Iron Accumulation in the Brain may lead to AD and PD.

Multiple recent studies have been published pertaining to iron accumulation in the brain and a correlating incidence of neurological disorders. Many studies have been published particularly surrounding Alzheimer's and Parkinson's disease. Authored by Zecca et al., Iron, Brain Ageing and Neurodegenerative Disorders, focuses on this correlation.

Iron accumulation has been linked to multiple neurodegenerative diseases; it is believed that the build up iron causes an increased amount of oxidative stress which can be responsible for neurodegeneration. The iron accumulation in the brain increases preferentially in areas that are impacted by AD and PD. Some evidence seems to indicate that the accumulation of iron in the microglia induces the inflammatory response common amongst many neurodegenerative diseases.

In the case of Parkinson's Disease, increased iron accumulation is seen in the substantia nigra in extreme cases. Iron (III) specifically can be seen accumulated in the oligodendrocytes, astrocytes, microglia and portions of the substantia nigra of PD patients. In Alzheimer's Disease, iron seems to promote both deposition of amyloid-B and oxidative stress which are associated with plaque deposition.

This provides a unique link between metabolic needs, nutritional regulation and neurodegenerative diseases.

Reference for the article: http://www.nature.com/nrn/journal/v5/n11/pdf/nrn1537.pdf

New Clues to How Fish Oils Help Arthritis Patients

I've always heard that fish oils are good at reducing inflammation. I thought this article was interesting I tried finding a more specific and in depth summary of how Resolvin D2 promoted edothlial cells to produce NO to prevent the macrophages from attacking the cells. I'd like to hear other opinions on the subject. I's sure we can all agree nutrition is very important for arthritis patients. maybe we can find a more detailed summary of the pathway.

Findings may boost treatments for other inflammatory diseases, researchers say

Posted October 28, 2009

WEDNESDAY, Oct. 28 (HealthDay News) -- Researchers think they now understand the way that fish oils benefit people with rheumatoid arthritis and other conditions linked to inflammation.

The body converts an ingredient in fish oils called DHA into a chemical called Resolvin D2, which reduces the inflammation that can lead to various diseases, the scientists from Queen Mary, University of London and Harvard Medical School explained in their study published in the Oct. 28 issue of the journal Nature.

"We have known for some time that fish oils can help with conditions like arthritis, which are linked to inflammation. What we've shown here is how the body processes a particular ingredient of fish oils into Resolvin D2. We've also looked in detail at this chemical, determining at least some of the ways it relieves inflammation. It seems to be a very powerful chemical and a small amount can have a large effect," Mauro Perretti, a professor of immunopharmacology at Queen Mary, University of London, said in a university news release.

"This research is important because it explains at least one way in which fish oils can help in different types of arthritis. We can also work on this chemical and see if it can be used not only to treat or even prevent arthritis, but also as a possible treatment for a variety of other diseases associated with inflammation," said Perretti, who led the U.K. research team.

Unlike current anti-inflammatory drugs, Resolvin D2 doesn't appear to suppress the immune system, the researchers noted.

In arthritis, the body's immune system attacks healthy tissue. An important part of this process occurs when white blood cells (leukocytes) stick to the inner lining (endothelium) of blood vessels. In lab tests, Perretti and colleagues found that Resolvin D2 prompted endothelial cells to produce small amounts of nitric oxide, which acts as chemical signal that discourages white blood cells from sticking to the endothelium, thus preventing inflammation.

More information

The American Academy of Family Physicians has more about rheumatoid arthritis.

Link Between Pain Thresholds, Inflammation And Sleep Problems In Arthritis Patients

As a college student sleep is sometimes a luxury, I often find it difficult to find time to sleep with all the deadlines and daily activities. My concern for lack of sleep lead me to this lay article on RA and pain threshold for sleep disorders. I found it interesting and thought I'd share it with everyone. I thought it would be interesting to consider how sleep or more specifically sleep deprivation related to disease. can anyone think of any possible relationships between RA and sleep deprivation aside from increased stress and damage leading to increased inflammation?

Article Date: 29 Oct 2009 - 5:00 PDT

Despite recent advances in anti-inflammatory therapy, many rheumatoid arthritis (RA) patients continue to suffer from pain. Research published in BioMed Central's open access journal, Arthritis Research & Therapy found that inflammation is associated with heightened pain sensitivity at joint sites, whereas increased sleep problems are associated with heightened pain sensitivity at both joint and non-joint sites.

