Search

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.

Hypocomplementemia has been frequently reported in immunoglobulin G4-related kidney disease (IgG4-RKD). However, studies on the role of complement system in IgG4-RKD are lacking. A total of 40 429 renal biopsies from January 2010 to January 2018 were reexamined in the present study, and 17 patients were confirmed to meet the criteria of IgG4-RKD. According to the serum C3 levels, they were divided into 2 groups: the low-C3 group (C3 <0.8 g/L, n = 7) and the normal-C3 group (C3 ≥0.8 g/L, n = 10). Compared with the normal-C3-level group, the patients in the low-C3-level group had lower serum C4 concentrations (P = .025), higher serum IgG4 concentrations (P = .003), higher positive rates in rheumatoid factor (P = .033), more severe storiform fibrosis (P = .007) at diagnosis, and higher blood urea nitrogen levels at the latest test (P = .04). The serum levels of C3 were in negative correlation with the serum levels of IgG4 (P = .003), the levels of rheumatoid factor (P = .002), renal deposition of C1q (P = .028), storiform fibrosis (P < .001), scores of interstitial fibrosis (P = .015), the amount of renal IgG4-positive (IgG4 + ) plasma cells (P = .020), the ratios of IgG4 + plasma cells/CD138 + cells (P = .018), and the blood urea nitrogen concentrations at the last test (P = .023). Our study shows that IgG4-RKD is a relatively rare entity. Complement system may participate in the development of IgG4-RKD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A 62-year-old woman presented with a one month history of a hard, nonmobile subcutaneous mass along the right nasojugal fold. Hematological studies showed elevated serum immunoglobulin G4 levels. Histopathological examination of the biopsy sample disclosed immunoglobulin G4-positive lymphoplasmacytic infiltration with a storiform fibrosis, vein occlusion, and epithelioid granulomas with necrosis. Systemic review corresponded to a sarcoidosis. Without treatment, the eyelid mass did not recur six months after the excisional biopsy.

Immunoglobulin G4-associated (IgG4) autoimmune diseases are systemic multiorgan diseases with variable clinical presentation. Principally, all organs can be affected. All IgG4-associated diseases have the same morphological correlate in common, which includes lymphoplasmacellular inflammation with abundant IgG4-positive plasma cells, obliterative phlebitis and storiform fibrosis, each with a variable manifestation. The exact pathogenesis is not yet completely understood; however, as in most cases glucocorticoids induce a prompt clinical response to therapy, this new multisystemic disease must be taken into consideration not only by pathologists but also by radiologists.

IgG4-related kidney disease (IgG4-RKD) occasionally progresses to chronic renal failure and is pathologically characterized by IgG4-positive lymphoplasmacyte-rich tubulointerstitial nephritis with storiform fibrosis (bird's-eye pattern fibrosis). Although radiology reveals a heterogeneous distribution of affected areas in this disease, their true distribution within the whole kidney is still unknown because of difficulty in estimating this from needle biopsy samples. Using 5 autopsy specimens, the present study histologically characterized the distribution and components of interstitial inflammation and fibrosis in IgG4-RKD. Interstitial lymphoplasmacytic infiltration or fibrosis was observed in a variety of anatomical locations such as intracapsular, subcapsular, cortical, perivascular, and perineural regions heterogeneously in a patchy distribution. They tended to be more markedly accumulated around medium- and small-sized vessels. Storiform fibrosis was limited to the cortex. Immunostaining revealed nonfibrillar collagens (collagen IV and VI) and fibronectin predominance in the cortical lesion, including storiform fibrosis. In contrast, fibril-forming collagens (collagen I and III), collagen VI, and fibronectin were the main components in the perivascular lesion. In addition, α-smooth muscle actin-positive myofibroblasts were prominently accumulated in the early lesion and decreased with progression, suggesting that myofibroblasts produce extracellular matrices forming a peculiar fibrosis. In conclusion, perivascular inflammation or fibrosis of medium- and small-sized vessels is a newly identified pathologic feature of IgG4-RKD. Because storiform fibrosis contains mainly nonfibrillar collagens, "interstitial fibrosclerosis" would be a suitable term to reflect this. The relation between the location and components of fibrosis determined in whole kidney samples provides new clues to the pathophysiology underlying IgG4-RKD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin G4-related disease (IgG4-RD) is characterized by extensive infiltration of IgG4(+) plasma cells and fibrosis in various organs. However, the involvement of the ovary in IgG4-RD has never been reported. A 59-year-old woman presented with urinary retention. Magnetic resonance imaging and computed tomography revealed a huge multinodular pelvic mass and common iliac/para-aortic lymph node swelling. A laparotomy was performed under the suspicion of advanced ovarian cancer, and the pelvic mass was identified as ovary in origin. Histopathology of the excised tumor revealed massive lymphoplasmacytic infiltration (>90% were IgG4(+) plasma cells), storiform fibrosis, and obliterative phlebitis; thus leading to a diagnosis of IgG4-RD. We conclude that IgG4-RD can present as a bilateral ovarian mass along with lymphadenopathy, therefore mimicking ovarian cancer., (© 2015 Japan Society of Obstetrics and Gynecology.)

