Rheumatoid arthritis and lymphoma: risky business for B cells.

Convincing evidence indicates that patients with rheumatoid arthritis (RA) have about a 2-fold increased risk of developing lymphoma1-4. The results of a large recent case-control study show that the risk of lymphoma is highly correlated with RAdisease activity and not with specific therapy5. This editorial will discuss the context of these findings, and the implications for management of RA. Over 90% of lymphomas are of B cell origin despite a similar frequency of B and T cells in humans. Advances in understanding basic pathogenesis of B cell development and proliferation provide insights into how lymphomas develop. The processes that enable B cells to respond and proliferate to specific antigens increase the risk of developing malignancy6. The central thesis in lymphoma development holds that chronic stimulation of B cells by antigen or by virus, coupled with local inflammation, and immunosuppressioninduced decreased surveillance by tumor-infiltrating immune cells, both T and non-T cells, lead to a heightened risk of malignant B cell lymphomas. A critical role in normal B cell development is played by the B cell receptor for antigen, a cell-surface structure composed of heavy and light-chain immunoglobulins. Normal B cell differentiation takes place in distinct stages based upon differentiation of this receptor. Early B cells leave the bone marrow when their B cell receptor rearranges to become functional. These naive but mature B cells then migrate to lymph node germinal centers. Here, upon exposure to antigen and under the influence of T cells, these B cells undergo vigorous clonal proliferation. The B cell receptor genes undergo editing in a process that involves somatic hypermutation and class-switch recombination, allowing B cells to refine specificity of the B cell receptor. However, this genetic editing also leads to increased risk of B cell transformation. What mechanisms lead to transformation and emergence of a B cell lymphoma? Although transformation to a malignant clone is a multistep process, a hallmark of B cell nonHodgkin’s lymphoma (NHL), seen in up to 90% of cases, is the presence of a chromosomal translocation between an immunoglobulin (Ig) and a proto-oncogene gene locus, particularly BCL-67. The process of Ig somatic hypermutation in normal B cells, which involves cleavage and rearrangement of Ig genes, causes DNA strand breaks that affect other, non-Ig gene partners, primarily BCL-6 and the tumor suppressor gene CD95. The result is control of the oncogene by the active Ig gene, leading to deregulated, constitutive expression of the oncogene and/or other tumor-regulating genes, with uncontrolled proliferation6. Class-switching and somatic hypermutation occur in germinal center B cells and do not occur in T cells, which may explain why germinal center B cells are more prone to undergo malignant transformation compared to T cells. Additional transforming events may affect other non-Ig gene targets, also likely as a result of somatic hypermutation in germinal center B cells, causing mutations in other oncogenes (BCL-2, cmyc) and tumor suppressor genes (TP53), genomic amplifications, and translocations not involving Ig loci. Nearly all B cell NHL express the B cell receptor, suggesting that chronic antigen stimulation plays a central role in their emergence6. An increased risk of lymphoma is found among individuals with several chronic inflammatory conditions, including RA, persistent infections, or immunodeficiency states, which may account for the 2-fold rise in lymphoma incidence over the past several decades8. The failure of the antigenic stimulus to subside, as occurs with persistent infections or with endogenous autoantigens, can increase the chance of B cell transformation as described above. Very little is known regarding the nature of the antigens inciting lymphomas, although Martin, et al found that Ig products of the neoplastic B cells were rheumatoid factors in salivary gland lymphomas of patients with Sjögren’s syndrome9. Other examples of chronic stimulation by antigens leading to lymphoma include hepatitis C10 and Helicobacter pylori11.