Special Issue Editors

Prof. Dr. Hiroki Takahashi

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Guest Editor

Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
Interests: clinical immunology

Prof. Kenji Notohara

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Guest Editor

Kurashiki Central Hospital, Kurashiki 710-8602, Japan
Interests: surgical pathology

Prof. Dr. Kazunori Yamada

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Guest Editor

Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa-ken 920-0293, Japan
Interests: clinical immunology; clinical nephrology

Special Issue Information

Dear Colleagues,

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by elevated serum IgG4 concentrations, tissue infiltration by IgG4-positive cells, and storiform fibrosis in various organs, including the pancreas, salivary and lacrimal glands, kidneys, retroperitoneum, etc. In particular, those findings regarding IgG4 reported in the early 21st century from Japan provided an important basis for establishing IgG4-RD as a new disease concept. The characteristics of IgG4-RD, such as hypergammaglobulinemia, synchronous or metachronous clinical course, and prompt responsiveness to glucocorticoids, strongly suggest that an autoimmune mechanism exists in the pathophysiology of this disease. In fact, several autoantibodies have recently been reported from some facilities. Considering the pathogenic role of T cells, T helper type 2 cells’ and regulatory T cells’ dominant milieu in the blood and lesions of IgG4-RD has been emphasized so far. Recently, new players have been attracting attention in relation to the pathophysiology of this disease. For example, it has been pointed out that the counts of follicular helper T cells and peripheral helper T cells in peripheral blood each correlate with the numbers of affected organs and serum IgG4 levels. Although these findings suggest that autoimmune abnormality would cause the development of IgG4-related disease, T cell independent immune reaction has also been suggested to be involved in the pathogenesis of IgG4-RD. Accordingly, the question of whether IgG4-RD is an autoimmune disease is an issue that must be elucidated when considering the disease management

Prof. Dr. Kazunori Yamada
Prof. Dr. Hiroki Takahashi
Prof. Kenji Notohara
Guest Editors

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Keywords

IgG4-related disease
fibroinflammatory condition
autoimmune pancreatitis
Mikulicz’s disease
follicular helper T cell
peripheral helper T cell
autoantibody

Published Papers (3 papers)

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Review

13 pages, 1219 KiB

Open AccessReview

Recent Progress on the Roles of Regulatory T Cells in IgG4-Related Disease

by Kazushige Uchida

Immuno 2022, 2(2), 430-442; https://0-doi-org.brum.beds.ac.uk/10.3390/immuno2020026 - 31 May 2022

Cited by 1 | Viewed by 2561

Abstract

IgG4-related disease (RD) is a proposed concept of systemic inflammatory condition from Japanese researchers. Patients with IgG4-RD manifest several immunological and histological characterizations in the organs involved, including elevated levels of serum IgG4 and lympho-plasmacytic infiltration, storiform fibrosis, IgG4-positive plasma cells infiltration, and obstructive phlebitis. Nevertheless, the pathogenesis of IgG4-RD still remains unclear. It has been made clear that several immune cells with regulatory function play a vital part in several diseases. In particular, abnormalities in the function and proportion of regulatory T cells (Tregs) are implicated in several diseases, and their part in IgG4-RD has been investigated. This review offers an overview of the research in IgG4-RD related to Tregs. Herein, the basic information of Tregs, knowledge gained from animal models involving Tregs, and the role of IgG4-RD has been provided. We also included the immunological mechanisms of IgG4-RD based on the data accumulated so far in our hypothesis. Full article

(This article belongs to the Special Issue Is IgG4-Related Disease a Systemic Autoimmune Disease?)

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Figure 1

15 pages, 2431 KiB

Open AccessReview

Orchestration of Immune Cells Contributes to Fibrosis in IgG4-Related Disease

by Naoki Kaneko, Masafumi Moriyama, Takashi Maehara, Hu Chen, Yuka Miyahara and Seiji Nakamura

Immuno 2022, 2(1), 170-184; https://0-doi-org.brum.beds.ac.uk/10.3390/immuno2010013 - 10 Feb 2022

Cited by 2 | Viewed by 3041

Abstract

This review summarizes recent progress in understanding the pathogenesis of IgG4-related disease (IgG4-RD), with a focus on fibrosis. Several studies reported that CD4⁺ T cells with cytotoxic activity promoted by the secretion of granzyme and perforin, cytotoxic CD4⁺ T cells (CD4⁺CTLs), and disease-specific activated B cells, infiltrated inflamed tissues and cooperated to induce tissue fibrosis in autoimmune fibrotic diseases such as IgG4-RD, systemic sclerosis, and fibrosing mediastinitis. An accumulation of cells undergoing apoptotic cell death induced by CD4⁺CTLs and CD8⁺CTLs followed by macrophage-mediated clearing and finally tissue remodeling driven by cytokines released by CD4⁺CTLs, activated B cells, and M2 macrophages may contribute to the activation of fibroblasts and collagen production. In IgG4-RD, this process likely involves the apoptosis of non-immune, non-endothelial cells of mesenchymal origin and subsequent tissue remodeling. In summary, CD4⁺CTLs infiltrate affected tissues where they may cooperate with activated B cells, CD8⁺CTLs, and M2 macrophages, to induce apoptosis by secreting cytotoxic cytokines. These immune cells also drive fibrosis by secreting pro-fibrotic molecules in IgG4-RD. Full article

(This article belongs to the Special Issue Is IgG4-Related Disease a Systemic Autoimmune Disease?)

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Figure 1

11 pages, 2671 KiB

Open AccessReview

Recent Advances in Understanding the Role of TIGIT+ Follicular Helper T Cells in IgG4-Related Disease

by Mitsuhiro Akiyama and Yuko Kaneko

Immuno 2021, 1(4), 380-390; https://0-doi-org.brum.beds.ac.uk/10.3390/immuno1040026 - 26 Oct 2021

Cited by 2 | Viewed by 2501

Abstract

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by elevated serum IgG4 levels and massive infiltration of IgG4+plasma cells. Although storiform fibrosis, obliterative phlebitis and IgG4+plasma cell infiltration are well described pathological features in this disease, the excessive formation of tertiary lymphoid organs (TLOs), particularly in the early phase of the disease lesions, has gained much attention. TLOs of IgG4-RD are orchestrated by specific immune cell subsets including follicular helper T cells (Tfh), CD20+ B cells, and CD21+ follicular dendritic cells (FDCs). Tfh is the key player of this disease because recent studies have suggested the pathological role of this immune cell subset in formation of TLOs, helping IgG4+plasma cell differentiation, inducing storiform fibrosis by secreting interleukin-4, and activating cytotoxic T cells by secreting interleukin-21. We have recently identified a new Tfh subset which expresses T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). TIGIT+Tfh efficiently produces interleukin-21 through OX40 signal, and the increase in peripheral TIGIT+Tfh cells reflects disease activity in IgG4-RD. TIGIT is important to mediate the retention and positioning of TIGIT+Tfh within TLOs through interaction with CD155 expressed on CD21+ FDCs. In this review, we summarize and discuss recent progress in understanding the pathogenesis of IgG4-RD, focusing on TIGIT+Tfh. Full article

(This article belongs to the Special Issue Is IgG4-Related Disease a Systemic Autoimmune Disease?)

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