Regular Article CLINICAL TRIALS AND OBSERVATIONS Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease

Multicentric Castleman disease (MCD) is a polyclonal Blymphoproliferative disorder characterized by inflammatory flares, including fever, cachexia, lymphadenopathy, splenomegaly, cytopenias, and hypoalbuminemia. MCD was first recognized as an idiopathic condition. More recently, a form caused by Kaposi sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), has been recognized. Almost all cases of MCD in the setting of HIV are KSHV-associated. Although the symptoms of KSHV-MCD may wax and wane, the disease is almost universally fatal if untreated. KSHV is also the etiologic agent of Kaposi sarcoma (KS) and primary effusion lymphoma. Its life cycle is characterized by latent and lytic phases, and its genome is notable for having pirated several genes homologous to cellular genes, including a viral homolog of human interleukin-6 (hIL-6) called viral IL-6 (vIL-6). Viral IL-6 can activate cells by binding to the broadly expressed gp130 subunit for the IL-6 receptor without involving the specific IL-6 receptor a (CD126) chain, thus potentially activating a broader range of cells; it may also have intracellular actions in KSHV-infected cells. Compared with hIL-6, vIL-6 is about one thousandth less potent in activating the IL-6 receptor. KSHV can also induce the expression of cellular cytokines, including IL-6 and IL-10. KSHV-MCD is unique among herpesvirus-associated lymphoproliferative disorders in that a proportion of the pathogenic plasmablasts express KSHV in a lytically active form. Involved lymph nodes demonstrate hypocellular germinal centers with KSHV-infected polyclonal but monotypic plasmacytoid cells predominantly in the intrafollicular area. A proportion of the KSHV-infected cells express lytic genes, in particular vIL-6. Notably though, B lymphocytes in affected nodes are largely uninfected plasmacytoid cells that can produce hIL-6 but not vIL-6. Many clinical manifestations of idiopathic MCD are thought to be caused by overexpression of hIL-6. Overexpression of IL6 in murine models gives rise to a syndrome resembling MCD. Patients with KSHV-MCD have elevated serum levels of vIL-6, and much work on KSHV-MCD pathogenesis has focused on this cytokine. KSHV-MCD flares have also been shown to exhibit elevated KSHV viral loads (VLs) and dysregulation of other cytokines including hIL-6, resolving with symptom resolution. Although both vIL-6 and human cytokines including hIL-6 have been studied separately in small KSHV-MCD cohorts, their respective