Ross River Infection causes arthritis in humans and mice.

So, there haven't really been many pathogens discussed here so far, and I figured I'd write a little about a virus that's really unique in the way that your immune system clears it.

Ross River Virus (RRV), is a negative sense, enveloped, single stranded RNA virus in the family Togaviridae and was first isolated in 1959 from a mosquito in Australia. It is one of the members of the Old World alphaviruses, and symptoms in humans are usually a rash, followed 2 weeks or so later by various musculoskeletal symptoms in the extremities. These can include arthritis/arthralgia, as well as muscle pain. The interesting thing about these symptoms is that they do not go away in a matter of days as one would normally expect. They can instead persist for weeks to months, and in rare cases, years after infection. There are also currently no treatments, and no vaccine against this or any other arthritic alphavirus.

Figure 1. The Ross River is designated by the marker "A".

In comparison to encephalitic alphaviruses, very little is understood about arthritic disease cause by alphaviruses. It was not until 2006 that a mouse model of RRV infection was published. (Morrison et al, 2006) These preliminary studies showed that infection of mice with RRV resulted in massive inflammation of bone, joint, and skeletal muscle tissues in the hind limbs. Further analysis showed that the cells causing this inflammatory response were macrophages, NK cells, CD4+ and CD8+ lymphocytes. Current studies are looking at the which type of macrophage is involved, as well as how the virus is causing this massive immune response.

The greatest advantage to this model system is that the disease process in mice closely resembles that seen in humans, therefore, presumably, any advances made in understanding viral pathogenesis in the mouse can be transferred into the human disease with a fair amount of confidence.

Figure 2. Photograph of a patient infected with Ross River Virus.

As if that wasn't enough, an avirulent strain has been isolated which contains 45 amino acid substitutions when compared to the WT. This avirulent virus has been shown to replicate just as efficiently as the WT virus, however it does not induce any of the inflammation seen in WT RRV infection. Current studies on comparing these two genomes have identified 2 independent genetic virulence determinants in regions of the genome that contain only 11 AA changes. Site directed mutagenesis of each one of these 11 AA residues will hopefully identify 1 or 2 particular AA residues which are critical to viral pathogenesis.

Figure 3. Histology of Mouse quadriceps tissue. A. Mouse infected with wild type RRV. B. Mouse infected with avirulent strain of RRV. Both mice received the same amount of virus during infection.

The hope is that these virulence determinants might allow researchers to begin working on a possible therapeutic vaccine. The other hope is that these particular AA residues may be conserved across different species of alphaviruses such as Chikungunya and others, and that it might be possible to transfer any finding gleaned from RRV and incorporate them in the battle against Chikungunya. (If you're interested in reading about Chikungunya, feel free to check out: http://en.wikipedia.org/wiki/Chikungunya.)

References:

Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of arthritis and myositis.

Morrison TE, Whitmore AC, Shabman RS, Lidbury BA, Mahalingam S, and Heise MT.

Journal of Virology, 2006, 80(2):737-49.

No Finger Prints from Inflammation

If you watch television then you’ve seen a drug commercial with a list of side effects. One commonly used cancer treatment drug, capecitabine, has a side effect which can get you into trouble at the airport – capecitabine can erase finger prints!

Capecitabine is prescribed regularly to prevent cancer from returning and is known to cause inflammation and blistering of the palms and soles of the feet. Using it a lot can cause swelling and blistering and leave patients without finger prints. Sometimes the swelling isn’t pronounced enough to affect patients and cause doctors to remove capecitabine from their drug regimens.

This is exactly what happened to one patient chronicled by the BBC. This patient was travelling to the United States where he was held by immigration officials for four hours. Their reasoning? The man’s finger prints had vanished!!!

