miRNA regulates immune system

MicroRNAs (miRNA) are transcribed in the nucleus and exported into the cytoplasm to control gene expression by binding to messenger RNAs (mRNAs) and cleaving or reducing their translational efficiency. They are considered to play a substantial role in gene regulation of cellular proliferation, differentiation, cell fate, apoptosis, signal transduction, and organ development; however, with the numerous miRNA identified scientist still remain to be fully understand their mechanism. miRNA’s role in post-translational modification in addition to other post-transcription modification can express a gene in varying ways, affecting proteins’ conformational fold and function. With this in mind, miRNAs have recently changed the view of immune development and regulation. It has been established that miRNA contribute to immune cell fate, regulation of Toll-like receptor and cytokine response. In addition, miRNAs have been found to contribute to inflammatory diseases., regulate hematopoiesis, immune responses (innate response, T cell activation and differentiation), and antiviral immunity. With the dynamic and complex nature of miRNA, it is hoped miRNA will serve a use as therapy in treating diseases.

Seminars in Cancer Biology
Volume 18, Issue 2, April 2008, Pages 131-140
Postgenetic Oncology - MicroRNA and Cell Proliferation

Bird Flu

The avian flu strain H5N1 commonly known as the Bird flu made it's first biggest hit in Asia in 2004 claiming the lives of~30 people is now reemerging. To this year, ~300+ cases resulting in death have been recorded. The natural host of the H5N1 strain are ducks but the virus can cross the species barrier and infect humans as well. The most recent cases reported by WHO (World Health Organization) in December 2008 occurred in Indonesia and Cambodia. In two of the three cases, the victims are confirmed to have been around birds.
Since we've talked about vaccines in class, I wonder how much Baxter would help out if people in this area are vaccinated with it? I don't know if these countries (people within these countries) are able to afford this vaccine.

References:
http://www.who.int/en/

The Varicella-Autoantibody Syndrome

Varicella (Chicken Pox) was a very common virus that many children from our generation were infected with. Although most of us had to deal with the typical symptoms, some children also developed life threatening blood clots. A very interesting phenomenon that we discussed in our Immunology class was to blame; Cross-reactivity. The varicella virus produced an immune response that cross-reacted with a protein found in blood called Protein S. The purpose of Protein S is similar to that of an anticoagulant. It basically helps regulate clot formation by deactivating pro-coagulant proteins. Three study groups were analyzed to determine the cause of this antibody and why some children were forming life-threatening clots.

The study groups consisted of 52 children without acute varicella virus exposure and 43 patients with varicella (VZV) exposure. The second group was further broken down into 17 children with thromboembolism (blood clots) or purpura fulminans and VZV and 26 with uncomplicated VZV exposure. There were significant differences between the group without VZV exposure and the group with VZV exposure. Those exposed to VZV frequently developed a lupus anticoagulant (measured by dilute Russel Viper Venom Time dRVVT) and several other antibodies to phospholipids regardless of whether they had uncomplicated exposure or if they developed thromboembolism. Although there was no difference between the two groups when it came to antibodies made in the acute phase, the difference came in duration of antibodies and their effect on Protein S. Those that developed a thromboembolism or purpura fulminans had significantly lower Protein S levels and significantly higher levels of antibodies to Proteins S.

The interesting question that I brought from this paper is: what the difference is between these two groups of children? They both are producing a cross-reactive antibody to VZV and Protein S, but only a small portion develop low levels of Protein S and high levels of antibodies which lead to thromboembolism. Could this be a problem with T cell regulation in these patients? If not, what is different with these patients?

Pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?otool=uchsclib&term=the%20varicella-autoantibody%20syndrome&cmd=search&db=pubmed

DVT - Deep Vein Thrombosis

In class last month Dr. Cohen briefly mentioned vein blood clots. Where could that clot dislodge to? Answer: the lungs.

