AID also initiates the switch of the constant regions of the immunoglobulin heavy chain IgH , which defines the antibody isotype. The IGH locus contains multiple constant- region-encoding genes. Upstream of each constant region are switch regions, which contain multiple AID hotspot motifs.
Upon deamination of cytidines in these hotspots, two abasic sites on opposite DNA strands can occur in close proximity and result in double-strand breaks. The simultaneous induction of double-strand breaks in different switch regions can lead to DNA recombination. The intervening DNA is excised and the variable regions are coupled to the respective downstream heavy-chain constant region.
The different constant regions mediate distinct functions. As the first immunoglobulin expressed during B cell development, IgM displays low antigen affinity but is efficient in opsonizing coating antigens for destruction by multimeric interactions. IgG is the main antibody isotype found in serum, and has complement-activating and pathogen-neutralizing abilities. Secretory IgA is crucial at protecting mucosal surfaces by means of direct neutralization of toxins or pathogens, or by preventing their binding and tissue invasion.
The constant domain of IgE binds with high affinity to mast cells and neutrophils, and is associated with hypersensitivity and allergic reactions Viruses and intracellular bacteria are capable of infecting and persisting within cells, raising the possibility that B cells could be a reservoir for some pathogens.
Indeed, B cells are targeted during certain viral infections, a role that was first discovered through the study of B cell lymphomas. Furthermore, B cells can also provide an infection niche for intracellular bacteria.
B cells as viral reservoirs. Infection of B cells by viruses Table 1 has long been associated with the direct suppression of protective B cell responses, which is exemplified by both viruses responsible for persistent infections, such as cytomegalovirus, and viruses that cause acute infections, such as the measles virus 21 , 22 , However, the best-known virus targeting B cells is Epstein—Barr virus EBV , against which protective antibodies are efficiently generated.
Entry of EBV into B cells is mediated by the viral glycoprotein gp, which binds to CD21 on the B cell surface, and by gp42, which interacts with surface MHC II molecules, triggering endocytosis and subsequent fusion with the endocytic membrane. By contrast, EBV entry into epithelial cells is mediated by direct fusion with the cell membrane and is impeded by the viral gp42 protein Notably, the gp42 complexes are degraded in the B cell endoplasmic reticulum, resulting in the generation of viral particles that express low numbers of these molecules and are more infectious for epithelial cells EBV is thus able to modify its cellular tropism and potentially uses B cells to facilitate dissemination.
More importantly, EBV has been reported to transform infected B cells into long-lived resting memory B cells 26 , This mechanism occurs in parallel with the evolution of EBV into latency and presumably allows the virus to hide from antibody-mediated immune responses and immune surveillance, while persisting in the host.
Another virus that infects B cells is mouse mammary tumour retrovirus, which predominantly infects B cells in gut-associated lymphoid structures and can disseminate from these structures Dissemination is facilitated by the presentation of a viral superantigen to T cells, which results in nonspecific polyclonal T cell activation.
Superantigen-activated helper T cells activate infected B cells independently of cognate interaction, inducing B cell proliferation and leading to the establishment of a reservoir of infected lymphocytes in mouse infections 29 , 30 , Similarly, the polyoma JC virus infects human B cells in vitro and in vivo , and has been suggested to rely on these cells as a vehicle to disseminate to the brain, possibly by using B cells to cross the blood—brain barrier 32 , 33 , B cells as bacterial reservoirs.
Gram-negative Brucella spp. Similarly to viruses, these bacteria can infect B cells Table 1. Interestingly, some bacteria show a preference for particular B cell populations. For example, Brucella abortus preferentially targets marginal zone B cells in the mouse spleen B cells infected with B. Intriguingly, brucellosis is more rapidly cleared in B cell-deficient mice owing to a reduction in the levels of IL and an increase in protective T cell responses, suggesting that B.
Salmonella enterica subsp. Typhimurium might use the bone marrow as a long-term infection niche Following the in vitro infection of human blood lymphocytes with S. Typhimurium, bacteria are found inside IgM-producing memory B cells. Infection of these cells results in B cell activation and the induction of specific antibody production, but also leads to increased survival and intracellular persistence of bacteria in infected B cells Several mechanisms have been described for the internalization of bacteria by B cells.
