What are B cells?
B cells are a type of immune cell that is present in your blood and circulates throughout your body. Their primary role is to help target foreign invaders – viruses, bacteria and other foreign cells – in the body for destruction to prevent illness.
On top of that, B cells have a couple different functions. One is making antibodies; another is activating other immune cells in the body, such as T cells.
Why do immune cells target the insulin producing cells in the pancreas in type 1 diabetes? Can you talk about B cell activation and “anergy”?
Typically what should occur with immune cells in the body, such as B cells or T cells, is that they should only recognize foreign invaders as bad and target them for removal. However, in the case of autoimmunity, immune cells mistakenly think cells in the body, such as the insulin-producing beta cells in the pancreas, are foreign and start attacking them instead. In type 1 diabetes, what we think is occurring is B cells are inappropriately recognizing cells in the pancreas as foreign, allowing them to become activated. B cells can pick up little pieces of the pancreas and show them to the body’s T cells. This activates the T cells, which then go on to destroy the insulin-producing cells of the pancreas. These attacks on insulin-producing cells lead to type 1 diabetes.
We believe one reason B cells in type 1 diabetes are recognizing the cells in the pancreas as foreign and becoming activated is an impairment of anergy.
Anergy is a term that we use to describe a self-reactive or auto-reactive B cell that is not activated and is not responding to stimulation. This is a good thing – we don't want your self-reactive B cells to be responding. Normally what happens is when a B cell and the body recognizes itself – the pancreas, thyroid gland, etc. – it should be removed or deleted so it doesn’t enter the peripheral blood (the blood circulating in the body).
Sometimes that process is not perfect. And even in healthy people, sometimes there's escape of these self-reactive B cells into the peripheral blood. The body’s way of keeping these cells in check is through anergy, which is a negative feedback loop telling any self-reactive B cells that have escaped into the peripheral blood to not respond to anything.
How long does it take for the body to go from a misfiring, activated B cell to showing symptoms of type 1 diabetes?
We know that B cells can make antibodies targeting the pancreas years before someone is even diagnosed.
We don't think the antibodies themselves are pathogenic, but they're good indicators that the autoimmune process has begun. Even with these indicators, it can take up to years for the insulin-producing cells to be destroyed enough to require exogenous (outside the body, injectable) insulin.
Do you see B cell activation at a specific age in your research?
Normally people think of type 1 diabetes as juvenile diabetes, but there's data now that supports the idea that there are two kinds of endotypes in type 1 diabetes – those who develop it at a young age, such as less than 10 years old, and those who develop it at an older age, even in adulthood. In our research, we think rogue B cell activation is more important in the younger individuals who are developing type 1 diabetes compared to adults.
Has your research shown so far that type 1 diabetes is genetic?
There's definitely a genetic risk factor component to development of type 1 diabetes. However, what we see here at the Barbara Davis Center, and colleagues have seen elsewhere, is that up to 75% of the people that are recently diagnosed with type 1 diabetes don't actually have a family history of type 1 diabetes.
At the same time, there are a number of different genes that have been associated with the development of type 1 diabetes. Some of those genes are important in B cells and B cell development. We believe that if you have a single mutation in some of these genes, it impairs the ability of these B cells to be properly turned off through anergy, which allows those cells to become activated and participate in disease.
In our research we have found that impairment of B cell anergy can occur in first-degree relatives who are not autoantibody positive or diagnosed with type 1 diabetes, demonstrating a likely genetic component to loss of B cell anergy.
What are you hoping is the next iteration of your research?
One of the goals we have at the Barbara Davis Center is to understand which B cell subset is particularly important in the development of type 1 diabetes and what their exact function is. We recently received a grant to study the transcriptome and repertoire of self-reactive B cells on a single-cell level in both recently diagnosed type 1 diabetes individuals and controls.
The goal is to take that information and hopefully develop more targeted therapies to specifically delete the B cell subsets responsible for initiation of disease for prevention or delay of development of type 1 diabetes.