No abstract

Kaposi Sarcoma-associated herpesvirus/ Human Herpesvirus 8 (KSHV/HHV8) associated multicentric Castleman disease (MCD) is a polyclonal B cell lymphoproliferative disorder mainly occurring in immunocompromised hosts. The diagnosis relies on lymph node biopsy demonstrating KSHV infected cells located in the mantle zone with a marked interfollicular plasma-cell infiltration. Infected cells are large cells positive for IgM,  light chain, and CD38, described initially as infected "plasmablasts". We show that IgM+λ+CD38high cells were also detectable in the peripheral blood of 14/18 (78%) patients with active KSHV-MCD and absent from 40 controls. Using immunofluorescence and flow-FISH, we demonstrate that these cells are KSHV infected and expressed both latent and lytic KSHV transcripts. These KSHV infected viroblasts (KIV) harbor a distinct phenotype compared to conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, as KIV displayed an overall decrease of co-stimulatory molecules with a remarkable lack of CD40 expression and are IL-10 producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements in the understanding of KSHV-MCD but also raises new questions that need to be clarified.

PRTS-0004 and 'Investissements d'avenir' program ANR-10-IA; AT Europe (https://www.ateurope.

Epstein–Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137–CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.