Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease
Hamid Mattoo,Vinay Mahajan,Takashi Maehara,Vikram Deshpande,Emanuel Della-Torre,Zachary S. Wallace,Maria Kulikova,Jefte M. Drijvers,Joe Daccache,Mollie N. Carruthers,Flavia V. Castelino,James R. Stone,John H. Stone,Shiv Pillai +13 more
TLDR
IgG4-RD is prominently linked to clonally expanded IL-1β- and TGF-β1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions.Abstract:
Background IgG 4 -related disease (IgG 4 -RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4 + T cells constitute the major inflammatory cell population in IgG 4 -RD lesions. Objective We used an unbiased approach to characterize CD4 + T-cell subsets in patients with IgG 4 -RD based on their clonal expansion and ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4 + effector/memory T cells in a cohort of 101 patients with IgG 4 -RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4 + SLAMF7 + cytotoxic T lymphocytes (CTLs) and CD4 + GATA3 + T H 2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. Results CD4 + effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG 4 -RD. Next-generation sequencing revealed prominent clonal expansions of these CD4 + CTLs but not CD4 + GATA3 + memory T H 2 cells in patients with IgG 4 -RD. The dominant T cells infiltrating a range of inflamed IgG 4 -RD tissue sites were clonally expanded CD4 + CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4 + CTLs. Conclusions IgG 4 -RD is prominently linked to clonally expanded IL-1β– and TGF-β1–secreting CD4 + CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4 + T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.read more
Citations
More filters
Journal ArticleDOI
IgG4-related disease.
TL;DR: Advances in understanding the pathophysiology of IgG4-RD have proceeded swiftly, leading to the identification of a number of potential targeted treatment strategies, which have direct implications for the development of targeted strategies for the treatment of this condition.
Journal ArticleDOI
Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer.
David Y. Oh,Serena S. Kwek,Siddharth S. Raju,Tony Li,Elizabeth E. McCarthy,Eric D. Chow,Dvir Aran,Arielle Ilano,Chien-Chun Steven Pai,Chiara Rancan,Kathryn Allaire,Arun Burra,Yang Sun,Matthew H. Spitzer,Serghei Mangul,Sima P. Porten,Maxwell V. Meng,Terence W. Friedlander,Chun Jimmie Ye,Lawrence Fong +19 more
TL;DR: A gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1, and several tumor-specific states are found, including multiple distinct states of regulatory T cells.
Journal ArticleDOI
Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients.
Mikael Ebbo,Aurélie Grados,Maxime Samson,Matthieu Groh,Anderson Loundou,Aude Rigolet,Benjamin Terrier,Constance Guillaud,Clarisse Carra-Dalliere,F. Renou,Agnieszka Pozdzik,Pierre Labauge,S. Palat,Jean-Marie Berthelot,Jean-Loup Pennaforte,Alain Wynckel,C. Lebas,Noémie Le Gouellec,Thomas Quemeneur,Karine Dahan,Franck Carbonnel,Gaëlle Leroux,Antoinette Perlat,Alexis Mathian,Patrice Cacoub,Eric Hachulla,Nathalie Costedoat-Chalumeau,Jean-Robert Harlé,Nicolas Schleinitz +28 more
TL;DR: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution, and maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy.
Journal ArticleDOI
IgG4-related disease: an update on pathophysiology and implications for clinical care.
TL;DR: The central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion.
Journal ArticleDOI
Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis
Takashi Maehara,Hamid Mattoo,Miho Ohta,Vinay Mahajan,Masafumi Moriyama,Masaki Yamauchi,Jefte M. Drijvers,Seiji Nakamura,John H. Stone,Shiv Pillai +9 more
TL;DR: The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+ CTLs that secrete IFN-γ, and this cells secrete interferon-gamma at lesional sites.