Here is a link to more similar stories:

http://www.handresearch.com/news/cancer-patient-no-fingerprints-hand-foot-syndrome.htm

Tumor Immunology in the News

I just stumbled upon this interesting article about an article by Mooney et al. that utilizes a sponge-like matrix coated with pro-inflammatory molecules (bacterial DNA), cytokines and crude melanoma lysates as an anti-tumor 'vaccination' for melanoma. The components of the matrix basically mimick a local pro-inflammatory environment and provide the infiltrating DCs with peptides of the melonoma which can then in turn be presented to antigen-specific T cells in the draining LN. The reason for the excitement about this approach is quoted as "[...] it has all of the molecular and cellular signatures of a strong vaccine reaction.[...]". As always, the detailed reasons of why this works so well are not known.

Maybe it is almost, but not quite yet, time for tumor immunology to shine.


P.S.: It seems that the original article is not in PubMed yet, as I could not find it. I will post a proper link once it is up.

Anti-Inflammatory Foods

In the spirit of Thanksgiving and all the holiday food we will be consuming this holiday weekend, I was doing some research on Anti-Inflammatory drugs and all of sudden my stomach told me to go eat some dinner and then it hit me to search if foods can help reduce inflammation. I came across this article that explain which foods we all should eat or stay away from.

What is Inflammation?
Inflammation is defined as a localized reaction of tissue to irritation, injury, or infection. Symptoms of inflammation include pain, swelling, red coloration to the area, and sometimes loss of movement or function. We commonly think of inflammation as the painful component of arthritis. Inflammation is also a component of chronic diseases such as heart disease and strokes.

Avoid Pro-Inflammatory Foods
Pro-inflammatory foods will increase inflammation, increase your pain from the inflammation and may also raise your risk for chronic disease. Loading up on junk foods, high-fat meats, sugar and fast foods will increase inflammation in your body. This is partially due to the unhealthy fats used in preparing and processing these foods, especially trans fats and saturated fats.

Processed meats such as lunch meats, hot dogs and sausages contain chemicals such as nitrites that are associated with increased inflammation and chronic disease.
Saturated fats are also found in meats, dairy products and eggs. While all of these foods are important source of minerals and vitamins, you don't need the extra saturated fat. These foods also also contain fatty acids called arachidonic acid. While some arachidonic acid is essential for your health, too much arachidonic acid in the diet may make your inflammation worse. Be sure to choose low fat milk and cheese and lean cuts of meat, which will not promote inflammation.

Diets high in sugar have also been associated with inflammation, obesity and chronic disease such as diabetes. Eliminate high sugar foods such as sodas, soft drinks, pastries, pre-sweetened cereals and candy.

Choose Anti-inflammatory Foods

Fats and Oils
The right types of fats in your diet will impact pain and inflammation in a positive way. Omega-3 essential fatty acids are very powerful anti-inflammatory agents. They are found in cold water oily fish, walnuts, flax seeds, canola oil and pumpkin seeds. Adding omega-3 fatty acid supplements from flax oil or fish oil may also help reduce inflammation, just be sure to speak with a doctor or nutritionist before taking larger, therapeutic doses of any supplement, or follow label instructions.

Protein
Your body needs protein to build healthy body tissues. Good protein sources include lean poultry, fish and seafood, nuts, legumes and seeds. Red meats may trigger inflammation, so cut back on fatty red meats. When you do eat red meat, choose lean cuts of bison, venison and other game meats, or the lowest-fat cuts of beef, preferably grass-fed beef.
Soybeans, tofu, and soy milk are three great sources of soy proteins that may help to reduce your pain and inflammation.

Carbohydrates and Fiber
Most of your carbohydrates should come from whole grains, vegetables and fruits. The bread, cereal and pasta in your diet should be mostly be 100% whole grain products. Whole grains are excellent sources of fiber, and a high fiber diet will reduce your inflammation.

Choose green leafy vegetables, green and brightly colored vegetables and lots of fresh whole fruits. You should eat at least five and preferably more servings of fruits and vegetables each day. Green vegetables and whole fruits are also important as sources of dietary fiber.