For example, a role for phagocytosis of B. The BCR can also be involved in bacterial internalization by B cells.
By contrast, internalization of S. Typhimurium into B cells has been reported to involve interaction with an antigen-specific BCR Typhimurium pathogenicity island 1 and 2, respectively ; the number of intracellular bacteria found in B cells was substantially reduced when the bacterial T3SS was made non-functional Typhimurium forces its entry into B cells by triggering active invasion processes More recently, Shigella flexneri was also shown to invade human B cells in a process that is dependent on the T3SS but independent of B cell-mediated phagocytosis, as only bacteria carrying a functional T3SS were found inside B cells, both in vitro and in an ex vivo intestinal infection model Long-lived plasma cells and memory B cells normally constitute the B cell compartment and provide protection from reinfection.
However, some pathogens have been reported to deliberately induce short-lived, polyclonal plasma cells in order to dilute long-lived, specific antibody responses. The activity of the parasite-produced trans -sialidase is dependent on Bruton's tyrosine kinase BTK This results in lower affinity, lower neutralizing activity and lower complement-mediated toxicity of E2-specific antibodies 57 , Dashed arrows indicate normal pathways that are weakened or impaired during infection.
Taken together, these studies show that the entry of pathogenic bacteria into B cells is not only mediated by phagocytosis, but can also involve active invasion processes mediated by bacterial secretion systems. This process is similar to those used by certain viruses, such as EBV that target specific host cell populations through the expression of viral glycoproteins. Together, these data demonstrate that some pathogens have evolved mechanisms to force their entry into B cells, leading to the establishment of intracellular reservoirs.
Besides using B cells as a reservoir, some pathogens have evolved mechanisms to interfere with immune signalling and B cell differentiation to impair the maturation of B cells into protective memory B cells and plasma cells Table 1.
Diversion of B cell maturation by parasites. During infection, parasites can modulate B cell responses and stimulate the production of low-affinity antibodies, which, in some cases, has been associated with the dilution of specific, long-lived antibodies Fig. For example, Trypanosoma cruzi , the causative agent of Chagas disease, attacks B cells at different developmental stages, depleting immature B cells during their development in the bone marrow but also inducing polyclonal expansion of mature B cells in the spleen, which is thought to allow the parasite to avoid B cell-mediated responses and to persist in the host 42 , Indeed, nonspecific B cell activation can be triggered by a variant antigen of the Trypanosoma spp.
Additionally, certain cytosolic and secreted proteins, such as T. The exact mechanisms of B cell activation by parasitic T cell-independent antigens are often unknown, but the activation of B cells by the T. Interestingly, trans -sialidase also induces the secretion of the pro-inflammatory cytokine IL by B cells, in a process that involves the activation of BTK and SRC kinases in conjunction with the expression of CD45 by B cells B cell production of IL was shown to have an immunoregulatory role during T.
Therefore, trans -sialidase seems to have a dual role during infection by promoting both the production of non-protective antibodies and the induction of regulatory B cells.
Leishmania major also affects B cell differentiation, which results in the generation of immunosuppressive regulatory B cells. Furthermore, adoptive transfer of regulatory B cells induced following L. However, only a few studies have addressed how regulatory B cells are induced by direct contact with Leishmania spp. For example, antigens that induce IL production by mouse spleen B cells in vitro include soluble proteins, such as Leishmania infantum tryparedoxin, or sugars, such as lacto- N -fucopentaose III, which is found on soluble egg antigens of L.
However, the B cell signalling pathways involved in this process are unknown. A number of pathogens have been reported to induce the differentiation of regulatory B cells to suppress protective immune responses. IL has recently been shown to have a role in B cell regulatory function during S. Typhimurium infection Diversion of B cell maturation by viruses. The induction of B cell activation leading to polyclonal antibody responses that dilute the production of specific antibodies has also been reported as a strategy used by several viruses to skew protective immune responses Fig.
