Hodgkin lymphoma and interleukin-10: shall we go down from the tip of the iceberg?

Hodgkin lymphoma (HL) is a malignant lymphoproliferation most commonly affecting young adults. Although the disease was first described more than 150 years ago, unraveling the pathogenesis and cellular nature of HL has been painstakingly slow [1]. Two findings, in particular, make HL a unique malignant hematopoietic disease: first, the malignant mononucleated Hodgkinand the multinucleated Reed-Sternberg (HRS) cells represent only a small fraction of cells in the affected lymph nodes and are embedded in an infiltrate of reactive hematopoietic cells [2]. Among others, these reactive cells are composed of Band T-lymphocytes, eosinophils and plasma cells, and they are usually considered to be non-malignant. These reactive cells consist of more than 99% of the tumor and form an inflammatory environment, which are responsible for the perpetuation of the rare malignant HRS cell [1,2]. It is now widely believed that the clinical and histological features of HL are primarily due to a plethora of cytokines and chemokines produced by the HRS cells and the surrounding cellular infiltrate in response to inflammatory signals triggered by unknown mechanisms and known etiological factors such as Epstein-Barr virus (EBV). It is also known that EBV can be detected in the HRS cells in 25– 50% of cases of HL [2]. In this issue of the journal, Rautert et al. [3] studied 30 cytokines, chemokines and soluble receptors in pre-treatment serum samples from 47 patients with advanced stage HL with early treatment failure (cases) matched with 47 patients with advanced stage HL in complete remission (controls). Only interleukin-10 (IL-10) serum levels were an IPS-independent risk factor for early treatment failure. The idea of IL-10 playing a role in the pathogenesis and prognosis of patients with HL is not new. In 1999, Sarris et al. [4] showed that elevated serum IL-10 levels are associated with poor outcome in patients with HL, which was confirmed by Bohlen et al. [5] in the following year. In 2003, Herling et al. [6] studied the relationship between the expression of EBV latent membrane protein-1 (LMP-1) in HRS cells and elevated serum IL-10 levels. Hence, the originality of Rautert’s et al. [3] work relies, particularly, on the multiple cytokines screened and on the methodological design. The diversity of cytokines, chemokines and soluble receptors studied is one of the highlights of this article together with the selection of cases and the thorough and meticulous selection of matched controls. However, the data provided by Rautert et al. [3], although pointing toward a promising direction, should be interpreted with caution. Measuring serum/plasma cytokines levels has major drawbacks. Because of the essentially local effects of cytokines, the study of their circulating levels only represents the ‘tip of an iceberg’ and provides limited results. A variety of techniques – such as the development of other approaches to assess the ability of cells to produce cytokines such as the ELISPOT assay, the measurement of cell-associated cytokines by flow cytometry, and the study of cytokine secretion by isolated peripheral blood mononuclear cells or by whole blood test – associated with a local detection of cytokines by immunohistochemistry or in situ hybridisation and reverse transcriptase polymerase chain reaction (RT-PCR), appear to be complementary tools for a better understanding of the multiple aspects of the biology of cytokines.