Berries are also a great food choice, especially blueberries and strawberries which are packed with anti-inflammatory phytochemicals and anti-oxidants. The pigments in brightly colored fruits, vegetables and berries contain many phytochemicals that have anti-inflammatory properties. One example is quercetin, which is found in apple and red onion skins and has strong anti-inflammatory properties.

It was discussed in lecture this past week that altering one's daily life style can help with regulating chronic inflammation. We also agreed in class that in reality, it takes discipline and personal responsibility to conduct a routine that consists of the daily activities which helps a person reduce the risk of being diagnose with chronic inflammation. However, I commented that not everybody will take the necessary steps to alter their daily live activities to reduce the risk of chronic inflammation but maybe a person would be more willing to alter their daily diet? To be honest I think it depends on the each person, each person has their own beliefs to what is good for them and will do whatever makes he or she happy.

Are you a person who would be willing to alter your daily activities or alter your daily diet or both to help fight against being diagnose with chronic inflammation?

Photopheresis for GVHD

This is an interesting immunological intervention that is approved by FDA, but the mechanism of action is not well known. I am surprised many treatments that are routinely used (empirical) but we do not really know why it works. Probably steroids were/are one of those medications which has long history without knowing the mechanism of action.

Extracorporeal photopheresis (ECP) is a relatively new technique used to treat immunological disorders and complications, such as cutaneous T-cell lymphoma(CTCL), graft-versus-host disease(GVHD), solid organ transplant, and Crohn disease. GVHD will be discussed mainly as the observation of what happens through ECP is quite interesting.

The procedure consists of: 1) the photopheresis system draws blood from the patient, 2) Blood is separated by centrifugation into its cellular components and plasma, and red blood cells are returned to the patient, 3) white blood cells are treated with 8-methoxypsoralen(8-MOP) and exposed to ultraviolet A(UVA) radiation, and 4) the phtoactivated white blood cells are returned to the patient.

ECP was believed to work due to DNA damage and subsequent lymphocyte apoptosis by 8-MOP in the presence of UVA. Then later, researchers started thinking that it doesn’t really make sense as only 5 to 10 percent of lymphocytes are treated during a cycle of treatment. Additionally, research found that induced production of TNF-alpha by monocyte, and a shift in the profile of cytokine production and the balance of Th1 and Th2 response after treatment. Currently a more plausible theory is that the apoptotic lymphocytes produced during ECP increased their display of tumor associated antigens, dividing monocyte activation and the maturation of dendritic cells. That mediates regulatory T-cell production and results immune tolerance.

One of the biggest advantage of ECP is that it doesn’t cause systemic immunosuppression. In actual practice, the ECP is combined with immunosuppressives anyway, and cautions are needed. However, utilizing ECP are expected to help less invasive and effective therapy to be used in organ/stem cell transplantation for GVHD. Again, it is going to be interesting to see what theory is going to fully explain the phenomenon.

References
Knobler, R., Barr, M., Couriel, D., et al. (2009). Extracorporeal photopheresis: past, present and future. Journal of American Academy of Dermatology, 61(4), 652-665.
Xia, C., Canpbell, K., and Clare-Salzler, M. (2009). Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells. Current Opinion in Organ Transplantation, 14, 338-343.

Party with red wine and chocolate!

Red Wine

The researchers from the University of Barcelona studied the difference between red wine and gin (gin represented for any other type of alcoholic beverage) and found that red wine contains many complex compounds including polyphenols which induces a much greater anti-inflammatory effect than other alcoholic beverages.
Dr. Emanuel Rubin, a distinguished professor of pathology at Jefferson Medical College in Philadelphia said that consumption of any form of alcohol will help in lowering inflammatory markers; however, red wine has a much greater effect.

