• Humans
• Immunoglobulin G4-Related Disease/drug therapy
• Immunoglobulin G4-Related Disease/immunology
• Molecular Targeted Therapy/methods
• Animals
• Glucocorticoids/therapeutic use

• APRIL
• Behçet’s disease
• ocular

• Autoimmune pancreatitis
• Fungi
• IgG1
• IgG4
• IgG4-related disease

• IgG-AID
• IgG-RD
• IgG4
• Systemic lupus erythematosus

• Humans
• Lupus Erythematosus, Systemic/immunology
• Immunoglobulin G/immunology
• Immunoglobulin G/blood
• Autoantibodies/immunology
• Autoantibodies/blood
• Antibodies, Antinuclear/immunology
• Antibodies, Antinuclear/blood
• Animals

• GM-CSF
• bronchoalveolar lavage
• pulmonary alveolar proteinosis
• rituximab
• whole-lung lavage

• Pulmonary Alveolar Proteinosis/therapy
• Pulmonary Alveolar Proteinosis/diagnosis
• Pulmonary Alveolar Proteinosis/pathology
• Humans
• Bronchoalveolar Lavage
• Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
• Pulmonary Surfactants/metabolism
• Pulmonary Surfactants/therapeutic use
• Macrophages, Alveolar/metabolism

• Clinical picture
• IgG4-related disease
• IgG4-related sialadenitis/dacryoadenitis
• Pathogenesis of IgG4-RD
• Treatment

• Humans
• Immunoglobulin G4-Related Disease/diagnosis
• Immunoglobulin G4-Related Disease/pathology
• Autoimmune Diseases/pathology
• Delayed Diagnosis
• Salivary Glands/pathology
• Sialadenitis/diagnosis
• Immunoglobulin G

• Belimumab
• IgG4-related disease
• Systemic lupus erythematosus

• Male
• Humans
• Aged
• Immunoglobulin G4-Related Disease/complications
• Immunoglobulin G4-Related Disease/diagnosis
• Immunoglobulin G4-Related Disease/drug therapy
• Lupus Erythematosus, Systemic/complications
• Lupus Erythematosus, Systemic/diagnosis
• Lupus Erythematosus, Systemic/drug therapy
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antibodies, Monoclonal/therapeutic use
• Glucocorticoids/therapeutic use
• Immunoglobulin G
• Immunosuppressive Agents/therapeutic use
• Treatment Outcome

• B-lymphocytes
• T-lymphocyte subsets
• autoimmune diseases

• Humans
• Immunoglobulin G4-Related Disease/genetics
• Leukocytes, Mononuclear
• Submandibular Gland
• Single-Cell Gene Expression Analysis
• Immunoglobulin G

Autoimmune pancreatitis (AIP), a chronic inflammation caused by the immune system attacking the pancreas, usually presents imaging and clinical features that overlap with those of pancreatic ductal adenocarcinoma (PDAC). Serum biomarkers, substances that quantitatively change in sera during disease development, are a promising non-invasive tool with high utility for differentiating between these diseases. In this way, the presence of AIP is currently suspected when serum concentrations of immunoglobulin G4 (IgG4) antibody are elevated. However, this approach has some drawbacks. Notably, IgG4 antibody concentrations are also elevated in sera from some patients with PDAC. This review focuses on the most recent and relevant serum biomarkers proposed to differentiate between AIP and PDAC, evaluating the usefulness of immunoglobulins, autoantibodies, chemokines, and cytokines. The proposed serum biomarkers have proven useful, although most studies had a small sample size, did not examine their presence in patients with PDAC, or did not test them in humans. In addition, current evidence suggests that a single serum biomarker is unlikely to accurately differentiate these diseases and that a set of biomarkers will be needed to achieve adequate specificity and sensitivity, either alone or in combination with clinical data and/or radiological images.

• Autoimmune pancreatitis
• Pancreatic ductal adenocarcinoma
• Serum
• Biomarkers
• Differentiation

The IgG4-related disease (IgG4-RD) is an immune-mediated disorder with fibrotic manifestations. However, the transcriptional profiles of immune cell subsets at single-cell level are unknown. Herein, single-cell sequencing was used to assess the specific cell subpopulations and pathways in peripheral blood mononuclear cells (PBMCs) of IgG4-RD.

Single-cell sequencing was performed using the PBMCs from four patients with IgG4-RD and three healthy controls (HCs). Functional enrichment and cell analysis were performed through re-clustering of PBMCs to assess functional pathways and intercellular communication networks in IgG4-RD. Western blot and flow cytometry were used to verify sequencing and functional enrichment results.

