Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Nov 26. [Epub ahead of print]
The association between lymphopaenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28-CD57+), highly proliferative (Ki67+), oligoclonal, memory-like CD4 and CD8 T cells (CD197–CD45RA- or CD197-CD45RA+) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopaenic than their non-autoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopaenia-associated autoimmunity in humans.
It is well known that an adverse effect of alemtuzumab is antibody mediated autoimmunities, and others develop autoantibodies. This study suggests that the autoimmunities develop after a repopulation of T cells, but with a restricted set of specificities, but it does not say how to stop these developing