Abstract
BackgroundThe success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated.MethodsWe considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells.ResultsSecreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease.ConclusionsOur findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.
Highlights
The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses
Human astrocytes support B cell survival and increase their co-stimulatory molecule expression While human B cells cultured alone survived poorly, survival of B cells co-cultured with human astrocytes was significantly enhanced (Fig. 1a, representative donor; Fig. 1b, summary, n = 9), whether the astrocytes were previously cultured under basal conditions (p < 0.001, n = 9), or pre-activated with IFNγ and IL1β (p < 0.001, n = 9) as a proxy for astrocytes pre-activated by an inflammatory environment
While the enhancement of B cell survival mediated by exposure to astrocytes was similar whether the astrocytes had been pre-activated or not (Fig. 1b), B cells exposed to pre-activated astrocytes exhibited significant upregulation of the T cell costimulatory molecule CD86 (B7.2), as indicated by the percentage of B cells expressing CD86 (Fig. 1c; p < 0.001, n = 8) and their CD86 mean fluorescence intensity (MFI) (Fig. 1d; p < 0.001, n = 8)
Summary
The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Studies of immune mechanisms that contribute to multiple sclerosis (MS) pathophysiology have traditionally highlighted processes of aberrant peripheral immune-cell activation and their subsequent trafficking into the central nervous system (CNS). This paradigm, commonly studied in animal models such as experimental autoimmune encephalomyelitis (EAE), continues to provide a useful framework for understanding as well as therapeutically targeting peripheral immune responses that underlie MS relapses. A major unmet clinical need in MS is represented by a relentless, progressive (non-relapsing) disease course, eventually experienced by most patients The biology underlying such progression is less well understood but is thought to reflect, at least in part, ongoing inflammation that is compartmentalized within the CNS. An attractive hypothesis currently being pursued in the field is that progressive subpial cortical injury may reflect the consequences of one or more soluble factors secreted by immune cells fostered in the meninges
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