Reviews

B cells in central nervous system

disease: diversity, locations
and pathophysiology
Rajiv W. Jain and V. Wee Yong ✉

Abstract | B cells represent a relatively minor cell population within both the healthy and diseased
central nervous system (CNS), yet they can have profound effects. This is emphasized in multiple
sclerosis, in which B cell-​depleting therapies are arguably the most efficacious treatment for the
condition. In this Review, we discuss how B cells enter and persist in the CNS and how, in many
neurological conditions, B cells concentrate within CNS barriers but are rarely found in the
parenchyma. We highlight how B cells can contribute to CNS pathology through antibody
secretion, antigen presentation and secretion of neurotoxic molecules, using examples from
CNS tumours, CNS infections and autoimmune conditions such as neuromyelitis optica and, in
particular, multiple sclerosis. Overall, understanding common and divergent principles of B cell
accumulation and their effects within the CNS could offer new insights into treating these
devastating neurological conditions.

B1 B cells
B cells were originally identified through studies search- discovery, the study of how B cells contribute to CNS
A subset of mature B cells with ing for the cellular source of antibodies, which led to the immunity and pathology independently of antibody
limited B cell receptor diversity discovery of antibody-​secreting plasma cells and, even- production and from a distance are a growing field
predominantly found within tually, their precursors, the B cells. Similarly, the study of study. There are still many unanswered questions
the peritoneal and pleural
cavities that typically
of B cells in the context of central nervous system (CNS) regarding whether B cells contribute to these disorders
differentiates directly into disorders has often started as a result of antibody detec- from within or outside the CNS, which B cell subsets
plasma cells, forming few tion in cerebrospinal fluid (CSF) or at sites of injury. The are responsible for promoting pathology and repair, and
memory cells. first indication that B cells could contribute to multiple what mechanisms B cells use to influence CNS pathol-
sclerosis (MS) was the detection of antibodies in CSF1. ogy. In this Review, we will focus specifically on the role
Follicular B cells
A subset of mature B cells,
The study of the antigenic targets of these antibodies of B cells within the CNS, covering their representation
also known as B2 B cells, that led to the discovery of the autoimmune diseases neuro­ and localization in health and CNS disorders. We review
represents the majority of myelitis optica (NMO) and myelin oligodendrocyte how B cells enter and persist in the CNS and what effec-
B cells in the body and are glycoprotein (MOG) antibody-​associated disorder and tor functions they use to promote pathology with a par-
commonly found within all
lymphoid organs.
their designations as separate entities from MS. Many ticular focus on MS as the vast amount of relevant data
other autoimmune encephalitides have been discovered, has come from the MS field. These discussions empha-
Marginal zone B cells such as anti N-​methyl-​d-aspartate receptor (NMDAR) size B cells as important regulators of CNS responses in
A subset of mature B cells with encephalitis, wherein antibodies target various neuronal both homeostasis and disease.
limited B cell receptor diversity
proteins and contribute to these disorders1. Antibodies
that is predominantly found
in the marginal zone of the
may also influence neurodegenerative processes in A refresher on B cells
spleen and which typically Parkinson disease and Alzheimer disease1 as well as For a thorough refresher on B cell immunology, we
differentiates directly into in CNS infections2. suggest reading the reviews cited here and in Fig. 1 as
plasma cells but can also The notion that B cells can contribute to CNS pathol- we will only cover basic B cell immunology. Mature
generate memory cells.
ogy independently of antibody production was first B cells are those that have completed development.
Hotchkiss Brain Institute and hinted at in MS, where the depletion of CD20+ B cells They are broadly separated into antigen-​experienced or
the Department of Clinical was shown to be an effective treatment3. This was an antigen-​inexperienced (naive) B cells. Naive B cells can
Neurosciences, University
of Calgary, Calgary,
unexpected result as B cells represent a minor popula- be further differentiated into B1 B cells, follicular B cells
Alberta, Canada. tion of immune cells in the CNS during MS and, as we (also known as B2 B cells) and marginal zone B cells. Naive
✉e-​mail: vyong@ucalgary.ca will discuss in this review, are not appreciably found in B cells are recruited to participate in immune responses
https://doi.org/10.1038/ the CNS parenchyma at sites of damage but are instead through B cell receptor (BCR) stimulation initiated by
s41577-021-00652-6 found behind barriers of entry into the CNS. Since this antigen binding in combination with co-​stimulatory

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Germinal centre B cells signalling or in combination with T cell help to induce description of how these barriers interact with immune
This subset of activated B cells a T cell-​dependent immune response 4 (Fig. 1) . The cells; for more in-​depth descriptions see refs6,7.
is an intermediate stage of products of T cell-​dependent immune responses are Post-​capillary venules in the CNS are surrounded
differentiation and is the differentiated B cell subsets such as memory B cells, by a thick extracellular matrix with barrier properties
precursor of higher-​affinity
T-​bet+ memory B cells and plasma cells. maintained by endothelial cells, pericytes, astrocytes,
memory B cells and
plasma cells. B cells contribute to immunity through antibody microglia and neurons; this barrier retains immune cells
production, antigen presentation and production of around the blood vessel in areas known as Virchow–
Memory B cells secreted products. When antibodies bind their tar- Robin spaces8. The meninges is separated into the
A subset of B cells that is
gets, they can initiate antibody-​dependent cellular dura mater that is in contact with the skull, arachnoid
antigen experienced and
has reacquired a quiescent
cytotoxicity, complement-​dependent cytotoxicity or mater and the innermost pia mater that overlies the
phenotype and can participate phagocytosis5. Antigen presentation is a process wherein parenchyma7. Blood vessels are present in the subarach-
in secondary immune B cells endocytose antigens, then process and load noid space of the meninges where immune cells can
responses, or sometimes them onto MHC class II molecules to present to CD4+ migrate across these blood vessels into the subarach-
refers to activated B cells that
retain an activated phenotype.
T cells. Antigen presentation by B cells is essential in noid space and CSF. Directly associated with the pia
maintaining germinal centres and to activate and polar- mater, astrocyte end-​feet maintain the glial limitans, a
T-​bet+ memory B cells ize CD4+ T cell responses. Another major mechanism barrier that prevents immune cell entry into the paren-
A subset of memory employed by B cells to affect immune responses is the chyma. During inflammation, immune cells may be able
B cells that expresses the
secretion of pro-​inflammatory and anti-​inflammatory to cross the pia mater to enter the CNS parenchyma7
transcription factor T-​bet
whose numbers tend to
cytokines. Regulatory B (B reg) cells generally pro- although this process is incompletely described. Immune
increase with age as well as duce anti-​inflammatory cytokines while antigen-​ cells entering the choroid plexus first extravasate across
in autoimmune disorders experienced B cells generally secrete pro-​inflammatory capillaries to enter the choroid plexus stroma; they then
and viral infections. cytokines3. cross the choroid plexus epithelial cell barrier to enter
Plasma cells
the CSF6.
Terminally differentiated B cells Where are B cells in the healthy CNS? In mice, B cells are rarely found in the healthy CNS
that produce large amounts of Before immune cells can enter the CNS parenchyma, parenchyma and are only found in small numbers in
antibodies and are short-​lived they must first pass through restrictive barriers of the CSF, the choroid plexus and the subdural meninges.
unless they find a survival
post-​capillary venules (blood–brain barrier (BBB)), However, B cells are constitutively present in the dural
niche allowing long-​term
maintenance.
meninges (blood–meningeal barrier) and choroid meninges and represent ~15–30% of the total CD45hi
plexus (blood–CSF barrier). Here, we provide a brief cells in this location9–11. The vast majority of B cells in

Lymph node Memory

B cell

Germinal centre Secondary germinal centre

Activated
Naive B cell Germinal
B cell
centre Follicular
MHC B cell dendritic
class II cell
TCR

T follicular
helper cell
Naive T cell
Dendritic
cell

T-bet+

Low-affinity Memory
memory B cell B cell

Germinal centre-independent differentiation

Antibodies
Differentiation along the germinal centre pathway
Low-affinity High-affinity Germinal centre-dependent differentiation
plasmablast plasmablast

Fig. 1 | T cell-dependent B cell differentiation. T cell-​dependent B cell B cells that re-​enter the B cell follicle with T follicular helper cells to seed a new
differentiation is initiated when B cells engage with their antigen through their germinal centre4. The germinal centre is composed of germinal centre B cells,
B cell receptor (BCR) and a cognate T cell response is activated (left side of T follicular helper cells and supportive cells, such as follicular dendritic
figure). Activated B cells and T cells then move to the border of the B cell follicle cells, that organize and maintain the germinal centre environment4. In the
and T cell zones by modifying their expression of chemokine receptors119 and germinal centre, T follicular helper cells induce somatic hypermutation
form cognate pairs through physical interactions. These interactions can induce in germinal centre B cells and direct them to differentiate into high-​affinity
B cell class-​switch recombination to change their initial IgD and IgM isotypes short-​lived and high-​affinity long-​lived plasma cells and into T-​bet– or T-​bet+
to IgG, IgA or IgE120. These interactions drive the differentiation of mostly IgM+ memory B cells4,12. Memory B cells can then later participate in an immune
low-​affinity memory B cells, low-​affinity plasmablasts, and pre-​germinal centre response if they are re-​exposed to antigen (secondary germinal centre).

