title: HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy.
abstract: Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human herpes virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new subclassification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative MCD or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.
authors.affiliation: Center for Orphan Disease Research and Therapy, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: David C
authors.initials: DC
authors.lastname: Fajgenbaum
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Nabel
mesh_terms: D005871:Castleman Disease / Q000097:blood* / Q000209:etiology* / Q000628:therapy; D016207:Cytokines / Q000097:blood*; D015497:HIV-1 / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008954:Models, Biological
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators