This report describes the nodal and extranodal lesions observed in 15 patients with a generalized disorder that had been histologically diagnosed as Castleman's disease. The disorder was characterized by severe constitutional symptoms, constant involvement of multiple peripheral lymph nodes, and frequent hepatosplenomegaly, in association with clinical and laboratory features reminiscent of a "collagen disease." The clinical course was chronic, with remissions and exacerbations in seven patients, and aggressive and fatal in eight. The material examined included multiple lymph node biopsies, four surgical specimens of spleen, one open lung biopsy, and material from four autopsies. The diagnostic morphological findings were observed in the nodes and were represented by the following histologic triad: diffuse marked plasmacytosis, from the medulla to the subcapsular areas; prominence of the germinal centers; and good preservation of the architecture. One variant of this basic pattern featured abundant immunoblasts and blood vessels. The process appears to be a systemic reactive proliferation of B-lymphocytes, perhaps resulting from faulty immune regulation. Morphologic similarities indicate a relationship between this multicentric disorder and Castleman's disease of plasmacellular type. However, there are distinct differences between them in clinical presentation and evolution, and, consequently, in therapeutic approach.
"Several KSHV-infected PEL cell lines have been established, and EBV is frequently lost in the course of establishment (Arvanitakis et al., 1996; Gaidano et al., 1996; Renne et al., 1996; Said et al., 1996; Carbone et al., 1997, 1998; Katano et al., 1999). MCD is a plasmacytic lymphadenopathy with polyclonal hyper-immunoglobulinemia and high levels of serum IL-6 (Frizzera et al., 1983; Yoshizaki et al., 1989). "
[Show abstract][Hide abstract] ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) is thought to be an oncogenic member of the γ-herpesvirus subfamily. The virus usually establishes latency upon infection as a default infection pattern. The viral genome replicates according to the host cell cycle by recruiting the host cellular replication machinery. Among the latently expressing viral factors, LANA plays pivotal roles in viral genome replication, partitioning, and maintenance. LANA binds with two LANA-binding sites (LBS1/2) within a terminal repeat (TR) sequence and is indispensable for viral genome replication in latency. The nuclear matrix region seems to be important as a replication site, since LANA as well as cellular replication factors accumulate there and recruit the viral replication origin in latency (ori-P) by its binding activity to LBS. KSHV ori-P consists of LBS followed by a 32-bp GC-rich segment (32GC). Although it has been reported that LANA recruits cellular pre-replication complexes (pre-RC) such as origin recognition complexes (ORCs) to the ori-P through its interaction with ORCs, this mechanism does not account completely for the requirement of the 32GC. On the other hand, there are few reports about the partitioning and maintenance of the viral genome. LANA interacts with many kinds of chromosomal proteins, including Brd2/RING3, core histones, such as H2A/H2B and histone H1, and so on. The detailed molecular mechanisms by which LANA enables KSHV genome partitioning and maintenance still remain obscure. By integrating the findings reported thus far on KSHV genome replication, partitioning, and maintenance in latency, we will summarize what we know now, discuss what questions remain to be answered, and determine what needs to be done next to understand the mechanisms underlying viral replication, partitioning, and maintenance strategy.
Frontiers in Microbiology 01/2012; 3:7. DOI:10.3389/fmicb.2012.00007 · 3.99 Impact Factor
"It is remarkable that almost 20 years after discovery of HHV-8 we do not have such basic assays to study the virus. It is postulated that HHV-8 infection drives B cells to an early plasmablast-like state in MCD and a preterminal plasma cell stage of differentiation in PEL (Frizzera et al., 1983; Miller et al., 1984; Cesarman et al., 1995; Nador et al., 1995; Agematsu et al., 1997; Matolcsy et al., 1998; Dupin et al., 2000; Du et al., 2001; Klein et al., 2003; Chadburn et al., 2004, 2008; Hassman et al., 2011). Hassman et al. (2011) recently showed that latencyassociated nuclear antigen (LANA) + B cells express IgM and the λ light chain at 2.5–3.5 days post-HHV-8 infection in vitro. "
[Show abstract][Hide abstract] ABSTRACT: Professional antigen presenting cells (APC), i.e., dendritic cells (DC), monocytes/macrophages, and B lymphocytes, are critically important in the recognition of an invading pathogen and presentation of antigens to the T cell-mediated arm of immunity. Human herpesvirus 8 (HHV-8) is one of the few human viruses that primarily targets these APC for infection, altering their cytokine profiles, manipulating their surface expression of MHC molecules, and altering their ability to activate HHV-8-specific T cells. This could be why T cell responses to HHV-8 antigens are not very robust. Of these APC, only B cells support complete, lytic HHV-8 infection. However, both complete and abortive virus replication cycles in APC could directly affect viral pathogenesis and progression to Kaposi's sarcoma (KS) and HHV-8-associated B cell cancers. In this review, we discuss the effects of HHV-8 infection on professional APC and their relationship to the development of KS and B cell lymphomas.
Frontiers in Immunology 01/2012; 3:427. DOI:10.3389/fimmu.2012.00427
"Several HHV8-pos- itive cell lines have been established from PEL (Arvanitakis et al., 1996; Gaidano et al., 1996; Renne et al., 1996; Said et al., 1996; Carbone et al., 1997, 1998; Katano et al., 1999a), and used as provider cells of HHV8. MCD is also a rare disease characterized by plasmacytic lymphoadenopathy with polyclonal hyperimmunoglobulinemia and high levels of serum IL-6 (Frizzera et al., 1983; Yoshizaki et al., 1989; Chen, 1984). Follicular hyperplasia with proliferation of plasma cells and hyaline vascular alterations in the lymph node are the histopathological hallmarks of MCD. "
[Show abstract][Hide abstract] ABSTRACT: To investigate the expression of human herpesvirus 8 (HHV8)-encoded proteins in the cells of primary effusion lymphoma (PEL), Kaposi's sarcoma (KS) and multicentric Castleman's disease (MCD), nine rabbit polyclonal antibodies to K2, ORF26, K8, K8.1, K10, K11, ORF59, ORF65, and ORF73 were developed. Western blot analysis in PEL cell lines (TY-1 and BCBL-1) revealed that the expression of these proteins, except ORF73 (LANA), was induced by tetradecanoylphorbol acetate (TPA) treatment, indicating that these proteins are lytic proteins. Immunofluorescence assay in primary PEL cells derived from pericardial effusion and PEL cell lines with and without TPA treatment revealed that primary PEL cells exhibited the same expression pattern as noninduced PEL cell lines, and the treatment changed localization of K8, ORF59, and ORF65 proteins. Immunohistochemistry revealed that 90% of KS spindle cells expressed the ORF73 protein, whereas a small population of KS cells expressed K8, K10, K11, ORF59, and ORF65 proteins. In MCD, ORF73, ORF59, K8, K2, and K10 proteins were expressed in the cells at mantle zone of the follicle. These data indicate that KS and PEL cells expressed predominantly latent proteins, whereas MCD expressed both latent and lytic proteins, suggesting that HHV8 plays a different role in the pathogenesis of HHV8-associated diseases.
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