Whereas the early immune response to some viruses, such as influenza virus, mediates protection, antibodies generated in response to hepatitis C virus HCV infection fail to clear the virus in patients with persistent infections and lymphoproliferative disorders such as B cell lymphomas 55 , This was shown by incubating B cells with HCV E2 protein in vitro , but was also directly linked to the observation that B cells infected in vivo show higher expression of activation markers Additionally, E2 binding and subsequent viral infection of B cells induces the upregulation of AID and SHM of the immunoglobulin heavy chain in hybridoma cell lines that produce E2-specific antibodies, resulting in the production of antibodies with lower affinity, lower neutralizing capacity and lower complement-mediated toxicity, and this could explain why, in patients, serum HCV-specific antibodies fail to neutralize the virus Therefore, HCV is an intriguing example of how normal B cell maturation can be 'hijacked' by viruses to induce diluted antibody responses Fig.
HIV-1 infection is also associated with B cell dysregulation and exhaustion of the B cell compartment. This interaction, in conjunction with activation of B cell activating factor BAFF signalling, induces the production of polyclonal antibodies independently of T cell help Interestingly, Nef shuttles from infected macrophages to B cells by hijacking long-range intercellular conduits, such as nanotubules, which allows HIV-1 to inhibit CSR in lymphoid follicles in vivo Taken together, these studies highlight how direct interaction between HIV-1 and B cells induces a shift from the production of T cell-dependent specific antibodies to the production of nonspecific antibodies in a T cell-independent manner, thereby promoting viral immune escape Fig.
The induction of regulatory B cells also contributes to immune escape during viral infections, as reported for cytomegalovirus, hepatitis B virus and HIV-1 Refs 63 , 64 , 65 Table 1. However, mechanistic insight into the induction of regulatory B cells by these viruses is limited. Interestingly, following infection with polyoma virus, IL production by B cells is induced by virus-like particles in a TLR4-dependent manner, suggesting that this pathway might be involved in the generation of regulatory B cells 66 Fig.
Diversion of B cell maturation by bacteria. Similarly to parasites and viruses, bacteria also trigger polyclonal activation of B cells to impair protective immune responses mediated by the production of specific antibodies Fig. For example, mouse models of infection with Ehrlichia muris and Borrelia burgdorferi are characterized by T cell- and GC-independent expansions of non-switched, IgM-secreting plasma cells, which impairs the development of a protective antibody response 67 , Similarly, binding of the M.
TLR9 signalling is also involved in the proliferative and IgM-producing response of human polyclonal IgD memory B cells during Neisseria gonorrhoeae infection in vitro. Notably, this response is specific to N. In addition to the dilution of the specific antibody response, which results from polyclonal B cell activation, bacteria can produce virulence effectors that directly manipulate B cell signalling pathways.
Anthrax lethal toxin from the Gram-positive Bacillus anthracis directly binds to B cells by the anthrax protective antigen and is able to cleave mitogen-activated protein kinase kinases MAPKKs through the lethal factor protease, which results in the inhibition of B cell proliferation and immunoglobulin production, both in vitro and in vivo Similarly, several Gram-negative bacteria use T3SSs to deliver virulence effectors into the host cell cytoplasm and manipulate B cell functions.
For example, following infection with Yersinia pseudotuberculosis , primary B cells isolated from the spleens of hen egg lysozyme HEL -specific immunoglobulin-transgenic mice showed reduced activation upon stimulation with their cognate antigen Through the use of bacterial mutants, the authors showed that the impairment of B cell activation was T3SS-dependent and identified the tyrosine phosphatase YopH as the bacterial virulence effector responsible for this phenomenon.
Intracellular bacteria such as Chlamydia abortus , B. Typhimurium can also affect ongoing immune responses by favouring the generation of immunosuppressive regulatory B cells 8 , 15 , 16 Fig. Typhimurium infection, suggesting that these signalling pathways are directly activated by the bacterium, repressing protective innate immune responses 16 Fig.
Additionally, IL has recently been shown to contribute to B cell regulatory function during S. Collectively, these studies show that pathogens use two main strategies to divert B cell maturation and impair protective immune responses: the induction of short-lived plasma cells which secrete antibodies of low affinity, leading to the dilution of specific, long-lived antibody responses Fig.