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Regulatory B (Breg) cells

the dura meninges are B2 B cells and a large fraction of in CSF26 or have reported expansion27 of these popu-
This subset of B cells these are immature B cells generated in the skull’s bone lations in patients with neurological manifestations of
suppresses inflammation marrow10,11. Most mature CNS B cells are naive IgM+ COVID-19.
through the secretion of cells10 with unmutated BCRs although there are some CNS pathology induced by coronaviruses is not
anti-​inflammatory proteins or
IgA+ B cells11. Furthermore, B cells in the CNS are mainly unique to COVID-19, as many other coronaviruses,
through physical interactions.
tissue resident cells that were generated locally10,11. The including the original severe acute respiratory syn-
Plasmablasts capacity of peripheral B cells to take up residence in drome virus and Middle East respiratory syndrome28
The precursor to plasma cells the healthy CNS is limited in young mice but increases virus, drive pathology within the CNS. In mouse models
that has begun to produce
as mice age and this increase is primarily due to of CNS coronavirus infection, peripheral plasmablasts,
antibodies but also retains
some features of B cells, such
age-​associated B cells — whose phenotype overlaps with memory B cells and naive B cells29 are recruited into the
as surface B cell receptor and T-​bet+ B cells12 — accumulating in the brain10. In young CNS. Plasma cells enter the parenchyma, where they
MHC class II expression, animals IgA+ plasma cells dominate the meninges13 but, can contribute to localized antibody production that
and is still proliferating. as mice age, IgG+ and IgM+ plasma cells become more is associated with protection from infection30, whereas
common10. Of note, the population of IgA+ plasma cells naive B cells stay within the perivascular and menin-
found in the healthy CNS is partially derived from IgA+ geal compartments31. Thus, the mouse models of CNS
plasma cells that are generated in the gut13. coronavirus infection support a protective role of B cells
In humans, B cells and plasma cells are rarely found in entering the CNS.
the parenchyma of the healthy CNS although small num- Evidence of B cells playing a protective role from
bers are reported14,15. They are present in low numbers within the CNS is also seen in other CNS-​t rophic
in perivascular spaces14–16 and more frequently found in viral and bacterial infections. In these conditions,
the meninges16, particularly in the dura mater11,13. B cells virus-​specific or bacteria-​specific antibodies are pro-
can be detected in healthy CSF in humans; however, few duced within CSF and the parenchyma of infected CNS
plasma cells are found, corresponding with the low levels tissue where antibodies are presumed to contribute to
of antibody seen in CSF17,18. viral and/or bacterial clearance2,32,33.

B cells in neurological conditions Autoimmune diseases. B cells have a major role in con-
B cells can be recruited to the CNS as a result of CNS tributing to immune responses through their capacity to
infection13 and even due to sleep disruption19. Indeed, in secrete antibodies. However, the secretion of antibodies
many neurological conditions, increased levels of IgM, can be detrimental in certain circumstances as exempli-
IgA and IgG are seen in CSF17. Here, we review B cells in fied by the autoimmune CNS disorders NMO (which
the context of CNS cancers, infections of the CNS and is associated with anti-​aquaporin 4 antibodies), anti-​
autoimmune disorders affecting the CNS finally focusing NMDAR encephalitis (associated with anti-​NMDAR
on MS. The locations of B cells and plasma cells in these antibodies) and MOG antibody-​associated disorder1.
disorders are summarized in Supplementary Table 1. B cells and plasma cells within the CNS may also con-
tribute to neuropsychiatric forms of systemic lupus ery-
Cancers of the CNS. Glioblastoma is a deadly tumour thematosus based on studies in animal models34 and also
that arises within the CNS. The immune cell composi- on the finding that oligoclonal bands of immunoglobu-
tion of glioblastoma predominantly consists of microglia lin are detected in the CSF of 26.5% of patients with sys-
and macrophages, while B cells and T cells are present temic lupus erythematosus who have neuropsychiatric
in small numbers in these tumours. By flow cytometry, manifestations35.
0.66% of the immune cells found in glioblastoma are There is evidence of antibody production from clon-
B cells20. In meningiomas, which are tumours that form ally expanded plasma cells within the CSF of patients
in the meninges, B cell frequencies are highly variable with NMO or with anti-​N MDAR encephalitis 36,37.
but, on average, they represent 0.03% of all cells in the Nonetheless, only patients with anti-​NMDAR encephali-
tumour21. Cancers of the CNS also include those that tis show a concentration of pathogenic antibodies within
have metastasized from extra-​cranial locations. Patients the CNS and, in patients with MOG antibody-​associated
with B cell lymphomas can have metastasis to the CNS22, disorder and patients with NMO, most autoreactive anti-
which present as solid tumours of B cells retained bodies are produced peripherally1,36. Indeed, unlike in
within the meninges or perivascular spaces or as dif- patients with MS, where oligoclonal bands of immuno-
fuse tumours that spread through the parenchyma22. globulin are consistently detected in CSF, only 15–30% of
Whether B cells promote or suppress tumour growth patients with NMO have oligoclonal bands of immuno­
likely depends on the types of B cells in the tumour. globulin in CSF, suggesting that plasma cell expansion in
Glioblastoma promotes the conversion of B cells into the CSF of patients with NMO is not robust1.
Breg cells that sustains tumorigenicity23. However, in the
right inflammatory environment, B cells can elicit an B cells in MS
anti-​glioblastoma immune response24. MS is an inflammatory and degenerative disease of the
CNS where oligodendrocytes and neurons are lost in
CNS infections. Many patients infected with coronavirus white and grey matter leading to the accumulation of
disease 2019 (COVID-19) develop signs of neurological neurological deficits. The progression of MS is broadly
dysfunction with evidence of pathology ongoing in the separated into a relapsing–remitting MS (RRMS) phase,
CNS25. Single-​cell sequencing-​based studies have either in which neurological deficits manifest and recede,
found no evidence of B cell and plasma cell expansion and a phase of secondary progressive MS (SPMS; if

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Dura mater

Diffuse meningeal
inflammation

Grey matter

Sulci Leptomeninges CSF

Inactive lesion

Demyelination Follicle-like
Venule structure

Inactive core

Active rim
Active lesion

Mixed active–inactive lesion

White matter

Plasma Activated
T cell B cell Macrophages
cell microglia

progression follows RRMS) or primary progressive MS with meningeal inflammation, and white matter lesions.
(PPMS), wherein neurological disability accumulates The latter can be active lesions filled with immune cells,
with minimal periods of recovery. Monoclonal anti- mixed active–inactive lesions that have an actively demy-
bodies that deplete CD20+ B cells are highly effective in elinating rim associated with macrophage/microglia
treating the relapsing phase of MS and, in some patients, and a demyelinated immunologically inactive centre,
also the progressive forms of MS3. Although B cells can or inactive demyelinated lesions (Fig. 2). Active and
contribute to MS pathology from the periphery38, there mixed active–inactive lesions can be further subdivided
is considerable evidence that B cells enter CNS barrier into demyelinating and post-​demyelinating based on
regions to participate in CNS pathology. whether myelin proteins are present or absent within
macrophage/microglia, respectively. We encourage the
Locations of B cells in the CNS of patients with MS. reader to follow the recent consensus39 on the nomencla-
MS lesions can be broadly segregated into grey matter ture of MS lesions that addresses the ambiguities of old
lesions, where the cortical locations are often associated naming conventions present in older papers.

