Disordered Balance of T‐Cell Subsets in Arterial Tertiary Lymphoid Organs in Immunoglobulin G4–Related Vascular Disease

Background Arterial/aortic tertiary lymphoid organs (ATLOs), characterized by germinal centers, control local arterial immune responses. T follicular helper cells (Tfh), resident in germinal centers, regulate immunoglobulin production and germinal center development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as regulatory T cells and migrate into germinal centers. Immunoglobulin G4 (IgG4)–related diseases manifest in vascular lesions as frequently formed inflammatory aneurysms (IgG4‐related abdominal aortic aneurysm [IgG4‐AAAs]). IgG4‐AAAs contain several ATLOs. Methods and Results We performed whole‐slide immunohistochemical image analysis in surgical specimens of IgG4‐AAAs (n=21), non–IgG4‐related inflammatory AAAs (n=17), atherosclerotic AAAs (n=10), and Takayasu arteritis (n=5). IgG4‐AAA was characterized by numerous, large, irregular‐shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared with others. The morphologic abnormalities (in number, area, and form) of ATLOs in IgG4‐AAAs and the increased number of Tfr cells are closely related to the activity of IgG4‐related diseases. All T‐cell subsets were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4‐AAAs was associated with ATLO formation. Increased Tfh17 cells were found in Takayasu arteritis, and atherosclerotic AAA and non–IgG4‐related inflammatory AAAs were characterized by increased Tfh1 cells. Conclusions In the classification of vascular lesions, considering the imbalance in T‐cell subsets, IgG4‐AAA should be positioned as adventitial vasculitis with predominant Tfr and Tfh2 cells, accompanied by the abnormal appearance of ATLOs.