The aetiology of B-cell lymphoid malignancies with a focus on chronic inflammation and infections.

Abstract

B-cell malignancies are a heterogeneous group of lymphoproliferative disorders with different molecular characteristics and clinical course. It is increasingly recognized that the group displays considerable heterogeneity also regarding aetiologic factors. Here, we summarize the latest developments in the aetiology of B-cell lymphoid malignancy subtypes focusing on immune perturbation. Severe immune suppression constitutes a strong and well-established risk factor for aggressive subtypes (e.g. diffuse large B-cell and Burkitt lymphoma), but appears unrelated to risk of common low-grade subtypes (e.g. follicular and mantle cell lymphoma). Inflammation and infections are known co-factors amongst the immunosuppressed; however, immune stimulation is now recognized as a crucial determinant of lymphomagenesis also amongst immunocompetent individuals. This is best exemplified in marginal zone lymphomas where local chronic inflammation and infection in the stomach, ocular adnexa and salivary glands have been directly linked with the development of oligoclonal and monoclonal malignant B-cell populations. Aggressive subtypes (e.g. diffuse large B-cell lymphoma) are increasingly linked with features of systemic immune stimulation including autoimmune/inflammatory disease and subclinical cytokine elevations. Lifestyle factors (e.g. high body mass index, cigarette smoking) are associated with risk of diffuse large B-cell and follicular lymphoma, respectively, possibly mediated through inflammation. Recent genome-wide association studies further underline the importance of immune function by linking several subtypes to variations in the human leucocyte antigen (HLA) class genes. In the future, improved knowledge of mechanistic pathways of inflammation/infections in lymphoma development may translate to active measures of prevention or treatment, as is already the case for some low-grade lymphoma subtypes.