In addition to living inside B cells and manipulating B cell maturation, pathogens can influence B cell responses by modulating the intricate balance of pathways that determines whether a B cell lives or dies Fig. Several pathogens have been reported to directly interfere with B cell survival and death pathways.
By contrast, translocation of the virulence factor CagA leads to extracellular signal-regulated kinase ERK and mitogen-activated protein kinase MAPK phosphorylation and induction of the anti-apoptotic protein B cell lymphoma 2 BCL-2 , thereby preventing B cell death 87 , Manipulation of B cell survival by parasites.
Both Trypanosoma brucei and T. In mice, T. Similarly to Trypanosoma spp. However, whether B cell death occurs owing to direct contact with Trypanosoma spp. Interestingly, T. These parasites also induce the dilution of antibody responses, and their effect on B cells seems to be dependent on the B cell subpopulation that is targeted. Therefore, Trypanosoma spp.
Manipulation of B cell survival by viruses. Viruses that cause the development of B cell lymphomas often have the capacity to directly increase B cell survival 59 , 78 , 79 Table 1.
Whereas EBV persists intracellularly in B cells, where it hides from antibody responses, HCV can induce non-protective antibody responses and lymphoproliferative disorders. These two viruses provide an intriguing example of how the induction of B cell survival can facilitate infectious processes. In contrast to viruses that induce B cell survival, influenza A virus leads to the induction of B cell death.
Mouse B cells carrying a BCR specific for influenza haemagglutinin were found to be infected in vitro and in vivo in the lungs, failed to produce antibodies and ultimately died These data suggest that targeting of antigen-specific B cells at the infectious site could be an efficient mechanism to impair or delay the adaptive immune response to infection.
Manipulation of B cell survival by bacteria. Similarly to viruses and parasites, bacterial pathogens can manipulate the survival and cell death pathways of B cells Table 1. For example, Listeria monocytogenes infection results in high cytotoxicity for B cells. Interestingly, L. Apoptosis of B cells in vitro has also been described following infection with Francisella tularensis Similarly to F.
Interestingly, induction of apoptosis in uninfected B cells requires a functional T3SS, but is independent of the translocation of T3SS-dependent virulence effectors.
Instead, the virulence effector IpaD — the needle-tip protein of the Shigella spp. The presence of an as yet unidentified bacterial co-signal or multiple co-signals is necessary for the triggering of IpaD-mediated cell death, as apoptotic B cells were only detected when cells were co-incubated with IpaD and non-pathogenic S.
Notably, the co-incubation with non-pathogenic bacteria results in the loss of both mitochondrial membrane potential and the upregulation of mRNA encoding TLR2.
Shigella spp. Helicobacter pylori infection has also been shown to lead to translocation of AIF and induction of apoptosis in a B cell line, which has been associated with the persistence of H. By contrast, translocation of the H.
Whereas the induction of apoptosis has been suggested to facilitate persistence by deletion of protective B cells, the increased survival of B cells has been associated with H. Whether one or both of these mechanisms occur in vivo in infections with H.
In contrast to bacteria that induce B cell death, S. Typhimurium induces B cell survival, which has been suggested to benefit the bacterium as it uses B cells as a survival and dissemination niche Notably, S. Typhimurium infection, which prevents activation of the inflammasome and the induction of cell death Interestingly, inhibition of the inflammasome occurs in both infected and uninfected cells and requires the S.
Together, these studies highlight that pathogens can interfere with both survival and cell death pathways in B cells. Interestingly, pathogens that use B cells as a niche for survival or dissemination or that divert B cell maturation often increase B cell survival, presumably to facilitate their persistence in the host. Acute, recurrent infections, however, are often accompanied by B cell death and impaired protective immune responses, suggesting that reinfection is facilitated by the deletion of the cell population that confers protective immunity.
Increasing evidence is emerging that several pathogenic parasites, viruses and bacteria interact directly with and manipulate B cells. Such direct targeting, in addition to the indirect effect of the infection-induced local microenvironment, illustrates the diversity of mechanisms used by pathogens to evade host protective immunity. Pathogens manipulate B cells using three main strategies: the use of B cells as a reservoir, the diversion of B cell maturation either by the induction of short-lived plasma cells that secrete antibodies of low specificity or by the induction of immunosuppressive regulatory B cells , and the modulation of B cell survival.
