Posted on NIH. 6 August, 2020
The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent ground-breaking NIH research.
Interleukin IL-17A has often been associated with several types of uveitis, a disease that causes up to 15% of cases of blindness in the U.S. In autoimmune uveitis, immune cells become abnormally activated and begin to destroy healthy cells, including light-sensing photoreceptors and neurons. Autoimmune uveitis and optic neuritis are often predecessors of multiple sclerosis and may share some common mechanisms of pathology.
Th17 lymphocyte, an immune cell involved in this response, produces several pro-inflammatory molecules called cytokines. Th17 cells produce IL-17A, which attracts immune cells called neutrophils that in turn can cause tissue damage.
Multiple clinical trials studying the treatment of autoimmune uveitis or multiple sclerosis with drugs that block IL-17A have not shown promise in the treatment of these diseases. In models of autoimmune diseases of the eye and brain, the NEI research team has shown that blocking IL-17A increased the presence of other inflammatory molecules produced by Th17 cells, immune cells that produce IL-17A and are involved in neuroinflammation. Their finding could explain why IL-17-targeted treatments for conditions autoimmune uveitis and MS have failed. A report on the findings was published in Immunity.
Dr. Rachel Caspi, Chief of the Laboratory of Immunology at NEI has indicated that IL-17 is the prototypical inflammatory immune molecule blamed for autoimmunity in the neuro-retina and the brain, but there’s been some controversy about the role it plays. In their model of autoimmune uveitis, without the presence of IL-17, the amount of tissue damage unexpectedly stayed the same but showed higher levels of other inflammatory molecules.
Dr. Caspi and the NEI research team found that when IL-17A binds to its receptor on Th17 cells, it triggers a signaling cascade that causes an increase in the cells’ production of an anti-inflammatory molecule, interleukin-24 (IL-24), which was not previously known to be produced by Th17 cells. IL-24 in turn suppresses the rest of the Th17 cells’ inflammatory program, turning down the production of cytokines like IL-17F, GM-CSF and possibly IL-22. In the absence of IL-17A, this autocrine loop does not happen, triggering the overproduction of other inflammatory cytokines by the Th17 cells, which in turn causes inflammation.
Anti-IL-17A therapy has shown great success in the treatment of diseases such as Psoriasis. “We expected that this would also apply to uveitis, but it turned out not the be the case,” said Caspi. “This study might explain why clinical trials targeting IL-17A to treat uveitis were not successful, and suggests that a combination approach involving both IL-17A and IL-24 may be more effective in treating autoimmune disorders of the nervous system.”
Genes, like people, have lineages that date back throughout time, spreading and morphing with each new iteration. The role of many of these ancient genes, often referred to as “junk DNA” is not well understood. Junk DNA is a DNA sequence that is part of the genome but is not known to encode protein or regulate the expression of genes. In a new study published in the journal PNAS, NIH researchers report that ancient human endogenous retrovirus (HERV-K) genes that were once considered “junk DNA” might play a role in the differentiation process.
These genes may be involved in human embryonic development, the growth of some tumors, and nerve damage during multiple sclerosis. Prior research by Dr. Avindra Nath’s team at National Institute of Neurological Disorders and Stroke (NIND has shown that amyotrophic lateral sclerosis (ALS) may also be linked to activation of the HERV-K gene.
In this current study led by NINDS scientist Dr. David Wang, the research team found that HERV-K genes inscribed into chromosomes 12 and 19 may help control the differentiation, or maturation, of human stem cells into the trillions of neurons that are wired into our nervous systems. Blood cells drawn from healthy volunteers at the NIH’s Clinical Center were genetically transformed into induced pluripotent stem cells, which then have the ability to turn into any cell type in the body. The researchers found that the surfaces of the stem cells were lined with high levels of HERV-K, subtype HML-2, which is an envelope protein used by viruses to attach onto and infect cells. Following two rounds of treatments with a “cocktail”, the cells progressed to an intermediate neural stem cell state and subsequently into neurons.
The researchers were able to speed up this process by turning off HERV-K, HML-2 genes in the stem cells or by treating the cells with antibodies against the HML-2 protein. They also found the ability to delay neural differentiation by artificially overloading the cells with the HML-2 It was also noted that interactions on the stem cell surfaces between HML-2 and another immune cell protein called CD98HC may slow or inhibit differentiation through the triggering of internal chemical reactions that are known to control cell growth and tumors. The results of this study indicated that the deactivation of the HERV-K gene may free stem cells to become neurons. Future studies for the team include the exploration of the role that HERV-K genes play in the wiring of the nervous system.
