Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis.

In multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity.

Cell type-specific Nrf2 expression in multiple sclerosis lesions.

Oxidative injury appears to play a major role in the propagation of demyelination and neurodegeneration in multiple sclerosis (MS). It has been suggested that endogenous anti-oxidant defense mechanisms within MS lesions are insufficient to prevent spreading of damage. Thus, current therapeutic approaches (e.g., fumarate treatment) target to up-regulate the expression of a key regulator of anti-oxidative defense, the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In this study, we show that Nrf2 is already strongly up-regulated in active MS lesions. Nuclear Nrf2 expression was particularly observed in oligodendrocytes and its functional activity is indicated by the expression of one of its downstream targets (heme oxygenase 1) in the same cells. In contrast, only a minor number of Nrf2-positive neurons were detected, even in highly inflammatory cortical lesions presenting with extensive oxidative injury. Overall, the most pronounced Nrf2 expression was found in degenerating cells, which showed signs of apoptotic or necrotic cell death. Via whole-genome microarray analyses of MS lesions, we observed a differential expression of numerous Nrf2-responsive genes, also involved in the defense against oxidative stress, predominantly in areas of initial myelin destruction within actively demyelinating white matter lesions. Furthermore, the expression patterns of Nrf2-induced genes differed between the white matter and cortical gray matter. Our study shows that in the MS brain, Nrf2 expression varies in different cell types and is associated with active demyelination in the lesions.

Full activation of CD4+ T cells early during sepsis requires specific antigen.

During sepsis, CD4 T cells express activation markers within the first 24 h. In the present study, the mechanisms of T-cell activation and its consequences were addressed in an acute peritonitis model in mice. The response of CD4+ T cells to sepsis induction was compared between OTII mice, characterized by ovalbumin-specific T-cell receptor-transgenic T cells, and C57BL/6 controls (wild type [WT] mice). Because ovalbumin was absent during peritonitis, the OTII CD4+ T cells could not be activated by canonical antigen recognition. In both OTII and WT control mice, CD4+ T effector cells and CD4+ Foxp3+ regulatory T cells (Tregs) expressed the activation marker CD69 early after sepsis onset. However, full activation with upregulation of CD25 and proliferation took place only in the presence of the antigen. Besides this, the fraction of Tregs was lower in OTII than that in WT mice. Sepsis mortality was increased in OTII mice. Our data show that, in sepsis, partial activation of CD4+ T cells is induced by a T-cell receptor-independent pathway, whereas full stimulation and proliferation require a specific antigen. Antigen-dependent T-cell effector functions as well as Treg activity may contribute to sepsis survival.

Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity.

Clinical trials revealed that systemic administration of B-cell-depleting anti-CD20 antibodies can hold lesion formation in the early relapsing-remitting phase of multiple sclerosis (MS). Throughout the secondary-progressive (SP) course of MS, pathogenic B cells may, however, progressively replicate within the central nervous system (CNS) itself, which is largely inaccessible to systemic anti-CD20 treatment. Utilizing the murine MS model of experimental autoimmune encephalomyelitis, we show that intrathecal (i.t.) administration of anti-CD20 alone very efficiently depletes meningeal B cells from established CNS lesions. In SP-MS patients, adding i.t. administration of anti-CD20 to its systemic use may be a valuable strategy to target pathogenic B-cell function.