That week my dad was diagnosed with a DVT - Deep Vein Thrombosis in his leg. He had been active and couldn't figure out why. He hadn't been on a long flight or anything similar that month. We were very concerned about a Pulmonary Embolism. Yes, the dislodged clot could travel to the lungs!! (capillaries) This is what killed young reporter, David Bloom, in Iraq.

Well, a couple of months earlier, my dad was recovering from eye surgery. He was told to stay on the couch until his detached retina healed. His doctor did mention that my dad should, however, get up every 30 minutes or so to "get the blood moving." This was great advice, but it wasn't quite enough exercise to prevent a DVT. (My dad's blood test was normal and he was on a low dose aspirin regimen before this.)

I just want to express how important exercise is --even when we are cramming for a test or finishing a long experiment. Anyone up for running the stairs at lunch break?

http://en.wikipedia.org/wiki/Deep_vein_thrombosis

Fake Blood Real Stokes

I ran across these articles while looking up biotech experiments. These articles talk about doctors using a perflurocarbon to supply oxygen to patients that suffer from brain injuries such as head trauma and stroke. Since the substance is "oily" it can squeeze through inflammed vessels more easily than blood can and carries much more O2.

Since one of the functions of inflammation is to increase blood flow, do you think supplying all this O2 can curtail some or any of the swelling and the potentially harmful effects of an inflammed brain?? Does the property of increased Oxygen delivery decrease the length of time it takes to bring down swelling, in effect speeding up the healing process? I think this chemical is lacking in anti-inflammatory properties and that O2 delivery just might be the only, yet important, characteristic, would you agree? Comments?

http://www.thescizone.com/news/articles/1481/1/Synthetic-Blood-Announces-Oxycyte-Development-Strategy/1.html

http://hamptonroads.com/2008/03/type-artificial-blood-may-be-key-surviving-brain-injury

Inflammatory Bowel Disease and the Hygiene Hypothesis

After visiting Liberia, West Africa, (before the civil war) I can see how people in Rwanda have nearly no occurance of Inflammatory Bowel Disease. The children actually get to play on the land! They are exposed to parasitic worms. It is normal for the worms' eggs to contaminate food, water, air, faeces, pets and wild animals. Women still wash the clothes in streams and wildlife is all around. Yes, I nearly ran into a dead deadly green mamba snake (I didn't know it was dead while I was running). I believe in the Hygiene Hypotheis and feel that too many Americans are too fearfull of germs.... and worms!

Anyway, I think the University of Iowa study is right on. Thanks Dr. Cohen for telling us!
Here is the publication:
Helminths and harmony
http://gut.bmj.com/cgi/content/full/53/1/7

Protecting virus

An article I read a while back discusses a novel method of controlling flu virus infection using a protecting virus. The concept was developed for influenza type A and involves a genetically modified version of the virus that has an 80% deletion on one of the 8 RNA strands. This deletion renders the virus harmless and interferes with the ability to reproduce once inside a cell. When it is joined by another normal influenza virus, the protecting virus replicates much faster than the normal influenza virus thereby crowding it out resulting in a slowed rate of progression. This delay allows the immune system time to develop and mount an immune response.

The implications of such a cascade are that any strain of influenza that you encounter will become it's own vaccine by giving the body time to recognize the virus and develop an effective response. Thus, protection is conferred against unforeseen strains and mutations that vaccines have a lesser ability to deal with. This is especially desirable for a virus that mutates often leaving vaccines that cannot protect against all variations. In addition, by using a live infection, you are creating a better immune response than by using peptides of the viral products alone. Current research shows that protection from infection happens immediately upon administration and can even be given 24 hrs after exposure while maintaining effectiveness.

Some experiments have been done to show that by putting the protecting virus in drinking water of animals they have gained protection from various strains of influenza. From our discussions in class regarding H5N1 and the jump from birds to humans, could this be useful to impact the spread of avian flu within bird populations? Because of the protecting virus' ability to act as a vaccine to highly mutable viruses, could this be a tool to use against other infections?

