Closing SessionSaturday, October 05, 2013, 10:30 - 10:50
Charcot LectureS. Hauser (San Francisco, US)
Beating MS: A story of B cells, with twists and turns
In contrast to earlier disease concepts of MS suggesting that pathogenic T cells were sufficient for full expression of the disease, it is now established that autoimmune B cells and humoral immune mechanisms also play major roles in mediating tissue damage. In MS, memory B cells, which cross the blood-brain barrier, are believed to undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation to antibody-secreting plasma cells within the highly supportive CNS environment. Clonally expanded populations of memory B cells and plasma cells are present in MS lesions and in cerebrospinal fluid, are responsible for the production of oligoclonal antibodies, can be detected even at the onset of clinical symptoms, and also appear to play a key role in mediating late progressive disease.
In phase II trials of relapsing MS, monoclonal antibodies that target CD20-positive B lymphocytes (rituximab and ocrelizumab) were found to dramatically reduce disease activity measured by MRI; secondary endpoints were also positive, including a reduction of clinical relapses. These beneficial effects occurred within weeks of the initial treatment, indicating that a direct effect on B cells - and not on putative autoantibodies - was responsible. Interference with the antigen presentation function of B cells is likely responsible for the effects of anti-CD20 therapies in MS. Remarkably, the duration of action was also sustained beyond the period of B cell depletion, suggesting that repopulating B-cells were less pathogenic, a conclusion also supported by studies of peripheral blood and CSF compartments. In a larger sense, the discovery that B-cell depletion has an impact on MS biology signals a paradigm shift in understanding how the inflammatory phase of MS develops; it focuses attention on elucidating the repertoire of B-cell dependent immune responses, and on identifying and tracking clonally expanded B-cell populations in patients. These efforts hold great promise for the future development of increasingly selective, effective, and safe therapies against culprit B-cells and related humoral immune system pathways. Finally, the B-cell story in MS highlights the essential, irreplaceable role of direct patient-based research to validate, and to periodically redirect, our preclinical models in order to maximize their relevance to human disease.
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