Four major cell types and 21 subtypes were identified. Further subclustering demonstrated that plasma B-cell proportions increased with increasing glycolysis/gluconeogenesis activity in IgG4-RD. Re-clustering of myeloid cells showed that EGR1 and CD36 expressions were significantly increased in CD14⁺ monocytes of IgG4-RD, as validated by Western blot analysis. Moreover, tumor necrosis factor (TNF) production pathways were positively regulated in CD14⁺ monocytes of IgG4-RD. In vitro stimulation showed that CD14⁺ monocytes of IgG4-RD could secrete higher levels of TNF-α . Notably, the proportions of CD8 central memory T (TCM) and TIGIT⁺ CD8 cytotoxic T (CTL) increased in patients with IgG4-RD compared with HCs. Further interaction analysis showed that B cell activation factor (BAFF) signaling pathways were enriched from myeloid cells subsets to B cells.

This study enhances the understanding of the cellular heterogeneity and transcriptional features involved in the pathogenesis of IgG4-RD, providing key clinical implications.

• B-Lymphocytes
• Humans
• Immune System Diseases
• Immunoglobulin G
• Immunoglobulin G4-Related Disease
• Leukocytes, Mononuclear
• Lymphocyte Activation

• National Natural Science Foundation of China

The immune-mediated invasion of IgG4-positive plasma cells in the liver is found in some autoimmune hepatitis. Giant-cell hepatitis (GCH) is a very rare pathological feature in adults, and the clinical characteristics of the simultaneous appearance of the two pathological phenomena are not clear.

A 68-year-old woman was hospitalized with fatigue, poor appetite, and yellow urine for 20 d. Liver function tests and immunological indexes were significantly abnormal and accompanied by elevated serum IgG4 levels. Liver pathology revealed severe inflammation of the interface between the portal tract and hepatocytes, portal area inflammation, plasma cell infiltration, formation of rosette cells, IgG4-positive plasma cells > 10/high-power field, IgG4/IgG > 40%, and multinucleated liver cell swelling. IgG4-related autoimmune hepatitis (AIH) combined with GCH was diagnosed, and methylprednisolone was administered at 40 mg/day. Two weeks later, the clinical symptoms disappeared, and the liver function and immunological indicators were significantly improved. Methylprednisolone was reduced at a rate of 4–8 mg per week to 8 mg/day for maintenance. A second liver biopsy 48 wk later indicated that liver inflammation and fibrosis were significantly improved. IgG4-positive plasma cells and GCH were not detected. A literature search was conducted to analyze articles reporting similar pathological phenomena.

AIH with simultaneous IgG4-positive plasma cell infiltration and GCH, liver inflammation, and fibrosis is possibly more severe than typical AIH but sensitive to corticosteroids.

• IgG4
• Autoimmune hepatitis
• Giant-cell hepatitis
• Case report

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory disorder associated with fibrosis and abundant tissue lymphoplasmacytic infiltrations. It typically affects the pancreas, the salivary glands, and the retroperitoneal space. However, it might also involve multiple other organs, including the orbit and the thyroid. Recent studies have suggested that IgG4 plays a role in the pathophysiology of autoimmune thyroid diseases. This ultimately led to the establishment of new clinical entities called IgG4-related thyroid disease and thyroid disease with an elevation of IgG4. The aim of this paper is to describe the pathophysiological, histopathological, and clinical features of Graves' Disease (GD) and Graves' Orbitopathy (GO) with elevated IgG4 levels. Multiple studies have demonstrated higher IgG4 serum concentrations in GD patients than in healthy euthyroid controls. Depending on the studied population, elevated serum IgG4 levels occur in 6.4-23% (average: 10.3%) of all patients with GD, 8.3-37.5% (average: 17.6%) of patients with GO, and 0-9.8% (average: 5.4%) of patients with GD without GO, while GO patients comprise 37.5-100% (average: 65.8%) of all GD patients with elevated IgG4 levels. Characteristic features of GD with elevated IgG4 levels include lower echogenicity of the thyroid gland on ultrasound examination, peripheral blood eosinophilia, higher prevalence of orbitopathy, and better response to antithyroid drugs with a tendency to develop hypothyroidism when compared to patients with GD and normal levels of IgG4. Typical signs of GO accompanied by increased concentration of IgG4 include younger age at diagnosis, and more severe course of the disease with a higher Clinical Activity Score (CAS).. We strongly recommend considering the diagnosis of GO with elevated IgG4 in patients with an established diagnosis of GD, elevated serum IgG4 levels, and clinical features of ophthalmic disease overlapping with those of IgG4-related orbital disease.

