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Hitting the Brakes When Cells Get out of Control

B cells

These figures show normal B cells (left) and those from SPPL2A mutant mice (right) with CD74 staining in green and nuclear staining in blue. In SPPL2A mutant mice, CD74 cannot be broken down so it accumulates around the nucleus. 

By Hsei-Di Law

By creating a “traffic jam” in the transport pathway of B cells, researchers have found a potential drug target to slow the proliferation of cancerous cells.

White blood cells are a crucial part of the immune system that defends the body against infectious microorganisms and foreign particles. There are several types of white blood cell in the body, each with a distinct role. One type of white blood cell, the B cell, functions to create and secrete antibodies.

Antibodies are proteins that chemically “fit” foreign particles and invading microorganisms, and neutralise these pathogens in a number of ways. They can bind to them and damage or destroy them, or they can coat pathogens and cause them to clump together so that they are unable to enter cells. Coating pathogens in antibodies also sends a signal to a different type of immune cell, phagocytes, which ingest pathogens and foreign molecules.

As the body’s antibody factories, B cells are a critical part of its defence system. Without B cells, the body is unable to protect itself and becomes “immunodeficient”.

Immunodeficiency leaves us extremely vulnerable to infections. An example of extreme B cell immunodeficiency is a genetic disease called Bruton’s agammaglobulinaemia. In this disease, a mutation prevents B cells from developing. People with this disease cannot survive their first year of life without treatment.

Patients with immunodeficiency need their immune systems boosted. This can be achieved through blood transfusions or medicines that activate white blood cells.

On the other side of the spectrum, some patients require immunosuppression – a deliberate reduction of the immune response. This seems perplexing given the vital role that B cells have in protecting our body by fighting off infections.

An example of this is in autoimmune diseases where B cells inappropriately attack their own body. In this disease, the antibodies that B cells produce chemically “fit” the body’s own tissues. These “self-reactive” antibodies attack one’s own tissues instead of foreign microbes. Patients with autoimmune disease require treatment to suppresses the immune system and calm the attack response.

A second example is in B cell lymphoma, a form of blood cancer. By random chance, a B cell can acquire the mutations that cause it to lose control of its growth processes. The now-cancerous B cell can start dividing more than it should. In most types of lymphoma, these mutated B cells overgrow and destroy vital organs. In this case it is clearly advantageous to be able to suppress B cells.

In order to design drugs that can suppress B cell growth in the body, we must first understand the molecular mechanisms of how B cells live and survive. PhD student Hannes Bergmann, working in the immunogenomics laboratory at the John Curtin School of Medical Research, has spent the past year-and-a-half investigating what makes B cells tick.

Led by Dr Anselm Enders and Prof Chris Goodnow, Bergmann and his co-workers have identified a factor that significantly influences the number of B cells surviving in the body – a protein called SPPL2A. The discovery has been published in the Journal of Experimental Medicine.

Evidence for the importance of this protein came from a mouse strain that carries a mutation in the gene that codes for SPPL2A. As a result of this mutation, mice from this strain are unable to produce the SPPL2A protein. This has a drastic effect: mutant mice possess one-twentieth as many B cells as normal mice.

Proteins like SPPL2A are called “critical molecules” as their absence alone causes abnormalities. The discovery of critical proteins is vital as they provide targets for the development of new drugs. However, this is no easy task. With more than two million protein candidates in our body, the protein haystack is vast indeed.

So how does SPPL2A affect B cell numbers? “SPPL2A is an enzyme that breaks down a molecule called CD74,” Bergmann explains. “CD74 exists within B cells. In mutant mice without SPPL2A, CD74 cannot be degraded and severely accumulates. We think this accumulation is toxic to cells and potentially damages their internal transport processes.”

The B cell’s transport processes are essential to its own survival and growth. This is because the cell’s transport system is responsible for commuting internally-made proteins to the cell surface. One such cell surface protein has the critical role of intercepting signals from the environment and transmitting those signals into the cell. Much like rooftop aerials, B cells display these “receptors” on their surface, ready to pick up signals from the extracellular space. This is crucial to the B cells’ own survival because the amount and intensity of “survival signals” that a B cell receives is what determines whether it lives or dies.

Receptor proteins are made within the interior of the cell and need to be transported to the B cell surface. This is where the cell’s transport system is needed. Freshly made receptors from within the depths of the cell are first packaged into tiny bubbles called vesicles. The cell’s internal transport system then shuttles these vesicles all the way to the cell’s surface, much like an elevator. Here, the protein-containing vesicle delivers its cargo onto the cell surface. On the cell surface membrane, the receptors proteins are unpacked and mounted onto the cell, where they begin capturing survival signals from the extracellular environment.

Bergmann and his colleagues found that B cells in mutant mice without SPPL2A displayed fewer receptor proteins on their surfaces. Because there is no SPPL2A protein to break down CD74, the researchers believe that the toxic accumulation of CD74 clogs normal cellular transport mechanisms. A kind of “molecular traffic jam” then occurs that blocks many receptor proteins from reaching the B cell’s surface.

Without sufficient numbers of surface receptors, these B cells do not receive the appropriate level of survival signals needed to keep them alive. This could explain why SPPL2A mutant mice show a significant reduction in B cell numbers. This finding may lead to new applications in medicine.

“If we can harness the role of SPPL2A in B cell survival and growth, we may be able to put a brake on B cell growth in situations where they have overgrown or in diseases where they have simply gone haywire,”Bergmann says.

It is hoped that by discovering a means to potentially suppress B cells, we may be able to control their growth in patients requiring immunosuppression. The discovery of SPPL2A’s critical role in B cell survival and growth means that a potential new drug target has been identified.

“We hope that drugs that inhibit SPPL2A will have the effect of reducing B cell numbers in patients with B cell lymphomas and certain autoimmune diseases,” says Bergmann, who will be spending the rest of his PhD refining our knowledge about the role of SPPL2A in the immune system.

Better understanding of the function of SPPL2A may soon enable us to fine-tune the level of survival signals within B cells, giving us more control over B cell growth and activity.

Hsei-Di Law is a research technician at the John Curtin School of Medical Research.