Introduction: the role of inflammation, autoimmune disease and infectious agents in development of leukaemia and lymphoma

Leukaemias and lymphomas are heterogeneous groups of malignancies with considerably different biological and clinical features. The exact aetiology is unknown for the majority of these entities, although mounting evidence has revealed associations between certain leukaemias/lymphomas and inflammation, autoimmune disease and infectious agents. In May 2008, the Journal of Internal Medicine arranged a 2-day symposium in Stockholm entitled Leukaemia and lymphoma development – the role of inflammation, autoimmunity and infections. The main purpose of this conference was to create a unique opportunity to bring together preclinical, clinical and epidemiological experts from various research fields, such as oncology, haematology, pathology and rheumatology, to discuss the risk factors and the possible mechanisms behind leukaemia and lymphoma development. The conference primarily focused on lymphoid malignancies, e.g. various B-cell lymphomas, Hodgkin lymphoma and chronic lymphocytic leukaemia (CLL) and incorporated broad topics, such as their association with autoimmune disease/inflammatory conditions, viral and bacterial infections and the intricate role played by cells of the innate immunity in these diseases. More specific areas, such as the recent findings of direct and indirect evidence for antigen selection in CLL, were also discussed. Following the conference, invited speakers from each session reviewed the current literature in their respective fields in four accompanying reviews11 A fifth review will be published separately, which covers the molecular and clinical aspects of infections in lymphoma development. , which are published in this issue of the Journal of Internal Medicine [1-4] and also summarized briefly below. The relationship between autoimmune disease and increased risk of lymphoma development has been well-described. However, considering the inherent heterogeneity amongst both autoimmune diseases and lymphomas, it has been challenging to identify significant associations. In a review by Smedby et al. [1], the links between a wide range of autoimmune diseases and lymphoma development have been detailed, both for diseases where a strong association exists along with conditions with a more ambiguous correlation. In particular, the authors describe risk levels, potential risk factors, such as inflammatory activity and type of treatment, and their relation to specific lymphoma subtypes. This review also explores biological mechanisms with the aim of clarifying the association between autoimmunity and the subsequent increased risk of lymphoma development. The latter will hopefully also help us to understand more about lymphoma pathogenesis in general. The interaction of malignant cells with surrounding nonmalignant cells has attracted much interest lately both in lymphoma and in cancer in general. The composition of these nonmalignant cells appears to contribute significantly to the biological and clinical features of lymphoma. The review by de Jong & Enblad [2] discusses the role of the innate and adaptive immune responses in both indolent and aggressive B-cell lymphomas as well as in Hodgkin lymphoma. The complexity of these cell–cell interactions is emphasized by that fact that the microenvironment can provide both growth-promoting and growth-suppressive signals depending on cell and tumour types. This intricacy will be challenging to clarify and requires further in-depth study to fully elucidate. For many years, infections have been either clearly linked to or postulated to play a role in lymphoma pathogenesis. One of the earliest observations was the association between Epstein Barr virus infection and development of Burkitt lymphoma and Hodgkin lymphoma. More recently, bacterial agents have also been linked to lymphoma development, for instance the causative role of Helicobacter pylori in MALT lymphomas which has garnered much attention. In the review by Hjalgrim & Engels [3], the authors outline epidemiological evidence for links between microorganisms and Hodgkin/nonHodgkin lymphoma. In addition, several viruses and bacteria and its relation to specific subsets of lymphomas as well as the criteria useful in assessing such potential associations are discussed. A separate review detailing the molecular and clinical aspects of infections will be published separately in a later issue of the Journal of Internal Medicine. In recent years, it has become evident that antigen selection may also play an important role in CLL pathogenesis, where both autoantigens and bacterial antigens have been implicated. The microenvironment appears to play a significant role in CLL pathology, where CLL cells require interaction with other cells, e.g. T cells and stromal cells, and soluble factors to survive. In the review by Ghia et al. [4], current evidence for antigenic stimulation in CLL is presented as well as the complex role of the microenvironment in this disease. The findings of restricted B-cell receptors in subsets of CLL have given indirect evidence for antigen involvement. Interestingly, several types of autoantigens have recently been described with specificity to CLL B-cell receptors. During this 2-day conference, different aspects of leukaemia and lymphoma aetiology were discussed by experts in the field. The association between autoimmunity and lymphoma development is indisputable and certain autoimmune conditions are already established risk factors for lymphoma. The challenge for the future is to understand the mechanisms behind lymphoma development in the context of autoimmune disease. The important role of innate immunity within the microenvironment is evident in several subtypes of lymphoma, but at the same time, it is a complex interplay of cells with different outcomes depending on lymphoma subtype as well as the treatment employed. The characterisation and verification of microbes/autoantigens in leukaemia and lymphoma development is indeed an interesting area of research and will yield more knowledge regarding the pathogenesis of these diseases and potentially open up the possibility of new treatment strategies. Taken together, it will be very exciting to follow this research area in the coming years and hopefully similar conferences can be arranged, which can facilitate the open discussion between researchers involved in leukemia/lymphoma and autoimmune disease. No conflict of interest to declare.