relapse vs remission: p = 0.0113, relapse vs HC: p = 0.0007). Following alemtuzumab, the distribution of B cells shifts towards naïve phenotype and Breg deficiency is restored. The frequency of CD19 + CD24 hi CD38 hi cells was significantly increased at 6 M and 9 M compared to 0 M (6 M vs 0 M: p = 0.0004, 9 M vs 0 M: p = 0.0079). At 9 M, the frequency of CD19 + CD24 hi CD38 hi cells started to decrease and by 12 M the frequency was reduced compared to 6 M, although it was significantly higher than baseline level (12 M vs 0 M: p = 0.0257). The absolute number was significantly increased at 6 M and 9 M post-alemtuzumab (6 M vs 0 M: p = 0.0063, 9 M vs 0 M: p = 0.02). The frequency of CD19 + PD-L1 hi cells significantly increased until 12 M (6 M vs 0 M: p = 0.0004, 12 M vs 0 M: p = 0.0036). The frequency of CD19 + PD-L1 hi cells at 12 M was significantly higher than 9 M (p = 0.0311). We further pinpoint that CD19 + CD24 hi CD38 hi cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery. Conclusions: Our results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19 + CD24 hi CD38 hi cells as a potential biomarker for disease activity.

AB - Background: Regulatory B cells (Bregs), which protect from autoimmunity, are deficient in multiple sclerosis (MS). Novel regulatory B cell subsets CD19 + CD24 hi CD38 hi cells and CD19 + PD-L1 hi cells, with disparate regulatory mechanisms have been defined. Alemtuzumab provides a long-lasting suppression of disease activity in MS. In contrast to its documented efficacy, alemtuzumab's mechanism of action is not fully understood and information about the composition of repopulating B cell pool is scarce. Aim: To characterize repopulated B cell subsets and elucidate alemtuzumab's mechanism of action in B cell perspective. Methods: The frequency and the absolute number of Bregs were studied in peripheral blood mononuclear cells (PBMC) of 37 MS patients and 11 healthy controls (HC). Longitudinal analysis of the frequency and the absolute number of Bregs in PBMC of 11 MS patients was evaluated, before and at 6, 9, and 12 months post alemtuzumab. Results: We found deficiency of CD19 + CD24 hi CD38 hi cells during relapse compared to remission and HC (relapse vs remission: p = 0.0006, relapse vs HC: p = 0.0004). CD19 + PD-L1 hi cells were deficient during relapse than remission and HC (relapse vs remission: p = 0.0113, relapse vs HC: p = 0.0007). Following alemtuzumab, the distribution of B cells shifts towards naïve phenotype and Breg deficiency is restored. The frequency of CD19 + CD24 hi CD38 hi cells was significantly increased at 6 M and 9 M compared to 0 M (6 M vs 0 M: p = 0.0004, 9 M vs 0 M: p = 0.0079). At 9 M, the frequency of CD19 + CD24 hi CD38 hi cells started to decrease and by 12 M the frequency was reduced compared to 6 M, although it was significantly higher than baseline level (12 M vs 0 M: p = 0.0257). The absolute number was significantly increased at 6 M and 9 M post-alemtuzumab (6 M vs 0 M: p = 0.0063, 9 M vs 0 M: p = 0.02). The frequency of CD19 + PD-L1 hi cells significantly increased until 12 M (6 M vs 0 M: p = 0.0004, 12 M vs 0 M: p = 0.0036). The frequency of CD19 + PD-L1 hi cells at 12 M was significantly higher than 9 M (p = 0.0311). We further pinpoint that CD19 + CD24 hi CD38 hi cells were deficient at severe relapses following alemtuzumab infusion and restored during recovery. Conclusions: Our results highlight the preferential reconstitution of Bregs as a possible mechanism of action of alemtuzumab and CD19 + CD24 hi CD38 hi cells as a potential biomarker for disease activity.

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