J Korean Assoc Oral Maxillofac Surg.  2020 Feb;46(1):3-11. 10.5125/jkaoms.2020.46.1.3.

Review of a novel disease entity, immunoglobulin G4-related disease

• Maehara T
• Moriyama M
• Nakamura S

• KMID: 2471106
• DOI: http://doi.org/10.5125/jkaoms.2020.46.1.3

Abstract

Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and tissue fibrosis. Patients with IgG4-RD who have active, untreated disease exhibit significant increase of IgG4-secreting plasmablasts in the blood. Considerable insight into the immunologic mechanisms of IgG4-RD has been achieved in the last decade using novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploring the interactions between CD4+ T cells and B lineage cells is critical for understanding the pathophysiology of IgG4-RD. Establishment of pathogenic T cell clones and identification of antigens specific to these clones constitutes the first steps in determining the pathogenesis of the disease. Herein, the clinical features and mechanistic insights regarding pathogenesis of IgG4-RD were reviewed.

Keyword

Immunoglobulin G4-related disease; Immunoglobulin G4-related dacryoadenitis and sialoadenitis; Mikuliçz's disease; Küttner's tumor; T cell

MeSH Terms

B-Lymphocytes
Clone Cells
Dacryocystitis
Diagnosis
Fibrosis
Humans
Immunoglobulins*
Molecular Biology
Plasma Cells
Sequence Analysis, RNA
Sialadenitis
T-Lymphocytes
Immunoglobulins

Figure

• 

  Fig. 1 Immunoglobulin G4-related disease (IgG4-RD) tends to form tumefactive lesions. A. A 60-year-old male with IgG4-RD showed multi-organ involvement. F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) showed multiple intense uptakes in the bilateral lacrimal glands, submandibular glands, lymph nodes, kidney, pancreas, and retroperitoneum (arrows). B. Ultrasonography shows hypoechoic areas with a nodal pattern and hyperechoic lines (upper). In Doppler mode, the nodal area shows relatively high vascularization (lower). C. Bilateral enlargement of the submandibular glands in an IgG4-RD patient.

• 

  Fig. 2 Histopathological features of a submandibular gland affected by fibro-inflammation in an immunoglobulin G4-related dacryoadenitis and sialoadeniti (IgG4-DS) patient. The inflammatory cell infiltrate mainly consists of lymphocytes and plasma cells, and fibrosis is evident throughout the tissue. A. Staining with H&E (×200) shows dense fibrosis with lymphocytes, plasma cells, and occasional eosinophils embedded within. B–D. Immunostaining for CD3 (×200), CD4 (×200), and CD8 (×200) shows that T cells are diffusely distributed. E, F. Immunostaining for IgG (×200) and IgG4 (×200) shows that most IgG-positive cells in affected tissues are also IgG4-positive.

• 

  Fig. 3 Immunological responses in immunoglobulin G4-related disease (IgG4-RD). Chronic stimulation via activated antigen-presenting cells induces differentiation of naïve T cells into CD4+ CTLs and follicular helper T (Tfh) cells. In secondary lymphoid organs, Tfh cells collaborate with B cells to drive IgG4 class switching, somatic hypermutation, and plasmablast differentiation of antigen-detecting B cells. Clonally expanded CD4+ CTLs and activated B cells, including IgG4 secreting plasmablasts, might cause IgG4-RD. Reactivation of CD4+ CTLs may require presentation of antigens, including galectin-3, by plasmablasts or other activated B cells at affected tissue sites. Activated CD4+ CTLs and CD8+ cytotoxic T cells may mediate fibrosis and inflammation associated with cytokine secretion or induction of cell death. Activated macrophages may contribute to fibrosis associated with pro-fibrotic cytokine expression.

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