Role of Lesional BCL6hiPD-1hi T Follicular Helper Cells As a Cardinal B-Cell Helper to Produce IgG4 in IgG4-Related Disease

IgG4-related disease (IgG4-RD) shows a chronic fibroinflammatory condition characterized by spread to various systemic organs, resulting in dysfunctions associated with IgG4 such as dacryoadenitis and sialadenitis and type 1 autoimmune pancreatitis. However, the pathogenesis of IgG4-RD remains unknown. Therefore, we examined T follicular helper (Tfh) cells in tissue lesions of IgG4-RD. Tfh (CD4+CXCR5+) cells in tissues of submandibular glands (SMGs) from patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS, n = 6), normal SMGs (n = 6), nasal polyps (n = 3), and palatine tonsils (n = 6) were analyzed. Expression of programmed death 1 (PD-1) and inducible T-cell co-stimulator in Tfh cells from those subjects was examined by flow cytometry. Sorted Tfh cells from IgG4-DS SMGs were characterized and compared with tonsillar and circulating Tfh cells. Functional analyses of sorted Tfh cells from IgG4-DS SMGs were also performed. Patients with IgG4-DS exhibited increased infiltration of activated Tfh cells highly expressing PD-1 in their SMGs. Lesional Tfh cells in IgG4-DS had higher expression of B-cell lymphoma (BCL) 6 and higher capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of PD-1hi Tfh cells in blood from patients with IgG4-DS was elevated compared with that in healthy volunteers and was correlated with clinical parameters. Our findings indicate that BCL6hiPD-1hi Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.