Interestingly, some pathogens use multiple mechanisms simultaneously to ensure their survival. For example, several viruses that cause persistent infections induce B cell survival, which can result in lymphoma formation.
Although it seems detrimental to the viruses to induce the survival of B cells, these viruses have often found ways to hide from or subvert the antibody response in order to persist within the host. By contrast, in the case of acute infections or host-restricted pathogens, pathogens have evolved mechanisms to facilitate reinfection. For instance, by inducing B cell death, S. Typhimurium suppresses immune responses by a different mechanism involving the induction of regulatory B cells, which modulate protective responses mediated by T cells and other innate immune cells 16 , Regulatory B cells have received increasing attention and are also induced in several viral and parasitic infections.
Although these cells show therapeutic potential in the treatment of autoimmune diseases, further insight into the mechanisms by which regulatory functions are triggered is needed to provide information on how to prevent their detrimental effects following infections. To elucidate cellular mechanisms of B cell manipulation by pathogens, a combination of in vitro and in vivo studies seems particularly promising.
For instance, a recent study using human and mouse norovirus strains elegantly shows that B cells provide a cellular target for the virus in vitro and in vivo , and that infection is promoted by enteric bacteria expressing histo-blood group antigen Notably, pathogens are often used as a simple tool for deciphering the generation of immune cell functions, but recent evidence highlights their ability to divert immune responses by expressing key virulence factors.
New approaches are thus needed to gain insights into the role of such weapons in infections. For instance, a fluorescence resonance energy transfer FRET -based assay to directly monitor the delivery of virulence effectors into host cells was recently used to investigate whether B cells are deliberate targets of T3SS-bearing bacteria in vitro and in vivo 91 , 92 , 93 , The identification of key virulence factors diverting host responses could also affect vaccine design, especially for live attenuated vaccine candidates, which involve the identification and deletion of virulence factors that have a negative effect on the host-protective immune responses.
For example, the S. The recent demonstration that IpaD induces B cell death, but only in the presence of bacterial cofactors 41 , suggests that IpaD-specific antibodies elicited upon immunization would not only prevent cell invasion but also the induction of B cell death triggered during infection. Therefore, an IpaD-based subunit vaccine seems particularly promising in the fight against S. Additionally, systems biology approaches targeted at detecting infection and vaccination signatures in people may help us to gain insights into how protective immune responses are established.
For example, systems analysis and bioinformatics integration of various 'omics' approaches, in combination with traditional experimental approaches, have contributed to a better characterization of the host immune response against West Nile virus infection To combine such an analysis with insights into manipulation strategies used by pathogens would substantially increase our knowledge of how protective B cell responses are elicited and diverted during particular infections, which may lead to novel therapeutic and vaccination approaches in the future.
Cooper, M. Delineation of the thymic and bursal lymphoid systems in the chicken. Nature , — Tonegawa, S. Somatic generation of antibody diversity. Plotkin, S. Vaccines: correlates of vaccine-induced immunity. PubMed Google Scholar. Ruprecht, C. Pone, E.
Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination: relevance to microbial antibody responses. Rawlings, D. Integration of B cell responses through Toll-like receptors and antigen receptors.
Nature Rev. CAS Google Scholar. Montes, C. Polyclonal B cell activation in infections: infectious agents' devilry or defense mechanism of the host? Leukocyte Biol. This review describes both positive and negative effects of polyclonal B cell activation on the protective immune response during infections.
B-cell-deficient mice show an exacerbated inflammatory response in a model of Chlamydophila abortus infection. Moseman, E. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. They are able to induce both pro- and anti-inflammatory T cells, controlled by the expression density of co-stimulatory molecules on myeloid APC and their distinct secretion of cytokines. Besides being equipped with molecules required for direct cell-cell contact, B cells provide a variety of cytokines for inter-cell signaling.
