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

Joanne Jones, Sarah L Thompson, Priscilla Loh, Jessica Davies, Orla Tuohy, Allison Curry, Laura Azzopardi, Grant Hill-Cawthorne, Michael Thomas Fahey, Alastair Compston, Alasdair Coles

Research output: Contribution to journalArticleResearchpeer-review

109 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)20200 - 20205
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number50
DOIs
Publication statusPublished - 2013

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