Rest and the Immune System

Following on from yesterday's post, this short video from Weimar TV talks about how vital it is to get enough rest. HIV patients will relate to any ideas on how to strengthen the immune system but HIV patients who also suffer from neuropathy, which frequently is at its worst at night, will feel somewhat between a rock and a hard place. In this case, we know what we should do but when you can't control your nervous system at night, it's difficult to achieve optimal sleep patterns.

Rest and the Immune System from WeimarTV on Vimeo.

IMMUNE CELLS IN LIVER DRIVE FATTY LIVER DISEASE LIVER CANCER

Fatty liver disease -- alongside fatty liver due to massive alcohol consumption -- is mainly caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary life style. This is referred to as non-alcoholic fatty liver disease (NAFLD). If NAFLD becomes chronic -- e.g. through the constant uptake of high lipids and high sugar combined with lack of excercise a chronic inflammatory response is triggered in the liver tissue in addition. This can lead to non-alcoholic steatohepatitis (NASH) -- a liver disease with clear detectable pathologic alteratons of the tissue.

These liver diseases (NAFLD and NASH), along with chronic viral infections, are the most common causes of liver cancer, or hepatocellular carcinoma (HCC). In the United States, about 90 million people suffer from NAFLD. In Europe, the figure is more than 40 million, and even in threshold countries like India and China, the number of people affected is rising due to increasingly unhealthy lifestyles. More worrying, in all of the above mentioned states the numbers of NAFLD and NASH patients is constantly increasing. Consequently, the incidence of HCC resulting from NASH and NAFLD is also rising worldwide. In the United States, HCC is the fastest-growing form of cancer at the moment. No efficient causal therapy exists for HCC patients of which approximately 800,000 die every year.

T cells involved in the development of fatty liver disease, NASH and HCC

The mechanisms that cause diseases such as fatty liver disease, steatohepatitis and HCC are still not widely understood. However, immune cells, particularly CD8+ T cells and NK T cells seem to play an important role. This finding was made by a team of scientists led by Prof. Mathias Heikenwälder, Prof. Matthias Tschöp, Dr. Kerstin Stemmer, Dr. Kristian Unger, Prof. Ulrike Protzer and the working group of Dr. Hans Zischka from the Helmholtz Zentrum München together with a team headed by Prof. Percy Knolle of the Technische Universität München (TUM), Prof. Achim Weber from Zurich University Hospital and Dr. Monika Wolf, Institute of Surgical Pathology, University Hospital Zurich. The animal model which was used to examine the long-term effects of metabolic syndrome* enabled the scientists to elucidate new mechanisms that cause fatty liver disease and also show how it can develop into liver cancer.

Inflammatory events offer starting point for prevention and treatment

The scientists assume that an existing metabolic imbalance results in the activation and migration of immune cells to the liver. There, the immune cells interact with liver cells and trigger an inflammatory response that damages the liver tissue and also destabilizes the metabolic activity of the liver cells. "Initially it immune cells promote fatty liver degeneration. The inflammation, which is triggered by specific immune cells, encourages the progression of fatty liver pathology and causes NASH to develop. These processes are the basis for liver cell degeneration, which can cause HCC," explains Prof. Heikenwälder, who led the study. "Our results provide completely new insights into the development of these serious liver diseases. Building on this knowledge, we now want to develop new, preventive and therapeutic strategies to combat these diseases." The initial studies are already under way in the preclinical model.

*Metabolic syndrome: a combination of obesity / abdominal adiposity, insulin resistance, raise levels of lipids in the blood and raised blood pressure.

How Immune Cells Cause Nerve Pain

Today's post from relief.news (see link below) is another one revealing how studies at cellular and molecular level are providing a great deal of information about how pain is caused and how we feel it. All well and good you may say but when will it lead to a drug to control it? The point is that by discovering what activates pain and how that works, will eventually lead to the discovery of means to block those signals and with nerve pain, that is essential. This article talks about a protein called CSF1 which is released by damaged nerve cells to activate the immune system cells to come and help. These cells are called microglia - you may have come across the word in other articles. The fact that these immune cells can't help repair the damage, leads to the constant painful symptoms we're all aware of as pain signals are repeatedly sent. It's enormously complex (as many of these studies are) but this article helps explain how the research was carried out.
 

Discovering the Missing Link in Neuropathic Pain

A key protein, called CSF1, is released from injured nerve cells to cause activation of the immune system, leading to pain in mice. 

Neuropathic pain—the type that results from nerve injury—is one of the most difficult forms of pain to treat in people. Researchers know that after nerve injury, immune cells in the central nervous system called microglia increase in number and become activated, contributing to the onset of neuropathic pain. Yet, the signal that injured nerve cells (neurons) send out that prompts this response from microglia has remained elusive—until now. A new mouse study published online December 7 in the journal Nature Neuroscience reports that the signal is colony-stimulating factor 1 (CSF1), a protein that belongs to a class of signaling molecules known as cytokines.

“We have long known that microglia are involved in the development and maintenance of pain after nerve injury. This new study really elegantly and convincingly fills in the gap about how a nerve tells the spinal cord, and the microglia within it, that an injury has happened,” said Simon Beggs, a pain researcher at the University of Toronto, Canada, who was not involved with the new work.

In the study, researchers led by Zhonghui Guan, Julia Kuhn and Allan Basbaum at the University of California, San Francisco, US, injured the sciatic nerves of mice; this is a commonly used experimental procedure undertaken in animals to learn more about pain. After nerve injury, the animals had a painful increase in sensitivity to mechanical pressure (a phenomenon known as mechanical hypersensitivity).

Then, to identify the molecular signal released by the injured nerves that caused microglia to become activated, the researchers looked at gene expression—which genes were turned on, and which ones were turned off—in response to the nerve injury.

“Hundreds and hundreds of genes changed [after nerve injury],” said Basbaum. The researchers were particularly intrigued to learn that the gene that makes the CSF1 protein was turned on, as was the gene that makes the CSF1 receptor, which is a molecule in microglia to which CSF1 attaches.

“We were struck by this, because they [CSF1 and CSF1 receptor] have long been known to be necessary for the development of microglia,” explained Basbaum. “We found that was worth pursuing,” he added.

Further experiments showed that CSF1 was not present in healthy neurons, but rather was made in injured neurons following nerve injury and transported to the spinal cord. There, CSF1 interacted with the CSF1 receptor.

The researchers also found that CSF1 was both necessary, and sufficient on its own, to activate microglia and cause mechanical hypersensitivity, in the experimental model of nerve injury pain.

Finally, the investigators reported that the activated microglia released another protein, called DAP12, which led to the development of pain.

Overall, the results provide a better understanding of how nerve injury leads to the activation of microglia and pain—and could have relevance to people suffering from chronic pain too, if the same signaling mechanisms are at play. In fact, the results offer the possibility that drugs could be designed that interfere with the signaling between the proteins identified in the study.

“The new findings potentially provide several new [drug] targets—CSF1, CSF1 receptor, and DAP12—that have huge therapeutic potential for neuropathic pain” in people, said Beggs. —Allison Marin.

To read about the research in more detail, see the related Pain Research Forum news story here.

Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.

http://relief.news/discovering-the-missing-link-in-neuropathic-pain/