Researchers from the Division of Rheumatology and Pain Management Center of Brigham and Women's Hospital, and the Chronic Pain and Fatigue Center of the University of Michigan Medical School, assessed experimental pain sensitivity, disease activity, sleep problems and psychiatric distress in 59 women with RA. The researchers used questionnaires to assess the women's sleep problems and psychiatric distress and measured the levels of C-reactive protein as an indicator of disease activity. They also measured pain sensitivity with pressure pain threshold testing at joint and non-joint sites. Lower pain thresholds are indicative of higher pain sensitivity.

"Sleep problems were inversely associated with pain threshold at all sites, suggesting a defect in central pain processing", state the authors. This finding emphasises the need for research into the mechanisms underlying sleep disorders and pain in RA patients, particularly given the common occurrence of sleeping problems among these patients. This autoimmune disease, causing chronic inflammation, affects nearly 1% of the population and sufferers often report ongoing pain in spite of successful anti-inflammatory treatment.

"Since differences in pain sensitivity may shape the course of pain complaints and influence treatment decisions, it is important to understand the factors associated with enhanced pain sensitivity", lead author Yvonne Lee says, adding, "Physicians and researchers should consider both inflammatory and non-inflammatory factors when evaluating pain in research settings and in the clinic."

Notes:
The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study
Yvonne C Lee, Lori B Chibnik, Bing Lu, Ajay D Wasan, Robert R Edwards, Anne H Fossel, Simon M Helfgott, Daniel H Solomon, Daniel J Clauw and Elizabeth W Karlson
Arthritis Research & Therapy (in press)
http://arthritis-research.com/

Source:
Charlotte Webber
BioMed Central

Blood Brain Barrier Breakdown Precedes Infiltration in MS

As we discussed in class, Multiple Sclerosis is currently an idiopathic disorder with no known precipitating cause. Clinically it manifests itself as demyelinated areas of the central nervous system called lesions that contain blood derived immune monocytes. Because the immune system and the central nervous system are normally separated the immune cells are unable to discriminate between brain antigens and foreign antigens.
It is for this reason Multiple sclerosis has been considered an autoimmune disorder and therapies have centered around attempting to modify the inflammatory response and try to depress what seems to be considered an overactive immune system response. In the review article from last class by Martino and associates, it was noted that the blood brain barrier showed enhanced leakiness around the sites of the lesions but it was unknown whether this preceded or was a result of an already initiated immune response. I see this as a pivotal question to answer in the quest for a treatment of multiple sclerosis. Obviously at some point damage is done by the blood born immune system but is this behavior due to an aberrant immune response in need of correction or is it simply working perfectly against antigens that it should never have had the opportunity to encounter in the first place?
According to a paper by Floris and associates in the journal Brain, they were able to determine that in animal models with allergic encephalomyelitis (EAE) MRI imaging with gadolinium showed that vascular leakage and onset of neurological signs occurred concomitantly BEFORE the infiltration of immune monocytes. This suggests that cerebrovascular leakage and monocyte infiltration are two distinct events in the development of the lesions. This may be a very important consideration in the direction of research and the development of new therapies for multiple sclerosis.

The 1976 Swine Flu Vaccination Program

I recently read an article written by the David J. Sencer, the director of the Center for Disease Ccontrol in 1976. I found it interesting what with all of the recent publicity about the H1N1 vaccine. I have written a brief summary and added some links to the original article and to the CDC’s H1N1 factsheet.

http://www.cdc.gov/ncidod/EID/vol12no01/pdfs/05-1007.pdf
http://www.cdc.gov/h1n1flu/general_info.htm

In 1976 at Fort Dix Army base more than 200 soldiers became infected with a swine flu strain (H1N1) similar to the virus that caused the 1918 outbreak in which an estimated 50 million people died worldwide. It was decided that mass quantities of the vaccine would be needed to vaccinate the entire population to prevent a pandemic like that of 1918. The director of the CDC recommended that the federal government contract private pharmaceutical companies to produce the vaccine. A nationwide immunization program was launched by the federal government at a cost of $137million. Before any vaccine was released however, the vaccine manufacturers required that the federal government underwrite them against claims of adverse reactions prior to any vaccine delivery. The federal government agreed and the vaccinations began.

Soon cases of Guillain-Barré Syndrome were identified in patients days or weeks after receiving the vaccination. By December of 1976 more than 40 million people had been vaccinated against H1N1, of which about 500 people developed GBS. According to the NIH Guillain-Barré syndrome is a disorder in which the body's immune system attacks part of the peripheral nervous system by destroying the myelin sheath that surrounds the axons of many peripheral nerves. Sometimes it destroys the axons themselves. It usually occurs a few days or weeks after a viral infection. While there is no known cure for GBS there are treatments that can lessen the severity and speed recovery.

