There is growing recognition that B cell contributions to normal immune responses extend well beyond their potential to become antibody-producing cells, including roles at the innate–adaptive interface and their potential to modulate the responses of other immune cells such as T cells and myeloid cells. These B cell functions can have both pathogenic and protective effects in the context of central nervous system (CNS) inflammation. Here, we review recent advances in the field of multiple sclerosis (MS), which has traditionally been viewed as primarily a T cell–mediated disease, and we consider antibody-dependent and, particularly, emerging antibody-independent functions of B cells that may be relevant in both the peripheral and CNS disease compartments.
MS, one of the most common causes of neurological disability in young adults, is the prototypic acquired inflammatory demyelinating condition of the CNS, and it causes injury to both myelin and axons1,2. For most individuals with MS (approximately 85–90%), clinical onset is initially marked by relapsing and then remitting neurological deficits (which may appear to resolve fully or incompletely), a condition referred to as relapsing-remitting MS. The disease course often later exhibits ongoing worsening without obvious remission, a condition referred to as secondary progressive MS3. Approximately 10–15% of patients exhibit gradual worsening of neurological function from clinical onset (no remissions), a condition referred to as primary progressive MS (PPMS)3. The cause of MS, which remains unknown, is thought to reflect the consequences of several environmental exposures affecting a genetically susceptible host. Genome-wide association studies have implicated more than 200 genetic risk variants for MS4, many of which encode molecules involved in immune-system responses, thus lending support to the prevailing concept that MS is primarily an immunologically mediated disease. Current studies aim to elucidate how the environmental risk factors implicated in MS (e.g., low levels of vitamin D, infection with Epstein–Barr virus, smoking and early-life obesity) interact with susceptibility genes and how they contribute to early disease mechanisms in the context of both the immune system and the CNS as the target organ5. Considerable evidence from studies of both patients with MS and the most commonly used MS animal model, experimental autoimmune encephalomyelitis (EAE)6, has contributed to the common view of MS as a T cell–mediated disease7, involving an abnormal balance between regulatory T cells (Treg cells) and CNS-reactive effector T cells (Fig. 1a). Therapeutic efforts over the years have aimed to elucidate and correct or limit the presumed contributions of effector T cell responses and/or restore the balance between implicated effector and regulatory T cell responses8,9.
Evolving concepts and distinct disease compartments in MS
An updated conceptual framework of MS immunopathophysiology has emerged on the basis of the striking ability of anti-CD20 antibodies to limit new MS relapses10,11,12,13,14,15. This finding has shifted attention to potential contributions of B cells to CNS inflammatory disease activity, particularly the antibody-independent functions of B cells that have been implicated in mediating new relapsing MS disease activity as part of cascades of cellular immunological interactions in the periphery. Another important conceptual advance in the field of MS has been the recognition that inflammatory CNS injury in MS involves both systemic and CNS-compartmentalized inflammatory responses2,16,17,18. Systemic responses, which contribute to the classical relapsing–remitting aspects of disease, involve cascades of aberrant activation of immune cells in the periphery and their subsequent trafficking across CNS endothelial barriers into the CNS, where they are thought to reactivate and contribute to injury in a perivascular distribution. This relapsing aspect of MS has been reasonably modeled in EAE19. In contrast, CNS-compartmentalized inflammation in MS, which is less well understood (and not as well modeled to date), might play a key role in propagating the steady, unrelenting CNS injury underlying progressive forms of the disease16,18,20. Chronically activated microglia and infiltrating macrophages within the CNS tissue21,22,23, as well as B cell–rich aggregates of immune cells in the meninges surrounding the brain and spinal cord, are being actively studied as potential mediators of this CNS-compartmentalized inflammation16,18,20. Hence, with respect to the potential roles of B cell responses in MS, it is important to consider how B cells contribute to inflammatory disease processes both in the periphery and in the CNS in patients. Though we focus here on MS, the themes discussed have relevance across multiple immunologically mediated conditions including rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus (SLE), and researchers have also come to recognize the diversity of functional responses with which B cell populations might participate in disease modulation both outside and within the target organs involved. Further elucidation of the molecular mechanisms underlying the functional diversity of human B cells, their contribution to health and disease, and the potential to more selectively target them, are areas of active and shared interest across disease disciplines.