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration and tissue destruction of exocrine glands such as salivary glands. Although the formation of ectopic lymphoid tissue in exocrine glands and overproduction of autoantibodies by autoreactive B cells highlight the critical involvement of B cells in disease development, the precise roles of various B cell subsets in pSS pathogenesis remain partially understood. Current studies have identified several novel B cell subsets with multiple functions in pSS, among which autoreactive age-associated B cells, and plasma cells with augmented autoantibody production contribute to the disease progression. In addition, tissue-resident Fc Receptor-Like 4 (FcRL4)⁺ B cell subset with enhanced pro-inflammatory cytokine production serves as a key driver in pSS patients with mucosa-associated lymphoid tissue (MALT)-lymphomas. Recently, regulatory B (Breg) cells with impaired immunosuppressive functions are found negatively correlated with T follicular helper (Tfh) cells in pSS patients. Further studies have revealed a pivotal role of Breg cells in constraining Tfh response in autoimmune pathogenesis. This review provides an overview of recent advances in the identification of pathogenic B cell subsets and Breg cells, as well as new development of B-cell targeted therapies in pSS patients.

• B cells
• pathogenesis
• primary Sjögren’s syndrome
• regulatory functions
• treatment

Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4⁺ plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements.

Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD.

In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy.

Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.

• Galectin-9
• IgG4-related disease
• Immune checkpoint molecules
• T cell immunoglobulin and mucin-containing-molecule-3

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.

• Biomarker
• Autoimmune pancreatitis
• Immunoglobulin G4-related disease
• Plasmacytoid dendritic cells
• Cytokine
• Chemokine

• Animals
• Autoimmune Diseases/diagnosis
• Autoimmune Pancreatitis
• Biomarkers
• Humans
• Immunoglobulin G4-Related Disease/diagnosis
• Mice
• Pancreatitis/diagnosis

• Abatacept
• biologic
• corticosteroids
• fibrosis
• glucocorticoids
• igg4
• igg4-related disease
• rituximab
• therapy
• treatment

Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP.

BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles.

In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively), and BALF BAFF and APRIL levels were significantly increased versus disease controls (p < 0.0001 and p < 0.01, respectively). Serum BAFF levels (but not APRIL levels) were significantly correlated with Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, SP-A, and lactate dehydrogenase (p < 0.0001). There was no significant correlation between serum BAFF or APRIL levels and anti-GM-CSF autoantibody. BAFF and APRIL were negatively correlated with single-breath diffusion capacity for carbon monoxide (DLco) (p = 0.004) and forced vital capacity (p = 0.04), respectively. BAFF (but not APRIL) in BALF was negatively correlated with vital capacity (p = 0.04) and DLco (p = 0.006). There were significant correlations between disease severity and BAFF levels in serum (p = 0.04) and BALF (p = 0.007). Serum levels of anti-GM-CSF autoantibody, BAFF, and APRIL were not significantly affected by WLL or inhalation of recombinant human GM-CSF.

BAFF and APRIL levels of sera and BALF in APAP were significantly increased compared with healthy volunteer and disease control, and the BAFF and APRIL pathway might have important specific roles in pathogenesis of APAP. Our data suggest a new perspective of future treatment for APAP.

• Autoimmune pulmonary alveolar proteinosis
• B cell‐activating factor
• Biomarker

• autoimmunity
• immunological disorders
• biomarkers
• medical research
• rheumatology

• Adult
• Biomarkers/blood
• Female
• Humans
• Immunoglobulin G/blood
• Immunoglobulin G4-Related Disease/blood
• Immunoglobulin G4-Related Disease/drug therapy
• Immunoglobulin G4-Related Disease/immunology
• Immunoglobulin Light Chains/blood
• Immunosuppressive Agents/therapeutic use
• Male
• Middle Aged
• Phenotype

• The Binging Site Group Ltd

• Adrenal Cortex Hormones/therapeutic use
• Biomarkers/blood
• Glucocorticoids/therapeutic use
• Humans
• Immunity, Innate
• Immunoglobulin G/blood
• Immunoglobulin G/immunology
• Immunoglobulin G4-Related Disease/diagnosis
• Immunoglobulin G4-Related Disease/physiopathology
• Magnetic Resonance Imaging
• Neck/diagnostic imaging
• Neck/pathology
• Phenotype
• Tomography, X-Ray Computed
• Treatment Outcome

• B lymphocytes
• B-cell activating factor
• cutaneous leishmaniasis
• hypergammaglobulinemia
• interferon-gamma
• interleukin-6
• mucocutaneous leishmaniasis

This study aimed to investigate the contribution of a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) superfamily implicated in plasma cell survival, to the development of plasma cell–rich lesions in immunoglobulin G4–related disease (IgG4-RD).

