Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease

Published on Sep 1, 2016in The Journal of Allergy and Clinical Immunology10.228
· DOI :10.1016/J.JACI.2015.12.1330
Hamid Mattoo21
Estimated H-index: 21
(Harvard University),
Vinay S. Mahajan23
Estimated H-index: 23
(Harvard University)
+ 11 AuthorsShiv Pillai50
Estimated H-index: 50
(Harvard University)
Sources
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.
📖 Papers frequently viewed together
205 Citations
60 Citations
278 Citations
References61
Newest
#1Susan B. Johnson (WRAIR: Walter Reed Army Institute of Research)H-Index: 12
#1Susan R. Johnson (WRAIR: Walter Reed Army Institute of Research)H-Index: 32
Last. Hendrik Streeck (University of Duisburg-Essen)H-Index: 35
view all 16 authors...
CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcripti...
53 CitationsSource
#1Terumi KamisawaH-Index: 60
#2Yoh Zen (Kobe University)H-Index: 69
Last. John H. Stone (Harvard University)H-Index: 76
view all 4 authors...
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions ...
561 CitationsSource
#1Hamid Mattoo (Harvard University)H-Index: 21
#2Vinay S. Mahajan (Harvard University)H-Index: 23
Last. Shiv Pillai (Harvard University)H-Index: 50
view all 9 authors...
Background IgG 4 -related disease (IgG 4 -RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG 4 -expressing plasma cells at disease sites. Objective The role of B cells and IgG 4 antibodies in IgG 4 -RD pathogenesis is not well defined. We evaluated patients with IgG 4 -RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disea...
205 CitationsSource
#1Emanuel Della-Torre (Harvard University)H-Index: 25
#2Hamid Mattoo (Harvard University)H-Index: 21
Last. John H. Stone (Harvard University)H-Index: 76
view all 8 authors...
Midline destructive lesion (MDL), also known as ‘lethal midline granuloma’, represents a fibroinflammatory condition characterised by relentless erosion of the nose, paranasal sinuses and palate.1 ,2 Disease attribution remains elusive for many cases, which continue to be labelled ‘idiopathic’.2 Four patients, two males and two females, were referred because of progressive erosion of midline facial structures that had occurred over 2–3 years. Their median age was 40 years (range 27–54). Presenti...
27 CitationsSource
#1Jaime De Calisto (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 11
#2Ninghai Wang (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 22
Last. Cox Terhorst (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 84
view all 6 authors...
Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B cell responses. Additionally, the expression of SAP in double-positive (DP) thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Sla...
27 CitationsSource
#1Hamid Mattoo (Harvard University)H-Index: 21
#2Emanuel Della-Torre (Harvard University)H-Index: 25
Last. Shiv Pillai (Harvard University)H-Index: 50
view all 5 authors...
IgG4 related disease (IgG4-RD) is characterized by a lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, tumefactive lesions, obliterative phlebitis, and mild to moderate eosinophilia. It has been suggested that IgG4-RD is characterized by allergic manifestations and is potentially driven by enhanced T helper type 2 (Th2) responses. We aimed to investigate the potential contribution of atopy to enhanced Th2 responses in IgG4-RD. Peripheral blood mononuclear cells from 39 patients were i...
79 CitationsSource
#1E. Della Torre (Harvard University)H-Index: 1
#2Hamid Mattoo (Harvard University)H-Index: 21
Last. John H. Stone (Harvard University)H-Index: 76
view all 6 authors...
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that can affect virtually every organ system. T helper type 2 responses have been presumed to be pathogenic in this disease and a high proportion of IgG4-RD patients are reported to have longstanding allergies, peripheral blood eosinophilia, and serum IgE elevation. It has therefore been proposed that allergic mechanisms drive IgG4-RD. However, no epidemiological assessment of atopy, peripheral blood eosinophilia, serumIgEconcentrati...
145 CitationsSource
: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesi...
213 CitationsSource
#1André Veillette (McGill University)H-Index: 60
#2Huaijian Guo (McGill University)H-Index: 8
Abstract Signaling lymphocytic activation molecule (SLAM) family receptors have been implicated in normal immunity, immunodeficiencies and autoimmunity. CS1 (also known as CRACC, CD319 and SLAMF7) is a member of the SLAM family expressed on several normal hematopoietic cell types. It is also highly and nearly universally expressed on multiple myeloma (MM) cells. This review focuses on the biology of CS1, both in normal hematopoietic cells and in MM cells. It also discusses the preclinical and cl...