Red wine has long been associated with a lowered risk of heart attack and stroke. An experiment was performed by the Jefferson-led team[1], they measured inflammatory biomarkers in the blood to compare the different effects of red wine and gin on heart health.
The results of this study confirmed that red wine significantly lowered the level of inflammatory molecules such as adhesion molecules (inflammatory markers), proteins that cause white blood cells to stick to the walls of the arteries, which can lead to the formation of atherosclerotic plaques.

The benefits of red wine to a person’s health have been well documented. Numerous research suggesting that a moderate consumption of red wine could help to reduce the chance of getting heart diseases, various cancers, as well as reducing blood pressure and cholesterol levels.

Red wine has a number of antioxidant compounds, one of them is resveratrol --- a compound which has been linked with cancer prevention.
Scientists have been doing research on resveratrol’s role as a potential treatment against sepsis, appendicitis and peritonitis. Severe sepsis is known to have few effective treatments and a high percentage of mortality; however, scientists and research groups have found positive effects of resveratrol and its role of down regulating inflammation. Although further understanding and research is required, resveratrol may play an important role as an effective anti-inflammatory drug in the future.[2]


Chocolate

There is a review article which discussed the anti-inflammatory impact of cocoa flavanols. The article mentioned that cocoa-based products are the richest functional foods based upon flavanols. Flavanols modify the production of pro-inflammatory cytokines, the synthesis of eicosanoids, the activation of platelets and NO-mediated mechanisms. There have been studies suggesting that the regular or occasional consumption of cocoa-rich compounds result in beneficial effects on blood pressure, insulin resistance, vascular damage, and oxidative stress.[3]

Similar to red wine, polyphenols are also found in chocolate which makes it beneficial for health as well. Polyphenols are found in beverages (wine, coffee and tea), fruits and vegetables (apples, broccoli, onions, blueberries, blackberries, cherries, strawberries, plums and red grapes). [4] Although the best way to get plenty of polyphenols is to consume lots of fruits and vegetables, having chocolate every once a while will not hurt!

MODERATE consumption of red wine + MODERATE consumption of chocolate = FUN anti-inflammatory protection




[1] Red Wine Has Greater Anti-Inflammatory Action Than Other Alcohols. NUTRA ingredients.
http://www.nutraingredients.com/Research/Red-wine-has-greater-anti-inflammatory-action-than-other-alcohols
[2] Scientists Uncork Anti-Inflammatory Secrets of Red Wine. Family Health Guide. http://www.familyhealthguide.co.uk/scientists-uncork-anti-inflammatory-secrets-of-red-wine.html
[3] Chocolate at heart: The anti-inflammatory impact of cocoa flavanols. Carlo Selmi, Claudio A. Cocchi, Mario Lanfredini, Carl L. Keen, and M. Eric Gershwin. http://www.worldcocoafoundation.org/scientific-research/research-library/documents/Selmi2008.pdf
[4] Cocoa in Chocolate May Be Good for the Heart. Bio-Medicine http://www.bio-medicine.org/medicine-news-1/Cocoa-in-Chocolate-May-Be-Good-for-the-Heart-59974-1/

FX125L

Article: "New Anti-Inflammatory Molecule Safe" from Medpage Today.

I tried to do some research to find the original article that this article by Michael Smith from Medpage Today was referencing based on the citation at the end, but it turns out that it is actually an oral presentation by P. Wiesel and associates at the American College of Allergy, Asthma, and Immunology Conference in July 2009. This article describes a new and innovative drug, FX125L, that is considered an oral anti-inflammatory and is targeted for the treatment of mainly asthma and COPD. They claim that at even relatively high doses, the medication is safe. Based on the article, a very recent study was performed with 66 volunteers regarding the drug and doses ranging from 0.3 to 3,000 mg. I don't know about you, but that is a VERY large range of dosing. According to the abstract of the presentation, there were no serious side effects, but some effects were adverse with the most common side effect being headache (4 on FX125L and 2 on placebo), dizziness (1 on FX125L and 1 on placebo), and nausea (1 on FX125L and 1 on placebo).

