Possible relationship between fibrosis of IgG4-related thymitis and the profibrotic cytokines, transforming growth factor beta 1, interleukin 1 beta and interferon gamma: a case report

Abstract

BackgroundIgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4-positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry.Case presentationA 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery).ConclusionsOur results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4-related thymitis as well as in the other affected lesions of IgG4-related disease.

Marginal zone B-cell lymphoma: lessons from Western and Eastern diagnostic approaches

“…The differential diagnoses include multilocular thymic cyst, lymphoepithelial sialadenitis-like thymic hyperplasia, thymic follicular hyperplasia, and thymic IgG4-related disease. [76][77][78] Thymic MALT lymphomas have a high frequency of trisomy 3, a low incidence of trisomy 18, and an absence of translocations involving MALT1 or IGH. 79,80 Deletion of TNFAIP3 (encoding A20, an NF-kB inhibitor) has been reported in one case.…”

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease

“…Recently, a bunch of fibrosis-related inflammatory mediators have been successively discovered. These fibro-inflammatory mediators include IL-1 family (IL-1α, IL-1β, IL-18, IL-33, IL-36 α, IL-36β and IL-36γ) [ 107 ], Th1 cytokine (IFN- γ) [ 108 ], Th2 cytokines (IL-4, IL-5, IL-10 and IL-13), Th17 cytokines (IL-17 and IL-22), innate immune cell-derived proinflammatory cytokines (IL-6 and TNF- α), growth factors (TGF-β, PDGF, CTGF, IGF, FGF, EGF and VEGF) and chemokines (CCL2, CCL3, CCL4, CCL20) [ 109 ]. Furthermore, Kotsiou et al [ 110 ] have documented that IL-33/ST2 (suppression of tumorigenicity 2) axis can facilitate EMT process of various cell types and abnormal FB proliferation, ultimately leading to tissue fibrosis.…”

A case report on the cytokine signature profile of immunoglobulin G4-related disease

“…IL-13 also induces fibrosis, another hallmark of IgG 4 -related disease. Other profibrotic cytokines, such as IL-1β and interferon-γ, were elevated in this case (5).…”