Statistically the number of GBS cases in the vaccinated population was higher than what would be found in the normal population in 1976 (according to the CDC about 1 more case per 100,000 that were vaccinated). As a result federal health officials decided that even the idea that GBS could be linked with the vaccine warranted ending the vaccine program immediately, so that the possibility could be investigated. In the Media the vaccination program was considered a debacle, and the director of the CDC was fired. In addition, the anticipated H1N1 pandemic of 1976 failed to happen.

According to the CDC the link between flu vaccine and GBS has been studied and in most cases no link was found. However in two studies it is suggested that 1 more person out of 1 million people vaccinated with the seasonal flu are likely to develop GBS. (http://www.cdc.gov/h1n1flu/vaccination/factsheet_gbs.htm )

Any thoughts?


More information on Guillain-Barré from the NIH at http://www.ninds.nih.gov/disorders/gbs/gbs.htm

Mystery Colors in Lymph Tissue

Since we recently discussed tattoo inks that elicit type 4 immune responses, I thought I'd mention another interesting phenomenon that arises from tattooing:
A patient presented with a lump in the right armpit that had been there for 6 months. After investigation, there could be no conclusion made about the cause of the lump. This necessitated an excision biopsy. The resulting H&E stained sample is shown above. Beyond some hyperplasia, the only noticeable defect was a black "discoloration". Immediately, it was suspected that the black spots were metastases of malignant melanoma (which is notorious for its dark pigmentation). However, after more vigorous examination and a specific, stain-based testing, they determined that this was not a melanoma. In fact, this black color was due to a tattoo that the patient had gotten 30 years previously. It has been well documented that tattoo inks end up in spleen and lymph tissue. However, it had not previously been reported that such an old tattoo could cause enlargement of a lymph node (it had been assumed that such an effect occurs within the immediate timeframe of recieving the tattoo).

Presumably, the presence of tattoo inks in immune tissues is due to uptake in the skin by antigen presenting cells which then migrate to the lymph nodes or spleen. It is interesting to note that tattoos are not only sometimes the victims of attack by the immune system within the skin, but can also cause some interesting pathology within tissues of the immune system. Since tattoo inks are not regulated, its frightening to wonder what sort of unintended chemistry might find its way into some of your body's most important defensive tissues.

That said, I'll probably still get a tattoo when I pass my comprehensive exam.


CM Jack, A Adwani and H Krishnan. Tattoo pigment in an axillary lymph node simulating metastatic malignant melanoma. International Seminars in Surgical Oncology. 2005, 2:28

Are you choosing who you are attracted to or is it your MHC region?

We know that there are many genes in the MHC I and II regions and that they are highly polymorphic. Combinations of these genes and polymorphisms are important because they are related to the number of peptides that can be presented to t-cells.
It has been shown in fish (arctic charr) that they can discriminate between MHC identical siblings and siblings with different MHC genotypes (Olsen, et al, 1997). Fish chose swimming in water scented with a sibling who had the same MHC genotypes over water in siblings who did not. In mice it has been shown that MHC genes influence individual body odor in mice and that mice also prefer MHC-dissimilar mates (Chaix, et al, 2008).
In humans, there have also been studies looking at odor preference and MHC region, although there have been no studies that have linked odor preference and attraction. In several “sweaty t-shirt” experiments women were asked their preference to smells found on t-shirts that had been worn by males with different MHC genes. Females significantly preferred the odor of males with dissimilar MHC regions to their own. Another study looked at the genetic similarity at the MHC region between spouses, which included 30 European American couples from Utah and 30 African American couples in which there was found an association between mate selection and MHC dissimilarity in the European American couples(Chaix, et al, 2008).
So if you have problems in your relationships it may not be your fault!

Alzheimer vaccine

Neuropathological analysis ofAD-affected brains reveals extensive atrophy due to neuronal loss, and accumulation of neurofibrillary tangles and neuritic plaques, surrounded by a tract of neuroinflammation (i.e. astrocytosis and activated microglia). Neuritic plaques consist of deposits of variously sized peptides collectively called b-amyloid (Ab), which is widely believed to be the key player in the pathogenesis of AD. Within this context, reducing AD amyloidosis represents one of the main therapeutic strategies under investigation for AD. Examples of this approach include the Ab vaccine (which reduces brain amyloidosis by several mechanisms), inhibitors of secretases, Ab-disaggregants, non-steroidal anti-inflammatory agents, cholesterol-lowering compounds and estrogen, all of which are known to reduce the production and/or accumulation of Ab .

