Inkt And Memory B-Cell Alterations In Hhv-8 Multicentric Castleman Disease

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic gamma-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We analyzed iNKT cells in both blood (n=26) and spleen (n=9) samples from 32 patients with HHV-8 MCD and compared them with patients withKS (n524) and healthy donors (n529). Wedetermined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8MCDand were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8MCDdisplayed a proliferative defect after stimulation with a-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8-related MCD.