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

Area of Science:

• Immunology
• Neuroimmunology
• Autoimmune Diseases

Background:

• Multiple sclerosis (MS) is traditionally viewed as a CD4, Th17-mediated autoimmune condition.
• Evidence supporting the T cell-mediated model is often circumstantial and questioned by treatment outcomes.
• The efficacy of CD4-depleting antibodies in relapsing MS has raised doubts about this paradigm.

Purpose of the Study:

• To investigate the impact of current multiple sclerosis (MS) treatments on B cell populations.
• To propose a unifying concept for MS pathogenesis and treatment centered on memory B cells.

Main Methods:

• Analysis of how various MS therapies, including beta-interferons, glatiramer acetate, and targeted biologics, affect B cell subsets.
• Observation of the effects of CD52 and CD20 depletion on MS disease activity and B cell populations.
• Assessment of the impact of B cell activating factor (atacicept) and tumor necrosis factor (infliximab) on MS.

Main Results:

• Current MS treatments, irrespective of their primary mechanism, significantly deplete CD19+, CD27+ memory B cells.
• CD52 and CD20 depletion led to substantial, long-term reduction in memory B cells and sustained MS inhibition.
• Augmentation of memory B cells by B cell activating factor and tumor necrosis factor blockade correlated with MS worsening.

Conclusions:

• Memory B cells, not T cells, may be central to multiple sclerosis (MS) pathogenesis.
• Therapeutic strategies targeting memory B cells offer a unifying approach consistent with clinical, pathological, and etiological findings in MS.
• This perspective reframes the understanding of MS and its treatment strategies.