Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease

Tanaka, Akihiko; Moriyama, Masafumi; Nakashima, Hitoshi; Miyake, Katsuhisa; Hayashida, Jun Nosuke; Mitsui, Takashi; Shinozaki, Seiji; Kubo, Yoshiaki; Nakamura, Seiji

doi:10.1002/art.33320

Cited by 215 publications

(172 citation statements)

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“…It has been suggested that these distinctive features are caused by the T helper 2 cell cytokines interleukin (IL)4 and IL5 and the regulatory T-cell cytokines IL10 and transforming growth factor beta 1 (TGFb1). 5,6 These cytokines are upregulated in the tissues affected by IgG4-related disease, where IL4 and IL10 are thought to stimulate B cells and plasma cells to induce lymphoplasmacytic infiltration and IgE and IgG4 production, whereas TGFb1 is thought to induce interstitial fibrosis. On the basis of these observations, T helper 2 and regulatory T cells have been considered to have a key role in the pathogenesis of IgG4-related disease.…”

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confidence: 99%

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

et al. 2014

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IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffinembedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFb1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

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confidence: 99%

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

et al. 2014

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“…In addition, eosinophilic diseases have been associated with TNF-a [17], IL-5 [18], IL-10 [19]. Furthermore, IL-5, TNF-aand eotaxin-3 were correlated with eosinophilia in IgG4-related disease [20].…”

Section: Discussionmentioning

confidence: 97%

A case of IgG4-related kidney disease complicated by eosinophilic lung disease

et al. 2014

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IgG4-related disease is a systemic chronic inflammatory disorder characterized by a high blood level of IgG4 and the organ injuries by marked infiltration of IgG4-positive plasma cells and fibrosis. A 71-year-old male was hospitalized for a cough, malaise and anorexia. IgG4-related disease was suspected due to marked elevation of the serum IgG4 level. However, on lung biopsy, only eosinophil infiltration was demonstrated with no plasma cell infiltration. Otherwise abdominal contrastenhanced CT showed mild enlargement of the bilateral kidneys and many differed contrasted areas and FDG PET-CT. Moreover, renal biopsy specimens showed typical tubulointerstitial nephritis with a large number of IgG4-positive plasma cells infiltration (the IgG4/IgG-positive cell rate, 89 %) and fibrosis. We diagnosed this patient as typical IgG4-related kidney disease. He was treated by the moderate dose of prednisolone (0.8 mg/kg/day) alone, and showed prompt response in the clinical condition, and both the lung and kidney lesions. In this case, it was useful for diagnosis of IgG4-related diseases to evaluate an image such as abdominal contrast-enhanced CT and FDG PET-CT. Our case might be one of the possible patterns of IgG4-related lung diseases. In addition, we thought that there might be an association between hypereosinophilia and IgG4-related kidney disease.

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“…IL-4 activates macrophages to produce high levels of IL-10. IL-21 produced by Th2 and T follicular helper cells, is important in the formation of germinal centers and stimulates production of IgG4 and infiltration of IgG4-positive plasma cells in affected tissues (8,11,12). Inflammatory monocytes also play an important role in the formation of ectopic lymphoid follicles in IgG4-RD (13).…”

Section: Pathogenesis Of Igg4-related Diseasementioning

confidence: 99%

“…Th2 induces an allergic immune response with eosinophilia and increased serum IgE (8,9). Activated mast cells, strongly positive for IgE, promote the differentiation of naïve T cells to Treg cells (10).…”

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

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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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Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease

Cited by 215 publications

References 55 publications

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

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

A case of IgG4-related kidney disease complicated by eosinophilic lung disease

IgG4-related disease: A relatively new concept for clinicians

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