T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

Takeuchi, Mai; Sato, Yasuharu; Ohno, Kyotaro; Tanaka, Satoshi; Takata, Katsuyoshi; Gion, Yuka; Orita, Yorihisa; Ito, Toshihiro; Tachibana, Tomoyasu; Yoshino, Tadashi

doi:10.1038/modpathol.2013.236

Cited by 82 publications

(60 citation statements)

References 29 publications

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“…17 Moreover, mast cells have been reported to participate in the development of fibrosis. [10][11][12] Mast cells may promote fibrosis by inducing fibroblast proliferation, migration, contraction, and collagen production through the release of a range of stored cytokines such as TGF-β from mast cells that act in a paracrine fashion to stimulate fibroblasts. 18 Recently, it was shown that fibrosis in IgG4-related diseases is induced by cytokines (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…However, a recent study showed that TGF-β-producing mast cells, and not Treg cells, are the main participants in fibrosis. 12 Mast cell proliferation is induced by IL-3, IL-13, and stem cell factor (SCF). [13][14][15][16] We investigated the association of fibrosis in lymph nodes (LNs) of patients with CHL through histological examination of the expression of cytokines associated with fibrosis and mast cell proliferation (TGF-β, IL-3, IL-13, and SCF) and by determining the degree of mast cell infiltration in NSCHL compared with that in non-NSCHL (MCCHL or LRCHL).…”

Section: Introductionmentioning

confidence: 99%

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Role of mast cells in fibrosis of classical Hodgkin lymphoma

Nakayama

Yokote

Hiraoka

et al. 2016

Int J Immunopathol Pharmacol

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The underlying mechanism of fibrosis in classical Hodgkin lymphoma (CHL) remains uncertain. This study aimed to investigate the association of fibrosis in the lymph nodes of patients with CHL through histological examination of the expression of cytokines associated with fibrosis and mast cell proliferation. Additionally, we sought to determine the degree of mast cell infiltration in a nodular sclerosis subtype of CHL (NSCHL) compared with that in non-NSCHL. We analyzed lymph nodes from 22 patients with CHL, of which eight were of the NSCHL and 14 of the non-NSCHL subtype, using immunohistochemical staining of forkhead box P3 (FOXP3), transforming growth factor (TGF)-β, interleukin (IL)-3, IL-13, and stem cell factor (SCF). Mast cells were positive for TGF-β and IL-13, and FOXP3-positive cells were negative for TGF-β. Only the expression of IL-13 in Hodgkin and Reed-Sternberg (HRS) cells was significantly more frequently observed in NSCHL than that in non-NSCHL (P = 0.0028) and was associated with a higher rate of fibrosis (P = 0.0097). The number of mast cells was significantly higher in NSCHL than that in non-NSCHL (P = 0.0001). A significantly positive correlation was observed between the rate of fibrosis and the number of mast cells (correlation coefficient, 0.8524; 95% CI, 0.6725-0.9372) (P <0.0001). The number of mast cells was significantly higher in the group with IL-13-positive HRS cells than that in the group with IL-13-negative HRS cells (P = 0.0157). Based on these findings, we hypothesize that IL-13 production by HRS cells may lead to fibrosis, and furthermore, promote mast cell proliferation and infiltration. This in turn might further produce the fibrotic cytokines IL-13 and TGF-β, resulting in fibrosis typical of NSCHL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of mast cells in fibrosis of classical Hodgkin lymphoma

Nakayama

Yokote

Hiraoka

et al. 2016

Int J Immunopathol Pharmacol

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“…Together with the increases in the IL-4, IL-5, IL-10, and IL-13 levels, increased levels of the Th2-type cytokine can lead to elevation of the serum IgE and eosinophil levels. Moreover, IL-10 and transforming growth factor-β are produced by activated Treg cells, which in turn can result in increases in the IgG4 levels and in fibrosis [10]. Among the 40 cases with PTGC-type IgG4-related lymphadenopathy reported by Sato et al [9], the serum IgE levels were elevated in 12 of 13 cases (92%), and the peripheral blood eosinophil count was increased in 18 of 34 (53%).…”

Section: Discussionmentioning

confidence: 90%

“…In terms of the mechanism of IgG4-RD occurrence, the immune responses of type 2 helper T (Th2) and regulatory T (Treg) cells play very important roles [1,10]. Together with the increases in the IL-4, IL-5, IL-10, and IL-13 levels, increased levels of the Th2-type cytokine can lead to elevation of the serum IgE and eosinophil levels.…”

Section: Discussionmentioning

confidence: 99%

Mikulicz's Disease with Progressively Transformed Germinal Centers-type Immunoglobulin G4-related Lymphadenopathy Mimicking Sjögren's Syndrome

