Abstract
Burkitt lymphoma is unusually common in parts of Africa where malaria is widespread, but the reason for the association has been unclear. A new study suggests that parasitic infection triggers dramatic B-cell proliferation and increased expression of the enzyme activation-induced cytidine deaminase, which generates more potent antibodies—and causes mutations that lead to cancer.
Burkitt lymphoma, a B-cell cancer, is unusually common in parts of Africa where malaria is widespread, but the reason for the association has been unclear. A new study in Cell suggests that parasitic infection triggers dramatic B-cell proliferation and increased expression of the enzyme activation-induced cytidine deaminase (AID), which generates more potent antibodies—and causes mutations that lead to cancer.
The immune response and increased AID expression “are very useful and very dangerous at the same time,” says co-author Davide Robbiani, MD, PhD, an associate professor of molecular immunology at The Rockefeller University in New York, NY. “They're required to protect from infection, but they are jeopardizing the integrity of the genome.”
AID modifies the sequences of immunoglobulin genes to produce higher-affinity antibodies. Previous work showed that AID also could induce chromosomal translocations in c-myc that had been found in patients with Burkitt lymphoma. However, no one had linked this process to malaria, which is caused by Plasmodium falciparum and other parasites.
Robbiani's team infected mice with the related parasite Plasmodium chabaudi, which causes a disease similar to human malaria. The animals' spleens showed a 63-fold increase in the number of B lymphocytes in germinal centers, structures that make the cells more effective at fighting infection. The B cells also expressed high levels of AID. When the researchers searched the B cells of infected mice for genomic damage, they found tens of thousands of chromosomal translocations, including c-myc translocations.
The team then infected mice whose B cells were missing p53, which is often mutated in Burkitt lymphoma. Some of the animals also lacked AID. Only one third of the mice without AID developed cancer. In contrast, all of the mice with AID died from lymphoma, and the features of their disease—such as the maturity of the cancerous B cells and the presence of translocations—were similar to those of Burkitt lymphoma.
The study is the first to show experimentally that parasitic infection can cause the translocations linked to Burkitt lymphoma, says Uttiya Basu, PhD, assistant professor of microbiology and immunology at Columbia University in New York, NY. “That's a major advancement,” he says.
More work will be needed to determine if antimalarial treatments reduce cancer risk, says Basu. Lymphoma rates are not high in all areas where malaria is common, so other factors may be involved. Furthermore, the results must be interpreted cautiously because the disease caused by P. chabaudi is not exactly the same as human malaria. Robbiani's team is now investigating how AID causes off-target mutations, in the hope that treatments can be developed to limit the damage.
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