Role of Autophagy in the immune response

I have been reading about the cellular process of autophagy, which involves the phagocytosis of components within the cell and fusion of the autophagosome with a lysosome. Autophagy is used by the cell to dispose of protein aggregates, and damaged organelles. One of the main stimuli for induction of autophagy is cellular stress, but recently it has been studied in the context of viral invasion. Autophagy has been shown to be important during the antiviral response, but whether it is beneficial to the host or to the virus is still a matter of debate. For instance, retroviruses have been shown to use autophagy proteins to aid in assembly of viral capsid proteins [1]. However, it has also been proposed that autophagy might be important for cross presentation of endogenous viral antigens on MHC class II molecules in dendritic cells [2].

I find it very interesting that basic cellular processes like autophagy can have dual roles in either aiding our own immune system, or aiding a pathogen. What are some other ways you think autophagy can help our immune system, or ways it can help the pathogen?

Here is a nice review on the role of autophagy in innate and adaptive immunity: 

http://www.ncbi.nlm.nih.gov/pubmed?term=Unveiling%20the%20roles%20of%20autophagy%20in%20innate%20and%20adaptive%20immunity

[1] Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages.
http://www.ncbi.nlm.nih.gov/pubmed?term=Autophagy%20pathway%20intersects%20with%20HIV-1%20biosynthesis%20and%20regulates%20viral%20yields%20in%20macrophages

[2] Nimmerjahn, F. et al. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33, 1250–1259 (2003).

How about you change the litter box? How to respond after the reply is NO

While waiting for the vet, I decided to explore some pamphlets displayed on the office wall.  Although this was first discovered in the late 1960’s, I was unaware of the potential consequences of exposure to Toxoplasma gondii.  Toxoplasmosis, which is caused by T. gondii, is a parasitic zoonotic disease.  This rare, but serious blood infection may be of particular relevance if you are 1.) a cat owner and 2.) plan to become pregnant.  Domestic cats are a primary host of T. gondii.  Cats are infected as a result of consuming infected animals, such as rodents or birds.  Other sources of concern consist of unpasteurized milk or uncooked meat.

 The CDC has some helpful tips if you meet the above criteria:

• Avoid changing cat litter if possible. If no one else can perform the task, wear disposable gloves and wash your hands with soap and warm water afterwards.
• Ensure that the cat litter box is changed daily. The Toxoplasma parasite does not become infectious until 1 to 5 days after it is shed in a cat's feces.
• Feed your cat commercial dry or canned food, not raw or undercooked meats.
• Keep cats indoors.
• Avoid stray cats, especially kittens. Do not get a new cat while you are pregnant.
• Keep outdoor sandboxes covered.
• Wear gloves when gardening and during contact with soil or sand because it might be contaminated with cat feces that contain Toxoplasma. Wash hands with soap and warm water after gardening or contact with soil or sand.

Not surprisingly, if you have been exposed to the parasite before gestation, your immunity may protect your unborn child.  This likely plays a factor in one of the above tips, “Do not get a new cat while you are pregnant”.  Unfortunately, if you aren't immune and are exposed while pregnant, infection is likely to result.  In the U.S., it is estimated that between 1 per 1,000 and 1 per 8,000 babies are born with toxoplasmosis.  Infected offspring can be asymptomatic at birth, but might develop blindness or mental disability later, and in some cases, eye or brain impairment may exist at birth. 

As expected, IgE mediates the killing of intracellular T. gondii.  A few interesting studies have shown increased levels of IgE and cytokines, IL-5, IL-6 and very elevated levels of IL-10 among infected patients. 

Ultimately, if you are pregnant, now you have peer-reviewed evidence as to why you shouldn't change the litter box. 

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109627/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685994/

http://www.cdc.gov/parasites/toxoplasmosis/gen_info/pregnant.html

http://www.americanpregnancy.org/pregnancycomplications/toxoplasmosis.html

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0018289

Inflammatory Monocytes and Vaccines

Monocytes are key cells in innate immunity with their protection against pathogens and transformation into macrophages, but there has been research on their potential pathologic role in diseases such as immune suppression at tumor sites and in the case of this post, a suppressive role in vaccine immunity.  Dr. Steven Dow’s lab at Colorado State University found that high amounts of vaccine adjuvants were able to mobilize monocytes from the bone marrow and into the lymph nodes where they interact with T-cells to affect vaccine immunity.  Adjuvants are used to increase the immune response to a vaccine to speed and increase immunity.  They were interested in the effects on normal healthy mice and knockouts of CCR2 which is a receptor important in monocyte chemotaxis.  To their surprise, they found that inflammatory monocytes mobilized from the bone marrow after vaccination actually decreased the immunity gained from the vaccine!  In this study they looked at local (site of injection) inflammation, chemokine release, and monocyte recruitment, but also utilized monocyte depletion by CCR2 knockout , compounds that block migration or by providing extracellular cysteine.  Interaction of these monocytes with T-cells was also explored and they found that after vaccination, inflammatory monocytes potentially sequester cysteine which is required for activation and proliferation of T-cells and in doing so decreased the immune response to the vaccine.   I thought the role of monocytes was fairly simple…to travel to a site and differentiate into macrophages, but it seems, just like in all of immunology, there is a lot more to these cells than previously thought.  This research gives possible pathways to increase vaccine effectiveness in certain populations or diseases that were tough to vaccinate against through temporary manipulation of monocytes or the treatment of cysteine with the vaccine.