This is important as T cell activation does not only rely on the strength of co-stimulatory signals, but furthermore the cytokine milieu provided by the presenting cell Figure 1B. For instance, interleukin IL -6 secreted by B cells fosters the differentiation of Th17 cells, while it prevents the generation of regulatory T cells 14 , B cells isolated from the blood of MS patients though exhibit an abnormal pro-inflammatory cytokine profile when compared to healthy controls.
The observation that these abnormalities were apparent upon polyclonal stimulation suggests that not only autoreactive B cells but rather the B cell pool at large is deregulated in individuals with MS 11 , In the small MS cohort investigated, therapeutic removal of B cells including the latter memory B cell subpopulation resulted in a diminished pro-inflammatory IL-6 response by macrophages in a GM-CSF-dependent manner An observation that points toward an inflammation-promoting potential of B cells in MS.
However, a similar investigation aiming to assess the activation of myeloid APC in blood before and after therapeutic B cell removal in MS and NMO patients did not reveal such uniform results. This suggests that B cell depletion had a differential effect on the activation of myeloid cells in individual patients, with either pro-inflammatory, or anti-inflammatory outcomes Figure 1C.
Moreover, it indicates that in a subgroup of MS patients, B cells may exert immune regulatory functions prior to their therapeutic removal. In all of these studies, augmented EAE severity went along with an increased number of differentiated, pro-inflammatory Th1, and Th17 cells, suggesting that anti-inflammatory cytokines secreted by B cells were required to limit the pathogenic T cell response during EAE.
In humans, similar regulatory B cell properties have been described 24 and are assumed to be impaired in MS patients However, further research is required to validate this assumption and to ascertain whether regulatory B cells are equally relevant in MS as they are in EAE. If this proves true however, future therapies should aim to maintain or restore regulatory B cell functions, while targeting pro-inflammatory properties selectively; an issue that currently available therapies cannot address 25 , In this context, a promising approach may be the inhibition of Bruton's tyrosine kinase Btk , an enzyme that is present in B cells, and innate immune cells, such as myeloid APC, but not in T cells.
B cells require Btk for proper B cell receptor signaling, where it rather modulates the signal responsiveness, than turning it on or off Thus, its inhibition does not deplete B cells, but presumably lowers their response to B cell receptor stimuli In this way, Btk inhibition is assumed to foster the induction and maintenance of tolerogenic B cells, while it counteracts their antigen-mediated pro-inflammatory activation 29 — In mice with collagen-induced arthritis and in a murine lupus model, both autoimmune disorders with pathogenic B cells involvement, an orally applied Btk inhibitor reduced the amount of circulating autoantibodies and inhibited the development of disease 32 , showing its ability to limit a pathogenic B cell response.
Montalban X. Oct 12, ; These preliminary results suggest that a monotherapy aiming to inhibit Btk can be promising in MS. Moreover, Btk inhibition may be suitable as maintenance therapy after initial anti-CDmediated B cell depletion to avoid recurrence of pathogenic B cells. As mentioned before, the process of antigen presentation does not only activate the responding T cell but in turn induces the proliferation of the presenting B cell and its subsequent differentiation into memory cells and antibody-producing plasma cells.
Hence, the presence of persisting oligoclonal immunoglobulins Ig termed oligoclonal bands OCB in the cerebrospinal fluid CSF of most MS patients 33 — 35 can be construed as a first evidence of the pathogenic activation of B cells in MS.
In addition, intrathecal B cells show signs of somatic hypermutation and clonal expansion 37 , 38 pointing toward a germinal center-like reaction with antigen-driven affinity maturation within the CNS.
However, there is new evidence that these terminally differentiated B cells in the CSF were not solely a product of intrathecal maturation, but can cross the blood-brain barrier and interact with the peripheral immune system 39 — How this migration though influences the maturation of intrathecal B cells in detail and whether it affects the peripheral B cell response is not yet fully understood.
Up to now, the expression pattern of OCB in the CSF do not have an apparent correlate in the blood, indicating that despite the ability of B cells to exchange, antibody-secreting plasma cells mainly accumulate within the CNS of MS patients. However, the pathogenic relevance of these CNS-located B cells and their products for the pathogenesis of MS is still controversially discussed.
The presence of co-localizing Ig and complement depositions in ongoing MS lesions 43 suggests that autoantibodies are involved in CNS injury.
