Type 1 Diabetes Researchers Solve Immune System Mystery
On April 25, 2016, scientists from the University of Lincoln, led by Dr. Michael Christie, announced that they had identified a previously unknown molecule attacked by the immune system in those with type 1 diabetes.
This is incredibly important for prevention and treatment of the disease, as it could lead to better identification of those at risk of developing type 1 diabetes and guide the development of new therapies to prevent the disease from developing.
Type 1 diabetes is an autoimmune disorder that develops when a person’s immune system reacts to certain molecules in the pancreas that it would usually ignore. Previously, scientists had identified four of these molecules, but the fifth one remained unknown for 20 years. Now, these researchers have identified the fifth molecule as Tetraspanin-7. Those with type 1 diabetes have antigens in their blood that are specific to each of these five molecules.
Why Is This Diabetes Research Important?
Doctors use tests that look for antibodies specific to these molecules in order to assess the risk of developing type 1 diabetes; the more antibodies a test detects, the higher the person’s chances are of developing diabetes. Discovering this fifth molecule means that these tests can be even more accurate.
Ultimately, though, this discovery goes beyond detecting a risk for diabetes. Scientists are currently looking for ways stop an immune attack before diabetes develops, and they hope that eventually, by detecting these antibodies and assessing the risk of type 1 diabetes, they can prevent it from ever developing.
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First Working Synthetic Immune Organ With Controllable Antibodies
When exposed to a foreign agent, such as an immunogenic protein, B cells in lymphoid organs (such as the spleen) undergo germinal center (immune defense) reactions. The image on the left is an normal immunized mouse spleen with activated B cells (brown) that produce antibodies. At right, top: a scanning electron micrograph of synthetic porous synthetic immune organoids that enable rapid proliferation and activation of B cells into antibody-producing cells. At right, bottom: primary B cell viability and distribution is visible 24 hours following encapsulation of B cells from the mouse lymphoid organ into the synthetic organoids. (credit: Singh Lab)
Cornell University engineers have created a functional, synthetic immune organoid (a lab-grown ball of cells with some of the features of a normal organ) that produces antibodies. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research.
The first-of-its-kind immune organoid was created in the lab of Ankur Singh, assistant professor of mechanical and aerospace engineering, who applies engineering principles to the study and manipulation of the human immune system.
Simulating the body’s immune response
The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from a hydrogel (a soft, nanocomposite gelatin-like biomaterial), reinforced with silicate nanoparticles to keep the structure from melting at body temperature.
This biomaterial is also seeded with B cells. It mimics the body’s normal anatomical microenvironment of lymphoid tissue, which produces lymphocytes and antibodies in the lymph nodes, thymus, tonsils, and spleen.
Like a real organ, the organoid converts B cells — which make antibodies that respond to infectious invaders — into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. (Germinal centers are a sign of infection and are not present in healthy immune organs.)
The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D lab cultures and can produce activated B cells up to 100 times faster.
A new tool for studying immune functions
Silicate nanoparticles (SiNP) are used for ionic crosslinking of gelatin to form stable hydrogel at body temperature (credit: Alberto Purwada et al./Biomaterials)
According to Singh, the organoid could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature, and could also be used to study specific infections and how the body produces antibodies to fight those infections — from Ebola to HIV.
“You can use our system to force the production of immunotherapeutics at much faster rates,” he said. Such a system also could be used to test toxic chemicals and environmental factors that contribute to infections or organ malfunctions.
The process of B cells becoming germinal centers is not well understood, and in fact, when the body makes mistakes in the genetic rearrangement related to this process, blood cancer can result.
“In the long run, we anticipate that the ability to drive immune reaction ex vivo [outside the body] at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs,” Singh said.
The work was published online June 3 in Biomaterials and will appear later in print.
