Journal ArticleDOI
Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
Bernice Lo,Kejian Zhang,Wei Lu,Lixin Zheng,Qian Zhang,Chrysi Kanellopoulou,Yu Zhang,Zhiduo Liu,Jill M. Fritz,Rebecca A. Marsh,Ammar Husami,Diane Kissell,Shannon Nortman,Vijaya Chaturvedi,Hilary Haines,Lisa R. Young,Jun Mo,Alexandra H. Filipovich,Jack J. Bleesing,Peter Mustillo,Michael C. Stephens,Cesar M. Rueda,Claire A. Chougnet,Kasper Hoebe,Joshua J McElwee,Jason D. Hughes,Elif Karakoc-Aydiner,Helen F. Matthews,Susan Price,Helen C. Su,V. Koneti Rao,Michael J. Lenardo,Michael B. Jordan +32 more
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TLDR
Patients with an autoimmune disorder caused by deficiency of a protein called LRBA responded dramatically to the drug abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)–immunoglobulin fusion drug, and the relationship between the two proteins was revealed: LRBA controls the intracellular trafficking and degradation ofCTLA4.Abstract:
Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency The biological role of LRBA in immunologic disease is unknown We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)–immunoglobulin fusion drug Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3+ regulatory and activated conventional T cells In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathwayread more
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Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee
Stuart G. Tangye,Waleed Al-Herz,Aziz Bousfiha,Talal A. Chatila,Charlotte Cunningham-Rundles,Amos Etzioni,José Luis Franco,Steven M. Holland,Christoph Klein,Tomohiro Morio,Hans D. Ochs,Eric Oksenhendler,Capucine Picard,Jennifer M. Puck,Troy R. Torgerson,Jean-Laurent Casanova,Kathleen E. Sullivan +16 more
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References
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Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
Paul Waterhouse,Josef M. Penninger,Emma Timms,Andrew Wakeham,Arda Shahinian,Kelvin P. Lee,Craig B. Thompson,Henrik Griesser,Tak W. Mak +8 more
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Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Elizabeth A. Tivol,Frank Borriello,A N Schweitzer,W P Lynch,Jeffrey A. Bluestone,Arlene H. Sharpe +5 more
TL;DR: In this article, the authors showed that CTLA-4-deficient mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age.
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Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
Takeshi Takahashi,Tomoyuki Tagami,Sayuri Yamazaki,Toshimitsu Uede,Jun Shimizu,Noriko Sakaguchi,Tak W. Mak,Shimon Sakaguchi +7 more
TL;DR: Interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells.
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Common variable immunodeficiency disorders: division into distinct clinical phenotypes
Helen Chapel,M Lucas,Martin Lee,Janne Björkander,David Webster,Bodo Grimbacher,Bodo Grimbacher,Claire Fieschi,Vojtech Thon,M. R. Abedi,M. R. Abedi,Lennart Hammarström +11 more
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Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.
Desirée Schubert,Desirée Schubert,Claudia Bode,Rupert Kenefeck,Tie Zheng Hou,James B. Wing,Alan Kennedy,Alla Bulashevska,Britt-Sabina Petersen,Alejandro A. Schäffer,Björn Grüning,Susanne Unger,Natalie Frede,Ulrich Baumann,Torsten Witte,Reinhold E. Schmidt,G Dueckers,Tim Niehues,Suranjith L. Seneviratne,Maria Kanariou,Carsten Speckmann,Stephan Ehl,Anne Rensing-Ehl,Klaus Warnatz,Mirzokhid Rakhmanov,Robert Thimme,Peter Hasselblatt,Florian Emmerich,Toni Cathomen,Rolf Backofen,Paul Fisch,Maximilian Seidl,Annette M. May,Annette Schmitt-Graeff,Shinji Ikemizu,Ulrich Salzer,Andre Franke,Shimon Sakaguchi,Lucy S. K. Walker,David M. Sansom,Bodo Grimbacher +40 more
TL;DR: Taking together, mutations in CTLA4 resulting inCTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
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