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◀ Fig. 2 | Locations of B cells in multiple sclerosis lesions. Depictions of lesions are subtypes is found in spinal cords of patients with MS
approximations of the average number of B cells relative to T cells and macrophage/ although B cell aggregates are less common than in the
microglia in the meninges and in grey and white matter lesions. B cell and plasma brain42. Generally, patients that have one B cell aggregate
cell populations are expanded in the cerebrospinal fluid (CSF) of patients with in their brain are more likely to have additional B cell
multiple sclerosis but only represent 0.5–11% and 0.25–12% of total immune cells,
aggregates throughout their CNS42,52.
respectively32,44,48,121. Grey matter lesions can be split into those that have diffuse B cell
infiltration or the formation of large collections of B cells in B cell aggregates in the
B cell invasion of the CNS in patients with MS or in
meningeal space that typically form at the bottom of sulci16,40–42,52. Relative to diffuse animal models of experimental autoimmune enceph-
B cells in the meningeal space, B cell aggregates are associated with increased infiltration alomyelitis (EAE) has been studied in sufficient detail
of macrophages, T cells and some plasma cells into the central nervous system parenchyma, to provide an overview of the specific B cell subsets
grey matter demyelination and proximal microglial activation41,42,52,54,55,58. In white matter encountered in the CNS (Supplementary Table 2).
lesions, B cells and plasma cells are commonly found in the perivascular spaces of post-​
capillary venules but are rarely found in the parenchyma15. Plasma cells are found in the Association of B cells with MS lesions. An important
same locations as B cells but are more likely to enter the parenchyma of the central question is whether the B cells in the CNS of patients
nervous system than B cells regardless of the lesion type14,15. with MS are contributing to disease directly or whether
they are simply bystanders attracted to the CNS by the
In patients with MS, B cells and plasma cells in the inflammatory environment. Suggesting an active role,
CNS are primarily found in the meninges and perivas- patients that have a CSF immune cell repertoire biased
cular locations but they are also present in the paren- towards B cells and plasma cells over other immune cell
chyma in small numbers40–42 (Fig. 2). There is preliminary types show faster disease progression53. When compar-
evidence of B cells entering the choroid plexus in MS43 ing cortical lesions that do or do not have B cell aggre-
but this requires confirmation. B cells and plasma cells gates in post-​mortem samples, individuals with B cell
are also expanded in the CSF from patients with MS rel- aggregates are more likely to have transitioned earlier to
ative to that from healthy humans44,45, especially during being wheelchair-​bound and to have died earlier in both
periods of active disease where class-​switched B cells PPMS and SPMS16,40,41,52,54. In a study of SPMS autopsies
and plasma cells clonally expand46. B cells are also 1–3 with or without B cell aggregates in the meninges, there
times more prevalent in the CSF of patients with RRMS is a strong correlation between the presence of B cell
relative to those with progressive MS47,48. aggregates and cortical demyelination54. When menin-
Based on post-​m ortem studies, meningeal and geal inflammation is not segregated by the presence
perivascular B cell aggregates are highly variable in MS, of B cell aggregates in patients with SPMS, there is an
where they can be nearly absent in the lesions of some inconsistent and weak correlation between the degree of
patients or dominate the lesions of others15. Meningeal meningeal immune cell infiltration and cortical demyeli-
and perivascular B cells are more numerous in RRMS and nation, suggesting that B cell aggregates are the primary
SPMS relative to PPMS, whereas plasma cells are more locations driving cortical demyelination41,52. Meningeal
prevalent in progressive over RRMS14,15. B cells are more B cell aggregates may also be associated with demyeli-
common in the parenchyma and perivascular spaces of nation in adjacent white matter42,49,55,56; however, this
active lesions relative to mixed active–inactive or inac- relationship has not been found in all studies52,54.
tive lesions whereas plasma cells are common in mixed B cell aggregates are also associated with pronounced
active–inactive or inactive lesions14,15,49,50. Both B cells local neuronal damage57. Biopsies taken from patients
and plasma cells are rare in normal-​appearing white during early MS or following clinically isolated syn-
matter14,49,50. drome (which is the first manifestation of a demyelinat-
Cortical lesions associated with meningeal inflam- ing event) suggest that meningeal inflammation, either
mation often have B cells that largely remain in the diffuse or concentrated in density in the meninges, is
meninges15. In one study using high resolution MRI associated with demyelination in the cortex but that
analysis of patients with MS, meningeal inflammation neuronal loss is only seen underneath dense aggregates
was found in ~33% of patients with progressive MS and in the meninges of subpial lesions57,58. Similar results
in ~19% of patients with RRMS51, although the specific have also been seen in post-​mortem studies comparing
percentages can vary between studies. Meningeal B cell patients with SPMS with or without B cell aggregates41,52
inflammation can be diffuse or extensive, the latter and this damage can even extend to the spinal cord42.
often associated with large ‘follicle-​like’ structures42. Neuronal loss typically occurs in a gradient from the
These structures are referred to as follicle-​like due to upper layers of the cortex and progresses inwards54
their resemblance to B cell follicles in secondary lym- and is associated with apoptotic markers in neurons58.
phoid organs, and they are characterized by separate Indeed, the presence of B cell aggregates in the meninges
zones of B cells and T cells and by large numbers of is associated with faster cortical thinning54. This gradient
associated plasma cells42,52 (Fig. 2). As the resemblance of damage emanating away from the meningeal B cell
of these structures to follicles remains controversial, aggregates suggests that B cells are secreting factors
we will refer to them as B cell aggregates. Based on that diffuse into the surrounding CNS parenchyma and
post-​mortem histology studies, the frequency of B cell either directly damage CNS cells or may indirectly injure
aggregates in SPMS is estimated to be ~40%16,40,52. Similar them by promoting inflammatory polarization of micro-
studies in PPMS found that ~30% of PPMS have B cell glia as iNOS+ TNF+ phagocytes are found in proximity
aggregates although these meningeal aggregates do not to B cell aggregates54. Nonetheless, while prominent
achieve the same levels of organization seen in SPMS41,52. meningeal inflammation is associated with the upregu-
A similar frequency of B cell aggregates between MS lation of inflammatory cytokines locally and within CSF,

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T helper 17 (TH17) cells

it is also associated with increased expression of IL-10 in structure but the overall process of moving from blood
A subset of CD4+ T cells both MS59 and EAE60. Thus, while B cell aggregates are into these locations proceeds similarly (Fig. 3). Below, we
characterized by the associated with worse pathology, some components may will outline the mechanisms B cells use to pass through
expression of the transcription also inhibit inflammation. these barriers. Of note, T helper 17 (TH17) cells play
factor RORγT and the
expression of IL-17A that is
B cell aggregates may also affect the recruitment of an important role in opening the BBB and creating an
commonly associated with other cell types into the parenchyma of the CNS. The environment for B cells to persist in the CNS, adding
immunity against extracellular parenchyma and small vessels in the cortex of areas another layer of complexity to CNS B cell recruitment
pathogens. associated with B cell aggregates are seen to have more and persistence beyond what is discussed here61.
CD8+ T cells, B cells, macrophages and plasma cells, par-
ticularly in the upper layers of the cortex16,54,55 (Fig. 2). Rolling stage of B cell recruitment. Mice with genetic
CD4+ T cells and macrophages also accumulate in the deletion of L-​selectin (also known as CD62L), used
meninges associated with B cell aggregates16,55. by B cells to enter lymph nodes, show no deficiency
Although the relevance of B cells in white matter of B cell infiltration into the CNS in the EAE model62.
inflammation is less well researched, one study found Indeed, B cells in the CNS of animals with EAE have
that the absence of B cells from white matter lesions low levels of L-​selectin expression63 and the ligands for
is associated with slower and less severe disease pro- L-​s electin are not well represented in EAE or MS
gression, reduced T cell infiltration into lesions, lesions64; this suggests that L-​selectin is not important
lower incidence of mixed active–inactive lesions, and for B cell recruitment into the CNS. One factor known to
reduced incidence and intensity of oligoclonal bands50. affect the rolling stage is the adhesion molecule ALCAM,
Furthermore, another study that separated white mat- which is upregulated on activated B cell subsets in MS65.
ter lesions by the presence or absence of IgM or IgG ALCAM-​deficient B cells roll at a faster rate on activated
deposits found that there is more B cell and plasma cell endothelial cells in vitro and ALCAM-​blocking antibod-
infiltration into white matter lesions when immuno­ ies reduce disease severity and B cell recruitment into
globulins are present, particularly for lesions containing the CNS in mice with EAE65. Nonetheless, deletion of
IgG deposits49. Indeed, IgG deposition in lesions is asso- this single molecule does not completely prevent rolling
ciated with increased B cell and plasma cell infiltration on the endothelium, suggesting that other molecules
into perivascular spaces, the parenchyma of the lesion, affect the rolling stage of B cell recruitment.
and increased B cell influx into the meninges near the
lesion. Thus, B cells and plasma cells in white matter Chemokines associated with B cell entry. Several chemo­
lesions contribute to MS pathology. kines associated with B cell migration have been studied
in MS and EAE, including CXC-​chemokine ligand 10
Recruitment and survival in the CNS (CXCL10), CXCL12, CXCL13, CC-​chemokine ligand 19
Much of what is known of B cell recruitment into (CCL19) and CCL21. Each of these is known to affect
the CNS comes from the MS literature. B cells can be specific B cell subsets and have different patterns of
recruited through the BBB, meningeal barriers and cho- expression in MS lesions (Supplementary Table 3).
roid plexus. Each of these sites differs with respect to Three other chemokines associated with B cell entry

Astrocyte

Perivascular
space

B cell Lumen
Tethering Diapedesis
Integrin
activation Endothelial cell

Rolling Chemokine signalling Adhesion and diapedesis

• ALCAM • CXCL13 • CCL19 • ALCAM
• PSGL1? • CXCL12 • CCL21 • VLA4
• CXCL10 • CCL2/CCL20/CXCL8? • LFA1?

Fig. 3 | Mechanisms of B cell recruitment into the CNS. Immune cells are recruited into the central nervous system (CNS)
by first rolling along the lumen of the blood vessel and being activated by locally produced cytokines. Activation of B cells,
including by chemokines found on endothelial cells, then induces conformational changes in integrins, allowing high
affinity interactions and firm tethering to the vessel; this enables cells to migrate across the endothelial cell layer into CNS
barriers such as the perivascular space6,7. Although this process is not fully understood in the context of B cell entry into
the CNS, several molecules shown in the boxes are known to affect their migration into the CNS at distinct stages whereas
other molecules remain contentious or inadequately studied. CXCL, CXC-​chemokine ligand; CCL, CC-​chemokine ligand.