According to the 6th edition of Immunology - A Short Course by Coico, et.al, asthma involves cytokine-induced recruitment of inflammatory cells (mainly eosinophils) that can cause tissue injury due to toxic substances released by these cells that can include oxygen radicals, nitric oxide, and cytokines. Cytokines released by TH2 cells and mast cells (IL-4, IL-13, and TNFalpha) upregulate expression of leukocyte and endothelial adhesion molecules such as ICAM-1 and E-selectin. Because of these adhesion molecules, there in an increase in eosinophil-endothelial cell adhesion that causes migration and prolonged survival within lung tissue.

So, what is FX125L? It seems to be a broad-spectrum chemokine receptor inhibitor. FX125L acts similar to a corticosteroid, but the article claims that it doesn't have as adverse effects as corticosteroids. According to theasthmacenter.org, corticosteroids (like Advair and Pulmicort) in asthma suppress the inflammatory reaction that causes swelling and narrowing of the bronchi. It is normally used when asthma can't be controlled with bronchodilaters like albuterol. The most significant side effects with corticosteroids is usually caused by a high daily oral dose over a period of months to years.

The exact molecular action of FX125L was hard to find. The only thing I could find was that it blocked migration of inflammatory cells. This would obviously prevent the inflammation from occuring if the cells associated with inflammation are unable to chemotax to the site. Also, according to the presentation abstract, FX125L inhibits neutrophil recruitment to the lung. Neutrophils are the first line of defense against fungal and bacterial infections, but when recruited to the lung, can release chemokines and cytokines that enhance inflammation such as IL-6, IL-8, IL-1beta, andTNFalpha.

The term "broad-spectrum" usually refers to being effective over a wide range. It would be interesting to know exactly how this is accomplished. If FX125L targets a specific receptor, how can it be broad-spectrum? I think about antibiotics and how there are broad-spectrum ones that are used to treat a number of strains of bacteria that cause infections so it can be prescribed for many infections. How does FX125L target chemokine receptors in general and manage to target a particular one? Maybe it targets a specific receptor that is associated with inflammation in general or in most to all cases. This is one of many questions that I hope will be explained soon as the research progresses.


"ACAAI: New Anti-Inflammatory Molecule Safe" Medpage Today. Ed. Michael Smith. 9 Nov. 2009. Web. 16 Nov. 2009. .
Presentation - Wiesel P, et al "First clinical experience with FX125L, an anti-inflammatory oral small molecule with an entirely novel mechanism of action" Ann Allergy Asthma Immunol 2009; 103(5)(suppl 2): Abstract 5
Corticosteroids - http://www.theasthmacenter.org/manual/part2-12.html
Neutrophils - http://www.springerlink.com/content/j71781x837m85n12/fulltext.pdf

Strenuous Exercise linked to memory Loss

This study was presented at the Alzheimer’s Association 2009 International Conference on Alzheimer’s disease. Long-term strenuous physical activity has been shown to decrease lifetime exposure to ovarian hormones in women and has been found to play a protective role against breast cancer. However a decrease in ovarian hormone exposure has been associated with increased risk of cognitive impairment. Also, long-term physical activity is associated with improved cognition but the intensity required to preserve cognition is not known. Mary C. Tierney, PhD, and professor at the University of Toronto wanted to examine the relations between both long-term strenuous and moderate activity and cognition in recently postmenopausal women. The study had 90 women aged 50-63 years old who gave details on the amount of their strenuous and moderate physical activities from high school to menopause. Eight memory and brain function tests were administered to all participants. The researchers found that long-term strenuous activity was always associated with poorer performance on all eight of the tests. Moderate physical activity was always associated with better performance on all eight of the tests. The results suggest that long-term strenuous activity may increase the risk of cognitive impairment in recently postmenopausal women, but moderate long-term physical activity may improve later life cognition. Dr. Tierney says that further study is needed.