This pioneering research was done by Nigel Dimmock at the University of Warick and continues within a startup company at the university.

Emerging viruses in transplantation

In class we have discussed several pitfalls in transplantation of organs and bone marrow. A classic case was of the boy in the bubble who died from donor derived EBV effects on immunocompromised individuals. This paper describes an increased understanding of other viral infections and their associated risks for transplant patients that would not normally have high rates of morbidity and mortality. Usually, the focus is on CMV and EBV but 12 other viral threats have been described here, some of which I have never heard even heard of. They include Adenovirus, Boca virus, corona virus, HHV-6, lymphocytic choriomeningitis virus, meta pneumovirus, mumps, measles, parainfluenza, Parvovirus B19, respiratory syncytial virus, rotavirus and west nile virus. Some of these are donor derived and some are community derived. All of these can be detected and characterized easily with advanced techniques such as PCR on easily obtained patient samples such as sputum and nasopharangeal washes. Not long ago the diagnosis was limited in specificity and was performed using primarily serology and histochemical techniques. As solid organ and stem cell/ bone marrow transplants are on the rise as effective therapies, it is important to use the techniques available to increase the longevity and quality of life for these patients. Examples of increased morbidity and mortality due to these viruses were discussed in this paper. Adenovirus can cause many types of infection including that of the respiratory tract. In healthy people, a 5-10% mortality rate can be seen with some infections. In transplant recipients, some adenovirus diseases have mortality rates of up to 80% and can occur up to 4 years after transplantation. Some manifestations are asymptomatic and affect many tissues and cell types. After detection, antivirals and intravenous Ig (IVIg) have been associated with positive outcomes.
HHV-6 is another common virus and is latent in ~90% of adults in immune, salivary and bronchial epithelial cells. Immunocompromised individuals reactivate with replication in CD4+ cells further suppressing the patient immune response ultimately leading to high mortality rates of up to 58%. Once detected as an active infection, antivirals have been seen to be effective treatments. Mumps and measles have a slightly different approach to deal with in immunocompromised patients as there are no specific antiviral treatments. It is recommended to vaccinate for example, stem cell transplant patients 2 years after the transplant. However, this leaves a small gap in time where people are susceptible with high attack rates and associated high mortality rates. The evaluation of viral infection, diagnosis and treatment continue in this paper but all remain serious threats and deserve attention as they can be major factor in increasing the longevity of transplant patients.

Emerging Viruses in Transplantation: There Is More to Infection After Transplant Than CMV and EBV.
Transplantation. 86(10):1327-1339, November 27, 2008.
Fischer, Staci A.

Chemokine microbicides

At a presentation on World AIDS day last week, anti-HIV microbicides were discussed. One microbicide, PSC-RANTES, showed considerable effectiveness but was proclaimed to be too costly and unsuitable for common use especially in developing countries. This paper therefore caught my attention as it talks about analogues to that microbicide that do have suitable characteristics for common use. The analogues are recombinant proteins making them easy and inexpensive to produce like all other recombinant proteins such as human growth factor (rHGH) or insulin. The preliminary evaluation of these analogues show stability at 40˚C for a week or longer with very little change in biological equivalence which facilitates transport and storage outside of the cold- chain required for many protein based therapeutics. They also withstood low pH conditions that resemble environments where they will be used as a prophylactic and be expected to maintain biological activity. A desired characteristic is that protection also be maintained for longer duration after a single dose. It appears that biological activity is suitable in that it is maintained for at least 24 hrs.
Both analogues tested show equivalent potency against viral replication as compared to PSC-RANTES invitro and in macaque challenge models. They achieve this in the same manner as PSC-RANTES by inhibiting the CCR5 receptor availability to the virus. One analogue causes the CCR5 receptor to sequester intracellularly but the other analogue doesn’t utilize this method and a mechanism was not described here. In the absence of a vaccine, the meaning of this very exciting discovery is enhanced due to the need of other avenues to slow the spread of virus. At the lecture, a recent study was also presented that statistically, we could treat out way out of this epidemic by affecting the spread of the disease. This is clearly a step in that direction while research to develop vaccines continue.

