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A new study, published in Science Advances and led by researchers at NDCN, reveals how the body fails to stop self-targeting B Cells in a rare autoimmune brain disease called CASPR2-antibody encephalitis, an illness where the body’s immune system mistakenly creates antibodies that attack a brain protein called CASPR2.
B cells are immune cells that produce antibodies. Normally, the immune system will remove B cells that can attack our own body, and the paper focused on two ‘checkpoints’ in the body where this happens.
The first checkpoint, ‘central tolerance’, eliminates harmful B cells in bone marrow. ‘Peripheral tolerance’ is the second checkpoint, which deals with escaped B cells in the body’s circulation. In patients with CASPR2-antibody encephalitis, both these checkpoints failed and allowed B cells to evolve into memory B cells. These memory cells undergo additional mutations to bind more strongly to CASPR2, enabling them to produce high-potency, disease-causing antibodies.
Using a mouse model, the team demonstrated that mature, CASPR2-specific memory B cells caused behavioural changes which mirror those seen in human CASPR2-antibody encephalitis.
Unexpectedly, researchers also found that even healthy people had early-stage B cells that can bind to CASPR2. However, in these people, the B cells were effectively blocked from becoming disease-causing memory B cells. This finding shows the critical importance of peripheral checkpoints in preventing B cell–mediated autoimmune disease.
Lead author Dr Bo Sun, NIHR Academic Clinical Lecturer in Neurology and The Brain Tumour Charity Future Leaders Fellow, said:
Our work uncovers a vital model of how tolerance mechanisms can break down, leading to autoimmune diseases. Identifying the pathways of peripheral tolerance will be crucial for developing therapies that aim to restore these immune safety nets
Dr Sun also recently co-authored a study which suggested that a Cytomegalovirus (CMV) infection before a skin cancer diagnosis could improve patient response to immunotherapy (a form of treatment that harnesses the immune system to target cancer), which was published in Nature Medicine.