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


ABSTRACT: 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 (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) 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.

SUBMITTER: Jones JL 

PROVIDER: S-EPMC3864306 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Jones Joanne L JL   Thompson Sara A J SA   Loh Priscilla P   Davies Jessica L JL   Tuohy Orla C OC   Curry Allison J AJ   Azzopardi Laura L   Hill-Cawthorne Grant G   Fahey Michael T MT   Compston Alastair A   Coles Alasdair J AJ  

Proceedings of the National Academy of Sciences of the United States of America 20131126 50


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 ale  ...[more]

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