Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis

Abstract

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19 +, CD27 + memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

“…Disease-driving lymphocytes, including B-cells, are believed to migrate to the CSF and CNS from peripheral stores during phases of MS disease activity (8,11,12). Due to their immunological properties and functionality, SM B-cells are generally believed to be highly relevant to the immune pathology of MS (35). Indeed, when persistent PB SM cells were clonally related to second time-point CSF B-cells, these T2-CSF cells were nearly always SM and PC.…”

Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

“…We selected Cladribine for the following reasons: (1) class I evidence of efficacy of the active compound in people with relapsing MS10, 15, 22; (2) selective lymphocyte mechanism of action not requiring cell‐proliferation and notably B cell targeting potential that appears to be associated with effective control of active MS23, 24; (3) CNS penetration for peripheral and CNS immune cell inactivation and modulation16, 23; (4) safety comparable or better than similarly effective, current treatments12; (5) known relative safety in people with advanced MS15; (6) induction therapy potential requiring only short courses of treatment10 with rapid elimination from the body potentially allowing additional use of neuroprotection and symptomatic treatments without complications due to drug‐drug interactions23; and importantly, (7) convenience for the patient with easy and rapid administration during brief hospital visits to our day case unit, and few monitoring needs compared to some of the current DMT. This will limit travel requirements for someone restricted to a wheelchair.…”

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

“…Decreased frequency of B cells following treatment with DMF has been reported by several investigators (Chaves et al, ; Claes et al, ; Diebold et al, ; Fleischer et al, ). It has been shown that DMF preferentially targets the B memory cells, which are worthy targets for MS immunotherapy (Baker et al, ; Smith et al, ). Although DMF reduced the incidence of CD27 + IgD memory B cells it increased the incidence of CD27 ‐ IgD + naıve B cells (Smith et al, ).…”