B cell tolerance and MS
Autoreactive B cells are present in the immunological repertoires of healthy individuals24,25,26. Their physiological roles as part of ‘normal autoimmunity’ remain incompletely understood, although they are normally maintained in a tolerant state. Two major checkpoints contribute to normal elimination and control of autoreactive B cells: central tolerance and peripheral tolerance27. Central B cell tolerance is established in the bone marrow and involves the elimination of approximately 75% of self-reactive B cells, whereas peripheral tolerance takes place in the secondary lymphoid organs, where most other self-reactive B cells are controlled. B cell receptor– and Toll-like receptor (TLR)-signaling pathways play important roles during the selection of B cells in the bone marrow, whereas the CD40–CD40L receptor–ligand pair, the major histocompatibility complex (MHC) and Treg cells28,29 are considered important for control of autoreactive B cells in the periphery27. Through analysis of self-reactive antibody profiles, deficiencies in both central and peripheral B cell tolerance have been documented in people with SLE, rheumatoid arthritis and type 1 diabetes30,31,32. In contrast, B cells from people with MS appear to display abnormalities only in peripheral tolerance29,32. In this regard, the tolerance abnormality observed in MS B cells may plausibly be a consequence of the dysfunction of Treg cells. In MS, both the frequency and the immunosuppressive function of Treg cells have been reported to be lower than those in healthy control individuals33,34. Questions remain as to whether and how peripheral tolerance of B cells can be restored in people with MS. Some individuals with MS who are undergoing selective B cell depletion experience durable quiescence of their MS disease activity even as their B cells (largely naive) reemerge, thus suggesting that a form of tolerance may have been achieved. In contrast, B cells reconstituting after less selective depletion with anti-CD52 therapy—which primarily targets T and B cells—in MS commonly manifest as a breach in tolerance and the development of secondary (typically antibody-mediated) autoimmune diseases35. Development of this form of secondary autoimmune disease might reflect earlier reconstitution of autoreactive B cells in the face of relatively delayed reconstitution of Treg cells, thereby resulting in a breach in peripheral tolerance.
B cells and antibody responses within the CNS in MS
Early studies implicating B cell antibody responses and CNS injury in MS have come from pathologic studies of perivascular MS lesions, which have identified antibodies bound to myelin fragments within phagocytic cells36,37. The presence of abnormally elevated immunoglobulin synthesis rates and a typical oligoclonal band (OCB) pattern of immunoglobulins in the cerebrospinal fluid (CSF) are hallmarks of MS and an indication that immunoglobulin is being abnormally produced within the CNS (referred to as intrathecal production). Immunoglobulin G (IgG) OCBs can be found in most patients with MS. Immunoglobulin M (IgM) OCBs are present in approximately 30–40% of patients38, and their presence has been associated with more active disease39 and potentially with therapeutic responses to B cell–directed therapy40. The findings suggesting intrathecal immunoglobulin production are supported by somatic hypermutation analysis of B cells and plasma cells, which has demonstrated a restricted number of expanded clones within the CNS in people with MS41,42,43,44. Such cells isolated from CSF from patients with MS have been found to generate the antibodies that make up their OCBs45. Serial CSF studies have suggested the persistence of the same clones within the CNS in individual patients over time46, and the same B cell and plasma cell clones can be shared among different CNS subcompartments (CSF, parenchyma and meninges) of the same patient47. More recent somatic hypermutation studies have demonstrated that, in individual patients, identical B cell clones can be shared between the CNS and the periphery48,49,50,51. These studies provide evidence of bidirectional trafficking of distinct B cell clones (both into and out of the CNS) and in fact suggest that much of the clonal expansion of these B cells occurs in the deep cervical lymph nodes rather than in the CNS. Indeed, the traditional view that the CNS is ‘immunologically privileged’ (including specialized endothelial cells of the blood–brain barrier restricting immune cell trafficking into the CNS) has evolved to recognize that normal immunological surveillance can involve ongoing low-level immune cell trafficking across additional and molecularly distinct barriers (blood–leptomeningeal and blood–choroidal interfaces), and that the CNS also has a system of lymphatic egress that appears to involve drainage into deep cervical lymph nodes52,53,54. Intriguingly, B cell contributions to MS relapses may possibly involve not only B cells residing in peripheral lymphoid tissues but also B cells that dynamically traffic into and out of the CNS, potentially present CNS antigens in deep cervical lymph nodes and trigger new waves of CNS-targeted inflammation. Relatively little is known about the molecular mechanisms involved in B cell trafficking both in and out of the CNS17,55,56,57. Levels of the B cell and/or plasma cell chemoattractants CXCL10, CXCL12 and CXCL13 are elevated in the CSF in people with MS57 and, among these, CXCL13 levels have been suggested to predict an optimal response to B cell–depletion therapy58. When and how B cells enter the CNS across distinct interfaces, how they migrate between the CNS subcompartments, what determines their egress from the CNS and the roles that they might play on both sides of the CNS barriers are topics of active investigation.