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T follicular helper cells

into the CNS based on in vitro studies are CCL20, IL-8 that promote the survival of B cells77. Plasma cell survival
A subset of CD4 T cells
+ (also known as CXCL8) and CCL2 (refs66,67); however, is enhanced by fibronectin and hypoxic conditions75,
characterized by the expression in vivo evidence of a role for these chemokines is lacking which can be found in MS lesions.
of the transcriptional repressor in MS or EAE. Additionally, CC-​chemokine receptor 5 Another important factor that influences B cell
Bcl6 and the chemokine
(CCR5) is overexpressed on CSF B cells in MS46 but it and plasmablast survival in the CNS is their interac-
receptor CXCR5 allowing
these cells to co-​localize with is unknown whether this affects B cell migration into tion with T cells. Both activated B cells and plasma-
B cells and promote their the CNS. blasts are susceptible to cell death but can be rescued
differentiation through physical by CD4+ T cell help78. These interactions are likely to
interactions.
Integrins and cell adhesion molecules. B cells express sev- occur given that autoreactive T cell clones derived from
eral integrins and cell adhesion molecules that facilitate the CNS of patients with MS induce the proliferation
their entry into the CNS. ALCAM promotes B cell dia- of autoreactive B cells, suggesting that they form stable
pedesis across brain endothelial cells65. Other important interactions38. Furthermore, invasion of the CNS by
molecules are the integrin LFA1 and its cell adhesion T follicular helper cells in EAE is associated with B cell
molecule ligand ICAM1, both of which are upregulated population expansion in the CNS79. Thus, B cell–T cell
on activated B cells in MS65. Blocking ICAM1 reduces interactions are likely important in maintaining B cells
human B cell migration across brain endothelial cell in the CNS.
layers in culture65,66 but there is no in vivo evidence
supporting this. B cell recruitment and survival in other CNS diseases.
The best characterized molecule affecting B cell CXC-​chemokine receptor 3 (CXCR3) expression by
trafficking into the CNS is VLA4. This integrin is plasma cells is associated with plasma cell entry into
expressed highly on activated B cells in EAE and MS65,68 the CNS in NMO 80 and viral encephalomyelitis 30.
and is needed for B cells to cross brain endothelial cells Additionally, the CXCR3 ligands, CXCL10 and
in vitro65,66. In mouse models, deletion of VLA4 on CXCL9, are upregulated in the CNS during viral
B cells reduces B cell recruitment into the CNS69,70 and encephalomyelitis30. In B cell lymphoma and in the
leads to reduction of EAE severity in B cell-​dependent healthy CNS, CXCL12 is expressed highly on the blood
EAE70. Nonetheless, the effects of VLA4 blockade on vessel endothelium, resulting in B cell recruitment
EAE severity could be due to inhibition of peripheral into perivascular spaces81. However, CXCL12 also pro-
B cell activation69. Blocking VLA4 in patients with MS motes egress from perivascular spaces unless coun-
is known to affect memory B cell trafficking3 leading tered by astrocyte-​derived CCL19, which results in
to the concentration of memory B cells in blood corre- B cell accumulation in perivascular spaces and entrance
sponding with therapeutic benefit68. In contrast, treating to the parenchyma. Notably, the same study showed
patients with MS with anti-​VLA4 antibodies led to no that increased expression of VCAM1 and ICAM1 on
changes in B cell and plasma cell numbers in CSF, and the blood endothelium in itself is not sufficient for
biopsies of white matter lesions showed slight elevations B cell retention in the CNS. Many B cell lymphomas also
in plasma cell density71. Overall, the mouse data strongly express IL-15 that can induce the expression of CXCR3
supports the idea that VLA4 affects B cell recruitment and PSGL1, a selectin that can influence the rolling stage
into the CNS whereas the human data suggests that of recruitment, further promoting CNS recuitment82.
some but not all B cell types are affected. Despite high expression of the B cell survival factor
receptors BAFF-​R, BCMA and TACI by B cell lympho-
Antigen-​specificity in recruitment. Activated T cells, mas, there is no increase in BAFF expression in the CNS
regardless of their antigen specificity, are recruited to during CNS lymphoma relative to healthy CNS tissue83.
the CNS; however, only the T cells that encounter their By contrast, in a mouse model of CNS viral infection,
antigen in the CNS are retained at this site in large num- there is evidence of increased BAFF and APRIL expres-
bers over time72. In the context of inflammation, B cells sion within the CNS84. Thus, in combination with the
are recruited to the CNS in an antigen-​independent data from the MS literature, inflammation in the CNS
manner that does not appear to follow the same rules as is likely needed to induce increased expression of these
T cell recruitment72. Similarly, plasma cells specific for survival factors.
ovalbumin protein, rotavirus and non-​self-​antigens can
be recruited into the CNS during EAE73,74 and can even B cell functions in MS lesions
persist as long-​lived cells73. Thus, specificity for an anti- B cells as direct mediators of damage. Antibodies con-
gen within the CNS is not explicitly required for B cells tribute to the pathology of MS lesions and in animal
to take up residence in the CNS. models through several different mechanisms, includ-
ing opsonization, initiation of complement deposition,
B cell survival in the CNS. The primary factors that influ- facilitating B cell and T cell activation, and antibody-​
ence B cell survival are BAFF and APRIL, both of which dependent cellular cytotoxicity (Fig. 4). Of note, there is
are available in MS lesions (Supplementary Table 3). currently no consistently identified autoantigen target
Mature B cells are dependent on BAFF and, as they for antibodies in MS85 although antibodies are seen in
commit to plasma cell differentiation, they become MS lesions.
increasingly more dependent on APRIL75,76. In contrast, Some patients with MS have what are referred to as
memory B cells are much less dependent on survival ‘pattern II lesions’, which have antibody and comple-
factors relative to other B cell subsets76. Beyond BAFF ment deposits in white matter86, providing the potential
and APRIL, astrocytes make undefined survival factors of formation of a membrane attack complex that can be

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T helper 1 (TH1) cells

destructive (Fig. 4). Individual lesions within the same peripherally produced antibodies as therapeutic plasma
A subset of CD4+ T cells patient can differ, with some lesions having IgM or IgG exchange that removes circulating serum antibodies ben-
characterized by the deposits but not others87. Most active, mixed active– efits these subjects90. In favour of CNS-​produced anti-
expression of the transcription inactive and inactive lesions have either IgM or IgG bodies contributing to antibody deposition, antibodies
factor T-​bet and the expression
of IFNγ that is commonly
deposits, with IgG being more common87. Various anti- from the CSF of patients with RRMS or with progressive
associated with cellular body isotypes are detected in MS lesions and each has MS bind human cerebellum sections91. Similar results
immunity. typical deposition patterns. IgG and IgM are found in have been produced using cloned antibodies derived
lesions in proximity to demyelinated axons, degrad- from single B cells, plasma cells or antibodies from CSF92
ing myelin and myelin debris, dying cells, and within albeit not in all studies93,94. Thus, the question of whether
macrophages49,87,88. Both IgM and IgG have been asso- antibodies are pathogenic in MS is equivocal.
ciated with oligodendrocytes in lesions, normal appear- Another possibility that has been highlighted more
ing white matter, and in newly forming lesions87,88. IgA recently is that B cells may be contributing to MS in a
is reported in lesions typically bound to axons and non-​conventional manner: through the production of
vasculature89. However, it remains unclear whether the pathogenic microvesicles or exosomes. The evidence
pathology of these lesions is driven by CNS-​derived or for this comes from results showing that large secreted

Exosome secretion Antibody secretion Enhanced

Antibody- Enhanced
tagged antigen T cell entry
Exosome antigen presentation into the
parenchyma
Direct CNS damage

Toxic RNA? Myelin

Protein? phagocytosis
Plasma cell Membrane
Complement
deposition attack complex
formation
Neuron and
oligodendrocyte Enhanced B cell
death activation
B cell

B and T cell interactions Cytokine secretion

Macrophage activation
GM-CSF ↑ IL-6, IL-12
MHC
↑ ROS, TNF, IL-1β
class II
TCR
• Plasma cell
differentiation
IL-6
• TFH and TH17 cell
B cell differentiation
Indirect CNS damage

B cell T cell
Development of
LTα follicle-like structures
Peripheral • Reduced T cell
reactivation proliferation and
of T cells TGFβ,
inflammatory functions
IL-35
• Promote Treg cell
Plasma cell response
TH1/TH17 cell T cell reactivation Entry into
polarization in CNS barriers CNS barriers Promote Treg cell response
IL-10 and anti-inflammatory
macrophages

Entry into the TNF, Microglial cell activation

CNS parenchyma IFNγ and subsequent neuronal
damage

Fig. 4 | Direct and indirect mechanisms that B cells use to affect multiple upregulation (bottom left panel). However, B cells can also inhibit T cell
sclerosis pathology. B cells can directly damage the central nervous system responses through expression of PDL1 (not depicted). B cell-​derived secreted
(CNS) using secreted molecules, including exosomes that induce death in cytokines also affect CNS pathology (bottom right panel): GM-​CSF promotes
oligodendrocytes and neurons, through unknown mechanisms (top left panel). macrophage-​driven pathology102; IL-6 enhances plasma cell differentiation and
Antibodies directly contribute to multiple sclerosis pathology by facilitating survival, T follicular helper (TFH) cell differentiation, and TH17 polarization125,126.
T cell reactivation in CNS barriers, promoting their migration into the Lymphotoxin-​α (LTα) is important for organizing large clusters of B cells in the
parenchyma122, and by promoting the deposition of complement on myelin86 meninges and for the formation of ‘follicle-​like’ structures61. TNF and IFNγ are
to enhance myelin phagocytosis88,123, membrane attack complex formation on associated with microglial cell activation and neuron and oligodendrocyte
myelin86, and the enhanced activation of B cell immune responses124 (top right death105–107. TGFβ1 and IL-35 reduce T cell proliferation and inflammatory T cell
panel). B cells can indirectly affect CNS pathology by inducing the polarization and promote regulatory T (Treg) cell responses112,114. IL-10 affects
differentiation of autoreactive T helper 1 (TH1) cell and TH17 cell responses in T cells similarly111,117 but also alters macrophage polarization and may promote
the periphery and within the CNS, in part through CD80 and CD86 remyelination127. ROS, reactive oxygen species.

