Disordered balance of T cell subsets in arterial tertiary lymphoid organs in immunoglobulin G4-related vascular disease

Abstract Background Arterial tertiary lymphoid organs (ATLOs) are ectopic lymphoid structures that control local arterial immune responses and are characterized by germinal centers (GCs). T follicular helper cells (Tfh), resident in GCs, regulate immunoglobulin production and GC development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as Tregs and migrate into GCs as Tfh cells. Immunoglobulin G4 (IgG4)-related diseases are systemic inflammatory fibrous lesions with elevated serum IgG4 and infiltration of IgG4-positive plasmacytes. These manifest in vascular lesions as frequently formed aneurysms with prominent adventitia thickening (IgG4-related abdominal aortic aneurysm; IgG4-AAA). IgG4-AAAs contain several ATLOs. However, the association of IgG4-AAA pathogenesis and ATLOs or ATLOs and immune cell subsets is poorly understood. Methods We performed whole-slide immunohistochemical image analysis in surgical specimens of IgG4-AAA (n = 21), non-IgG4-related inflammatory AAA (non-IgG4-IAAA, n = 17), atherosclerotic AAA (aAAA, n = 10), and Takayasu aortitis (TKA, n = 5). We examined the shape of ATLOs, the T cell subsets within and outside ATLOs, and the histological activity of IgG4-relataed disease. Results IgG4-AAA was characterized by numerous, large, irregular-shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared to patients with other vascular diseases. The morphological abnormalities (in number, area, and form) of ATLOs in IgG4-AAA and the increased number of Tfr cells are closely related to the activity of IgG4-related disease, including the number of IgG4-positive plasmacytes and the degree of adventitial thickness. All T cell subsets (Treg, Th1, Th2, and Th17) were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4-AAA was associated with ATLO formation. Increased Tfh17 cells were found in TKA, and aAAA and non-IgG4-IAAA 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. Clinical Perspective What is New? This prospective study uses a new histopathological method for whole slide analysis. We characterized IgG4-related vascular disease according to imbalances in T cell subsets related to morphological changes of arterial/aortic tertiary lymphoid organs. Compared to Takayasu arteritis and atherosclerotic changes, imbalances in T cell subsets—according to the predominance of follicular helper type 2 T cells and follicular regulatory T cells in IgG4-related vascular disease—suggested that IgG4-related vascular disease should be defined as adventitial vasculitis. What are the clinical implications? This relatively straightforward method for diagnosing vascular diseases based on imbalances in specific T cell subsets and arterial/aortic tertiary lymphoid organ changes can inform the pathological diagnosis of vasculitis, such as IgG4-related vascular disease and Takayasu arteritis. The hallmark of an imbalance in T cell subsets can enable serological diagnosis of vasculitis and use of circulating T cells to monitor disease activity.