Abstract of Ex vivo Engineered Immune Organoids for Controlled Germinal Center Reactions
Ex vivo engineered three-dimensional organotypic cultures have enabled the real-time study and control of biological functioning of mammalian tissues. Organs of broad interest where its architectural, cellular, and molecular complexity has prevented progress in ex vivo engineering are the secondary immune organs. Ex vivo immune organs can enable mechanistic understanding of the immune system and more importantly, accelerate the translation of immunotherapies as well as a deeper understanding of the mechanisms that lead to their malignant transformation into a variety of B and T cell malignancies. However, till date, no modular ex vivo immune organ has been developed with an ability to control the rate of immune reaction through tunable design parameter. Here we describe a B cell follicle organoid made of nanocomposite biomaterials, which recapitulates the anatomical microenvironment of a lymphoid tissue that provides the basis to induce an accelerated germinal center (GC) reaction by continuously providing extracellular matrix (ECM) and cell-cell signals to naïve B cells. Compared to existing co-cultures, immune organoids provide a control over primary B cell proliferation with ∼100-fold higher and rapid differentiation to the GC phenotype with robust antibody class switching.
Early Signs in Young Children Predict Type 1 Diabetes
New research shows that it is possible to predict the development of type 1 diabetes. By measuring the presence of autoantibodies in the blood, it is possible to detect whether the immune system has begun to break down the body’s own insulin cells.
“In the TEDDY study we have found that autoantibodies often appear during the first few years of life,” said Professor Åke Lernmark from Lund University, who is leading the study in Sweden.
The TEDDY study, funded by the US National Institutes of Health (NIH), involves 8 600 children from Sweden, the US, Germany and Finland. The children have an increased hereditary risk of type 1 diabetes, detected at birth through tests on blood from the umbilical cord. TEDDY stands for “The Environmental Determinants of Diabetes in the Young.”
Antibodies are part of the body’s immune system and the presence of antibodies in the blood is a sign that the immune system has reacted to an intruder such as a virus or a bacteria. Sometimes, the immune system mutinies and attacks the body. Autoantibodies are a sign of an autoimmune disease and form markers indicating that an attack is underway, for example on the body’s own insulin cells.
The new findings from the TEDDY study have been published in the journal Diabetologia and show that there are three ways to predict the development of type 1 diabetes.
Three ways to predict development of type 1 diabetes:
1. If the autoantibody first discovered attacks insulin (IAA) In Sweden this usually takes place at the age of 18 months. However, in the study as a whole most babies affected were less than a year old.
“If a second autoantibody is detected later, then the person will get diabetes — but it may take up to 20 years,” said Åke Lernmark.
2. If the first autoantibody targets GAD65 (GADA), a protein inside the insulin-producing cells In Sweden this usually happens at the age of two and half, whereas in the study as a whole it was most common at the age of two.
3. If both autoantibodies are first found together
“In TEDDY, 40 per cent of these children had already developed diabetes,” said Åke Lernmark
Of the participating children, 6.5 per cent had their first autoantibody before the age of six.
In 44 per cent of cases, they only had an autoantibody against insulin (IAA). Most of them had this by the age of 1-2.
In 38 per cent of cases, GAD65 autoantibodies (GADA) were detected. The numbers increased until the age of two and then remained constant.
In 14 per cent of cases both autoantibodies were found at the same time, with a peak at the age of 2-3.
The hereditary risk of type 1 diabetes determined which autoantibody the children had. However, it is still not known what causes the immune system to start attacking the body’s own insulin cells to start with. One theory is that a viral infection could be the trigger.
“It is possible that there are two different diseases involved. Perhaps one virus triggers the autoantibodies against insulin and another one the autoantibodies against GAD65,” said Åke Lernmark.
Footnote: Since the birth of the children in the TEDDY study, their parents have kept regular, detailed food diaries, submitted blood and stool samples, nail samples and information about illnesses and medication. When autoantibodies are detected in a child’s blood, the researchers begin the sizeable task of analysing all the material in the hunt for what it is that may have caused the immune system to mutiny.
Novel therapy initiative with potential path to preventing T1D by targeting TWO components of T1D development (autoimmune response and beta-cell survival)
