Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

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

doi:10.1136/annrheumdis-2012-201477

Cited by 144 publications

(119 citation statements)

References 44 publications

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“…Th2 cytokines produced in tissue may be involved in these systemic serological features [105,106]. IL-21 was recently proven to be up-regulated in IgG4-related sialodacryoadenitis [107]. This cytokine, which is produced by Th2 and T follicular helper (Tfh) cells, leads to germinal center formation [108].…”

Section: T Cell Responsementioning

confidence: 99%

IgG4-related sclerosing cholangitis: all we need to know

2016

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Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a ''benign'' disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell-or immunoglobulin-related (Fc-gamma receptormediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.

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Section: T Cell Responsementioning

confidence: 99%

IgG4-related sclerosing cholangitis: all we need to know

2016

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“…In a recent Japanese report, interleukin-21 was found to be significantly increased in MSGs from patients with IgG-RD compared to SS patients in association with the number of germinal centers and the IgG4:IgG ratio (15). Unfortunately, neither HLA genotyping nor cytokine levels were included in our initial study design.…”

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confidence: 98%

Elevated IgG4 Serum Levels Among Primary Sjögren's Syndrome Patients: Do They Unmask Underlying IgG4‐Related Disease?

Mavragani

Fragoulis

Rontogianni

et al. 2014

Arthritis Care & Research

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Objective. To determine IgG4 levels in a cohort of consecutive patients with primary Sjögren's syndrome (SS) and other autoimmune diseases and explore whether they associate with distinct clinical, serologic, and histopathologic features. Methods. Serum IgG4 levels were measured in 133 primary SS patients and 49 healthy donors (HDs). Seventy-four lupus and 54 rheumatoid arthritis (RA) patients served as disease controls. Immunohistochemical IgG4 analysis was performed in paraffin-embedded minor salivary gland (MSG) tissues. Results. Raised IgG4 serum levels (>135 mg/dl) were detected in 10 (7.5%) of 133 primary SS patients (high-IgG4 group), in 8 (10.8%) of 74 lupus patients, in 7 (12.9%) of 54 RA patients, and in 1 (2%) of 49 HDs. Compared to the normal-IgG4 (<135 mg/dl) primary SS group, high-IgG4 patients exhibited increased prevalence of IgG4-related features (autoimmune cholangitis, autoimmune pancreatitis, and interstitial nephritis), lower rates of antinuclear antibody positivity, and higher IgG2 and IgE levels. Positive staining for IgG4؉ plasma cells with an IgG4:IgG ratio >40% was detected in 3 of 6 available MSG tissues in the high-IgG4 group. Criteria of possible or definite IgG4-related disease (IgG4-RD) were fulfilled by 10 (7.5%) of 133 of our primary SS cohort. Conclusion. Raised IgG4 serum levels were detected in 7.5% of primary SS patients in association with IgG4-RD-reminiscent clinical, serologic, and histopathologic features. Whether this high-IgG4 primary SS group represents a misclassified IgG4-RD group or a distinct primary SS subtype remains to be further explored in future studies.

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“…4 The pathogenesis of the two diseases is also proven to be different based on the overexpression of interleukin-21 in patients with IgG4-related dacryoadenitis and sialadenitis but not in those with SS. 14 The manifestations of IgG4-RD, with possible involvement of other organs, need to be identified promptly to take advantage of emerging therapeutic approaches. B lymphocyte depletion therapy with rituximab was reported anecdotally to demonstrate effectiveness in reducing the serum IgG4 level; however, a swift clinical response 7,15 was limited to cases of IgG4-RD without extensive fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Orbital Manifestations of Immunoglobulin G4–Related Disease in Bilateral Lacrimal Glands, Optic Nerves, Trigeminal Nerves, and Maxillary Sinuses

Chen

Huang

Hsu

et al. 2014

Neuro-Ophthalmology

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Immunoglobulin G4 (IgG4)-related disease is characterised by numerous aggregates of IgG4-positive plasma cells in multiple organs. We report two patients who had bilateral proptosis associated with extensive inflammation bilaterally in lacrimal glands, optic nerves, trigeminal nerves, and maxillary sinuses. The patients were treated as idiopathic orbital inflammation syndrome with corticosteroid pulse therapy. As symptoms relapsed upon tapering, a reassessment of immunohistochemical stains of the lacrimal glands confirmed the diagnosis of IgG4-related disease. During 2 years of follow-up, the inflammation regressed spontaneously without any medical treatment in the first patient; however, inflammation in the other patient progressed, and he lost his vision. The extensive orbital involvement, characteristic pathological findings, and slowly progressive clinical course might help practitioners differentiate orbital IgG4-related disease from presumed idiopathic orbital inflammation syndrome.

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Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

Cited by 144 publications

References 44 publications

IgG4-related sclerosing cholangitis: all we need to know

IgG4-related sclerosing cholangitis: all we need to know

Elevated IgG4 Serum Levels Among Primary Sjögren's Syndrome Patients: Do They Unmask Underlying IgG4‐Related Disease?

Orbital Manifestations of Immunoglobulin G4–Related Disease in Bilateral Lacrimal Glands, Optic Nerves, Trigeminal Nerves, and Maxillary Sinuses

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