Interferon-beta is a drug approved for the treatment of secondary progressive multiple sclerosis (MS), a relapsing form of the inflammatory autoimmune disease where the body’s own immune system attacks and damages myelin that forms a protective, insulating sheath around neuronal projections called axons, in the brain and spinal cord. The mechanism of myelin degradation in MS is unknown.
A study published in the journal ACS Chemical Neuroscience (“Interferon-β Decreases the Hypermetabolic State of Red Blood Cells from Patients with Multiple Sclerosis”) reveals red blood cells in MS exist in a hypermetabolic state and clarifies the mechanism of action of interferon-beta, a drug that acts to normalize this state.
Multiple sclerosis affects nearly 2.8 million individuals worldwide. Myelin degradation and the consequent impairment of neuronal signaling leads to pain, numbness, and mobility issues in patients with MS that worsen over time.
Patients with MS have increased levels of zinc ions in blood plasma and in the membrane of red blood cells. This increases pathological mechanisms such as the division and differentiation of immune T lymphocytes, receptor affinity for various immune molecules, and microglia activation. The family of interferon-beta drugs contain zinc binding pockets, and are thought to work by decreasing the production of immune molecules that instigate inflammation and by increasing the production of molecules that quash inflammation.
Dana Spence, PhD, a professor of biomedical engineering at Michigan State University, and his team were interested in understanding whether interferon-beta drugs benefited MS patients through binding zinc alone. Their study enhances the prevailing view by demonstrating that interferon beta drugs not only bind zinc, but also bind connecting-peptide (C-peptide)—a molecule that is co-secreted from insulin-producing cells in the pancreas, and the plasma protein albumin, to red blood cells.
Measures obtained from brain tissue and blood show levels of both ATP (adenosine triphosphate), a universal energy currency in biosystems, and the gaseous signaling molecule NO (nitric oxide) are abnormally high in patients with MS compared to normal individuals. Zinc, C-peptide, and albumin bind to red blood cells. Moreover, red blood cells collected from patients with MS bind more C-peptide and release more ATP, than normal. Cells that constitute myelin in the brain and spinal cord—glial cells called oligodendrocytes—are sensitive to the presence of ATP and NO.
Red blood cells can release NO directly and can stimulate the lining of blood vessels to produce NO by releasing ATP. The released NO degrades myelin, eventually resulting in neuronal damage. In the presence of albumin and zinc, C-peptide in blood can bind to red blood cells and increase amounts of a glucose transporter molecule (GLUT1) that induces red blood cells to release ATP.
Spence and his team show red blood cells from MS patients bind more zinc, C-peptide, and albumin than red blood cells from control subjects, indicating a hypermetabolic state. By incubating red blood cells with interferon-beta, the researchers show the hypermetabolic state is normalized, indicated by a decrease in the binding of zinc, albumin, and C-peptide to red blood cells, as well as decreases in levels of GLUT1 and released ATP.
“Our results suggest that interferon-beta inhibits albumin binding to the red blood cells, thereby reducing its ability to deliver ligands such as C-peptide and Zn ions to the cell and normalizing the basal hypermetabolic state,” the authors noted. At present, Spence’s team is confirming whether interferon-beta blocks the complex of zinc, albumin, and C-peptide at the red blood cell membrane or binds to albumin to interfere with the complex.
Importantly, the data suggests that a reappraisal of the dosing regimen for interferon-beta is needed. The authors noted, “Rather than subcutaneous injections that are weeks apart, a daily, less concentrated dose prior to insulin/C-peptide release from pancreatic beta cells would be more appropriate.”