CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum.

Published on Feb 1, 2021in Journal of Immunology4.886
· DOI :10.4049/JIMMUNOL.2000433
Hugues Allard-Chamard6
Estimated H-index: 6
Faisal Alsufyani2
Estimated H-index: 2
+ 7 AuthorsShiv Pillai50
Estimated H-index: 50
Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.
📖 Papers frequently viewed together
22 Citations
11 Citations
298 Citations
#1Cory A. Perugino (Harvard University)H-Index: 13
#2Naoki Kaneko (Kyushu University)H-Index: 10
Last. Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
view all 28 authors...
Abstract Background IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs, the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and of apoptotic cell death remain undefined in IgG4-RD. Objective The goals of this study were to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribut...
9 CitationsSource
#1Takashi MaeharaH-Index: 20
#2Naoki Kaneko (MIT: Massachusetts Institute of Technology)H-Index: 1
Last. Shiv Pillai (MIT: Massachusetts Institute of Technology)H-Index: 50
view all 16 authors...
Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of thirty-five untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and...
22 CitationsSource
#1Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
#2Cory A. Perugino (Harvard University)H-Index: 13
Last. Naoki Kaneko (Kyushu University)H-Index: 10
view all 3 authors...
Purpose of reviewTo summarize recent advances in the understanding of the pathogenesis of IgG4-related disease.Recent findingsLimited data exist to explain genetic susceptibility to IgG4-related disease and the underlying triggers for this disease have not yet been identified. Cytotoxic CD4+ T cells
10 CitationsSource
#1Emanuel Della-Torre (UniSR: Vita-Salute San Raffaele University)H-Index: 25
#2Elena Rigamonti (UniSR: Vita-Salute San Raffaele University)H-Index: 9
Last. Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
view all 19 authors...
Background IgG4-related disease (IgG4-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. Objective In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG4-RD. Methods Total circulating CD19+ B lymphocytes, naive B cells, memory B cells, or plasmablasts from pati...
24 CitationsSource
#1Hang Liu (Ragon Institute of MGH, MIT and Harvard)H-Index: 5
#2Cory A. Perugino (Ragon Institute of MGH, MIT and Harvard)H-Index: 13
Last. Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
view all 7 authors...
OBJECTIVE: Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4-RD. METHODS: Au...
14 CitationsSource
#1Shiv Pillai (Ragon Institute of MGH, MIT and Harvard)H-Index: 50
Purpose of reviewTo summarize recent advances in the understanding of the pathogenesis of autoimmune fibrotic diseases. These diseases include IgG4-related disease, systemic sclerosis and lupus nephritis.Recent findingsRecent studies indicate that a poorly studied subset of helper T cells, cytotoxic
5 CitationsSource
#1Cory A. Perugino (Harvard University)H-Index: 13
#2Sultan B. AlSalem (KSU: King Saud University)H-Index: 1
Last. Shiv Pillai (Harvard University)H-Index: 50
view all 13 authors...
Background The antigenic trigger that drives expansion of circulating plasmablasts and CD4+ cytotoxic T cells in patients with IgG4-related disease (IgG4-RD) is presently unknown. Objective We sought to sequence immunoglobulin genes from single-cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG4-RD by using mass spectrometry. Methods Paired heavy and light chain cDNAs from dominant plasmablast clones were express...
52 CitationsSource
#1Masahiro Shiokawa (Kyoto University)H-Index: 12
#2Yuzo Kodama (Kyoto University)H-Index: 35
Last. Tsutomu Chiba (Kyoto University)H-Index: 81
view all 24 authors...
Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 2...
63 CitationsSource
#1Emanuel Della-Torre (UniSR: Vita-Salute San Raffaele University)H-Index: 25
#2Emanuele Bozzalla-Cassione (UniSR: Vita-Salute San Raffaele University)H-Index: 3
Last. Angelo A. Manfredi (UniSR: Vita-Salute San Raffaele University)H-Index: 62
view all 19 authors...
OBJECTIVE: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (TEM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+...
32 CitationsSource
#1Veena S. Patil (La Jolla Institute for Allergy and Immunology)H-Index: 10
#2Ariel Madrigal (La Jolla Institute for Allergy and Immunology)H-Index: 4
Last. Pandurangan Vijayanand (UCSD: University of California, San Diego)H-Index: 28
view all 12 authors...
CD4 + cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4 + memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene express...
107 CitationsSource
Cited By1