Although the same B cell and plasma cell clones tend to persist in the CNS of a given patient over time, they differ among patients43,46. Furthermore, and in spite of considerable efforts, defining specific CNS-reactive antibodies within the CSF that are shared across individuals with MS has been elusive59. Thorough examination of the immunoglobulin making up the CSF OCBs in MS has identified antibodies that primarily recognize ubiquitous intracellular self-proteins, thus suggesting that the OCBs might be generated as a response to dead-cell debris rather than being primary perpetrators of the injury60,61. Similarly, establishing pathogenic roles of circulating CNS-reactive antibodies in MS has been elusive. Early studies using solid-phase detection assays, such as enzyme-linked immunosorbent assays (which do not reliably detect antibodies to potentially more relevant conformational epitopes), have suggested that circulating antibodies against the myelin antigens myelin basic protein and myelin oligodendrocyte glycoprotein (MOG) might be involved in early MS disease mechanisms; however, these findings have not been confirmed in subsequent studies62. When measured in the appropriate assays, the presence of circulating anti-MOG in a subset of patients with CNS inflammatory demyelinating disease might actually identify patients who do not have MS63,64. Circulating antibodies specific to KIR4.1 (an ATP-sensitive inward rectifying potassium channel expressed primarily by glial cells) have been reported in approximately half of adults with MS65 as well as in children with CNS inflammatory demyelination66, though their presence does not appear to be associated with a particular clinical phenotype. Other studies have not reproduced the original results67,68, although there were several technical differences in the methods used, thus highlighting the challenge of using different techniques and the importance of direct assay comparisons69. The difficulty in establishing the disease relevance of circulating CNS-reactive antibodies in people with MS contrasts with the situation in other CNS inflammatory conditions in which specific CNS-reactive antibodies are strongly implicated in disease pathophysiology, including antibodies to aquaporin-4 in neuromyelitis optica spectrum disorders and to the N-methyl-d-aspartate receptor in autoimmune encephalitis.
Though the pathogenic role of immunoglobulin present in the CNS and the relevant antigenic specificities of B cells involved in MS remain unclear, CNS-compartmentalized B cells might contribute to the MS process independently of antibody production. In contrast to classical perivascular MS lesions, which typically contain few B cells and/or plasma cells, meningeal immune cell collections (meningeal inflammation) can be B cell or plasma cell predominant16,20. These ‘B cell–rich’ structures (occasionally recapitulating the features of ectopic lymphoid structures seen in other chronic inflammatory conditions70) can also contain T cells, follicular dendritic cells and stromal cells16,20. Autopsy findings of more substantial meningeal inflammation are associated with more aggressive MS course before death20 and more severe cortical pathology involving loss of oligodendrocytes and neurons as well as microglial activation18,20. This form of cortical injury, which appears to be unique to MS, develops in the most superficial part of the cortex subjacent to the meninges (referred to as ‘subpial’ cortical injury) and is now considered an important contributor to the pathology of progressive MS. Of interest is the possibility that meningeal inflammation, and particularly B cells, may contribute to propagation of the subpial cortical injury in MS. In this regard, soluble products of B cells isolated from people with MS but not controls) can be toxic to both oligodendrocytes and neurons in vitro71,72. This toxic effect persists even when immunoglobulin is removed from the B cell–soluble products, thus suggesting a potentially important antibody-independent function of B cells in the CNS inflammatory injury in MS. The observation that the same B cell clones are maintained over time within the CNS in people with MS suggests that these clones are fostered by factors in the local environment. These factors may include the B cell–survival factor BAFF, secreted by astrocytes17,73,74, as well as BAFF-independent mechanisms that might support not only B cell survival but also their activation and contribution to propagating CNS inflammation and injury75.