IgG4 cholangiopathy is a recently described distinctive type of hepatobiliary manifestation of IgG4-related disease. This is often misdiagnosed as a malignancy of the hepatobiliary system on clinical presentation and imaging. Accurate diagnosis is crucial for appropriate management. Histopathology provides crucial information and is characterized by IgG4-positive lymphoplasmacytic infiltration with storiform fibrosis and obliterative phlebitis. We present the clinicopathological spectrum of a retrospective series of 6 cases of IgG4 cholangiopathy that clinically masqueraded as hepatobiliary malignancies., (© The Author(s) 2015.)

Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory condition that may involve any organ in the body, including the kidneys. However, renal parenchymal lesions are not seen frequently and the treatment strategy remains unclear. We describe a case of IgG4-related renal mass, which resolved spontaneously. The patient presented with right loin pain, constitutional symptoms and raised inflammatory markers. Magnetic resonance imaging (MRI) showed a large infiltrative mass centered on the right renal hilum and biopsy demonstrated histological changes in keeping with IgG4-RD. A careful 'watch-and-wait' approach was taken and at six months following initial presentation, the patient's symptoms had fully resolved and inflammatory markers had normalised. Repeat MRI showed almost complete resolution of the mass. We propose that a careful 'watch-and-wait' approach could be considered as an alternative to immune suppression for IgG4-related renal masses, especially if they are not causing symptoms or organ compromise., (© Royal College of Physicians 2015. All rights reserved.)

Objectives: Our study aimed to clarify the immunological characteristics and the mechanism of interstitial fibrosis in immunoglobulin G4-related kidney disease (IgG4-RKD) by the immunohistological analysis., Methods: Immunohistological study was performed in the biopsied renal tissues of 16 IgG4-RKD, 16 Sjögren syndrome (SJS), and 17 idiopathic tubulointerstitial nephritis (ITIN) patients using antibodies against IgG; IgG1; IgG4; CD38; CD3; C-X-C chemokine receptor type 3 (CXCR3); chemokine (C-C motif) receptor 4 (CCR4); forkhead box 3 (Foxp3); Type I, Type III, Type IV, and Type VI collagens; and transforming growth factor (TGF)-β1., Results: Interstitial lymphoplasmacytic and eosinophilic infiltration and the severity of interstitial fibrosis were greater in IgG4-RKD than SJS and ITIN. The ratio of CXCR3+/CD3 + cells was greater in SJS as compared with that in IgG4-RKD and ITIN. The ratio of CCR4+/CD3 + cells was not different among the three diseases. The ratio of interstitial IgG4+/IgG+ plasma cells, Foxp3+/CD3 + cells, and TGF-β1 + cells/total infiltrating cells was higher in IgG4-RKD than SJS and ITIN. There was a positive correlation between the ratio of Foxp3+/CD3 + cells and that of IgG4+/IgG+ plasma cells in IgG4-RKD. Significant correlation was found between the ratio of Foxp3+/CD3 + cells and that of TGF-β1 + cells/total infiltrating cells in IgG4-RKD. Foxp3 + cells and TGF-β1 + cells were colocalized in the interstitium in IgG4-RKD. The significant correlation between the ratio of TGF-β1 + cells/total infiltrating cells and the severity of fibrosis was noticed in IgG4-RKD. The interstitial distribution of type III collagen and type IV collagen was higher in IgG4-RKD than in SJS., Conclusions: Our results suggest that regulatory T-cells (Tregs) may play a central role in IgG4 production in the interstitium and TGF-β1 induced by Tregs may play a pivotal role in the interstitial fibrosis including type III and type IV collagens in IgG4-RKD.

