BackgroundIgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates rich in IgG4+ plasma cells and CD4+ T cells (1). Given the longstanding history of atopy that characterizes a proportion of patients with IgG4-RD, it has been suggested that TH2 cytokines contribute to the pathogenesis of this condition (2). However, we recently demonstrated that allergic manifestations are not increased in patients with IgG4-RD compared to the general population (3). Similarly, CD4+TH2 cells are expanded only in the peripheral blood of IgG4-RD patients with concomitant atopy, questioning the hypothesis of IgG4-RD as a TH2 driven condition (4).ObjectivesWe aimed to characterize CD4+ T cell subsets in IgG4-RD subjects.MethodsWe used flow cytometry to identify CD4+ effector/memory T cells as well as Th1, Th2, and T regulatory cells in a cohort of 101 IgG4-RD patients. Gene expression analysis was used to further characterize expanded cells. Results were validated by flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+ T cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging.ResultsCD4+ effector/memory T cells with a cytolytic phenotype (cytotoxic T lymphocytes (CTLs)) were expanded in IgG4-RD patients compared to healthy controls. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not of CD4+GATA3+ memory TH2 cells in subjects with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4+CTLs that expressed granzyme A and perforin. Clinical remission induced by rituximab-mediated B cell depletion was associated with a reduction in disease-associated CD4+ CTLs.ConclusionsIgG4-RD is prominently linked to clonally-expanded CD4+ CTLs in peripheral blood as well as in inflammatory tissue lesions. A TH2 signature might be primarily linked to a concomitant atopic diathesis. CD4+ CTLs might be of pathogenic importance in other fibrotic conditions including IgG4-RD.ReferencesDella-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015 Aug;181(2):191–206.Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1136–39.Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy. 2014 Feb;69(2):269–72.Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy. 2014 Mar;69(3):399–402.Disclosure of InterestNone declared
Cytotoxicity was induced in lymphocytes (CL) from 10 out of 15 patients by autologous mixed lymphocyte tumor cell culture and further cultivation with recombinant interleukin-2. In cells from 3 of the 10 patients, cytotoxicity was suppressed by more than 50% when autologous peripheral blood mononuclear cells (PBMC) from the patients with large tumors were added to the autologous killing system. The cells responsible for suppressing the cytotoxicity in the effector phase were adherent or nonadherent to plastic depending on the patient examined. The T cell fraction from 1 patient significantly suppressed the cytotoxic activity, and this suppression was seen only in the autologous system. On the other hand, plastic adherent cells but not T cells from PBMC of 2 subjects suppressed the cytotoxic activity of CL. The reason why the main cell population suppressing the CL activity differed among the patients is unclear. However, the findings that the suppression was mostly abrogated following resection of the tumor mass suggested that suppressor cells, either of macrophage lineage or T cells, are induced in patients with a large tumor mass. This speculation is supported by the finding that the PBMC from a patient with tumor recurrence regained the suppressive activity.
A case of T cell origined malignant lymphoma with Mikulicz's syndrome was reported. The patient, 56 years old male, visited our clinic on May 21, 1982, complaining of synmetrical
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