Below is the article from Dr. Dow’s Lab.

Michell LA et al. Suppression of vaccine immunity by inflammatory monocytes.  J Immunol.  Nov 7 2012.

Anti-inflammatory Properties in Cinnamon?

Cinnamon is normally identified as being an essential spice to make some of our favorite sweet desserts such as churros and cinnamon rolls.  However, cinnamon is also becoming known for its anti-inflammatory properties through the chemical compound, cinnamaldehyde.
 
Cinnamaldehyde is an essential oil that can be extracted from the leaves of C. osmophloeum, an evergreen tree.  This extracted chemical compound contains anti-inflammatory properties by inhibiting the production of cytokines.  In a recent 2008 study, Cinnamaldehyde was shown to suppress the production of the pro-inflammatory cytokines Interleukin-1 beta (IL-1B) and tumor necrosis factor alpha (TNF-α) (Chao, Louis et al).  In order to trigger an inflammatory response that encouraged the release of these pro-inflammatory mediators by macrophages, murine J774A.1 macrophages were stimulated by lipopolysaccharide (LPS) from Escherichia coli.  Furthermore, the study found Cinnamaldehyde to also reduce reactive oxygen species release from these stimulated J774A.1 macrophages.  These findings that Cinnamaldehyde also contains anti-inflammatory properties in a dose-dependent manner give high hopes that this compound has the potential of having a pharmaceutical application in the future.
 
Chao, Louis et al. “Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling.” Science Direct (2008): 220–231. Print.

Celebrex: A Solution or a New Problem?

A previously used non steroidal anti-inflammatory drug, indomethacin, was commonly used for patients with inflammatory related diseases. However these patients experienced some serious side effects, particularly in the GI tract. Several studies were done, and finally the widely accepted mechanism causing these side effects was revealed: NSAIDs are non-selective COX inhibitors and are also particularly acidic. The combination of these things appears to be correlated with a topical effect and inhibition of COX-1 (which is known for secreting protective proteins, while COX-2 is recognized for its role in inflammation).

Because of the many potentially fatal side effects caused by typical NSAIDs, celecoxib was created. Celecoxib is a selective COX-2 inhibitor and is not especially acidic. Studies have shown celecoxib does not possess the same damaging potential as drugs like indomethacin, and appear to be much safer. So this sounds like a direct solution to the problem we had with indomethacin, right? At first glance it would seem that way, however more recent studies have shown Celebrex may cause an increase in cardiac risk. The drug has been compared to Vioxx, which was completely removed from the market because of dangerous side effects. There was even a cardiologist from Harvard Medical school, Dr. Elliott Antman, who distrusts Celebrex to the extent that he would go as far as recommending narcotics over Celebrex. While this seems extreme (especially considering the primary candidates are often elderly arthritis patients), there has been research showing an increase risk of heart disease with Celebrex. Still many doctors continue to prescribe Celebrex and believe it can help their patients deal with some unwanted inflammation. The belief most of these doctors have is that Celebrex is relatively safe to use in low doses, but the risk for heart disease increases significantly with higher doses. Realistically, only low doses are really necessary for most patients, which is probably why this drug is still on the market despite the controversy lasting almost 10 years. I think that all of the comparisons done with Celebrex and Vioxx are a major factor to what is scaring people and making them jump to conclusions that this drug is nowhere near safe (because of the reputation Vioxx has). Further studies will help in drawing a more defined conclusion, but for now it will remain a controversial issue (especially for the cardiologists).

Sources:
http://arthritis.webmd.com/news/20050217/study-low-dose-celebrex-poses-no-heart-risk
http://www.ahrp.org/infomail/05/02/01.php

Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs are a type of pain reliever at prescription doses, which also reduce inflammation.

There are over the counter and prescribed anti-inflammatory drugs. The non-steroidal anti-inflammatory drugs that can be purchased over the counter include

Brand Name	Generic Name
Advil, Motrin	Ibuprofen
Aleve	Naproxen sodium
Ascription, Bayer, Ecotrin	Aspirin

Ibuprofen is also available as a prescription at doses higher than the over the counter medications. The non-steroidal anti-inflammatory drugs that are available only with a doctor's prescription are

Brand Name	Generic Name
Anaprox	Naproxen Sodium
Celebrex	Celecoxib
Clinoril	Sulindac
Daypro	Oxaprozin
Disalcid	Salsalate
Dolobid	Diflunisal
Feldene	Piroxicam
Indocin	Indomethacin
Lodine	Etodolac
Mobic	Meloxicam
Naprosyn	Naproxen
Relafen	Nabumetone
Toradol	Ketorolac tromethamine
Vimovo	Naproxen/esomeprazole
Voltaren	diclofenac

All prescription non-steroidal anti-inflammatory drugs have a warning that the medications may increase the chance of having a heart attack, stroke, and stomach bleeding.

