Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation

JL Jones, SAJ Thompson, P Loh… - Proceedings of the …, 2013 - National Acad Sciences
JL Jones, SAJ Thompson, P Loh, JL Davies, OC Tuohy, AJ Curry, L Azzopardi…
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
The association between lymphopenia 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 …
The association between lymphopenia 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 (CD28CD57+), highly proliferative (Ki67+), oligoclonal, memory-like CD4 and CD8 T cells (CCR7CD45RA or CCR7CD45RA+) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.
National Acad Sciences