References
More filters
Journal ArticleDOI
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Journal ArticleDOI
Immunological and Inflammatory Functions of the Interleukin-1 Family
TL;DR: The IL-1 family includes members that suppress inflammation, both specifically within the IL-2 family but also nonspecifically for TLR ligands and the innate immune response.
Journal ArticleDOI
Mechanisms of fibrosis: therapeutic translation for fibrotic disease
TL;DR: How cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts is described.
Journal ArticleDOI
Consensus statement on the pathology of IgG4-related disease
Vikram Deshpande,Yoh Zen,John Kc Chan,Eunhee E Yi,Yasuharu Sato,Tadashi Yoshino,Günter Klöppel,J. Godfrey Heathcote,Arezou Khosroshahi,Judith A. Ferry,Rob C. Aalberse,Daniel Bloch,William R. Brugge,Adrian C Bateman,Mollie N. Carruthers,Suresh T. Chari,Wah Cheuk,Lynn D. Cornell,Carlos Fernandez-del Castillo,David G. Forcione,Daniel L. Hamilos,Terumi Kamisawa,Satomi Kasashima,Shigeyuki Kawa,Mitsuhiro Kawano,Gregory Y. Lauwers,Yasufumi Masaki,Yasuni Nakanuma,Kenji Notohara,Kazuichi Okazaki,Ji Kon Ryu,Takako Saeki,Dushyant V. Sahani,Thomas C. Smyrk,James Robert Stone,Masayuki Takahira,George Webster,Motohisa Yamamoto,Giuseppe Zamboni,Hisanori Umehara,John H. Stone +40 more
TL;DR: This statement proposes a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy, and advocates the use of strict criteria for accepting newly proposed entities or sites as components of the IgG 4- related disease spectrum.
Related Papers (5)
Consensus statement on the pathology of IgG4-related disease
Vikram Deshpande,Yoh Zen,John Kc Chan,Eunhee E Yi,Yasuharu Sato,Tadashi Yoshino,Günter Klöppel,J. Godfrey Heathcote,Arezou Khosroshahi,Judith A. Ferry,Rob C. Aalberse,Daniel Bloch,William R. Brugge,Adrian C Bateman,Mollie N. Carruthers,Suresh T. Chari,Wah Cheuk,Lynn D. Cornell,Carlos Fernandez-del Castillo,David G. Forcione,Daniel L. Hamilos,Terumi Kamisawa,Satomi Kasashima,Shigeyuki Kawa,Mitsuhiro Kawano,Gregory Y. Lauwers,Yasufumi Masaki,Yasuni Nakanuma,Kenji Notohara,Kazuichi Okazaki,Ji Kon Ryu,Takako Saeki,Dushyant V. Sahani,Thomas C. Smyrk,James Robert Stone,Masayuki Takahira,George Webster,Motohisa Yamamoto,Giuseppe Zamboni,Hisanori Umehara,John H. Stone +40 more
International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease
Arezou Khosroshahi,Zachary S. Wallace,J. L. Crowe,Takashi Akamizu,Atsushi Azumi,M. N. Carruthers,Suresh T. Chari,Emanuel Della-Torre,Luca Frulloni,Hiroshi Goto,Phil A. Hart,Terumi Kamisawa,Shigeyuki Kawa,Mitsuhiro Kawano,Myung-Hwan Kim,Yuzo Kodama,Kensuke Kubota,Markus M. Lerch,Matthias Löhr,Yasufumi Masaki,Shoko Matsui,Tsuneyo Mimori,Seiji Nakamura,Takahiro Nakazawa,Hirotaka Ohara,Kazuichi Okazaki,Jay H. Ryu,Takako Saeki,Nicolas Schleinitz,Akira Shimatsu,Toru Shimosegawa,Hiroki Takahashi,Masayuki Takahira,Atsushi Tanaka,Mark Topazian,Hisanori Umehara,George J. Webster,Thomas E. Witzig,Motohisa Yamamoto,W. Zhang,Tsutomu Chiba,John H. Stone +41 more