Antibody-independent functions of peripheral B cells in MS
The most compelling implication of the antibody-independent roles of B cells in MS has come from the robust and rapid decrease in new relapsing MS disease activity observed after B cell depletion with anti-CD20 (aCD20) therapy10,11,12,13,14,15,76. Plasmablasts and plasma cells (the actual antibody-secreting cells) express little or no CD20 and hence are not directly depleted by aCD20 therapy. Given the relatively long half-life of any antibodies already secreted, the rapid decrease in new disease activity after aCD20 therapy would seem unlikely to reflect removal of pathogenic antibodies. Indeed, direct assessment of the CSF in patients with MS before and after aCD20 treatment has revealed no major changes in the abnormal immunoglobulin levels, synthesis rates or OCB number and pattern77,78 at a time at which patients benefit from significantly less relapsing disease activity. Together, these observations suggest a key role of B cells in triggering new MS relapses and also indicate that such a role would probably reflect one or more antibody-independent functions of B cells, such as antigen presentation, T cell activation and/or cytokine production (Fig. 1b).
B cells as antigen-presenting cells and modulators of T cell responses in MS
Compared with professional antigen-presenting cells (APCs; for example, dendritic cells and tissue-resident macrophages), which specialize in linear epitope presentation, B cells can recognize three-dimensional ‘conformational’ epitopes79,80. They are more efficient at presenting protein antigens and appear to be the main source of APCs when antigen levels are low80,81. B cells are particularly effective APCs when they recognize the same antigen as T cells79,80,82. Such ‘cognate’ interactions appear to be important for both the activation of effector T cells and the generation of Treg cells83,84. The APC function of B cells has been highlighted in many disease contexts including infectious diseases and transplantation and autoimmune diseases82,85,86,87,88. In the context of CNS inflammatory disease, the potential APC function of B cells is supported by findings in EAE experiments in which B cell–specific MHC-II-knockout mice have been found to be resistant to recombinant MOG-induced disease82,89. Knocking out MHC-II on only B cells results in total abrogation of anti-MOG production in this highly B cell–dependent model of EAE, whereas injecting these mice with anti-MOG only partially recapitulates EAE severity. Together, these findings suggest an MHC-II-dependent but antibody-independent role of B cells in EAE. Crossing MOG B cell receptor–specific mice with MOG TCR–specific mice substantially increases the incidence of spontaneous EAE82, thus suggesting that enhancing cognate interactions between B cells and T cells can overcome CNS tolerance.
As part of APC–T cell interactions, the integration of co-stimulatory signals plays a key role in defining the T cell response. Of the more than 20 co-stimulatory molecule–receptor pairs identified to date90, CD80/86 and their T cell–activating binding partner CD28 are among the best characterized. In the resting state, a subset of human memory B cells express CD80 (ref. 91). Both CD80 and CD86 can be induced by various B cell–activating stimuli (both innate and adaptive) in vitro91,92. In vivo, selective knockout of CD80 and CD86 expression by B cells has been associated with decreases in both primary and secondary T cell responses93. Human B cells also stimulate T cells through both CD80 and CD86 (refs 91,94), and in MS, the frequency of circulating CD80+ B cells is abnormally elevated in patients with active disease95.
In addition to expressing co-stimulatory molecules, B cells express co-inhibitory molecules involved in downregulating the responses of effector T cells. For example, the ligand PD-L1, expressed by B cells, protects against EAE by downregulating T cell responses through its receptor, PD-1 (ref. 96). B cell expression of the ligand GITRL, another co-inhibitory molecule, directly induces Treg cell differentiation through its receptor, GITR97. In mice, memory B cells can be divided into two subsets, PD-L2+CD80+ and PD-L2–CD80– B cells, independently of their antibody isotype98. Double-positive B cells rapidly become antibody-secreting cells but cannot induce a germinal-center reaction, whereas double-negative B cells can induce a germinal-center reaction, but very few of them can become antibody-secreting cells98. These findings provide an initial basis for defining functionally distinct B cell subsets according to their different profiles of co-stimulatory- or co-inhibitory-molecule expression. Whether this annotation will prove useful in humans, and how different B cell subsets defined by co-stimulatory and co-inhibitory molecules might contribute to CNS inflammatory diseases including MS, remains to be explored.