Non-steroidal anti-inflammatory drugs work by blocking the production of certain chemicals in the body that cause inflammation, there are no fundamental difference in the ability of different drugs to reduce pain and inflammation. However, you might find that you get more relief from one drug over another and some drugs may have fewer side effects than others.

Although these non-steroidal anti-inflammatory drugs are reasonably safe medications, it is important that you are aware of potential side effects. The most common side effects are

• Stomach pain and heartburn
• Stomach ulcers
• Increased bleeding tendency while taking drugs, especially aspirin
• Headaches and dizziness
• Ringing in the ears may result from certain drugs, including aspirin
• Allergic reactions such as rashes, wheezing, and throat swelling
• Liver or kidney problems. These problems can be evaluated by blood tests in people who take drugs for prolonged periods
• High blood pressure
• Leg swelling

Non-steroidal anti-inflammatory drugs are prescribed in different doses depending on the condition. Dosages may range from one to four times per day, depending on how long each drug stays in the body. Your doctor may prescribe higher doses of the drug if you have a severe and painful condition such as rheumatoid arthritis (RA) for example, because frequently there is a significant degree of heat, swelling, redness, and stiffness in the joints in RA. Lower doses may be adequate for osteoarthritis and muscle injuries, since there is generally less swelling and often no warmth or redness to the joints. No single drug is guaranteed to work. Your doctor may prescribe several types of drugs before finding one that works best for you.

[1] http://www.celebrex.com/how-works.aspx?source=google&HBX_PK=s_anti+inflammatory+drugs&o=23040695|165564013|0&skwid=43700003586495244

[2] http://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm

[3] http://www.medicalnewstoday.com/articles/179211.php

[4] http://orthoinfo.aaos.org/topic.cfm?topic=a00284

Do anti-inflammatories for the treatment of tendon injuries actually hinder healing?

Tendon injuries, which are very common among athletes as well as in the sedentary population, generally present symptoms of swelling and pain. Therefore, the prescription of anti-inflammatories is essentially inevitable. However, recent studies show that although anti-inflammatories aid in reducing pain and swelling, they hinder structural healing of the injury. In this article, it is stated that "together with the fact that all chronic tendinopathy cases received anti-inflammatory management, it is logical to assume that suppression of inflammatory responses may interact with the failed healing of degenerative tendon injuries." Failed healing is described by the authors as the "histopathological characteristics of tendinopathy [...] which exhibited traits of both active repair and degenerative injuries" (Chan, and Fu). Because nearly all cases of chronic tendon injuries have received non-steroidal anti-inflammatory drugs by their physician, the authors suggest that there might be a potential interaction in some cases in which a mild inflammatory tendon injury could turn into chronic tendinopathy in predisposed individuals (Chan, and Fu).

Non-steroidal anti-inflammatory drugs (NSAIDS) are the most common anti-inflammatories prescribed for tendon injuries. NSAIDS work by inhibiting the production of pro-inflammatory prostaglandins through the COX pathway. However, prostaglandin E2 (PGE2) is "essential for early tendon healing such as control of vascular flow" (Chan, and Fu), therefore the use of NSAIDS could have a deleterious effect on the structural healing of the tendon. Corticosteroids, which are a group of anti-inflammatories that are generally utilized to treat chronic pain in chronic injuries, "may increase risk of spontaneous ruptures of tendon cells.
 The negative effects of corticosteroids were demonstrated on human culture tendon fibroblasts, which also included cell viability, proliferation and matrix synthesis. 
The authors also discuss the use of physical therapies, such as pulsed electromagnetic fields, low level laser treatments, and extracorporeal shockwave therapy, to reduce inflammation in tendon injuries. "It appears that these biophysical interventions also exerted anti-inflammatory actions through modulation of pro-inflammatory mediators" (Chan, and Fu), such as the suppression of PGE2 by pulsed electromagnetic fields and low level laser treatments, and the modulation of nitric oxide production by extracorporeal shockwave therapy. However, there is not much research regarding the "efficacy and underlying mechanisms" (Chan, and Fu) of these therapies  and they believe that "further exploration to consolidate their efficacies may yield a better clinical practice for anti-inflammatory management for chronic tendinopathy" (Chan, and Fu). 



If disturbed prostaglandin levels as one of the causes of failed healing in tendinopathy could be identified, then, the authors believe, that the development of effective treatment strategies for tendon injuries could be improved.

Source:

Chan, Kai-Ming, and Sai-Chuen Fu. "Sports Med Arthrosc Rehabil Ther Technol.." Sports Med Arthrosc Rehabil Ther Technol.. 1.23 (2009): n. page. Web. 2 Dec. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770552/>.