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Kaposi's sarcoma (KS), a vascular tumour that contains characteristic spindle cells forming slit-like spaces, may have an infectious aetiology. Recently, sequences of a new human herpesvirus, KSHV/HHV-8, have been identified in both HIV-associated and classical KS. We sought to identify the target cell of this virus in KS tumour tissue. Using PCR in situ hybridization (PCR-ISH) we show that KSHV/HHV-8 is present in the flat endothelial cells lining vascular spaces of KS lesions as well as in typical KS spindle cells. These findings show that KSHV/HHV-8 is present in the cell types thought to represent neoplastic cells in these lesions.

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function.

IntroductionInfectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of malignancies worldwide. The agents considered here, termed Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV-human herpesvirus 8 [HHV8]), are members of the gamma-herpesvirus subfamily. 1 Since its discovery as the first human tumor virus, EBV has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt lymphoma (BL), nasopharyngeal carcinoma, and Hodgkin and non-Hodgkin lymphomas (NHLs). KSHV, one of the most recently discovered human tumor viruses and the cause of Kaposi sarcoma (KS), 2 also plays a role in the pathogenesis of primary effusion lymphoma [PEL], and multicentric Castleman disease [MCD]). [3][4][5][6] Intriguingly, EBV and KSHV have been shown to associate with distinct lymphoproliferative diseases occurring most often in persons with HIV infection/ AIDS 7,8 or in association with other immunodeficiency conditions, such as iatrogenic immunodeficiency following solid organ transplantation. 9,10 HIV-associated lymphoproliferative disorders are a heterogeneous group of diseases that arise in the presence of HIV-associated immunosuppression, a state that permits the unchecked proliferation of EBV-and KSHV-infected lymphocytes. Traditionally, these aggressive disorders mainly include both central nervous system and systemic lymphomas, 11 whereas lymphomas specifically occurring in the setting of HIV infection include PEL and its solid variant, plasmablastic lymphoma (PBL) of the oral cavity type and large B-cell lymphoma arising in KSHV-associated MCD. [12][13][14][15][16][17][18] Thus, HIV-related lymphomas are closely linked to EBV infection of the tumor clone or are associated with KSHV. PEL and its variants often involve EBV in addition to KSHV. 19 We review here the current knowledge on these gammaherpesvirus-associated lymphomas in the setting of HIV infection. The focus will be on pathology, diagnosis and classification, pathogenesis, and treatment of these lymphomas specifically occurring in HIV-induced immunodeficiency. Gamma-herpesvirus-associated lymphomas in the setting of HIV infection EBV-associated lymphomasEBV has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including BL, classic Hodgkin lymphoma (HL), and lymphomas arising in immunocompromised individuals (posttransplantation and HIV-associated lymphoproliferative disorders; Figure 1). 1,2 It is also associated with B-cell lymphomas in association with congenital immunodeficiencies, such as X-linked lymphoproliferative syndrome (XLP). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal type natural killer/T-cell lymphoma, and other rare histotypes. 1,2 EBV-associated lymphomas in AIDS include BL, diffuse large B-cell lymphoma (DLBCL) with immunoblastic (IB) morphology, primary...