Pro- and anti-inflammatory cytokine-defined B cells in MS
B cells are now recognized for their abilities to both enhance and downregulate local immune responses according to their distinct cytokine-secretion profiles, thereby affecting both health and disease88,99,100. Circulating B cells from untreated people with MS exhibit an abnormal balance between pro- and anti-inflammatory cytokine responses100,101,102,103,104,105,106,107. B cells (particularly memory B cells) from individuals with MS, compared with healthy control individuals, can be activated to produce abnormally high amounts of the cytokines TNF, LTα, IL-6 and GM-CSF101,102,103,105,106. B cell IL-6 is particularly involved in the generation of type 17 helper T cell (TH17) responses88 and is considered pathogenic in both MS and EAE104. Selectively knocking out IL-6 from B cells results in decreased TH17 responses and diminished EAE severity82,104. GM-CSF-producing B cells, described in both humans and mice88,106,108,109,110, are particularly proinflammatory and may be pathogenic. People with MS exhibit increased frequencies and responses of GM-CSF-expressing B cells, which belong to the memory B cell pool, coexpress particularly high levels of both TNF and IL-6 (but not the cytokine IL-10), and efficiently enhance myeloid cell proinflammatory responses in a GM-CSF-dependent manner106. Anti-CD20-mediated B cell depletion in people with MS results in decreased inflammatory responses of both T cells (in a manner that appears to be partly dependent on B cell TNF, LTα and IL-6)103,104 and myeloid cells (in a manner dependent on B cell GM-CSF)106. In addition to providing a plausible therapeutic mode of action of B cell depletion in MS, these observations highlight the antibody-independent contributions of cytokine-expressing proinflammatory B cells as well as the importance of B cell–myeloid cell–T cell interactions (Fig. 1) in the peripheral immunological cascades that contribute to new inflammatory-disease relapses100.
The B cell profile that reconstitutes after aCD20 therapy is biologically different from the profile of B cells in untreated individuals with MS102,104,106. In most patients, reconstituting B cells are CD27– (naive) and produce less proinflammatory cytokines (TNF, LT, IL-6 and GM-CSF) but higher levels of IL-10 (refs 102,103,104,106), which appear to be associated with a persistent decrease in both T cell and myeloid-lineage proinflammatory responses during the reconstitution phase103,104,106. Of interest is whether reconstituting naive B cells after aCD20 treatment not only might lose their proinflammatory propensity but also might be able to exert a regulatory function (discussed below), thereby limiting new relapses. This prospect of ‘durability’ of a treatment effect that might persist even after B cells reconstitute requires further examination in MS. Whether monitoring the return of naive versus memory B cells will be helpful in guiding retreatment decisions with aCD20 therapy in MS remains to be seen. In any event, the opportunity to compare the biological-response profiles of reconstituting B cells in individuals who do or do not develop new disease relapses during B cell reconstitution should provide important insights into the contributions of functionally distinct B cells to MS disease activity.
B cells can also downregulate immune responses through the secretion of anti-inflammatory cytokines (including IL-10, TGF-β and IL-35), thereby limiting different stages of CNS inflammation99. In mice, selectively knocking out IL-10 from B cells results in more severe EAE111, and adoptive transfer of in vitro–induced IL-10-producing B cells suppresses EAE in an IL-10-dependent manner112,113,114. Inducing EAE in IL-10-reporter mice has implicated draining lymph nodes (rather than the spleen or CNS) as the sites where IL-10+ B cells regulate disease-relevant immune responses115. CNS inflammation in EAE can also be regulated by IL-10-secreting B cells that are induced through alteration of the gut microbiome116. Different stimuli induce IL-10 production from B cells, including engagement of TLRs, CD40, microbiota and cytokines112,114,117. In humans, both naive and memory B cells are capable of producing IL-10 in a context-dependent manner101,118,119,120. Human CD27– (naive) B cells, but not CD27+ (memory) B cells, produce IL-10 after engagement with isolated CD40 (refs 102,103,105,107,121), a response that has been found to be abnormally deficient in B cells of people with MS102,107. In contrast, B10 cells, described as IL-10-expressing B cells that are induced within the CD27+ memory pool by stimulation through TLR4 and TLR9, suppress TNF production by monocytes through an IL-10-dependent mechanism119. Unexpectedly, B10 cells have been found to increase after ex vivo stimulation of B cells in several human autoimmune diseases including MS119. TGF-β1 production by B cells has been shown to limit the induction phase of CNS inflammation in EAE through downregulation of APC function and decreased responses of encephalitogenic TH1 and TH17 cells122. In turn, a role of anti-inflammatory IL-35-producing B cells has been suggested in the recovery phase of both EAE and experimental autoimmune uveitis123,124. In these contexts, IL-35-expressing B cells inhibit proinflammatory immune responses either directly through IL-35 (ref. 123) or indirectly through induction of IL-10-producing B cells124. Notably, although they are referred to as B cells, the anti-inflammatory IL-10+ and IL-35+ cells in several of the above studies have been found to exhibit plasma cell or plasmablast markers, thus highlighting previously unappreciated antibody-independent functions of antibody-secreting cells. Plasma cells may also support proinflammatory responses, such as those through secretion of TNF and inducible nitric oxide synthase, independently of antibody secretion125.
