Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

Abstract

Objective:To study the effects of natalizumab treatment on subgroups of circulating peripheral blood B cell populations.Methods:We studied the proportions and absolute numbers of CD19+CD20+, CD10+, and CD5+ B cell populations, and determined very late activation antigen-4 and chemokine receptor CXCR3, CCR5, and CCR6 expression on B cells in the peripheral blood of 14 natalizumab-treated patients with relapsing-remitting multiple sclerosis. Five blood samples per patient were obtained longitudinally before and during the first year of treatment. Blood samples were analyzed by 6-color flow cytometry.Results:Proportions of B cells and CD10+ pre–B cells were significantly increased, and very late activation antigen-4 expression on the B cell surface was significantly decreased already after 1 week of natalizumab treatment. Natalizumab-induced sustained increase in the proportion and absolute number of CXCR3-expressing B cells was statistically significant after 1 month of treatment. There were no changes in the proportions of CCR5- or CCR6-expressing B cells.Conclusions:The rapid and persistent increase in circulating CXCR3-expressing B cells in response to natalizumab treatment possibly reflects the relevance of this chemokine receptor in controlling migration of B cells into the CNS in humans in vivo.

The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?

“…However, antiviral Th1 cells that lack CCR6 expression are strongly enriched in the CSF of patients with active MS [32], suggesting that the IP10/CXCR3 axis is relevant for relapses. Consistent with this notion, in the circulation of patients with MS where CNS homing is blocked by natalizumab, there is a selective increase in CXCR3 + B cells [145] and CXCR3-expressing Th1/17 cells [32,130]. The requirements for CXCL10/IP10 in different animal models of MS is variable [82], but a role for CXCL10/IP10 in MS is further suggested by the fact that it is expressed in brain lesions of patients with MS [80], and that SNPs in its gene locus are associated with a worse prognosis [146].…”

Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis

“…42 Especially pathogen-associated TLR9 and its ligand CpG-DNA have been shown to promote the development of Tbet + B cells in mice. 27,44,45 During these rebounds, Epstein-Barr virus-infected memory B cells that have accumulated in the blood show massive influx into brain tissues of MS patients. Likewise, CXCR3 surface expression was more enhanced under these conditions, reflecting the high CXCR3 levels on ex vivo IgG1 + B cells.…”

“…The importance of pathogenic immune cells in contributing to MS disease progression, such as CXCR3 + memory B cells, has been put forward by the recurrence of often-fatal clinical relapses in MS patients when discontinuing the use of natalizumab. 27,44,45 During these rebounds, Epstein-Barr virus-infected memory B cells that have accumulated in the blood show massive influx into brain tissues of MS patients. 45 Furthermore, persistent viral infections are suggested to sustain the development of T-bet-expressing B cells, 15 which further supports the enhanced differentiation and local recruitment of CXCR3(T-bet) high memory B cells in an organ-specific autoimmune disease such as MS (Fig 6).…”

“…To address this potential migration of CXCR3 + IgG + memory B cells into the CNS, we analyzed the distribution of these B-cell subsets in the blood of MS patients treated with the anti-α4β1 integrin (VLA-4) antibody natalizumab (see Table 1), a drug that effectively reduces MS disease activity by blocking lymphocyte recruitment to the CNS. 27 VLA-4 was most abundantly expressed on blood IgG + B cells from MS patients prior to natalizumab treatment (see Fig 2). Elevated frequencies of both IgM mem (pretreatment vs 6 months post-treatment p = 0.042 and 12 months post-treatment p = 0.011) and IgG + (pretreatment vs 6 months post-treatment p = 0.022 and 12 months posttreatment p < 0.001) B cells were found in the blood of MS patients both 6 and 12 months after versus before treatment.…”

Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B‐cell‐targeted therapies

“…However, it is important to consider that natalizumab therapy is also likely to inhibit B‐cell entry into the CNS, with reports of reduced numbers of B‐cells in CSF and increased numbers in the peripheral circulation of natalizumab‐treated MS patients (Stüve et al , ; Krumbholz et al , ). Furthermore, a disproportionate increase in peripheral pre B‐cells has been reported in MS patients following natalizumab therapy (Krumbholz et al , ; Saraste et al , ). Hence, it remains possible that the effects of natalizumab in MS are at least partially mediated through actions on B‐cells.…”