Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease

IgG4-related disease (IgG4-RD) shows a chronic fibroinflammatory condition characterized by an elevated level of serum IgG4 as well as tissue infiltration by IgG4-positive plasma cells in various organs. However, the underlying immunological mechanisms involved in IgG4-RD remain unknown. In this study, we examined T follicular helper (Tfh) cells in tissue lesions of IgG4-RD. Sorted Tfh (CD4+CXCR5+PD-1+) cells in tissues of submandibular glands (SMGs) from patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) and tonsils from patients with tonsillar hypertrophy were characterized by DNA microarray analysis or flow cytometry, and their results were compared. Functional analyses of sorted Tfh cells from those subjects were also performed. Patients with IgG4-DS exhibited increased infiltration of activated Tfh cells in their SMGs. Lesional Tfh cells in IgG4-DS had higher expression of B-cell lymphoma 6 and higher capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found abundant infiltration of CD8-positive and granzyme A-positive Tfh cells in SMGs compared with those in tonsils. Our findings indicate that dual-functional Tfh cells in tissue lesions of IgG4-RD, which potentially possess higher helper capacities to B cell and cytotoxic activities, may have distinctive features in acquired immune responses and play an important role in the pathogenesis of IgG4-RD.