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Young-adult-onset (15–44 years of age) Hodgkin lymphoma (HL) is believed to arise as a consequence of late primary infection in susceptible individuals. The properties of this susceptibility remain little understood. We have previously reported an increased occurrence of HL in patients with rheumatoid arthritis and among their offspring, suggesting that susceptibility to autoimmunity might be of importance also in the pathogenesis of HL. To explore this hypothesis, we assessed the association of personal and family history of diabetes mellitus, with risk of subsequent HL in a population-based case-control study, including as cases all individuals diagnosed with HL above 15 years of age 1964–1999 (n=6,873) in Sweden, and matched population controls (n=12,565). First-degree relatives of cases and controls were identified through linkage with the Multi-generation Register. We identified discharges listing diabetes mellitus through linkage with the Inpatient Register (1964–2000). We used odds ratios (OR) as measures of relative risk. Cases with young-adult-onset HL were less likely to have a personal (OR=0.5, 95% CI 0.2–1.1) or family (OR=0.7, 95% CI 0.6–0.8) history of diabetes mellitus. In contrast, HL diagnosed at older ages was neither associated with a personal (OR=1.0) nor family (OR=1.0) history of diabetes mellitus. These findings suggests that characteristics of the immune system associated with conditions such as diabetes mellitus type I are of importance in the pathogenesis of young-adult-onset HL. © 2005 Wiley-Liss, Inc.

Classical Hodgkin lymphoma (cHL) is characterized histologically by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by abundant inflammatory cells, generally believed to be of major importance in the pathophysiology of the disease. Here, we present data that link inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to the pathogenesis of cHL. Two HL cell lines, L1236 and KMH2, were shown to express functional CysLT1 receptors, responding with a robust calcium signal upon leukotriene (LT) D4 challenge. LTD4 stimulated protein release of tumor necrosis factor-α, interleukin-6 and -8 by L1236 cells and interleukin-8 by KMH2 cells. Importantly, all these LTD4-induced effects were blocked by the CysLT1 receptor-specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT1 receptor is expressed also by primary Hodgkin Reed-Sternberg cells. As these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as mediators in the pathogenesis of cHL, contributing to the aberrant cytokine network of this lymphoma. © 2008 Wiley-Liss, Inc.