BAFF and APRIL stimulate the accumulation of malignant HRS cells through autocrine and paracrine signals conveyed by TACI, BCMA, and HSPGs. Malignant HRS cells express TACI and BCMA, which deliver survival and growth signals upon engagement by paracrine BAFF and APRIL released by reactive myeloid cells, including macrophages, neutrophils, and eosinophils. TACI and BCMA are also engaged by autocrine BAFF and APRIL expressed on the membrane of and released by HRS cells. Binding of APRIL to TACI and BCMA is enhanced by HSPGs anchored on the membrane of HRS cells and (not shown) associated with the extracellular matrix. Engagement of CD30 and CD40 on HRS cells by CD30L and CD40L on eosinophils, CD4⁺ T cells, and/or B cells up-regulates expression of autocrine BAFF and APRIL by HRS cells, thereby further enhancing their survival and proliferation. The TNF family member RANKL and its receptor RANK are also indicated on HRS cells. Together with CD30L, CD40L, and RANKL, BAFF and APRIL trigger abnormal activation of NF-κB in HRS cells, thereby enhancing HL expansion.