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.
Highlights
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease, which was initially first reported from Japan [1,2]
These findings suggest that Tfh2 is a source of IL-4 and IL-21, which are involved in IgG4 production, induction of plasmablast/plasma cell differentiation, and fibrosis process
We previously reported the increase of activated PD-1+ CXCR5+ Tfh in peripheral blood in patients with IgG4-RD, correlating with their disease activity [52]
Summary
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease, which was initially first reported from Japan [1,2]. 2. Hyper Formation of Tertiary Lymphoid Organs in the Inflamed Tissues of IgG4-RD. IgG4-producing cells within lymphoid organs thecircle blue(c) circle (c) shown are at high field (d). CD3 staining (brown, low powerthat field) that CD20+ B cells mainly reside within tertiary lymphoid organs (e). A recent mation without fibrosis in the renal parenchyma and around medium-sized vessels when study has reported that kidney tissue affected by IgG4-RD demonstrated TLOs formathe biopsy was conducted in the very early stages of the disease [29]. Reside within tertiary demonstrates that CD21+ follicular dendritic cells shape like “meshwork” and reside within tertiary lymphoidorgans organs affected lacrimal gland of IgG4-RD. FDCs are shaped like a “meshwork” inside the TLOs of IgG4-RD to contact intimately with Tfh and B cells and directly activate Tfh to promote germinal centre reaction. We believe that FDCs are one of the culprit immune cells which play a crucial role in the upstream events of the IgG4-RD disease process
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