74 CitationsSource
#1Daniel Mucida (La Jolla Institute for Allergy and Immunology)H-Index: 40
#2Mohammad Mushtaq Husain (La Jolla Institute for Allergy and Immunology)H-Index: 2
Last. Hilde Cheroutre (La Jolla Institute for Allergy and Immunology)H-Index: 55
view all 25 authors...
CD4+ and CD8+ T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4+ T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs.
190 CitationsSource
Cited By150
Newest
#1Akane HaraH-Index: 2
#2Tomohiro WatanabeH-Index: 35
Last. Masatoshi KudoH-Index: 88
view all 6 authors...
Source
#2A. Pérez GómezH-Index: 2
Last. M. Álvarez-Mon SotoH-Index: 3
view all 4 authors...
Source
Source
#1Mitsuhiro Akiyama (Keio: Keio University)H-Index: 12
#2Katsuya Suzuki (Keio: Keio University)H-Index: 15
Last. Tsutomu Takeuchi (Keio: Keio University)H-Index: 68
view all 6 authors...
Objectives: Multiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh...
Source
#1Qicai Liu (Fujian Medical University)H-Index: 11
#2Yunfeng Lin (Fujian Medical University)H-Index: 1
Last. Feng Gao (Fujian Medical University)H-Index: 7
view all 9 authors...
1 CitationsSource
#1G. Saitakis (MEE: Massachusetts Eye and Ear Infirmary)
#2Bart K Chwalisz (Harvard University)H-Index: 5
Abstract Purpose of review IgG4-related disease (IgG4-RD) is emerging as a fibro-inflammatory entity affecting multiple organs, including manifold neurologic manifestations. This review discusses general characteristics of IgG4-RD neurologic disease including epidemiology, histology, clinical picture and treatment approaches. Recent findings IgG4-RD is increasingly recognized as an important underlying pathophysiology in multiple disorders of neurologic interest, including orbital inflammation, ...
Source
#1Naoki Kaneko (Ragon Institute of MGH, MIT and Harvard)H-Index: 10
#2Julie Boucau (Ragon Institute of MGH, MIT and Harvard)H-Index: 7
Last. Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
view all 19 authors...
The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with di...
Source
#1Marco Lanzillotta (UniSR: Vita-Salute San Raffaele University)H-Index: 14
#2Andreu Fernández-Codina (UWO: University of Western Ontario)H-Index: 9
Last. Emanuel Della-Torre (UniSR: Vita-Salute San Raffaele University)H-Index: 25
view all 7 authors...
INTRODUCTION Awareness of IgG4-related disease (IgG4-RD) is increasing worldwide and specialists are now familiar with most of its clinical manifestations and mimickers. IgG4-RD promptly responds to glucocorticoids and repeated courses are typically used to induce and maintain remission because the disease relapses in most patients. If left untreated it can lead to organ dysfunction, organ failure and death. Advancement in our understanding of IgG4-RD pathogenesis is leading to the identificatio...
Source
Objectives: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder affecting virtually any organ. Type 1 autoimmune (type 1 AIP) is its pancreatic manifestation. To date, steroids are considered the first-line pancreatitis treatment. The CD20-binding antibody rituximab (RTX) appears a promising steroid-sparing therapy, although long-term data are lacking. We aimed to bridge this gap with a cohort of IgG4-RD patients treated with RTX and to assess the potential value of the Respo...
Source
#1F Bach (Edin.: University of Edinburgh)
#2Munoz Sandoval D (USFQ: Universidad San Francisco de Quito)
Last. Philip J Spence (Edin.: University of Edinburgh)H-Index: 8
view all 15 authors...
Plasmodium vivax offers unique challenges for malaria control and may prove a more difficult species to eradicate than Plasmodium falciparum. Yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. In this study, we inoculated human volunteers with a clonal field isolate of P. vivax and used systems immunology tools to track their response through infection and convalescence. Our data reveal Pl...
Source