A scenario for the role of cytokines in EBV⁻ and EBV⁺ cHL.

RS cells commonly express TNFR family members such as TNFR, CD30, and CD40, and Th2 cytokines such as IL-13 and IL-5. (A) In cases of NSHL, which are typically EBV⁻, activation of NF-κB through TNFR family members and activation of STAT6 through IL-13 can contribute to RS cell proliferation and to the production of chemokines such as eotaxin, MDC, and TARC. These chemokines recruit Th2 cells and eosinophils (Eo) that constitute the characteristic reactive infiltrate. These reactive cells also contribute to RS cell proliferation through CD30L/CD30 and CD40L/CD40 interactions. (B) In EBV⁺ cases, which are predominantly MCHL, RS cell proliferation and recruitment of the reactive infiltrate are stimulated by many of the same pathways. The presence of EBV, however, provides another pathway for NF-κB activation through LMP-1 expression, and may lead to the development of a Th1 cell–mediated immune response through up-regulation of IP-10, Mig, and MIP-1α. However, this cell-mediated response appears to be ineffective, perhaps due to the production of IL-10 by surrounding cHL tissues.