A assumption that has been further fueled by studies demonstrating that antibodies isolated from the CSF of MS patients induce axonal damage and complement-mediated demyelination when applied to human CNS tissue ex vivo or in vitro 44 , Nevertheless, the particular antigen s recognized by these antibodies are still unclear Reiber et al. Others however proposed autoantibodies against CNS structures, such as myelin, astrocytes, and neuroglial cells to be part of this intrathecal humoral immune response.
However, the variety of proposed antibody specificities and the fact that some of the aforementioned findings were not easily reproducible by other laboratories 52 — 54 possibly reflect the complexity of MS pathogenesis. Alternatively, it suggests that MS may consist of multiple disease entities with distinct disease driving mechanisms. AQP4 is a water channel found both in peripheral organs such as the kidney 57 as well as in the CNS There it is mainly expressed on the end feet of astrocytes 59 , 60 , most densely in the optic nerve and spinal cord where astrocytes and oligodendrocytes are in close proximity Hence, these are the regions where NMO lesions predominantly occur.
Since AQP4 is not expressed on oligodendrocytes themselves 58 , astrocytes are suggested to be the main target in NMO 62 , Corroborating this notion, active NMO lesions contain areas of co-localizing Ig and complement depositions with a vast loss of AQP4 and glial fibrillary acid protein immunoreactivity that points toward an antibody-mediated destruction of astrocytes.
Older lesions however show in addition a reduced number of oligodendrocytes and extensive demyelination of gray and white matter 56 , 64 , 65 indicating that demyelination occurs secondarily in later stages of the disease as a result of the preceding astrocyte loss. Hence, NMO is nowadays recognized as an autoimmune astrocytopathy 66 which is, at least in part, mediated by autoantibodies against AQP4.
Interestingly, anti-AQP4 antibody titer are relatively low or even absent in the CSF of NMO patients even when the corresponding antibody titer in the blood are high Despite these pending mechanistic issues, the diagnosis of NMO is nowadays closely tied to the presence of antibodies against AQP4. Instead, about a third of them produce antibodies against myelin oligodendrocyte glycoprotein MOG in the blood 70 — MOG is a transmembrane protein expressed on the outermost lamella of the myelin sheath and the surface of oligodendrocytes Its extracellular localization and its lack of expression in the thymus renders MOG a plausible target for autoimmune responses 74 , Patients with autoantibodies against MOG have a severe disease course with high relapse rates, strong brainstem, and spinal cord involvement and do hardly respond to several disease-modifying treatments It delineates them distinctly from MS patients, which show an accumulation of Ig in the CSF, but have no apparent reflection of these antibody patterns in the blood.
However, the pathogenic role of these autoantibodies outside the CNS is still elusive. In mice, it has been demonstrated that peripheral anti-MOG antibodies foster the activation of encephalitogenic T cells in the periphery by opsonization of otherwise unrecognized traces of CNS antigen, which results in the induction of EAE 82 , How these endogenous CNS antigens though reach the periphery is uncertain, but presumably by being drained from the CNS to peripheral lymph nodes along lymphatic vessels Even though it is not yet proven that this mechanism is of relevance for the human condition, it is conceivable as antibodies isolated from anti-MOG antibody positive patients were capable of opsonizing human MOG Furthermore, traces of myelin have been found in cervical lymph nodes of MS patients as well as healthy controls 85 , 86 indicating that also in humans, CNS structures can be made accessible to the peripheral immune system by this route.
Consequently, it includes the possibility that CNS antigens are recognized and opsonized by CNS-directed autoantibodies in the periphery. Overall, these findings suggest that anti-AQP4 antibody positive NMO as well as MOG antibody-associated disease is primarily driven by a pathogenic B cell activation in the periphery resulting in the generation of antibody-producing plasma cells, again in the first place in the periphery.
In contrast, in MS, B cells probably exert their pathogenic properties both in the periphery as well as within the chronically inflamed CNS itself, but most probably independent of CNS-specific peripheral antibodies. After activation, B cells migrate through blood or lymph vessels into peripheral lymphoid organs, where they undergo full activation and maturation.