Potential roles of insulin and IGF-1 in Alzheimer’s disease

Aging is characterized by a significant decline of metabolic and hormonal functions, which often facilitates the onset of severe age-associated pathologies. One outstanding example of this is the reported association of deranged signaling by insulin and insulin-likegrowth- factor 1 (IGF-1) with Alzheimer’s disease (AD).
Recent compelling biological data reveal effects of insulin and IGF-1 on molecular and cellular mechanisms underlying the pathology of AD.Emerging evidence suggests that insulin and IGF-1 have important functions in the brain, including metabolic, neurotrophic, neuromodulatory and neuroendocrine actions.Insulin, IGF-1, their receptors and IGF-1-binding proteins (IGFBPs) are all present in rodent and human brain.It is now known that insulin and IGF-1 are actively
transported across the blood–brain barrier and possibly even produced locally in the brain.
In addition to the physiological activities in the brain, a wealth of data points to a potential role of the insulin– IGF-1 pathway in the pathogenesis of age-related neurodegenerative diseases, such as Alzheimer’s disease.In particular, AD patients show changes in insulin and IGF-1 levels and their response to insulin is defective.

Alzheimer disease and Vit E

Many lines of evidence suggest that oxidative stress is important in the pathogenesis of Alzheimer disease. In particular, b-amyloid, which is found abundantly in the brains of Alzheimer disease patients, is toxic in neuronal cell cultures through a mechanism involving free radicals. Vitamin E prevents the oxidative damage induced by b-amyloid in cell culture and delays memory deficits in animal models.

AD and Type 2 Diabetes may have common link...

Various recent studies have delineated out a possible connection and predictor for the development of both Alzheimer's Disease and Type 2 Diabetes. As the both have an inflammatory component to them, the studies have linked them to a common duo of enzymes, butyrylcholinesterase and acetylcholinesterase. Both work to degrade and break down acetylcholine. Acetylcholine has been known to have anti-inflammatory actions. So, by degrading the anti-inflammatory biochemical, you ultimately have a double negative which results in an anti-anti-inflammatory or pro-inflammatory condition in the body. It is this pro-inflammatory condition which is believed to be the cause of both AD and Type 2 Diabetes.

Another common link that is extremely nascent in its research is the common link of Insulin Degrading Enzyme (IDE) in both AD and Type 2 Diabetes. Some research has shown that the dysfunction of IDE in some shape is present in both Type 2 Diabetes and AD.

I think this proves interesting because it connects two conditions that on the surface may not have ever seemed connected. To me, it reaffirms the fact that when we look at solving any conditions/disease within the body that we need to ensure we have take a holistic approach, particularly when inflammation is a common component.

A reference for the first study, titled "Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer’s disease" by Allam A. Rao, Gumpeny R. Sridhar and Undurti N. Das, is: http://www.sciencedirect.com.ezproxy1.library.arizona.edu/science?_ob=MImg&_imagekey=B6WN2-4NWW6SJ-2-1&_cdi=6950&_user=56761&_orig=search&_coverDate=12%2F31%2F2007&_sk=999309993&view=c&wchp=dGLzVzz-zSkWA&md5=047efd6e6ff36de91df59d9f0f740212&ie=/sdarticle.pdf

