CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease

Perugino, Cory A.; Kaneko, Naoki; Mitsui, Takashi; Mattoo, Hamid; Kers, Jesper; Allard-Chamard, Hugues; Mahajan, Vinay S.; Liu, Huan; Della‐Torre, Emanuel; Murphy, Samuel J.H.; Ghebremichael, Musie; Wallace, Zachary S; Bolster, Marcy B.; Harvey, Liam; Mylvaganam, Geetha; Tuncay, Yesim; Liang, Lloyd L.; Montesi, Sydney B.; Zhang, Xiuwei; Tinju, Akira; Mochizuki, Keita; Munemura, Ryusuke; Sakamoto, M.; Moriyama, Masafumi; Nakamura, Seiji; Yosef, Nir; Stone, John H.; Pillai, Shiv

doi:10.1016/j.jaci.2020.05.022

Cited by 65 publications

(61 citation statements)

References 47 publications

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“…The one CD4+ T cell subset that was clearly expanded in the lungs of COVID-19 patients was the CD4+SLAMF7+ CD4+CTL population (Figures 2A and B). A very similar increase was observed using CX3CR1 instead of SLAMF7 as a marker for CD4+CTLs (Figures S2C and D) (Weiskopf et al, 2015, Perugino et al, 2021). CD4+CTLs were increased both in terms of absolute numbers as well as proportions and this increase was most significant in late or resolving patients.…”

Section: Resultssupporting

confidence: 78%

“…Given the known links of CD4+CTLs to fibrosis in a number of diseases (Mattoo et al, 2016; Maehara et al, 2020; Perugino et al, 2021; Allard-Chamard et al, 2021; Wang et al, 2021), these T cells may be key contributors to the acceleration of apoptotic death, inflammation and possibly the eventual induction of lung fibrosis already documented in severe COVID-19.…”

Section: Introductionmentioning

confidence: 99%

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Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

Kaneko

Boucau

Huang

et al. 2021

Preprint

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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 disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

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Section: Resultssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

Kaneko

Boucau

Huang

et al. 2021

Preprint

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“…Della-Torre et al [133] have identified a subset of CD4 + SLAMF + CD8a -T EM (CD45RO), the cytotoxic T cells with effector memory phenotype, which is oligoclonally expanded in patients with active IgG4-RD and can be suppressed following glucocorticoid administration to remit disease. In short conclusion, both CD4 + CTL and CD8 + CTL in disease lesions of IgG4-RD may contribute to the induction of cell apoptosis and tissue fibrosis of the disease [116].…”

Section: The Immunopathologic Roles Of Aberrant Functions Of Treg T mentioning

confidence: 81%

“…It is particularly interesting that the antigen-presenting function of memory B cells can enhance proliferation and maturation of follicular helper T 2 cell (T fh2 ) to become CD4 + -and CD8 + -cytotoxic T cell (Tc) populations [104]. The two cytotoxic T cell subpopulations then secrete perforin and granzymes (A and B) to induce apoptosis of non-immune, non-endothelium mesenchymal cells, inflammation and finally fibrosis in IgG4-RD [116]. On the other hand, after receiving help signals from T fh2 cells, B cells mature to CD19 + plasmablasts, which can subsequently produce autoantibodies, proinflammatory cytokine (IL-1β) and profibrotic cytokines (TGF-β1, LOXL2 and PDGFB) to enhance collagen fiber synthesis and deposition driven by FBs and MFBs.…”

Section: Pathogenic Roles Of B Cell Subsets B Cell-derived Factors Amentioning

confidence: 99%

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

Hsieh

Shen

Liao

et al. 2020

IJMS

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IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part.

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“…It is currently believed that abnormal immune response against infection, allergen, or tissue injury may be the initiating factors in the pathogenesis of IgG4-RD, and then triggers can activate T follicular helper (Tfh) and T follicular regulatory (Tfr) cell immune response, and the subsequent production of IL-4/IL-10 cytokines can promote the production and class switch of IgG4 and IgE in plasmablasts, eosinophil recruitment, and fibroblast activation [ 2 , 30 , 31 ] Finally, it leads to the onset of IgG4-RD. Recent studies have identified that CD4+ cytotoxic T lymphocytes (CTLs) may also play a central role in this pathophysiological process [ 32 , 33 ]. It is well known that in some autoimmune diseases such as systemic lupus erythematosus, the emergence of certain autoantibodies is often associated with the heterogeneity in organ involvement and clinical manifestations [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical features and relapse risks of IgG4-related ophthalmic disease: a single-center experience in China

et al. 2021

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Background IgG4-related ophthalmic disease (IgG4-ROD) is one of the phenotypes of IgG4-related disease (IgG4-RD), and its lesions are mainly located in the ocular. Currently, there are few studies on IgG4-ROD and no study has compared the phenotypic differences between IgG4-ROD and non IgG4-ROD (nIgG4-ROD). Thus, it is difficult to establish the optimal treatment strategy for IgG4-ROD. The aim of this study was to identify the disparities between the two groups and to clarify the risk factors for IgG4-ROD relapse. Methods 434 IgG4-RD patients met comprehensive diagnostic criteria and diagnosed at Peking University People’s Hospital between January 2009 and January 2020 were recruited in this study. Patients were divided into IgG4-ROD and nIgG4-ROD group according to the ophthalmic involvement. Demographic, clinical, and laboratory data of two groups were collected and compared. Cox regression analysis was used to identify the independent risk factors for IgG4-ROD relapse. Results 255 IgG4-ROD patients were identified in this study. IgG4-ROD group had almost equal sex ratio, younger age of disease onset and diagnosis comparing with nIgG4-ROD patients. As compared to nIgG4-ROD group, higher percentage of IgG4-ROD patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) for IgG4-RD; moreover, IgG4-ROD patients had higher AECC scores and IgG4-RD responder index (RI). Allergic diseases and multiorgan involvement were more common in IgG4-ROD group. IgG4-ROD was frequently associated with salivary gland, paranasal sinus, lung, and lymph node involvement, while retroperitoneal fibrosis and biliary system lesions were more common in nIgG4-ROD. IgG4-ROD patients had higher serum IgG4 levels, IgG4/IgG ratio, IgE levels, and lower CRP levels. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse. IgG4-ROD patients treated with initial glucocorticoid plus immunosuppressant had longer relapse-free survival time than patients treated with initial glucocorticoid monotherapy. Conclusions IgG4-ROD patients had distinctive clinical features compared with nIgG4-ROD patients. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse, which could prolong the relapse-free survival time of IgG4-ROD patients. These findings may have important implications for understanding and management of IgG4-ROD.

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CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease

Cited by 65 publications

References 47 publications

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

Clinical features and relapse risks of IgG4-related ophthalmic disease: a single-center experience in China

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