The role of cytokines in classical Hodgkin lymphoma

Abstract

IntroductionClassical Hodgkin lymphoma (cHL) is a lymphoid malignancy with characteristic features that distinguish it from nodular lymphocyte-predominant HL (NLPHL) and non-Hodgkin lymphomas (NHLs). 1,2 The malignant cells in cHL, termed the Reed-Sternberg (RS) cells, constitute only a minor component of the tumor, whereas the majority of the malignancy is composed of a mixed inflammatory infiltrate variably composed of lymphocytes, eosinophils, fibroblasts, macrophages, and plasma cells. Patients with cHL also commonly present with constitutional symptoms such as fever, weight loss, and night sweats, and an apparent systemic defect in cell-mediated immune responses. Many of these distinctive clinical and histopathologic features of cHL reflect an abnormal immune response thought to be due largely to the effects of a wide variety of cytokines and chemokines that are primarily produced by the RS cells, but also secondarily by the surrounding reactive infiltrate. This review summarizes the data on cytokine production in cHL, examines cytokine signaling, and discusses the role of cytokines in the clinical and pathologic features of this disease.Classical HL is now considered a distinct clinicopathologic entity from NLPHL and can be divided into 4 morphologic subtypes: nodular sclerosis cHL (NSHL), mixed cellularity cHL (MCHL), lymphocyte-rich cHL (LRCHL), and lymphocytedepleted cHL (LDHL). 2 There are few data on cytokine involvement in LRCHL and LDHL, because each disease comprises less than 5% of all cHL cases. As a result, nearly all of the data on the role of cytokines in cHL are derived from the study of NSHL and MCHL cases.Cytokines are low-molecular-weight proteins with a wide variety of functions. They not only regulate immune and inflammatory responses but also contribute to hematopoiesis, wound healing, and other biologic processes. Cytokines are extremely potent molecules active in nanomolar to picomolar concentrations. Typically, a cytokine either acts in a paracrine manner to modulate the activity of surrounding cells, or in an autocrine fashion to affect the cell that produced it. In the context of cHL, cytokines produced by RS cells are thought to contribute to the pathogenesis of this disease both by acting as autocrine growth factors and by initiating and sustaining the reactive infiltrate. Alternatively, cytokines produced by surrounding reactive cells may be contributing to RS cell proliferation and survival.The expression and activity of cytokines in cHL can be studied using cell lines derived from RS cells and in primary cHL tissues. Each approach has its limitations, so that a combination of both strategies provides the most comprehensive information on the activity of a specific cytokine. Cell lines derived from RS cells have been extremely useful in the study of cHL. 3,4 However, outgrowth of such a cell line from cHL patient tissues is extremely rare, so that the few cell lines available may not represent the full spectrum of clinical and pathologic features of this disease. The RS cell li...

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

“…12,19,32,33 In cHL, the JAK2-STAT cascade is constitutively maintained at an active high level by multiple mechanisms, including stimulatory loops through interleukin (IL)-13 and its receptor IL13Ra1, gene dosage effect of the gained JAK2 locus at 9p24 in over 30% of cHL cases (present data) and aberrations of SOCS1. 19,21,34 These multiple mechanisms of JAK2-STAT activation in cHL point to its important oncogenic role. The essential nature of this pathway is emphasized by the fact that STAT3 downregulation in a HRSC line induces apoptosis.…”

Aberrant expression of cell cycle regulators in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma

“…In classical Hodgkin's lymphoma, however, we found no association between cell cycle markers and clinical outcome. Again, this reflects the atypical nature of this disease, the pathology of which is not caused by rapid accumulation of malignant cells, but rather by the accumulation of reactive lymphocytes and perturbation of the cellular and humoral immunity (reviewed in Skinnider and mak 33 ). We found a weak correlation between p21 CIP1 expression and disease-specific survival, which may be caused by induction of p53-dependent apoptotic pathways in a subset of classical Hodgkin's lymphomas.…”

The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells

“…These inflammatory cells are attracted by cytokines and chemokines secreted by the malignant cell population. 1,2 The complex interactions between HRS cells and bystander cells create a specific microenvironment that is thought to be critical for growth and survival of HRS cells. A detailed analysis of signals evoked by these interactions does not only contribute to a better understanding of HL pathogenesis, but might also provide a basis for the development of new treatment strategies.…”