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The B cell immunobiology that underlies CNS autoantibody-mediated diseases

Nature Reviews Neurology volume 16, pages 481–492 (2020)Cite this article

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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.

Key points

  • Autoantigen-specific B cells that target neuroglial surface proteins are responsible for the production of pathogenic neuroglial surface autoantibodies (NSAbs) in an increasing variety of antibody-mediated CNS diseases.

  • Pathogenic NSAbs are typically found at higher concentrations in the serum than in the cerebrospinal fluid.

  • Current evidence suggests that autoreactive B cells evade early B cell tolerance checkpoints in NSAb-mediated CNS diseases.

  • Enrichment of autoantigen-specific B cells in the cerebrospinal fluid in patients with NSAb-mediated diseases suggests that they migrate into this compartment and secrete pathogenic IgGs intrathecally.

  • Experimental and clinical evidence implicates both ongoing germinal centre reactions and long-lived plasma cells in the propagation of autoantibody production in NSAb-mediated diseases.

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Fig. 1: B cell tolerance checkpoints in humans.
Fig. 2: Sources of autoantibodies.
Fig. 3: Autoantibody access to CNS targets.
Fig. 4: Studies of intrathecal B cells.

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Acknowledgements

B.S. is supported by the Association of British Neurologists via the Patrick Berthoud Charitable Trust. M.R. is supported by the Austrian Science Fund (FWF J4157-B30). S.R.I. is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants (Vera Down grant (2013) and Margaret Temple grant (2017)), Epilepsy Research UK (P1201), the Fulbright UK–US Commission (MS Society research award) and the National Institute for Health Research (NIHR), Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health. K.C.O’C. is supported by the National Institute of Allergy and Infectious Diseases (NIAID) under award numbers R01-AI114780 and R21-AI142198, by a Neuromuscular Disease Research program award from the Muscular Dystrophy Association (MDA) under award number MDA575198 and by the Guthy-Jackson Charitable Foundation.

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  1. These authors contributed equally: Bo Sun, Melanie Ramberger

Authors and Affiliations

  1. Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Bo Sun, Melanie Ramberger & Sarosh R. Irani

  2. Departments of Neurology and Immunobiology, Yale University School of Medicine, New Haven, USA

    Kevin C. O’Connor

  3. Wellcome Centre of Human Genetics, University of Oxford, Oxford, UK

    Rachael J. M. Bashford-Rogers

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B.S., M.R. and S.R.I. researched data for the article and made substantial contributions to discussion of the content. All authors contributed to writing the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Sarosh R. Irani.

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Competing interests

R.J.M.B.-R. is a co-founder and consultant for Alchemab Therapeutics Ltd and has consulted for Imperial College London and VHSquared. S.R.I. and M.R. are co-inventors on a patent to improve the specificity of autoantibody detection. S.R.I. is a co-applicant and receives royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed for the development of assays for LGI1 and other voltage-gated potassium channel (VGKC)-complex antibodies. S.R.I. has received research support from CSL Behring, ONO Pharma and UCB. B.S. declares no competing interests.

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Glossary

B cell receptor

(BCR). An immunoglobulin molecule consisting of two paired identical heavy and light chains that forms a transmembrane receptor protein on the surface of B cells and signals to the B cell, largely via its interaction with its antigen or antigens.

Anergy

A cell state in which B cells persist in the periphery but have limited responses to antigen; anergy is a mechanism that silences many self-reactive B cells.

Receptor editing

A process in which autoreactive heavy or light chains of B cell receptors are exchanged, thereby changing the specificity of the antigen receptor and rescuing an autoreactive B cell receptor.

B cell-activating factor

(BAFF). A cytokine that belongs to the tumour necrosis factor ligand family and is expressed in B cell lineage cells, acting as a potent B cell activator.

Somatic hypermutation

The introduction of point mutations within the immunoglobulin variable regions in the presence of an antigen and T helper cells.

Germinal centre

A site within a secondary lymphoid organ where the genes that encode immunoglobulins in B cells undergo somatic hypermutation, thereby sequentially increasing their affinity for the antigen; a process that typically requires B cells to undergo rounds of proliferation, differentiation and interactions with antigen and T cells.

Unmutated common ancestors

(UCAs). Antibodies that are derived computationally and represent the most accurately matched germline B cell receptors from which the mutated antibodies were derived.

Tertiary lymphoid structures

Ectopic lymphoid-like tissues with features of secondary lymphoid organs, such as segregated T and B cell zones, mutational activity, follicular dendritic cell networks and high endothelial venules.

T follicular helper cells

Germinal centre resident CD4+ T follicular helper cells that provide potent survival and proliferative signals for B cells.

Human leukocyte antigen class II

(HLA class II). Proteins expressed on the surface of antigen-presenting cells and, if loaded with a cognate peptide, can activate antigen-specific CD4+ T cells. Also known as major histocompatibility complex class II.

Glutamic acid decarboxylase

(GAD). A cytoplasmic antigen, autoantibodies to which can be found at high levels in patients with neurological syndromes such as stiff-person syndrome, cerebellar ataxia, limbic encephalitis and forms of epilepsy and diabetes.

Antibody index

A calculation used to assess intrathecal IgG synthesis by comparing the ratio of specific autoantibody levels to total levels of IgG in serum and CSF (antibody index = Qspec/QIgG, where Qspec = CSF/serum quotient for specific IgG, and QIgG = CSF/serum quotient for total IgG; values >4 are taken as evidence for intrathecal autoantigen-specific IgG synthesis).

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Sun, B., Ramberger, M., O’Connor, K.C. et al. The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nat Rev Neurol 16, 481–492 (2020). https://doi.org/10.1038/s41582-020-0381-z

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