Follicular dendritic cells in multicentric Castleman disease present human herpes virus type 8 (HHV8)‐latent nuclear antigen 1 (LANA1) in a proportion of cases and is associated with an enhanced T‐cell response

Abstract

Multicentric Castleman disease (MCD) is a rare human herpes virus type 8 (HHV8)-associated lymphoproliferative disorder that occurs more frequently in patients infected with human immunodeficiency virus (HIV). In tissue samples, HHV8-infected plasmablasts localise to the mantle zones of the lymphoid follicles. We revisited the immunohistological features in 25 lymph node (LN) and three spleen samples of MCD. In five (20%) LN and one (33%) spleen sample, HHV8 latent nuclear antigen 1 (LANA1) staining was also noted on the follicular dendritic cells (FDC). The HHV8-positive FDC subgroup of patients had significantly higher numbers of CD3-positive T cells infiltrating the follicles when compared to the HHV8-negative FDC subgroup (P = 0.047). Furthermore, the numbers of HHV8-positive plasmablasts and serum HHV8 viral copy numbers were lower among the HHV8-positive FDC subgroup when compared to the HHV8-negative FDC subgroup (not statistically significant). Our findings show, for the first time, possible 'presentation' of an HHV8 antigen by FDCs in MCD.

Chronic and recurrent benign lymphadenopathy without constitutional symptoms associated with human herpesvirus‐6B reactivation

“…The peculiar HHV‐6B immunohistochemical findings observed in our patients with benign/reactive lymphadenopathy resemble those previously described in Rosai‐Dorfman disease or sinus histiocytosis with massive lymphadenopathy, an atypical benign lymphoproliferative disorder, in which HHV‐6 antigens have been detected by immunohistochimical analyses in both histiocytes and FDCs, with a suggested pathogenetic association (Luppi et al , ). It has also been reported that EBV is able to infect and transform FDCs in vitro (Lindhout et al , ), while a HHV‐8 antigen may be presented by FDCs in multicentric Castleman disease, potentially increasing anti‐viral immune response (El‐Daly et al , ). In our cases, the possibility is raised that HHV‐6B local reactivation may indirectly modulate and trigger the proliferation of lymphocytes, by locally affecting FDCs and lymph node microenvironment (Lindhout et al , ; Luppi et al , ; Allen & Cyster, ; El‐Daly et al , ; Rezk et al , ).…”

“…It has also been reported that EBV is able to infect and transform FDCs in vitro (Lindhout et al, 1994), while a HHV-8 antigen may be presented by FDCs in multicentric Castleman disease, potentially increasing anti-viral immune response (El-Daly et al, 2010). In our cases, the possibility is raised that HHV-6B local reactivation may indirectly modulate and trigger the proliferation of lymphocytes, by locally affecting FDCs and lymph node microenvironment (Lindhout et al, 1994;Luppi et al, 1998;Allen & Cyster, 2008;El-Daly et al, 2010;Rezk et al, 2013). However, we acknowledge that our findings do not conclusively indicate causality of HHV-6B in inducing lymph node enlargement.…”

Castleman Disease: The Great Mimic

“…Plasmablastic cells (plasmacytoid immunoblasts) express an HHV-8-related antigen, latency-associated nuclear antigen 1 (25,26). Plasmablastic cells (plasmacytoid immunoblasts) express an HHV-8-related antigen, latency-associated nuclear antigen 1 (25,26).…”

Dendritic cells: key players in human herpesvirus 8 infection and pathogenesis

“…Small percentages of fDC from lymph node and spleen samples of MCD cases have been found to express HHV-8 LANA-1. Interestingly, these same fDC are thought to facilitate the increase of T cell infiltration into these secondary lymphoid organs (El-Daly et al, 2010). This suggests that fDC serve as functional soldiers in the DC arm of defense.…”