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particles from B cells induce death in cultured oligo- of inflammatory microglia that directly associate and
dendrocytes and neurons95,96, which was attributed to phagocytose pre-​synapse proteins108. Later, the micro-
secreted exosomes95 (Fig. 4). Currently, there is no obvi- glial numbers contract to the density of healthy controls
ous mechanism by which these exosomes are inducing and microglia lose some of their inflammatory polari-
cell death in their targets or evidence to show whether zation, become more ramified and are associated with
exosomes are produced by B cells in the CNS in vivo. increased neuronal loss. Similar observations were made
analysing cortical lesions of MS patients108. Of note,
B cells indirectly promote CNS damage. In patients with T-​bet+ memory B cells can produce IFNγ12 and, thus,
MS and in animals with EAE, it is likely that B cells in the B cells could be self-​sufficient in driving TNF-​mediated
CNS can promote injury indirectly by supporting T cell and IFNγ-​mediated CNS pathology.
responses through physical interactions15,38,42,63 given The damage dealt by pro-​inflammatory cytokines
the close association of T cells and B cells in perivas- may be balanced by regulatory cytokines produced by
cular and meningeal compartments (Fig. 4). In EAE, Breg cells though several mechanisms (Fig. 4). Regulatory
B cells in both the periphery and the CNS upregulate roles for B cells are exemplified in B cell-​deficient or
the co-​stimulatory molecule CD80, suggesting that B cell-​depleted mice that develop worse EAE than mice
they are primed for interaction with T cells63,97. Indeed, with full B cell repertoires109,110. The anti-​inflammatory
autoantigen-​driven B cell–T cell interactions influence cytokines IL-10 (refs74,110,111), TGFβ1 (refs112,113) and
the incidence and induction of relapses, timing of dis- IL-35 (ref.114) have all been found to be made by subsets
ease onset, and chronicity of EAE79,97–99. These inter- of Breg cells in either EAE or MS. Additionally, Breg cells
actions primarily influence TH1 cell and/or TH17 cell can also inhibit T cell responses through physical inter-
polarization of CD4+ T cells and induce waves of T cell actions using PD-​L1 (ref.115). Although Breg cells mod-
infiltration into the CNS from the periphery and within ulate EAE, it is not clear whether these cells act in the
the CNS79,97,98,100. periphery or within the CNS. In support of Breg cells
The above is consistent with a recent study showing working within the CNS, IL-10+ plasma cells are seen
that memory B cells induce autoreactive T cell expansion in active/mixed active–inactive MS lesions15 and IL-10
in patients with MS during remission periods, ultimately is inducible in some B cells from EAE spinal cords116.
activating these T cells to enter the brain and reactivat- Moreover, in one EAE study, ~30% of B cells in menin-
ing them again within the CNS38. Inflammatory mem- geal B cell aggregates express mRNA for either IL-10 or
ory B cell subsets that highly express the co-​stimulatory IL-35 (ref.60). In contrast, others have found that large
molecules CD80 and CD86 concentrate within the CSF numbers of IL-10-​producing plasmablasts are seen in
of patients with MS, suggesting that B cells in the CNS lymph nodes that drain the site of immunization in EAE
are primed to interact with T cells44,68,101. This is partially but IL-10-​expressing B-​lineage cells are not seen in the
explained by inflammatory astrocytes producing soluble CNS of EAE111,117. Furthermore, preventing B cells from
factors that promote the expression of CD86 on B cells77. accessing these lymph nodes abolished the capacity of
Overall, there is considerable evidence for a pathogenic Breg cells to suppress EAE117. One population that clearly
role for B cell and T cell interactions in MS and EAE. enters the CNS in MS and EAE are IL-10+ gut-​derived
Another emerging and important role for B cells IgA+ plasma cells that suppress EAE severity18,74. Thus,
in MS is their capacity to make pro-​inflammatory there is a clear role for regulatory B cells in MS but
cytokines that can modify the inflammatory envi- whether the primary site of inhibition is within the CNS
ronment to activate cells such as macrophages and/or or in the periphery remains unanswered.
microglia and T cells. There is evidence of peripheral
B cells expressing several inflammatory cytokines in MS, B cell functions in other CNS disorders
including GM-​CSF, TNF, IL-6 and lymphotoxin-​α102–104; The entry of B cell lymphomas into the CNS is some-
CSF B cells are known to make lymphotoxin-​α and times associated with local damage but, more often, it
TNF103,104 although data on GM-​CSF and IL-6 are not is not associated with any damage, suggesting that the
available. These cytokines can modulate CNS damage presence of B cells in the CNS, even in large numbers,
and the immune response through several mechanisms is not necessarily enough to induce pathology22. Even
summarized in Fig. 4. when B cell lymphomas are associated with damage, it
Of note, TNF is expressed highly in cortical lesions is likely that a prior insult to the CNS led to the upreg-
associated with IFNγ59, particularly in those with B cell ulation of chemokines that promote B cell recruitment
aggregates 105. Bulk RNA sequencing of meningeal rather than the B cells being directly pathogenic22,81.
B cell aggregate-​associated grey matter lesions sug- Thus, B cell entry into the CNS is insufficient to induce
gest that an imbalance of TNF-​mediated death signal- CNS pathology, suggesting that a trigger is needed to
ling occurs through increased expression of TNFR1 convert B cells to an injurious state.
(which induces cell death) over that of TNFR2 (which The most commonly studied mechanism for B cells
induces survival pathways)106. In EAE, forced expres- to induce CNS damage is through the production of
sion or injection in the subarachnoid space of TNF and autoantibodies. An example of this is seen in NMO,
IFNγ leads to enhanced EAE induction characterized where anti-​AQP4 antibodies induce astrocyte death
by a gradient of microglial cell activation and neu- and destruction of CNS barriers by removing astrocyte
ronal loss and associated with demyelination emanat- endfeet1. Antibody deposition leads to complement dep-
ing away from cortical lesions105,107 reminiscent of MS. osition, antibody-​dependent cellular cytotoxicity and
Temporally, TNF and IFNγ induce an initial expansion enhanced T cell immunity. In MOG antibody-​associated

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disorder, antibodies induce demyelination emanating in the CNS. Precisely which mechanisms B cells use to
away from blood vessels in affected tissues1. In lesions, mediate CNS outcomes also remain unclear. Answers
antibodies are associated with complement deposition, to these questions are needed to define which subsets of
complement-​dependent cytotoxicity, macrophages B cells should be targeted to overcome CNS pathology
containing myelin and T cells. In contrast to these more and which subsets confer benefits in the CNS.
inflammatory disorders, anti-​NMDAR encephalomyeli- In the context of MS, several mechanisms have been
tis is driven by IgG4 antibodies that are not associated suggested to explain how B cells contribute to MS.
with complement deposition or antibody-​dependent Here, we have highlighted that B cells interact with
cellular cytotoxicity but, instead, it is likely that these T cells to promote T cell pathology and that several
antibodies affect the crosslinking and internalization of types of secreted B cell products, including cytokines,
NMDAR1. Thus, inflammation is not always required for extracellular vesicles and antibodies, may all contrib-
B cells to be pathogenic. Autoantibody-​driven pathol- ute to MS pathology. What is not clear is the degree to
ogy is also seen in patients with COVID-19. While which these various mechanisms are active within the
virus-​specific antibodies and BCRs are detected among CNS versus the periphery and which subsets of B cells
plasma cells and B cells in CSF, many of these cells are primarily use these disease mechanisms to promote
also reactive against CNS antigens27. Thus, in addition pathology. It has also been noted that, while B cell infil-
to autoimmune diseases, viral infection can trigger tration into the CNS in MS is associated with CNS dam-
secondary autoimmunity in the CNS. age, this is not universally true of all CNS conditions22.
Currently, it is not clear if there is a specific trigger that
Gaps of knowledge and new directions converts B cells into pathogenic entities or whether
We have discussed the diversity of B cells found in the their diverse roles are simply due to the chronicity of
brain in both health and disease as well as where to conditions or other factors. It is also clear that the gut
locate them. It is clear that B cells are present in the CNS microbiome can regulate B cell functions in the CNS118
in many disorders and that they affect disease outcomes. but this is poorly defined. A better understanding of
However, there are still many gaps in our understanding how B cells differ in the various conditions discussed
of precisely how these B cells contribute to disease and herein would be of great benefit to understand the
where B cells and plasma cells are located in the CNS mechanisms that B cells use to promote neurodegener-
during these conditions. Even in MS, where B cells have ation or neuroprotection and could potentially unlock
been studied in detail, there are remaining uncertainties needed therapeutic targets.
regarding the localization of specific subsets of B cells in
CNS lesions or whether particular B cell subsets exist Published online 13 December 2021