A 62-year-old woman was admitted to our hospital because of fever, renal dysfunction, eosinophilia, and the presence of MPO-ANCA. Based on the renal pathological examination which showed granuloma lesion with eosinophils and crescentic glomerulonephritis, eosinophilic granulomatosis with polyangiitis (EGPA) was diagnosed. On the other hand, laboratory examination showed elevated serum IgG4 levels and renal pathological examination showed marked lymphoplasmacytic infiltration and fibrosis surrounding nest "Bird's eye pattern," which were characteristic of IgG4-related kidney disease (IgG4-RKD). Because there are cases when EGPA has clinical features of IgG4-RKD, we should be careful about diagnoses of IgG4-RKD in patients with EGPA. [ABSTRACT FROM AUTHOR]

A 62-year-old woman presented with a one month history of a hard, nonmobile subcutaneous mass along the right nasojugal fold. Hematological studies showed elevated serum immunoglobulin G4 levels. Histopathological examination of the biopsy sample disclosed immunoglobulin G4-positive lymphoplasmacytic infiltration with a storiform fibrosis, vein occlusion, and epithelioid granulomas with necrosis. Systemic review corresponded to a sarcoidosis. Without treatment, the eyelid mass did not recur six months after the excisional biopsy. [ABSTRACT FROM AUTHOR]

IgG4 cholangiopathy is a recently described distinctive type of hepatobiliary manifestation of IgG4-related disease. This is often misdiagnosed as a malignancy of the hepatobiliary system on clinical presentation and imaging. Accurate diagnosis is crucial for appropriate management. Histopathology provides crucial information and is characterized by IgG4-positive lymphoplasmacytic infiltration with storiform fibrosis and obliterative phlebitis. We present the clinicopathological spectrum of a retrospective series of 6 cases of IgG4 cholangiopathy that clinically masqueraded as hepatobiliary malignancies. [ABSTRACT FROM AUTHOR]

Background IgG4-related disease is a multi-organ disorder characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive cells into affected organs. In routine studies, however, IgG subclasses are not estimated. In the present study, we attempted to clarify the light-microscopic characteristics of IgG4-related tubulointerstitial nephritis (TIN) to facilitate distinction from non-IgG4-related TIN in specimens obtained by renal biopsy using routine staining. Methods In specimens from 34 cases of TIN (13 IgG4-related and 21 non-IgG4-related), 9 nephrologists independently reviewed the following histological features of interstitial lesions: (i) cell infiltration extending into the renal capsule, (ii) cell infiltration into the renal medulla, (iii) regional lesion distribution, (iv) lymphoid follicles, (v) granulomatous lesions, (vi) necrotizing angiitis, (vii) eosinophil infiltration, (viii) neutrophil infiltration, (ix) tubulitis, (x) peritubular capillaritis, (xi) storiform fibrosis and (xii) the stage of interstitial fibrosis. The modified nominal group technique was applied to obtain a consensus in the pathological interpretation. Results Consensus was successfully attained among the diagnosticians for all but one pathological feature (regional lesion distribution). Storiform fibrosis was demonstrated in 12 of 13 (92.3%) cases of IgG4-related TIN but in none of the cases of other types of TIN. Cell infiltration extending into the renal capsule was also observed only in IgG4-related TIN. Conversely, neutrophil infiltration, severe tubulitis, severe peritubular capillaritis, granulomatous lesions and necrotizing angiitis were evident only in non-IgG4-related TIN. Conclusions This study revealed some useful and characteristic features for distinguishing IgG4-related from non-IgG4-related TIN on the basis of light-microscopic observation. [ABSTRACT FROM PUBLISHER]