Neurofilament light chain (NfL) is a biomarker associated with axonal damage across a wide variety of neurological disorders. Due to the ability to measure NfL by immunoassay in cerebrospinal fluid and plasma it is a useful marker for diagnosing and monitoring the extent of axonal damage in patients with ALS, MS, Alzheimer’s and Huntington’s disease.
In a recent study conducted by researchers from the NIH Clinical Center, it was shown that neurofilament light chain (NfL) also delivered superior diagnostic and prognostic performance as a blood biomarker for mild, moderate, and severe traumatic brain injury (TBI) when compared to blood proteins glial fibrillary acidic protein, tau, and ubiquitin c-terminal hydrolase-L1.
The NIH scientists studied four proteins from the brain that collect in the blood after a TBI from patients at the NIH Clinical Center who had mild, moderate, or severe injury. These proteins were compared on their ability to distinguish patients with TBI from the control group, and determine the extent of brain injury along with functional outcomes anywhere from one month up to five years following injury.
Serum NfL protein was the strongest predictor for identifying patients with mild, moderate, and severe TBI on an average of seven months after injury. There was also a strong correlation to functional outcomes, showing higher concentration of serum NfL in the blood of patients with worse of lower outcomes. The researchers determined that serum NfL was the only protein that distinguished TBI patients from uninjured controls with high accuracy even months to years after the injury, suggesting that a single TBI may cause long-term neuroaxonal degeneration.
“This study confirms the sensitivity of serum neurofilament light chain and its value as a biomarker of choice for all stages of brain injury, even when measured months to years after a single mild, moderate or severe traumatic brain injury,” said Dr. Leighton Chan, Chief of the Rehabilitation Medicine Department at the NIH Clinical Center.
Serum NfL also had the strongest association to advanced brain imaging, such as diffusion tensor MRI scans, than the other proteins. The results of this study suggests that serum NfL can provide clinicians with an easier, faster, and cost-effective diagnostic and prognostic option than advanced brain imaging.
Depression and anxiety are conditions that affect millions of people worldwide. Depressive states can result in the loss of interest in daily activities, social isolation, along with adverse physical symptoms of the disorder. New IRP research has found that psychological stress can also cause damage to the blood vessels in the brains of mice and dramatically alters the behavior of genes in certain blood vessel cells.
While psychological stress and affective disorders have been clinically associated with hypertension and vascular disease, the biological links between the conditions have not been fully explored. In a study recently conducted by researchers in Dr. Miles Herkenham’s lab at the National Institute of Mental Health (NIMH), this relationship was examined using chronic social defeat (CSD) stress, which produces anxiety-like and depressive-like behaviors in susceptible mice. Physical attributes associated with this decline include the production of cerebrovascular microbleeds in scattered locations.
An experimental chronic social defeat stress model involves exposing naïve mice to aggressor mice repeatedly over a period of several weeks. This emotionally stressful environment induces depressive behavior in mice similar to human symptoms of depression and anxiety. These behavioral changes include a loss of interest in social interaction coupled with a decreased willingness to leave their safe spaces to explore their surroundings.
“Social defeat is a very natural thing for social animals, which both mice and humans are,” says Dr. Herkenham, the new study’s senior author. “By looking at mice undergoing this kind of stress, we can gain insight into what a human might be going through.”
However, not all of the animals that experienced psychological stress showed changes in behavior following exposure to social defeat. Past studies in Dr. Herkenham’s lab have shown that for mice that behave differently following chronic social defeat, immune cells in the brain called microglia show changes in gene activity similar to those that occur when microglia are exposed to substances found in blood.
In this current study, the research team led by Dr. Herkenham and Dr. Michael Lehmann, determined that the mice that displayed behavioral changes following chronic social defeat also showed signs of microbleeds randomly distributed throughout their brains. In these susceptible mice, the endothelial cells that line blood vessels and keep blood out of the brain, showed dramatically altered activity in more than 3,000 genes, depending on how many consecutive days a mouse was exposed to chronic social defeat.
Dr. Lehmann concluded from the study that the damaged cells resulting from these stressors need to divide in order to replace the area that has been affected, and at the same time other cells come in to assist in the process. That’s the typical pattern seen in wound healing and that’s the pattern that was seen in the endothelial cells. All of which was triggered by psychological stress.
Further research will be required to confirm that the new study’s findings apply to humans through post-mortem examination of the endothelial cells in the brains of individuals with mood or anxiety disorders show similar changes in gene activity to those of mice exposed to chronic social defeat. Drs. Herkenham and Lehmann also plan to investigate whether certain factors such as exercise, positive cognitive reinforcement or medications that lower blood pressure, can prevent psychological stress from triggering behavioral changes in mice or psychological disorders in humans.
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