Currently available immune-modulating MS therapies are very efficient in targeting these peripheral immune cells, but have only little or no access to the CNS-compartmentalized cells 87 , New concepts though suggest that two, probably independent, inflammatory processes drive CNS injury in MS, and potentially involve B cells: on the one hand, de novo infiltration of immune cells from the periphery into the CNS that correspond with focal inflammation, MRI-detectable lesions, and relapses.
On the other hand, chronic progression supposedly driven by CNS-intrinsic inflammation that is promoted by CNS-resident immune cells in conjunction with CNS-trapped leukocytes The first mechanism is premised on abnormally activated immune cells that migrate from lymphatic tissue, the location of their priming, across the blood-brain barrier into the CNS.
There, these leukocytes are assumed to reactivate and contribute to the injury of axons and glial cells 90 — 92 forming focal lesions. These lesions are typically located perivascular and contain T cells, monocytes, B, and plasma cells Since anti-CDmediated B cell depletion is highly efficient in preventing the formation of such focal CNS lesions, its assumed therapeutic efficiency is mainly based on the abrogation of the aforementioned cellular B cell properties in the periphery, and within the perivascular space Chronic progression in contrast is characterized by gradual expansion of consisting lesions with myelin-containing macrophages at the lesion border, gray, and white matter atrophy as well as diffuse aberrant inflammation of the normal-appearing white matter 95 , In progressive MS, this cortical demyelination has been further associated with B cell-rich structures in the meninges 97 , 98 as well as with plasma cell accumulation in experimental CNS inflammation These findings point toward a gradual shift of disease-driving B cell functions from the periphery to the CNS with disease progression.
Furthermore, they indicate that B cells may be involved—directly or indirectly—in cortical injury. An observation that is further corroborated by the findings of Lisak et al. In line with these results, it is not surprising that even though anti-CD20 is highly efficient in limiting the formation of new CNS lesions, it does not entirely stop chronic progression. This further strengthens the assumption that chronic CNS injury in MS is not primarily caused by de novo infiltrating immune cells, but by an established CNS-compartmentalized inflammation, which results in a CNS-autonomous immune response over time.
Current research indicates that in MS, B cells contribute to the formation of relapses as well as to the progression of the disease independent of de novo CNS infiltration. In contrast, in NMO and anti-MOG antibody-associated demyelination, a peripherally generated CNS-targeting antibody response is suggested to be the main disease driver. Accordingly, these delineating disease entities may require MS-independent therapeutic strategies, a concept that is currently evolving.
Thus, therapies targeting distinct aspects of NMO-relevant B cell functions such as plasma cell differentiation and complement fixation are currently under evaluation. First trials showed promising results for the treatment with tocilizumab, an therapeutic antibodies against IL-6 receptor , , and eculizumab, an complement component 5-specific antibody Besides these pathogenic B cell properties, B cells, or B cells subsets likely exert a therapeutically desirable regulatory function in either disease, limiting tissue inflammation as well as pro-inflammatory activation of other immune cells.
Accordingly, one of the prime challenges for the long-term targeting of B cells in MS and related demyelinating diseases will be to delineate and specifically target pathogenic B cell properties by novel strategic concepts, such as the selective depletion of differentiated B cells, interference with their activation or ablation of a disease-driving antibody response.
SH-K drafted the manuscript and prepared the figure. MW drafted, wrote, and finalized the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Kinzel S, Weber MS. B cell-directed therapeutics in multiple sclerosis: rationale and clinical evidence. CNS Drugs — During the course of an infection, B cells can further alter the specificity of the antibody they produce.
When a mature B cell meets an antigen that its B-cell receptor recognises the B-cell receptor comprises the antibody the cell produces anchored on the cell surface then the B cell can undergo a process called somatic hypermutation. Here an enzyme called activation-induced cytidine deaminase AID makes random mutations in the antibody variable region genes. If the mutations result in an antibody that more strongly binds to their targets then these B cells will survive and may differentiate into antibody-producing plasma cells with the new specificity.
Register Log in. Paul A. Figure 1. Schematic diagram of an antibody molecule composed of two heavy chains and two light chains.
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