Mechanisms underlying B cell cytokine dysregulation
Given the ability of cytokine-expressing B cells to modulate immune responses, and the identification of abnormalities in these functions in MS and other disease conditions, elucidating the molecular mechanisms underlying human B cell cytokine regulation is of considerable interest. Prior work has shown that the transcription factors STAT5 and STAT6 reciprocally regulate human B cell expression of GM-CSF and IL-10 (ref. 106). Abnormally increased phosphorylation of STAT5 and STAT6 in the B cells of individuals with MS is associated with elevated production of GM-CSF and diminished production of IL-10, whereas dual STAT5–STAT6 signaling blockade during activation reverses the abnormal cytokine-response profile of MS B cells106. Epigenetic mechanisms such as histone modifications, DNA methylation and regulation by noncoding RNAs (microRNAs and long noncoding RNAs)126 may also contribute to the control and regulation of B cell responses and their potential roles in both disease initiation and propagation127. To date, most studies assessing epigenetic effects on B cells in disease have focused on their antibody-related functions, with implications of abnormalities in conditions such as SLE128. Several microRNAs have been found to be dysregulated in the B cells of patients with MS105,129. In particular, miR-132, which is overexpressed by MS B cells, has been found to enhance the secretion of TNF and LTα by targeting sirtuin-1 expression, whereas in vitro addition of the sirtuin-1 agonist resveratrol normalizes the exaggerated proinflammatory cytokine expression of MS B cells105. Future work will assess whether sirtuin-1 affects proinflammatory-cytokine programs of MS B cells through its effects on chromatin function, transcriptional repression through histone deacetylation and/or alterations in histone and DNA methylation. To date, defining master transcriptional regulators and unique surface markers of B cells with proinflammatory or anti-inflammatory potential has been elusive, thus possibly reflecting a greater capacity for functional plasticity. A better understanding of functionally distinct B cells and their roles in humans may facilitate the development of future therapies, including cell-based approaches, that either more selectively target or harness B cell responses for treatment of autoimmune diseases including MS.
Reassessing therapeutic targeting of B cells in MS
The aforementioned discoveries that B cells from untreated individuals with MS exhibit abnormal proinflammatory response profiles and can overactivate proinflammatory T cells and myeloid cells provide a plausible explanation for the therapeutic mode of action underlying the ability of aCD20 antibodies to robustly limit new MS relapses10,11,12,13,14,15,76. Such a view would suggest that selective depletion of B cells (including abnormally proinflammatory memory B cells) may remove their ability to contribute through antibody-independent mechanisms (for example, proinflammatory-cytokine-mediated activation and antigen presentation) to the peripheral cellular immunological cascades involved in triggering new relapses. Notably, a small subset of CD20+ T cells has been described in both the periphery and CNS in patients with MS. Although CD20+ T cells can express proinflammatory cytokines such as IL-17 and IFN-γ and can be effectively removed by anti-CD20 therapy, characterization of these T cells to date has not indicated a particular role in disease activity130. Further indirect support that the balance between proinflammatory- and anti-inflammatory-cytokine-producing B cells or plasma cells can contribute to the regulation of CNS inflammation has come from observations that CNS inflammatory disease activity is elevated (rather than diminished) in patients treated in clinical trials of Atacicept, a fusion protein of immunoglobulin and TACI, the receptor for the B cell–survival factors APRIL and BAFF131,132,133. The genetic variant of BAFF that leads to overexpression of this molecule has been implicated in both MS and SLE134. Unlike aCD20 therapy (which removes both naive and memory B cells but spares plasmablasts and plasma cells), Atacicept preferentially limits the survival of naive B cells and plasmablasts or plasma cells, but has a lesser effect on memory B cells135 (Table 1 and Fig. 2), thus reinforcing the view that memory B cells are the relevant disease-promoting subset. Notably, essentially all approved MS therapies (many designed to affect putatively disease-relevant T cell responses) also affect the response profiles of B cells in ways that might be relevant for their therapeutic effects (Table 1 and Fig. 2). For example, in patients with MS treated with fingolimod, a modulator of sphingosine 1 phosphate receptor, decreases have been observed in not only the total numbers of B cells in the circulation but also the proportion of memory B cells (whereas the proportions of regulatory and transitional B cells are increased), with a concomitant decrease in TNF expression and increase in IL-10 expression in circulating B cells136,137,138. Treatment with fingolimod also appears to enhance the migratory ability of regulatory B cells in an in vitro model of the blood–brain barrier138. Another example is dimethyl fumarate, the methyl ester of fumaric acid, which preferentially decreases the number of circulating memory B cells (but has a lesser effect on naive B cells and relative sparing of transitional B cells)139,140,141,142. In vitro, dimethyl fumarate preferentially limits B cell proinflammatory-cytokine expression through inhibition of the transcription factor NF-κB140,142.