Kim

Min

2015

J Rheum Dis

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Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease, and lymphadenopathy is frequently observed in these patients. Among the 5 subtypes of IgG4-related lymphadenopathy, progressively transformed germinal centers (PTGC)-type IgG4-related lymphadenopathy possesses a unique characteristic that differentiates it from the other 4 subtypes. Here, we report on a rare case of PTGC-type IgG4-related lymphadenopathy accompanying Mikulicz's disease. A 39-year-old female complained of a left cervical mass and bilateral upper eyelid hypertrophy. The serum level of IgG4 was elevated, and computed tomography showed enlargement of the bilateral lacrimal and submandibular glands and left cervical lymph node. Excisional biopsy of a submandibular gland and cervical lymph node was performed, and the histopathologic findings revealed Mikulicz's disease accompanied by PTGC-type IgG4-related lymphadenopathy. After treatment of the patient with oral prednisolone and azathioprine, the patient's appearance improved. To the best of our knowledge, no case of PTGC-type IgG4-related lymphadenopathy has been previously reported in Korea. (J Rheum Dis 2015;22:395-400)

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“…Activated mast cells, strongly positive for IgE, promote the differentiation of naïve T cells to Treg cells (10). IL-10 also known as anti-inflammatory cytokine promotes the differentiation of B cells to plasma cells and subsequent production of IgG4.…”

Section: Pathogenesis Of Igg4-related Diseasementioning

confidence: 99%

IgG4-related disease: A relatively new concept for clinicians

Vasaitis

2016

European Journal of Internal Medicine

100

119

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IgG4-related disease (IgG4-RD) is a recently recognized chronic fibrotic inflammation, which can affect almost every organ, and may come to clinical attention first due to visible organ swelling or organ dysfunction, or is identified incidentally by imaging and specific biopsy.The disorder has an allergic background and is immune-mediated. Up-regulated responses of T helper 2 and T regulatory cells and their cytokines play a major role in disease progression.About 30-50% of patients are atopic or have mild eosinophilia. IgG4-RD predominantly affects middle-aged male patients. The cornerstones of diagnosis of the disease are compatible clinical features and typical histopathology. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis (AIP) are the most common manifestations of the disease. However, other tissues and organs, such as retroperitoneum, lung, kidney, aorta, upper airways, thyroid gland, meninges, heart, mesenterium and skin may be involved. Typical histopathology is lymphoplasmacytic infiltration abundant in IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. Elevated serum IgG4 concentration supports the diagnosis. Characteristic imaging features such as a "capsule-like rim" surrounding the pancreatic lesions is highly specific to type 1 AIP. 18F-fluorodeoxyglucose positron emission tomography/computed tomography enables mapping the sites of inflammation, permits evaluation of the extent of the disease, helps in guiding biopsy decision, and may be used in monitoring response to treatment. Glucocorticoids alone or in combination with B-cell depletion with rituximab induces prompt clinical response to IgG4-RD.This article reviews the current understanding, different clinical manifestations, and approaches to diagnosis and treatment of IgG4-RD. 3Highlights Ø IgG4-related disease is a chronic fibrotic inflammation.Ø The disease affects multiple organs, is progressive, and impairs function.Ø The disorder has an allergic background and is immune-mediated.Ø Compatible clinical signs and typical pathology are the basis for the diagnosis.Ø Glucocorticoids and/or B-cell depletion induces prompt clinical response.Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibrotic inflammation, characterized by tissue infiltration by lymphocytes, IgG4-positive plasma cells, simultaneous development of fibrosis, and often, but not always, elevated serum levels of IgG4 (1, 2). The disease can affect multiple organs. Early diagnosis of IgG4-RD is not easy because of the indolent course of the disease with vague, nonspecific symptoms. It may first come to clinical attention as visible organ swelling or detected organ dysfunction due to fibrosis, or is identified incidentally by imaging and specific biopsy when the patient undergoes investigation of suspected tumor disease. Most forms of organ involvement in IgG4-RD, even in the advanced fibrotic stages, respond well to glucocorticoids (3, 4). 4A comprehensive search for all articles in E...

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T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

Cited by 82 publications

References 29 publications

Role of mast cells in fibrosis of classical Hodgkin lymphoma

Role of mast cells in fibrosis of classical Hodgkin lymphoma

Mikulicz's Disease with Progressively Transformed Germinal Centers-type Immunoglobulin G4-related Lymphadenopathy Mimicking Sjögren's Syndrome

IgG4-related disease: A relatively new concept for clinicians

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