1. Sabatino, J. J. Jr., Probstel, A. K. & Zamvil, S. S. 13. Fitzpatrick, Z. et al. Gut-​educated IgA plasma cells 23. Han, S. et al. Glioma cell-​derived placental growth
B cells in autoimmune and neurodegenerative central defend the meningeal venous sinuses. Nature 587, factor induces regulatory B cells. Int. J. Biochem.
nervous system diseases. Nat. Rev. Neurosci. 20, 472–476 (2020). Cell Biol. 57, 63–68 (2014).
728–745 (2019). This publication highlights how B and plasma cells 24. Lee-​Chang, C. et al. Activation of 4-1BBL+ B cells with
2. Gilden, D. H. Infectious causes of multiple sclerosis. accumulate in the dura mater in health and disease CD40 agonism and IFNgamma elicits potent immunity
Lancet Neurol. 4, 195–202 (2005). and identified the gut as a source of IgA plasma against glioblastoma. J. Exp. Med. 218, e20200913
3. Li, R., Patterson, K. R. & Bar-​Or, A. Reassessing B cell cells. (2021).
contributions in multiple sclerosis. Nat. Immunol. 19, 14. Frischer, J. M. et al. The relation between 25. Matschke, J. et al. Neuropathology of patients with
696–707 (2018). inflammation and neurodegeneration in multiple COVID-19 in Germany: a post-​mortem case series.
4. Akkaya, M., Kwak, K. & Pierce, S. K. B cell memory: sclerosis brains. Brain 132, 1175–1189 (2009). Lancet Neurol. 19, 919–929 (2020).
building two walls of protection against pathogens. 15. Machado-​Santos, J. et al. The compartmentalized 26. Heming, M. et al. Neurological manifestations
Nat. Rev. Immunol. 20, 229–238 (2020). inflammatory response in the multiple sclerosis brain of COVID-19 feature T cell exhaustion and
5. Kang, T. H. & Jung, S. T. Boosting therapeutic is composed of tissue-​resident CD8+ T lymphocytes dedifferentiated monocytes in cerebrospinal fluid.
potency of antibodies by taming Fc domain functions. and B cells. Brain 141, 2066–2082 (2018). Immunity 54, 164–175.e6 (2021).
Exp. Mol. Med. 51, 1–9 (2019). This paper has the most thorough quantification 27. Song, E. et al. Divergent and self-​reactive immune
6. Korn, T. & Kallies, A. T cell responses in the central of B and plasma cells in MS white matter lesions. responses in the CNS of COVID-19 patients with
nervous system. Nat. Rev. Immunol. 17, 179–194 16. Howell, O. W. et al. Meningeal inflammation is neurological symptoms. Cell Rep. Med. 2, 100288
(2017). widespread and linked to cortical pathology in (2021).
7. Rua, R. & McGavern, D. B. Advances in meningeal multiple sclerosis. Brain 134, 2755–2771 (2011). 28. Khateb, M., Bosak, N. & Muqary, M. Coronaviruses
immunity. Trends Mol. Med. 24, 542–559 17. Prasad, R. Immunoglobulin levels in serum and and central nervous system manifestations.
(2018). cerebrospinal fluid in certain viral infections of the Front. Neurol. 11, 715 (2020).
8. Agrawal, S. M. et al. Extracellular matrix central nervous system. J. Infect. Dis. 148, 607 29. Phares, T. W., DiSano, K. D., Stohlman, S. A.
metalloproteinase inducer shows active perivascular (1983). & Bergmann, C. C. Progression from IgD+ IgM+
cuffs in multiple sclerosis. Brain 136, 1760–1777 18. Probstel, A. K. et al. Gut microbiota-​specific IgA+ to isotype-​switched B cells is site specific during
(2013). B cells traffic to the CNS in active multiple sclerosis. coronavirus-​induced encephalomyelitis. J. Virol. 88,
9. Korin, B. et al. High-​dimensional, single-​cell Sci. Immunol. 5, eabc7191 (2020). 8853–8867 (2014).
characterization of the brain’s immune compartment. 19. Korin, B. et al. Short-​term sleep deprivation in mice 30. Tschen, S. I. et al. CNS viral infection diverts
Nat. Neurosci. 20, 1300–1309 (2017). induces B cell migration to the brain compartment. homing of antibody-​secreting cells from lymphoid
This is one of the few studies to precisely quantify Sleep 43, zsz222 (2020). organs to the CNS. Eur. J. Immunol. 36, 603–612
the number of immune cells in the healthy CNS 20. Kmiecik, J. et al. Elevated CD3+ and CD8+ tumor-​ (2006).
across the parenchyma, meninges and choroid infiltrating immune cells correlate with prolonged 31. DiSano, K. D., Stohlman, S. A. & Bergmann, C. C.
plexus. survival in glioblastoma patients despite integrated Activated GL7+ B cells are maintained within the
10. Brioschi, S. et al. Heterogeneity of meningeal B cells immunosuppressive mechanisms in the tumor inflamed CNS in the absence of follicle formation
reveals a lymphopoietic niche at the CNS borders. microenvironment and at the systemic level. during viral encephalomyelitis. Brain Behav. Immun.
Science 373, eabf9277 (2021). J. Neuroimmunol. 264, 71–83 (2013). 60, 71–83 (2017).
11. Schafflick, D. et al. Single-​cell profiling of CNS border 21. Domingues, P. H. et al. Immunophenotypic 32. Cepok, S. et al. Short-​lived plasma blasts are
compartment leukocytes reveals that B cells and identification and characterization of tumor cells the main B cell effector subset during the course
their progenitors reside in non-​diseased meninges. and infiltrating cell populations in meningiomas. of multiple sclerosis. Brain 128, 1667–1676
Nat. Neurosci. 24, 1225–1234 (2021). Am. J. Pathol. 181, 1749–1761 (2012). (2005).
12. Rubtsova, K., Rubtsov, A. V., Cancro, M. P. & 22. Kuhlmann, T., Lassmann, H. & Bruck, W. Diagnosis 33. Kowarik, M. C. et al. CXCL13 is the major
Marrack, P. Age-​associated B cells: a T-​bet-dependent of inflammatory demyelination in biopsy specimens: determinant for B cell recruitment to the CSF during
effector with roles in protective and pathogenic a practical approach. Acta Neuropathol. 115, neuroinflammation. J. Neuroinflammation 9, 93
immunity. J. Immunol. 195, 1933–1937 (2015). 275–287 (2008). (2012).

