title: 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.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Jones
authors.forename: Sara A J
authors.initials: SA
authors.lastname: Thompson
authors.forename: Priscilla
authors.initials: P
authors.lastname: Loh
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Davies
authors.forename: Orla C
authors.initials: OC
authors.lastname: Tuohy
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Curry
authors.forename: Laura
authors.initials: L
authors.lastname: Azzopardi
authors.forename: Grant
authors.initials: G
authors.lastname: Hill-Cawthorne
authors.forename: Michael T
authors.initials: MT
authors.lastname: Fahey
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Coles
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D015551:Autoimmunity / Q000276:immunology*; D001483:Base Sequence; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D004739:England; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016014:Linear Models; D008212:Lymphocyte Depletion / Q000009:adverse effects*; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D000074323:Alemtuzumab
keywords: T lymphocytes; immunotherapy; reconstitution