The B cell immunobiology that underlies CNS autoantibody-mediated diseases

Abstract

A rapidly expanding and clinically distinct group of CNS diseases are caused by pathogenic autoantibodies that target neuroglial surface proteins. Despite immunotherapy, patients with these neuroglial surface autoantibody (NSAb)-mediated diseases often experience clinical relapse, high rates of long-term morbidity and adverse effects from the available medications. Fundamentally, the autoantigen-specific B cell lineage leads to production of the pathogenic autoantibodies. These autoantigen-specific B cells have been consistently identified in the circulation of patients with NSAb-mediated diseases, accompanied by high serum levels of autoantigen-specific antibodies. Early evidence suggests that these cells evade well-characterized B cell tolerance checkpoints. Nearer to the site of pathology, cerebrospinal fluid from patients with NSAb-mediated diseases contains high levels of autoantigen-specific B cells that are likely to account for the intrathecal synthesis of these autoantibodies. The characteristics of their immunoglobulin genes offer insights into the underlying immunobiology. In this Review, we summarize the emerging knowledge of B cells across the NSAb-mediated diseases. We review the evidence for the relative contributions of germinal centres and long-lived plasma cells as sources of autoantibodies, discuss data that indicate migration of B cells into the CNS and summarize insights into the underlying B cell pathogenesis that are provided by therapeutic effects.

Fig. 1 |. B cell tolerance checkpoints in humans.

Pro-B cells in the bone marrow, which derive from common lymphoid progenitor cells, undergo B cell receptor heavy chain gene rearrangement. Newly rearranged heavy chains on pre-B cells acquire a surrogate invariant light chain to form a pre-B cell receptor (BCR). The suurogate invariant light chain is exchanged for a bona fide, paired light chain in the early immature B cell so that immunoglobulin M (IgM) is expressed on the B cell membrane. At this point (Checkpoint 1), autoreactive BCRs are negatively selected through apoptosis or rescued via receptor editing of paired functional light chains. Positively selected or rescued B cells then exit the bone marrow as new emigrant B cells. Further negative selection occurs at the transition between new emigrant and mature naive B cells (Checkpoint 2) in the periphery. Upon encountering their cognate antigen, mature naive B cells can enter germinal centre reactions, where T cell-dependent immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) occur, and they upregulate MHC class II. Within germinal centres, SHM can lead IgG⁺ switched memory B cells to inadvertently acquire autoreactive BCRs with pathogenic potential. IgM⁺ unswitched memory B cells can be further negatively selected (Checkpoint 3). The relative proportions of polyreactive and autoreactive B cells at each checkpoint are shown as the pie charts. MHCII, major histocompatibility complex class II.

Fig. 2 |. Sources of autoantibodies.

Two major sources of circulating autoantibodies have been proposed: plasmablasts that emerge from perpetually active germinal centre reactions in secondary lymphoid organs and long-lived plasma cells that reside in the bone marrow. Mature, naive B cells that encounter an autoantigen enter germinal centre reactions (1) and, in the presence of antigen and cognate CD4⁺ T helper cells, undergo somatic hypermutation to increase the affinity of their B cell receptors. After successful maturation, unswitched or switched memory B cells exit the germinal centre (2) and can give rise to circulating plasmablasts that secrete IgM, IgG or IgA (not shown) (3). Plasmablasts can differentiate into short-lived plasma cells with a limited lifespan; sometimes this can happen rapidly via an extrafollicular response with limited dependence on typical germinal centre reactions (4). Alternatively, long-lived plasma cells can migrate into the bone marrow survival niche (5), supported by IL-6-secreting stromal cells and C–X–C motif chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, where they can survive for many years. In the active germinal centre model, IgM and IgG are continually produced (6). By contrast, with a long-lived plasma cell response, IgG production is ongoing after a remote autoimmunization (7). CXCL13, C–X–C motif chemokine ligand 12; CXCR5, C–X–C motif chemokine receptor 5; FDC, follicular dendritic cell; MHCII, major histocompatibility complex class II.

Fig. 3 |. Autoantibody access to CNS targets.

Tissue destruction, either as a result of infection or a pro-inflammatory milieu, can release soluble neuronal autoantigens into the cerebrospinal fluid (1), from where they can drain via the recently (re)discovered cerebral lymphatic drainage system^, into cervical lymph nodes (2). Here, B cell responses can be induced against CNS-derived autoantigens, generating antigen-specific B cells, plasma cells and high concentrations of autoantibodies in circulation (3). Activated B cells can then migrate into the intrathecal compartment, driven, for example, by a gradient of the C–X–C motif chemokine ligand 13 (CXCL13). In the intrathecal compartment, clonal expansion, class switching, affinity maturation and differentiation into antibody-secreting cells (ASCs) that secrete pathogenic autoantibodies can occur (4) and can be associated with ectopic tertiary lymphoid structures. These intrathecal antibodies can directly lead to neuronal dysfunction (5). BBB, blood–brain barrier; GC, germinal centre.

Fig. 4 |. Studies of intrathecal B cells.

a | Median serum and cerebrospinal fluid (CSF) antibody titres in individuals demonstrate that autoantibodies are consistently present at higher levels in the serum than in the CSF, implying an initial peripheral generation of the autoantibodies. Data were adapted from multiple studies of different autoantibodies^{,,,,,,–,,,,,}. b | Immunoglobulin heavy chain (IgHV) somatic hypermutation of leucine-rich glioma inactivated protein 1 (LGI1)-specific (left) and NR1-specific (right) intrathecal B cells differs from that of non-target antigen-reactive B cells and among each other. This observation implies that different mechanisms operate to generate these two autoantibody populations and the non-antigen-specific cells. The proportions of immunoglobulin subclasses also differ between B cell populations (pie charts), again implicating different immunological pathways in the generation of each autoantibody population. Data adapted from previous studies^,. AQP4, aquaporin 4; CASPR2, contactin-associated protein-like 2; NMDAR, N-methyl-d-aspartate receptor; MOG, myelin oligodendrocyte glycoprotein; HSE; herpes simplex virus encephalitis.