Cerini, Fabrice *; Landay, Alan PhD + ; Gichinga, Carolyne + ; Lederman, Michael M MD ++ ; Flyckt, Rebecca MD [S] ; Starks, David MD [S] ; Offord, Robin E PhD || ; Le Gal, Francois PhD [P]; Hartley, Oliver PhD * , Chemokine Analogues Show Suitable Stability for Development as Microbicides. J Aquir Defic Syndr. 2008;49;472-476.

TRAIL: Apoptotic pathway important in influenza clearance

We’ve discussed CD8+ CTL cells and the mechanism recognition and killing of targeted cells using FasL and perforin mediated apoptosis. This paper discusses how another apoptotic pathway, TRAIL, is important in influenza infection. TRAIL has been seen to select for tumor cells and is an important tool for immune surveillance. The immune system also relies on TRAIL to clear some viral infections. The author show that TRAIL is directly associated with increased levels of influenza virus clearance and by inhibiting TRAIL using a monoclonal antibody, longer durations of influenza infection persisted. Using mice that express TRAIL normally and TRAIL deficient mice, they were able to make some interesting observations related to influenza. TRAIL positive mice could clear flu virus significantly in 6 days where as TRAIL deficient mice had increased morbidity and increased flu viral loads. Target cells in pulmonary infection also show the receptor for TRAIL, DR5, indicating that TRAIL might be very important for controlling flu virus. Actually, influenza was shown to increase TRAIL on CD8+ T-cells and it’s DR5 receptors on infected cells. This is a very interesting mechanism we have developed to control a virus. Usually, we are talking about how a virus has out-evolved us. Influenza specific CD8+ T-cells were also shown to have TRAIL while non-influenza specific CD8+ T-cells did not. Regardless of TRAIL expression, FasL, perforin, IFN-g, degranulation and total T-cell levels did not change indicating the importance of TRAIL for clearance as well as protection from lethal doses of influenza which killed over 80% of non-TRAIL expressing mice.

Can TRAIL deficiencies or inhibited expression be cause of virulence in some influenza infections? Could this also be related to other persistent viral infections?

E. L. Brincks, A. Katewa, T. A. Kucaba, T. S. Griffith, and K. L. Legge
CD8 T cells utilize TRAIL to control influenza virus infection.
J. Immunol., Nov 2008; 181: 7428.

The Tumor Promoting Role of the Immune System?

From our lecture on tumor immunology we focused on how components of the immune system fight tumor progression. Clearly the immune system is very important in this regard, and people with compromised immune systems have higher incidence of cancer. The immune system is not always beneficial though. There is a body of work that suggests a pro-tumorgenic role for macrophages in cancer progression.
The theory is that macrophages initially fight cancer cells but then can become subverted by the tumor to actually become tumor promoting. In many human tumors, a high number of infiltrating macrophages correlates with a poor prognosis. Tumors are actually able to attract macrophages through the release of various chemotactic agents. Molecular studies have elucidated many protumoral functions macrophages carry out once at the tumor. These are mediated through the improper release of various cytokines. One protumoral function is the expression of growth factors which increase the growth rate of cancer cells. Macrophages have also been show to release signals that promote the formation of blood vessels in the tumor which is a necessary step for tumor progression. Macrophages are also capable of suppressing adaptive immunity.
This theory initially seemed very unlikely to me since we usually associate the immune system with fighting disease but taken together with what we have learned about how macrophages work, it makes more sense. There is normally a division of labor with T cells recognizing a danger and then instructing macrophages to remove it. With this is mind, it is less of a stretch to see how a different cells type (ie. a tumor cell) could step in and instruct a macrophage to act much differently. In fact, one of the phenotypes of the macrophage protumorgenic switch is a reduction in IL-12. We have learned that this cytokine favors a Th1 T cell which in turn makes macrophages ‘angry’.
If you would like to learn more about this research, there are many reviews available. A few are listed below:

1. Ostrand Rosenberg. Immune surveillance: a balance between protumor and antitumor immunity. Current Opinions in Genetics and Development. 2008. 18:11-18.

