Elsevier

The Lancet Neurology

Volume 7, Issue 9, September 2008, Pages 852-858
The Lancet Neurology

Personal View
B cells and multiple sclerosis

https://doi.org/10.1016/S1474-4422(08)70192-3Get rights and content

Summary

Clonal expansion of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) have long been interpreted as circumstantial evidence of the immune-mediated pathogenesis of the disease and suggest a possible infectious cause. Extensive work on intrathecally produced antibodies has not yet clarified whether they are pathogenetically relevant. Irrespective of antibody specificity, however, the processes of antibody synthesis in the CNS of patients with MS are becoming increasingly clear. Likewise, targeting B cells might be therapeutically relevant in MS and other autoimmune diseases that are deemed to be driven predominantly by T cells. Accumulating evidence indicates that in MS, similar to rheumatoid arthritis, B cells aggregate into lymphoid-like structures in the target organ. The process of aggregation is mediated through the expression of lymphoid-homing chemokines. In the brain of a patient with MS, ectopic B-cell follicles preferentially adjoin the pial membrane within the subarachnoid space. Recent findings indicate that substantial numbers of B cells that are infected with Epstein-Barr virus (EBV) accumulate in these intrameningeal follicles and in white matter lesions and are probably the target of a cytotoxic immune response. These findings, which await confirmation, could be an explanation for the continuous B-cell and T-cell activation in MS, but leave open concerns about the possible pathogenicity of autoantibodies. Going beyond the antimyelin-antibody dogma, the above data warrant further work on various B-cell-related mechanisms, including investigation of B-cell effector and regulatory functions, definition of the consistency of CNS colonisation by Epstein-Barr virus-infected B cells, and understanding of the mechanisms that underlie the formation and persistence of tertiary lymphoid tissues in patients with MS and other chronic autoimmune diseases (ectopic follicle syndromes). This work will stimulate new and unconventional ways of reasoning about MS pathogenesis.

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that is characterised by persistent intrathecal synthesis of immunoglobulins—mainly oligoclonal IgG—and recruitment of activated T cells and macrophages into the CNS. The antigenic stimuli that initiate or perpetuate this abnormal immune reactivity are still a matter of intense research and debate. In the past few years, the concept of MS as an autoimmune disease that is mediated by myelin-reactive T cells has been challenged, and reassessment of the role of B cells in the pathogenesis of the disease is ongoing.1, 2 Three sets of new data—the characterisation of B-cell follicle-like structures in the brain meninges of patients with MS,3, 4, 5 which extends the earlier description of lymphoid tissue in MS lesions;6 the finding that a substantial proportion of the B cells or plasma cells that accumulate in these follicles and in white-matter lesions are infected with Epstein-Barr virus (EBV);7 and the results of a trial with the B-cell-depleting antibody rituximab8—now provide reciprocal conceptual support for the prominent role of B cells in the pathogenesis of MS and disclose a possible scenario that links abnormal B-cell activation to T-cell-mediated immunopathology.

Section snippets

Triggers of B-cell activation

Traditionally, B cells have been implicated in MS through their ability to produce pathogenic antibodies or autoantibodies, which can destroy tissue by recruiting macrophages that express the Fc receptor and by activation of the complement pathway. The results of histopathological analyses indicate that antibodies might have an important role in plaque initiation9 and in demyelination in patients with established MS.10 The list of candidate pathogenic antigens in MS has recently grown longer;

Where next and conclusions

After years of impasse, new data on B cells are stimulating unconventional ways of reasoning about MS pathogenesis. The identification of antibodies to neuronal antigens provides clues about the mechanisms that underlie damage to brain tissue and deserve further investigation. The identification of ectopic B-cell follicles as a niche for the generation of B cells and plasma cells in the brain of patients with MS reinforces the concept that humoral immunity has a role in the pathological changes

Search strategy and selection criteria

References were found by searching PubMed, between Jan, 2006, and March, 2008, with the terms “B cells”, “rituximab”, “natalizumab”, and “multiple sclerosis”. Articles identified from searches of the authors' own files were also included. Only papers written in English were included, which were further selected on the basis of originality and importance to the topic of the Personal View.

References (57)

  • F Aloisi et al.

    Lymphoid neogenesis in chronic inflammatory diseases

    Nat Rev Immunol

    (2006)
  • R Magliozzi et al.

    Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

    Brain

    (2007)
  • JW Prineas

    Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord

    Science

    (1979)
  • B Serafini et al.

    Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain

    J Exp Med

    (2007)
  • SL Hauser et al.

    B-cell depletion with rituximab in relapsing-remitting multiple sclerosis

    N Engl J Med

    (2008)
  • D Gay et al.

    Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study

    Brain

    (1991)
  • EC Breij et al.

    Homogeneity of active demyelinating lesions in established multiple sclerosis

    Ann Neurol

    (2008)
  • DM Wingerchuk et al.

    Comparative immuno-pathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis

    Curr Opin Neurol

    (2007)
  • SS Ousman et al.

    Protective and therapeutic role for αB-crystallin in autoimmune demyelination

    Nature

    (2007)
  • E Silber et al.

    Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit

    Neurology

    (2002)
  • A Bartos et al.

    Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis

    J Neurol

    (2007)
  • EK Mathey et al.

    Neurofascin as a novel target for autoantibody-mediated axonal injury

    J Exp Med

    (2007)
  • A Ascherio et al.

    Environmental risk factors for multiple sclerosis. Part I: the role of infection

    Ann Neurol

    (2007)
  • O Barzilai et al.

    Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report

    Ann N Y Acad Sci

    (2007)
  • HH Niller et al.

    Regulation and dysregulation of Epstein–Barr virus latency: implications for the development of autoimmune diseases

    Autoimmunity

    (2008)
  • JD Lünemann et al.

    Epstein-Barr virus: environmental trigger of multiple sclerosis?

    J Virol

    (2007)
  • GN DeLorenze et al.

    Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up

    Arch Neurol

    (2006)
  • S Cepok et al.

    Identification of Epstein–Barr virus proteins as putative targets of the immune response in multiple sclerosis

    J Clin Invest

    (2005)
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