522 | August 2022 | volume 22 www.nature.com/nri

0123456789();:
 Reviews

34. Stock, A. D. et al. Tertiary lymphoid structures in the and reduced inflammation in cortical multiple sclerosis 79. Quinn, J. L., Kumar, G., Agasing, A., Ko, R. M. &
choroid plexus in neuropsychiatric lupus. JCI Insight 4, lesions. Ann. Neurol. 50, 389–400 (2001). Axtell, R. C. Role of TFH cells in promoting T helper
e124203 (2019). 59. Magliozzi, R. et al. Inflammatory intrathecal profiles 17-induced neuroinflammation. Front. Immunol. 9,
35. Mok, M. Y., Chan, E. Y., Wong, W. S. & Lau, C. S. and cortical damage in multiple sclerosis. Ann. Neurol. 382 (2018).
Intrathecal immunoglobulin production in 83, 739–755 (2018). 80. Chihara, N. et al. Plasmablasts as migratory IgG-​
patients with systemic lupus erythematosus with 60. Mitsdorffer, M. et al. Formation and producing cells in the pathogenesis of neuromyelitis
neuropsychiatric manifestations. Ann. Rheum. Dis. 66, immunomodulatory function of meningeal B-​cell optica. PLoS One 8, e83036 (2013).
846–847 (2007). aggregates in progressive CNS autoimmunity. Brain 81. O’Connor, T. et al. Age-​related gliosis promotes central
36. Kowarik, M. C. et al. The cerebrospinal fluid 144, 1697–1710 (2021). nervous system lymphoma through CCL19-mediated
immunoglobulin transcriptome and proteome in 61. Pikor, N. B. et al. Integration of Th17- and tumor cell retention. Cancer Cell 36, 250–267.e9
neuromyelitis optica reveals central nervous system-​ lymphotoxin-​derived signals initiates meningeal-​ (2019).
specific B cell populations. J. Neuroinflammation 12, resident stromal cell remodeling to propagate 82. Williams, M. T. et al. Interleukin-15 enhances cellular
19 (2015). neuroinflammation. Immunity 43, 1160–1173 (2015). proliferation and upregulates CNS homing molecules
37. Malviya, M. et al. NMDAR encephalitis: passive 62. Grewal, I. S. et al. CD62L is required on effector in pre-​B acute lymphoblastic leukemia. Blood 123,
transfer from man to mouse by a recombinant cells for local interactions in the CNS to cause myelin 3116–3127 (2014).
antibody. Ann. Clin. Transl. Neurol. 4, 768–783 (2017). damage in experimental allergic encephalomyelitis. 83. Krumbholz, M. et al. BAFF is produced by astrocytes
38. Jelcic, I. et al. Memory B cells activate brain-​homing, Immunity 14, 291–302 (2001). and up-​regulated in multiple sclerosis lesions and
autoreactive CD4+ T cells in multiple sclerosis. Cell 63. Dang, A. K., Tesfagiorgis, Y., Jain, R. W., Craig, H. C. primary central nervous system lymphoma. J. Exp.
175, 85–100.e23 (2018). & Kerfoot, S. M. Meningeal infiltration of the spinal Med. 201, 195–200 (2005).
In this study, memory B cells from MS patients cord by non-​classically activated B cells is associated 84. DiSano, K. D., Royce, D. B., Gilli, F. & Pachner, A. R.
are shown to induce CD4+ T cell proliferation and with chronic disease course in a spontaneous Central nervous system inflammatory aggregates
induce these cells to enter the CNS. B cell-​dependent model of CNS autoimmune disease. in the Theiler’s virus model of progressive multiple
39. Kuhlmann, T. et al. An updated histological Front. Immunol. 6, 470 (2015). sclerosis. Front. Immunol. 10, 1821 (2019).
classification system for multiple sclerosis lesions. 64. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. 85. Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H.
Acta Neuropathol. 133, 13–24 (2017). & Aloisi, F. Detection of ectopic B-​cell follicles with The search for the target antigens of multiple sclerosis,
40. Bell, L., Lenhart, A., Rosenwald, A., Monoranu, C. M. germinal centers in the meninges of patients part 2: CD8+ T cells, B cells, and antibodies in the
& Berberich-​Siebelt, F. Lymphoid aggregates in the with secondary progressive multiple sclerosis. focus of reverse-​translational research. Lancet Neurol.
CNS of progressive multiple sclerosis patients lack Brain Pathol. 14, 164–174 (2004). 15, 317–331 (2016).
regulatory T cells. Front. Immunol. 10, 3090 (2019). 65. Michel, L. et al. Activated leukocyte cell adhesion 86. Lucchinetti, C. et al. Heterogeneity of multiple
41. Choi, S. R. et al. Meningeal inflammation plays a role molecule regulates B lymphocyte migration across sclerosis lesions: implications for the pathogenesis
in the pathology of primary progressive multiple central nervous system barriers. Sci. Transl. Med. 11, of demyelination. Ann. Neurol. 47, 707–717 (2000).
sclerosis. Brain 135, 2925–2937 (2012). eaaw0475 (2019). 87. Sadaba, M. C. et al. Axonal and oligodendrocyte-​
42. Reali, C. et al. B cell rich meningeal inflammation Using a combination of mouse models and live localized IgM and IgG deposits in MS lesions.
associates with increased spinal cord pathology in imaging, this publication identifies ALCAM as an J. Neuroimmunol. 247, 86–94 (2012).
multiple sclerosis. Brain Pathol. 30, 779–793 (2020). important mediator of B cell recruitment into the 88. Genain, C. P., Cannella, B., Hauser, S. L. & Raine, C. S.
43. Monaco, S., Nicholas, R., Reynolds, R. & Magliozzi, R. CNS and quantifies other recruitment molecules Identification of autoantibodies associated with myelin
Intrathecal inflammation in progressive multiple on B cells. damage in multiple sclerosis. Nat. Med. 5, 170–175
sclerosis. Int. J. Mol. Sci. 21, 8217 (2020). 66. Alter, A. et al. Determinants of human B cell migration (1999).
44. Corcione, A. et al. Recapitulation of B cell across brain endothelial cells. J. Immunol. 170, 89. Zhang, Y. et al. Clonal expansion of IgA-​positive
differentiation in the central nervous system of 4497–4505 (2003). plasma cells and axon-​reactive antibodies in MS
patients with multiple sclerosis. Proc. Natl Acad. 67. Haas, J. et al. The choroid plexus is permissive for lesions. J. Neuroimmunol. 167, 120–130 (2005).
Sci. USA 101, 11064–11069 (2004). a preactivated antigen-​experienced memory B-​cell 90. Keegan, M. et al. Relation between humoral
45. Schafflick, D. et al. Integrated single cell analysis of subset in multiple sclerosis. Front. Immunol. 11, pathological changes in multiple sclerosis and
blood and cerebrospinal fluid leukocytes in multiple 618544 (2020). response to therapeutic plasma exchange. Lancet
sclerosis. Nat. Commun. 11, 247 (2020). 68. van Langelaar, J. et al. Induction of brain-​infiltrating 366, 579–582 (2005).
46. Ramesh, A. et al. A pathogenic and clonally expanded T-​bet-expressing B cells in multiple sclerosis. 91. Silber, E., Semra, Y. K., Gregson, N. A. & Sharief, M. K.
B cell transcriptome in active multiple sclerosis. Ann. Neurol. 86, 264–278 (2019). Patients with progressive multiple sclerosis have
Proc. Natl Acad. Sci. USA 117, 22932–22943 (2020). 69. Hussain, R. Z. et al. alpha4-integrin deficiency in elevated antibodies to neurofilament subunit.
47. Di Pauli, F. et al. Features of intrathecal B cells does not affect disease in a T-​cell-mediated EAE Neurology 58, 1372–1381 (2002).
immunoglobulins in patients with multiple sclerosis. disease model. Neurol. Neuroimmunol. Neuroinflamm. 92. Blauth, K. et al. Antibodies produced by clonally
J. Neurol. Sci. 288, 147–150 (2010). 6, e563 (2019). expanded plasma cells in multiple sclerosis
48. Eggers, E. L. et al. Clonal relationships of CSF B cells in 70. Lehmann-​Horn, K., Sagan, S. A., Bernard, C. C., cerebrospinal fluid cause demyelination of spinal
treatment-​naive multiple sclerosis patients. JCI Insight Sobel, R. A. & Zamvil, S. S. B-​cell very late antigen-4 cord explants. Acta Neuropathol. 130, 765–781
2, e92724 (2017). deficiency reduces leukocyte recruitment and (2015).
49. Munoz, U. et al. Main role of antibodies in susceptibility to central nervous system autoimmunity. 93. Brandle, S. M. et al. Distinct oligoclonal band
demyelination and axonal damage in multiple Ann. Neurol. 77, 902–908 (2015). antibodies in multiple sclerosis recognize ubiquitous
sclerosis. Cell Mol. Neurobiol. https://doi.org/10.1007/ 71. Hausler, D. et al. CNS inflammation after natalizumab self-​proteins. Proc. Natl Acad. Sci. USA 113,
s10571-021-01059-6 (2021). therapy for multiple sclerosis: A retrospective 7864–7869 (2016).
50. Fransen, N. L. et al. Absence of B cells in brainstem histopathological and CSF cohort study. Brain Pathol. 94. Willis, S. N. et al. Investigating the antigen specificity
and white matter lesions associates with less severe 31, e12969 (2021). of multiple sclerosis central nervous system-​derived
disease and absence of oligoclonal bands in MS. 72. Tesfagiorgis, Y., Zhu, S. L., Jain, R. & Kerfoot, S. M. immunoglobulins. Front. Immunol. 6, 600 (2015).
Neurol. Neuroimmunol. Neuroinflamm. 8, e955 Activated B cells participating in the anti-​myelin 95. Benjamins, J. A. et al. Exosome-​enriched fractions
(2021). response are excluded from the inflamed central from MS B cells induce oligodendrocyte death. Neurol.
51. Absinta, M. et al. Gadolinium-​based MRI nervous system in a model of autoimmunity that Neuroimmunol. Neuroinflamm. 6, e550 (2019).
characterization of leptomeningeal inflammation allows for B cell recognition of autoantigen. This paper identified that exosomes produced from
in multiple sclerosis. Neurology 85, 18–28 (2015). J. Immunol. 199, 449–457 (2017). B cells can be toxic to oligodendrocytes, opening
52. Magliozzi, R. et al. Meningeal B-​cell follicles in 73. Pollok, K. et al. The chronically inflamed central an entire new field of study.
secondary progressive multiple sclerosis associate nervous system provides niches for long-​lived plasma 96. Lisak, R. P. et al. B cells from patients with multiple
with early onset of disease and severe cortical cells. Acta Neuropathol. Commun. 5, 88 (2017). sclerosis induce cell death via apoptosis in neurons
pathology. Brain 130, 1089–1104 (2007). 74. Rojas, O. L. et al. Recirculating Intestinal IgA-​ in vitro. J. Neuroimmunol. 309, 88–99 (2017).
53. Cepok, S. et al. Patterns of cerebrospinal fluid producing cells regulate neuroinflammation via IL-10. 97. Bettelli, E., Baeten, D., Jager, A., Sobel, R. A. &
pathology correlate with disease progression in Cell 176, 610–624.e18 (2019). Kuchroo, V. K. Myelin oligodendrocyte glycoprotein-​
multiple sclerosis. Brain 124, 2169–2176 (2001). This study identified that IgA+ plasma specific T and B cells cooperate to induce a Devic-​like
54. Magliozzi, R. et al. A Gradient of neuronal loss cells from the gut move into the CNS during disease in mice. J. Clin. Invest. 116, 2393–2402
and meningeal inflammation in multiple sclerosis. neuroinflammation and suppress EAE using IL-10. (2006).
Ann. Neurol. 68, 477–493 (2010). 75. Nguyen, D. C. et al. Factors of the bone marrow 98. Kuerten, S. et al. Tertiary lymphoid organ development
This publication provides strong evidence microniche that support human plasma cell survival coincides with determinant spreading of the myelin-​
that follicle-​like structures in the meninges are and immunoglobulin secretion. Nat. Commun. 9, specific T cell response. Acta Neuropathol. 124,
associated with severe cortical pathology not 3698 (2018). 861–873 (2012).
seen in other types of MS lesions. 76. Baker, D., Pryce, G., James, L. K., Schmierer, K. 99. Parker Harp, C. R. et al. B cells are capable
55. Howell, O. W. et al. Extensive grey matter pathology & Giovannoni, G. Failed B cell survival factor trials of independently eliciting rapid reactivation of
in the cerebellum in multiple sclerosis is linked to support the importance of memory B cells in multiple encephalitogenic CD4 T cells in a murine model of
inflammation in the subarachnoid space. Neuropathol. sclerosis. Eur. J. Neurol. 27, 221–228 (2020). multiple sclerosis. PLoS One 13, e0199694 (2018).
Appl. Neurobiol. 41, 798–813 (2015). 77. Touil, H. et al. Human central nervous system 100. Pierson, E. R., Stromnes, I. M. & Goverman, J. M.
56. Lovato, L. et al. Related B cell clones populate the astrocytes support survival and activation B cells promote induction of experimental autoimmune
meninges and parenchyma of patients with multiple of B cells: implications for MS pathogenesis. encephalomyelitis by facilitating reactivation of T cells
sclerosis. Brain 134, 534–541 (2011). J. Neuroinflammation 15, 114 (2018). in the central nervous system. J. Immunol. 192,
57. Lucchinetti, C. F. et al. Inflammatory cortical 78. Chan, T. D. et al. Antigen affinity controls rapid 929–939 (2014).
demyelination in early multiple sclerosis. N. Engl. T-​dependent antibody production by driving the 101. Claes, N. et al. Age-​associated B cells with
J. Med. 365, 2188–2197 (2011). expansion rather than the differentiation or proinflammatory characteristics are expanded in a
58. Peterson, J. W., Bo, L., Mork, S., Chang, A. & extrafollicular migration of early plasmablasts. proportion of multiple sclerosis patients. J. Immunol.
Trapp, B. D. Transected neurites, apoptotic neurons, J. Immunol. 183, 3139–3149 (2009). 197, 4576–4583 (2016).

