Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. METHODS: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. RESULTS: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren's syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-ß and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. CONCLUSIONS: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.

Non-tuberculous, adenosine deaminase-positive lymphocytic pleural effusion: Consider immunoglobulin G4-related disease.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic disorder. Pleural effusion is considered an uncommon manifestation of the disease. We describe a case series of patients with IgG4-RD and clinically significant pleural effusions. METHODS: A retrospective analysis of patients with histologically proven IgG4-RD treated for pleural effusion in our clinic. RESULTS: We identified 4 male patients with pleural effusion caused by IgG4-RD. The effusions were lymphocytic exudates, with especially high protein concentrations. All patients had hyperglobulinemia, elevated serum immunoglobulin G (IgG) levels and elevated levels subclasses IgG1 and IgG4. In two patients, levels of adenosine deaminase (ADA) were measured in the effusion and were elevated (309 and 108 IU/L). Tuberculosis was excluded in both cases by pleural biopsy. Involvement of other organs by IgG4-RD was the rule, especially thoracic lymphadenopathy which was prominent in all patients. In all cases, effusion responded to corticosteroids therapy. One patient developed radiological findings compatible with rounded atelectasis during remission. CONCLUSIONS: IgG4-RD may cause an ADA-positive, lymphocytic exudate with a high protein concentration, characteristics resembling tuberculous effusion. Thoracic lymphadenopathy, hyperglobulinemia, and an increased total IgG, IgG1, IgG4 may suggest the diagnosis. Not previously described, IgG4-RD pleural inflammation may result in rounded atelectasis. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 225-230).