T Cell Polarization toward T_H2/T_FH2 and T_H17/T_FH17 in Patients with IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of T_H1/T_H2/T_H17, T_FH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, T_H2, T_H17, and CD4⁺CXCR5⁺PD1⁺ T_FH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. T_FH increase was characterized by the specific expansion of T_FH2 (CCR6^-CXCR3^-), and to a lesser extent of T_FH17 (CCR6⁺CXCR3^-) cells. Interestingly, CD4⁺CXCR5⁺PD1⁺ T_FH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a T_H2/T_FH2 and T_H17/T_FH17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.