NAture Reviews | IMMuNoLogy volume 22 | August 2022 | 523

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Reviews

102. Li, R. et al. Proinflammatory GM-​CSF-producing 112. Bjarnadottir, K. et al. B cell-​derived transforming exacerbated experimental autoimmune
B cells in multiple sclerosis and B cell depletion growth factor-​beta1 expression limits the induction encephalomyelitis. J. Immunol. 178, 3323–3331
therapy. Sci. Transl. Med. 7, 310ra166 (2015). phase of autoimmune neuroinflammation. Sci. Rep. 6, (2007).
In this study, GM-​CSF-producing B cells are 34594 (2016). 125. Molnarfi, N. et al. MHC class II-​dependent B cell APC
shown to induce inflammatory polarization 113. Piancone, F. et al. B lymphocytes in multiple sclerosis: function is required for induction of CNS autoimmunity
of macrophages, creating a link between B cell Bregs and BTLA/CD272 expressing-​CD19+ lymphocytes independent of myelin-​specific antibodies. J. Exp.
and macrophage biology in MS. modulate disease severity. Sci. Rep. 6, 29699 (2016). Med. 210, 2921–2937 (2013).
103. McWilliam, O., Sellebjerg, F., Marquart, H. V. & 114. Shen, P. et al. IL-35-producing B cells are critical 126. Murakami, M., Kamimura, D. & Hirano, T. Pleiotropy
von Essen, M. R. B cells from patients with multiple regulators of immunity during autoimmune and and specificity: insights from the interleukin 6 family
sclerosis have a pathogenic phenotype and increased infectious diseases. Nature 507, 366–370 (2014). of cytokines. Immunity 50, 812–831 (2019).
LTα and TGFβ1 response. J. Neuroimmunol. 324, 115. Khan, A. R. et al. PD-​L1hi B cells are critical regulators 127. Pennati, A., Nylen, E. A., Duncan, I. D. & Galipeau, J.
157–164 (2018). of humoral immunity. Nat. Commun. 6, 5997 (2015). Regulatory B cells normalize CNS myeloid cell content
104. Stein, J. et al. Intrathecal B cells in ms have 116. Lehmann-​Horn, K. et al. CNS accumulation of in a mouse model of multiple sclerosis and promote
significantly greater lymphangiogenic potential regulatory B cells is VLA-4-dependent. Neurol. oligodendrogenesis and remyelination. J. Neurosci.
compared to B cells derived from non-​MS subjects. Neuroimmunol. Neuroinflamm. 3, e212 (2016). 40, 5105–5115 (2020).
Front. Neurol. 9, 554 (2018). 117. Matsumoto, M. et al. Interleukin-10-producing
105. Gardner, C. et al. Cortical grey matter demyelination plasmablasts exert regulatory function in autoimmune Acknowledgements
can be induced by elevated pro-​inflammatory inflammation. Immunity 41, 1040–1051 (2014). R.W.J. acknowledges postdoctoral fellowship funding from the
cytokines in the subarachnoid space of MOG-​ This study demonstrates that plasmablasts are University of Calgary Eyes High program, the Multiple
immunized rats. Brain 136, 3596–3608 (2013). a major regulatory population in EAE induced Sclerosis of Canada and Roche unrestricted educational fel-
106. Magliozzi, R. et al. Meningeal inflammation changes through immunization that inhibits T cell lowship. V.W.Y. acknowledges salary support from the Canada
the balance of TNF signalling in cortical grey matter responses in the lymph nodes where T cells Research Chair Tier 1 program and operating grant support
in multiple sclerosis. J. Neuroinflammation 16, 259 are differentiating. from the Canadian Institutes of Health Research and the
(2019). 118. Wang, A., Rojas, O., Lee, D. & Gommerman, J. L. Multiple Sclerosis Society of Canada.
107. James, R. E. et al. Persistent elevation of intrathecal Regulation of neuroinflammation by B cells and
pro-​inflammatory cytokines leads to multiple sclerosis-​ plasma cells. Immunol. Rev. 299, 45–60 (2021). Author contributions
like cortical demyelination and neurodegeneration. 119. Stebegg, M. et al. Regulation of the germinal center The authors contributed equally to all aspects of the article.
Acta Neuropathol. Commun. 8, 66 (2020). response. Front. Immunol. 9, 2469 (2018).
108. van Olst, L. et al. Meningeal inflammation in 120. Roco, J. A. et al. Class-​switch recombination occurs Competing interests
multiple sclerosis induces phenotypic changes in infrequently in germinal centers. Immunity 51, The authors declare no competing interests.
cortical microglia that differentially associate with 337–350.e7 (2019).
neurodegeneration. Acta Neuropathol. 141, 881–899 121. Lepennetier, G. et al. Cytokine and immune cell Peer review information
(2021). profiling in the cerebrospinal fluid of patients with Nature Reviews Immunology thanks S. Pillai and the other,
109. Fehres, C. M. et al. APRIL induces a novel subset of neuro-​inflammatory diseases. J. Neuroinflammation anonymous, reviewer(s) for their contribution to the peer
IgA+ regulatory B cells that suppress inflammation via 16, 219 (2019). review of this work.
expression of IL-10 and PD-​L1. Front. Immunol. 10, 122. Flach, A. C. et al. Autoantibody-​boosted T-​cell
1368 (2019). reactivation in the target organ triggers manifestation Publisher’s note
110. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., of autoimmune CNS disease. Proc. Natl Acad. Sci. USA Springer Nature remains neutral with regard to jurisdictional
Gray, D. & Anderton, S. M. B cells regulate 113, 3323–3328 (2016). claims in published maps and institutional affiliations.
autoimmunity by provision of IL-10. Nat. Immunol. 3, 123. Romanelli, E. et al. Myelinosome formation represents
944–950 (2002). an early stage of oligodendrocyte damage in multiple Supplementary information
111. Pennati, A. et al. Regulatory B cells induce formation sclerosis and its animal model. Nat. Commun. 7, The online version contains supplementary material available
of IL-10-expressing T cells in mice with autoimmune 13275 (2016). at https://doi.org/10.1038/s41577-021-00652-6.
neuroinflammation. J. Neurosci. 36, 12598–12610 124. Jegou, J. F. et al. C3d binding to the myelin
(2016). oligodendrocyte glycoprotein results in an © Springer Nature Limited 2021

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