Getting Closer: Finding Out Why the Immune System Attacks Itself

Biomolecular researcher has published a first-of-its-kind study -  a comprehensive profile of B cells in rheumatoid arthritis (RA). B cells are lymphocytes, or white blood cells, that make protein antibodies that attack a patient’s healthy proteins in patients with RA.

“To the best of our knowledge, this is the first study to conduct whole transcriptome profiling of antigen-specific B cells in any human autoimmune disorder,” said the researcher, whose results portray B cells not merely as auto-antibody producers, but also as a source of diverse molecules that can influence proliferation, differentiation and activation of other pathogenic cell types.

“We anticipate that these data will serve as a foundational data set for investigating multiple hypotheses on the roles of B cells in RA and other autoimmune disorders, and will enable drug discovery,” he said.

B Cells, good and bad
For every new pathogen encountered, a small subset of B cells activates to make an antibody that specifically recognizes that particular pathogenic protein. Every person has between 10-100 million unique B cells, each capable of making its own antibody. While antibodies are the natural way the body fights infections, in the autoimmune RA, these antibodies – that are supposed to fight foreign invaders – attack the body’s own proteins and are thus called auto-antibodies.

“We wanted to understand if there’s anything special about this class of white bloods cells, the autoreactive B cells that make autoantibodies, that would make them fight against healthy proteins,” he said.

Fewer than one in 1,000 B cells are autoreactive, so to find which one is the culprit, a postdoctoral researcher  designed a method to reliably identify and isolate the population, then used RNA sequencing to study all of the RNA being made by each cell.

A number of pathways associated with inflammation and protein modification, known to be amplified in rheumatoid arthritis, were found. At the molecular level, the team found two specific differences in the B cells of RA patients – the inclusion of the protein interleukin 15 receptor subunit alpha (IL-15Rα) and a high amount of the amphiregulin molecule, which can signal adjacent cells. Each was validated at the protein level in independent cohorts of RA patients and prioritized for further studies.

Autoreactive B cells, and they alone, have the protein IL-15Rα.

“We think that protein allows them to become bad actors,” he said. “People have been targeting this pathway for quite some time. This now sheds new light on these bad guys in the progression of this disease and how to target it.”

The team is the first to show that B cells make amphiregulin. Amphiregulin sits in a well-studied pathway, the epidermal growth factor receptor pathway (EGFR), and so the next step will be to determine if inhibiting the pathway impacts the B cells.

The research team also published a list of FDA-approved drugs, such as Xeljanz (tofacitinib), that target various pathways of the B cells, though they aren’t specifically approved for that purpose.

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Malaria increases risk of blood cancer in children

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 The enzyme that helps create antibodies to fight malaria also causes DNA damage that can lead to a highly aggressive type of blood cancer in children, as per new study.

In equatorial Africa, a region known as "lymphoma belt," children are ten times more likely than in other parts of the world to develop Burkitt's lymphoma, a blood cancer that can be fatal if left untreated, researchers said.

That area is also plagued by high rates of malaria, and scientists have spent the last 50 years trying to understand how the two diseases are connected.

The parasite that causes malaria infects red blood cells and liver cells, while Burkitt's lymphoma originates in infection-fighting white blood cells called B lymphocytes.

Researchers working with mice found that the same enzyme that helps create antibodies that fight the malaria parasite also causes DNA damage that can lead to Burkitt's lymphoma.

Though the body needs this enzyme in order to produce potent antibodies to fight malaria, in the process, the enzyme can cause substantial collateral damage to the cells that produce it, and that can lead to lymphoma.

In the study, the researchers infected mice with a form of the parasite that causes malaria, Plasmodium chabaudi. It resulted with the mice experiencing a huge increase in germinal centre (GC) B lymphocytes, the activated form of the white blood cells that can give rise to Burkitt's lymphoma.

As these cells rapidly increase, they also express high levels of an enzyme known as activation-induced cytidine deaminase (AID), which induces mutations in their DNA.

As a result, these cells can diversify to generate a wide range of antibodies. But in addition to beneficial mutations in antibody genes, AID can cause "off-target" damage and shuffling of cancer-causing genes.

The researchers bred mice lacking the p53 gene, which is known to protect cells from many types of cancer, including Burkitt's lymphoma.During experiment those mice expressed AID but not p53, they found that every single one developed lymphoma.

When these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similarly to what happens in Burkitt's lymphoma. This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other. If researchers can somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful. Let us hope for the best soon.