Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis

Abstract

Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial-dependent mechanisms. While unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell-depleting strategies.

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

“…48 We here reveal that human CXCR3(T-bet) + B cells are a product of T-and Bcell interaction. 35 The potential role of CXCR3(T-bet) + B cells as prime targets of this therapy is further supported by their abundant CD20 expression, as shown in the current study. 35 The potential role of CXCR3(T-bet) + B cells as prime targets of this therapy is further supported by their abundant CD20 expression, as shown in the current study.…”

“…Similar to SLE, such populations probably serve as potent antigen-presenting cells in CNS-specific autoimmune diseases such as MS. 31 Anti-CD20 therapy exerts immediate effects and is assumed to predominantly affect this function of B cells in MS patients. 35 The potential role of CXCR3(T-bet) + B cells as prime targets of this therapy is further supported by their abundant CD20 expression, as shown in the current study. The development of new targeted strategies to inhibit T-bet function have the potential to become a double-edged sword in MS by suppressing pathogenic, IFNγ-producing T (Th17.1) cells together with their counterpart CXCR3(T-bet) + B cells.…”

“…34,35 It has also been demonstrated that memory B cells of MS patients are the most potent antigen-presenting cells and likely have specific proinflammatory propensities, including the capacity to express enhanced levels of immune-activating molecules. 35 This is of special interest considering the presence of meningeal B-cell-rich follicle-like structures in MS and adjacent subpial cortical demyelinating injury, 8 which probably contributes to progressive loss of neurological function in patients with MS. Thus, identification of the particular B-cell subsets that can preferentially migrate into the CNS and clarification of how they may contribute to propagating local injury responses are of considerable interest in such an organ-specific disease.…”

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

“…Notably, when we looked at the biological functions that may be affected by the 741 MS-AIG, the CD40 signaling prevailed. CD40 is a main co-stimulatory pathway in B lymphocytes (the primary target of EBV infection), recently described as altered by MS risk variants (Smets et al, 2018), with possible consequences on the creation of memory B cells (Baker et al, 2018) and the activation of autoreactive CD4+ T lymphocytes (Jelcic et al, 2018;Baker et al, 2018). Our bioinformatics reworking on GWAS data disclosed an unanticipated relationship between CD40 and plasminogen activator gene in MS pathophysiology (La Starza et al 2019).…”

Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis

“…Decrease of B cell numbers during ATZ depletion in peripheral blood is more intense compared to lymphoid organs and bone marrow (32,33). Repopulation of immature and naïve B cells from precursor cells of bone marrow is thought to be responsible for the delayed overshot of B cell recovery after ATZ (2,14,34). Previous reports discussed prolonged altered phenotype and long-term shift to immature B cell subsets after ATZ that may contribute to efficacy in MS (2,14).…”