In addition to the strong implication of peripheral B cells in the pathophysiology of MS relapses, their potential to contribute to the pathophysiology of progressive MS has been suggested on the basis of the results of the ORATORIO aCD20 study, the first successful clinical trial in patients with PPMS76. Interpretation of the ORATORIO findings, in which aCD20-treated patients with PPMS experienced a modestly less severe trajectory of worsening neurological function than did placebo-treated patients, is not straightforward. First, of note, patients with MS can worsen neurologically over time (i.e., exhibit ‘progression’ or worsening of disability) both because of repeated relapses that did not fully remit and because of nonrelapsing worsening3. The biological processes underlying these two contributors to the progression of disability are not identical; both processes may coexist, and much of the injury to which they contribute might be subclinical (i.e., damage occurs that is not clinically evident yet diminishes CNS reserves). The concept that relapse biology might exist subclinically in individuals meeting the clinical criteria for PPMS is supported by the observation that approximately 25% of these individuals (especially younger ones closer to disease onset) exhibited focal gadolinium-enhancing lesions in brain magnetic resonance imaging at the time of study entry76. These lesions represent active perivascular inflammation thought to reflect relapse biology. Hence, all the benefits observed in the ORATORIO PPMS study might reflect aCD20’s robust effect on relapse biology. An alternate (and not mutually exclusive) explanation is that CD20-expressing cells may contribute in a different way to nonrelapsing progressive disease. In particular, B cells accumulating as part of CNS-compartmentalized inflammation might contribute through direct toxicity to CNS cells as well as through propagation of inflammatory processes within the CNS71,72, as noted above. Whether anti-CD20 monoclonal antibodies including ocrelizumab meaningfully access the CNS, and whether the molecular machinery required for B cell killing (e.g., complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity) is present to enable B cell depletion within the CNS compartment even if aCD20 is present, is not clear.
The success of aCD20 in MS treatment has led to interest in generating other potential B cell–targeting therapies. The monoclonal antibody MEDI-551 targets CD19, which is expressed on a broader range of the B cell lineage than CD20, including plasmablasts and some plasma cells. Treatment with MEDI-551 in MS appears to be safe and has provided hints of efficacy in a recent phase 1 study143. The potential use of Bruton’s tyrosine kinase inhibitors, which inhibit B cell–receptor signaling, is being explored in MS on the basis of initial studies in other immunologically mediated conditions including SLE144. Such use of small molecules that can also access the CNS may prove beneficial through limiting both the peripheral B cell contribution to the immunological cascades involved in MS relapses and the potential contributions of B cells within the CNS to CNS-compartmentalized inflammation implicated in progressive MS biology.
The opposing outcomes of different B cell–targeting therapies in MS underscore the need to better understand how B cells contribute to both regulation of normal autoimmunity and to immunologically mediated diseases including MS. This knowledge gap is particularly important to fill as new approaches to target B cells and their subsets are increasingly being clinically applied. Elucidating the particular B cell populations that contribute to disease processes and developing reliable tools for monitoring them and/or their effects on other disease-relevant immune responses should provide key biomarkers to aid in the optimization of treatment choices and to improve clinical decision-making.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.