2. Mantovani, Alberto et al. The inflammatory micro-environment in tumor progression: The role of tumor associated macrophages. Crit. Rev. Oncol./Hematol. 2007. 10:1016.

3. Eremin, O et al. Tumor-associated macrophages (TAMS):disordered function, immune suppression and progressive tumour growth. J.R Coll. Surg Edinb. 2000 Feb;45(1):1-16

To vaccinate, or not to vaccinate (really? this is still a question?)

In true procrastinator fashion, I am finally submitting a post. This topic is near and dear to my heart, as I’ve spent the last year working in vaccine formulations and prior to that, spent a year and a half working at a group home for autistic adults…

This year experienced a resurgence in the vaccine/autism debate, as Hannah Poling – the now 10-year-old daughter of Dr. Jon Poling, a neurologist, won their lawsuit against the Department of Health and Human Services. As a seemingly normal 18-month-old baby, Hannah, was taken in for her well-baby checkup and administered several routine vaccines. Two days after inoculation, Hannah developed a high fever, ceased responding to verbal stimuli, and for a short period – refused to walk. If you are interested in the case, the CNN News Report is a fairly unbiased source of general information on the case… http://www.cnn.com/2008/HEALTH/conditions/03/06/vaccines.autism/index.html however, since this IS an immunology course, I am not going to leave you thinking that Hannah’s vaccines were in fact responsible for her condition.

Dr. Paul Offit, chief of infectious disease, at Children’s Hospital of Philadelphia scientifically responded to the court’s ruling in an article in a May issue of the New England Journal of Medicine. Dr. Offit highlights that Hannah was special case. Born with a genetic mitochondrial enzyme deficiency, Hannah was succeptible to infection and while natural infection has been shown to aggrevate encephalopathy in these patients – vaccines HAVE NOT and are in fact recommended for these children.

Is it possible we can overwhelm the immune system? While I am sure there exists some case that demonstrates this, a typical child will have no problems (apart from slight discomfort) with the administration of the 14 recommended childhood vaccines which contain in total approximately 150 immunological components (vs. the 200+ immunological components of the smallpox vaccine formulation used 100 years ago).

Well, what is the harm in spreading the immunizations out over a course of time? The distribution of vaccines over a course of time provides a window for a not-yet-vaccinated-against infection to occur, which will compromise the immune system of the child and result in a higher risk of vaccine ‘injury’ (perhaps a rash, swelling, ect.).

Back to Hannah… if vaccinations for children with this genetic deficiency carry with them the risk of exacerbated encephalopathy, what should our strategy be for reducing this incidence – and when it does occur, who is to blame? As the role of genomics increases in medicine, will we find the answers?

Sadly and somewhat ignorantly, the resurgence of this heated debate has had an effect on U.S. vaccinations. This year, we have witnessed isolated outbreaks of measles resulting in the most cases we’ve seen in 12 years.

Let’s keep in mind that the incidence of autism is increasing – if vaccines were really the agent, wouldn’t we expect the incidence to decrease as our methods become more refined?

With all of this said, please speak with you pediatrician about any concerns you might have and don’t be too quick to dismiss the largest medical advance in the history of medicine (ok, so I may be a little bias – but it is with good intentions).

Offit, PA. N Engl J Med. 2008 May 15;358(20):2089-91.
http://www.immunize.org/catg.d/p2065.htm
http://www.chop.edu/consumer/jsp/division/generic.jsp?id=75807