We performed immunohistochemical staining for APRIL with Stalk-1 and Aprily-8 antibodies specifically recognizing APRIL-producing cells and secreted APRIL, respectively, in renal and submandibular lesions of IgG4-RD in comparison with those of Sjögren’s syndrome and sialolithiasis.

Numerous Stalk-1-positive APRIL-producing cells were detectable in lesions of IgG4-RD. These cells, identified as CD163-positive M2 macrophages, secreted APRIL that distributed close to and even on infiltrating plasma cells. In contrast, APRIL-producing cells and the secreted form of APRIL were rarely detectable in lesions of Sjögren’s syndrome or sialolithiasis. Notably, APRIL expression decreased concomitantly with the level of plasma cell infiltration after successful glucocorticoid treatment.

Abundant infiltration into tissue lesions of APRIL-producing M2 macrophages and retention of secreted APRIL in plasma–cell–rich areas support a role for APRIL in the pathogenesis of plasma cell–rich lesions in IgG4-RD.

• APRIL
• IgG4–related disease
• macrophages

• Adaptive immune
• IgG4-related disease
• Innate immune
• Pathogenesis

• DNA microarray
• IgG4-related disease
• Sjögren’s syndrome
• chemokine (C–C motif) ligand 18
• labial salivary glands

• igg4-related sialadenitis
• cryoglobulinemia
• igg4⁺ plasmocytes
• storiform fibrosis

• Cryoglobulinemia/complications
• Cryoglobulinemia/drug therapy
• Female
• Humans
• Immunoglobulin G4-Related Disease/complications
• Immunoglobulin G4-Related Disease/drug therapy
• Immunosuppressive Agents/therapeutic use
• Middle Aged
• Sialadenitis/complications
• Sialadenitis/drug therapy

• Biomarker
• Diagnosis
• Disease activity
• IgG4-RD
• Prognosis
• Treatment

• IgG4
• IgG4-related disease
• autoantigens
• biomarker
• pathogenesis

• IgG4-related disease
• autoimmune pancreatitis
• innate immunity

• B cells
• IgG4
• IgG4-related disease
• Plasmablasts
• Rituximab

• APRIL
• BAFF
• SLE
• TACI-Ig
• autoimmune disease

• IgG4-related disease
• IgG4-related sialadenitis
• Sjögren's syndrome

• autoimmune pancreatitis
• glucocorticoids
• igg4
• igg4-related disease
• rituximab

• Humans
• Immunoglobulin G
• Paraproteinemias/therapy

• Aged
• Cryoglobulinemia/complications
• Cryoglobulinemia/drug therapy
• Humans
• Immunoglobulin G/blood
• Male
• Mononeuropathies/complications
• Plasma Cells/pathology
• Prednisolone/therapeutic use
• Sialadenitis/complications
• Submandibular Gland/pathology
• Vasculitis/complications
• Vasculitis/drug therapy
• Vasculitis, Leukocytoclastic, Cutaneous

• Autoimmune Diseases/diagnosis
• Autoimmune Diseases/immunology
• Diagnosis, Differential
• Humans
• Immunoglobulin G/immunology
• Plasma Cells/immunology

• Autoimmune disease
• Diagnostic criteria
• Histology
• Lymphoproliferative
• Pancreatitis
• Plasma cells
• Sclerosing fibrosis

• CCL18
• Fibrosis;
• IL-10;
• IgG4-related dacryoadenitis and sialoadenitis;
• M2 macrophage;

IgG4-RD, a novel disease involving many immune-system components

IgG4-related disease (IgG4-RD) is a novel clinical entity proposed in Japan in the 21th century and is attracting strong attention over the world. The characteristic manifestations of IgG4-RD are increased serum IgG4 concentration and tumefaction by IgG4⁺ plasma cells. Although the clinical manifestations in various organs have been established, the pathogenesis of IgG4-RD is still unknown. Recently, many reports of aberrant acquired immunity such as T_h2-diminated immune responses have been published. However, many questions still remain, including questions about the pathogenesis of IgG4-RD and the roles of IgG4. In this review, we discuss the pathogenesis of IgG4-RD by focusing on the cross-talk between innate and acquired immunity.

• IgG4
• Th2
• regulatory T cell
• toll-like receptor