The researchers worked with transgenic mouse models that were engineered to overproduce a special cytokine – a hormone which regulates immunity – called BAFF, a B-cell activating factor that is elevated in patients with lupus and other autoimmune diseases. The B cells are responsible for the production of antibodies in the body. Mice overproducing BAFF develop systemic lupus erythematosis (SLE)-like disease, very similar to human lupus, which is estimated to affect one in a thousand Americans, 90 percent of them women.
The research study showed that that a compartment of the spleen called the marginal zone is where the majority of autoreactive B cells are found. The scientists transplanted immune cells from the spleen's marginal zone in the mice with lupus into mice without their own B cells, and found that they immediately gave rise to pathogenic antibodies.
When the enlarged marginal zone cell pool in the mouse model was removed or reduced, the disease was prevented or strongly diminished.
"The study proved without a doubt that the transplanted B cells were the source of lupus auto-antibodies," said Gregg Silverman, M.D. professor of medicine in UCSD’s Translational Oncology Program and contributor to the paper. "Identifying the spleen’s marginal zone as the likely source of these tissue-damaging antibodies gives us important insights into the cause of lupus as well as a target for new therapies."
The researchers also studied B-cell activation in two signalling pathways, called the classical and alternative NF-ÿB pathways, that contribute to the development of lupus. The scientists discovered that while each pathway is required for the pathogenesis of antibodies that cause the autoimmune disease, neither works alone.
"Either pathway would be a suitable target for therapy,” said Karin, whose lab first identified the two NF-ÿB pathways several years ago. "Both are critical to production of pathogenic B cells that destroy the body's own cells in lupus." However, he added that targeting one of the NF-ÿB pathways called the classical pathway would eliminate B cells throughout the entire body. This is the drawback of other therapies currently recommended for lupus patients, as they destroy the body’s immune cells which are needed to fight off other infection.
Karin added that genetic manipulation of the animals, or the timing of the splenectomy in the cycle of the lupus-like disease might have contributed to the outcome. Therefore more research is needed to draw a definite conclusion, though their studies ruled out the lymph nodes or the bone marrow – where B cells are born – as contributors to the effect.
"The study tells us important things about the pathogenesis of disease in a mouse model that is very close to human lupus," Karin said. In mice, as in humans, the disease leads to overproduction of anti-DNA antibodies and immune deposits in the kidneys, which can result in fatal kidney damage.
Lupus is a chronic autoimmune disease that, for unknown reasons, causes the immune system to attack the body's own tissue and organs, including the joints, kidneys, heart, lungs, brain, blood, or skin. Difficult to diagnose and treat, patients may see several physicians before learning they have lupus. The disease is much more common in women than men, usually is first diagnosed between the ages of 15 and 44 years, and is two to three times more common in persons of color. Patients often take many different medications to control lupus, which has symptoms ranging from mild to life-threatening, including aching or swollen joints, skin rashes, kidney damage, anemia and hair loss.
Debra Kain | EurekAlert!
A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital
Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...
Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.
A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
21.04.2017 | Physics and Astronomy
21.04.2017 | Health and Medicine
21.04.2017 | Physics and Astronomy