Alzheimer's Disease and IL1-BAPP interactions

A number of studies suggest that preventing the activation of microglia (and inflammatory cell infiltration in general) reduces the extent of neurological damage (in fact, I read a brand new study from the Nov. 9 Journal of Clinical Investigation found here http://www.ajc.com/health/content/shared-auto/healthnews/alzh/632918.html to reiiterate). Such has been the case in studies of experimental Alheimer’s, Parkinson’s, stroke, and multiple sclerosis (etc). We have discussed in great detail the immune responses and cell-to-cell interactions as they pertain to neurodegenerative diseases, particularly Alzheimer’s disease.
Microglia have long been thought of as the brain’s resident immune cell, similarly to macrophages and monocytes. Once stimulated in response to neurodegenerative events (whether it be aging or blunt trauma), microglia release a variety of proinflammatory mediators such as cytokines, free radicals, Nitric oxide, etc, all of which contribute to neuronal dysfunction and cell death, ultimately creating a vicious cycle. At the heart of that cycle is Interleukin 1. Many studies have shown IL-1 works in an autocrine and paracrine manner to further the progression of Alzheimer’s disease.
In the paracrine pathway, chronic overexpression of IL-1 reaches the periphery and overexpresses Beta Amyloid Precursor Protein and astrocytic S100B. This leads to the intrigue, because the brain of an alzheimer’s diseased patient shows severe brain volume reduction and degeneration of neurons and synapses. The degeneration is attributed to two characteristic lesions: extracellular deposits of Beta Amyloid peptide and the intracellular neurofibrillary tangles of the tau protein. Evidence linking IL-1 and B-APP is well documented (Griffin 1998), but what has not been completely understood is whether IL-1 is activating other cells to clean up the senile plaques, or if IL-1 furthers the progression of senile plaques. The Mayo clinic released an article declaring that Inflammation works to play a protective role during the progression of Alzheimer’s, which calls into question our current understanding of how cytokines are involved with B-APP (the obvious link to the formation of senile plaques) and quite possibly the future of treatment for Alzheimer’s Disease.

IFN-β as a treatment for MS

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that remains a major cause of disability. Interferon-β is a current effective treatment for relapsing-remitting (RR) MS that reduces the frequency of clinical exacerbations and delays the progression of disability. IFN-β is a pleiotropic cytokine with diverse and cell-specific mechanisms of action including potent anti-viral, immune-stimulating, and immunosuppressive activities. It has been shown that IFN-β can modulate the immune system in different ways including downregulation of class II major histocompatibility complex (MHC) molecules and limiting migration of immune cells across the blood brain barrier possibly through the downregulation of inflammatory genes like endothelial adhesion molecules, chemokines, and proteases. In addition, several studies have demonstrated the effect of IFN-β to mitigate the increased blood levels of T cell-derived cytokines IFN-γ, IL-4/IL13, and TNF-α in MS compared to normal subjects , which otherwise act to increase proinflammatory transcription factors STAT1, STAT6, and NF-κB observed in MS patients.

Do Vaccines cause allergies or autoimmune diseases?

Boulder CO has been known to not vaccinate their children in fear of them causing autoimmune diseases etc. Working for a Vet ER in boulder I have even noticed that they refuse to vaccinate their pets for the same fears. Here is an interesting abstract of an article.

Addressing Parents’ Concerns: Do Vaccines Cause Allergic or Autoimmune Diseases? Paul A. Offit, MD* and Charles J. Hackett, PhD
* Division of Infectious Diseases, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, and the Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania Division of Allergy, Immunology, and Transplantation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

http://pediatrics.aappublications.org/cgi/content/full/111/3/653


Anecdotal case reports and uncontrolled observational studies in the medical literature claim that vaccines cause chronic diseases such as asthma, multiple sclerosis, chronic arthritis, and diabetes. Several biological mechanisms have been proposed to explain how vaccines might cause allergic or autoimmune diseases. For example, allergic diseases might be caused by prevention of early childhood infections (the "hygiene hypothesis"), causing a prolongation of immunoglobulin E-promoting T-helper cell type 2-type responses. However, vaccines do not prevent most common childhood infections, and large well-controlled epidemiologic studies do not support the hypothesis that vaccines cause allergies. Autoimmune diseases might occur after immunization because proteins on microbial pathogens are similar to human proteins ("molecular mimicry") and could induce immune responses that damage human cells. However, wild-type viruses and bacteria are much better adapted to growth in humans than vaccines and much more likely to stimulate potentially damaging self-reactive lymphocytes. Consistent with critical differences between natural infection and immunization, well-controlled epidemiologic studies do not support the hypothesis that vaccines cause autoimmunity.
Flaws in proposed biological mechanisms that explain how vaccines might cause chronic diseases are consistent with the findings of many well-controlled large epidemiologic studies that fail to show a causal relationship.

Gender and Autoimmunity

Clinical and experimental evidence suggests that autoimmunity is more prevalent in women than men. For example, women develop rheumatoid arthritis and lupus at rates of ~ 4:1, and 9:1 compared to men, respectively. There are two likely explanations for this.

First, immune reactivity is more enhanced in females compared to males. This is generally attributed to sex hormone levels. The female sex hormones estrogen and prolactin are both immunomodulators and are implicated in autoimmunity. Also, in a mouse model of lupus oopharectomy (surgical removal of ovaries) postpones disease onset and ameliorates lupus activity. This and other data indicate that sex hormones can have an activating effect on the immune system, which could activate the immune system to the point of autoimmunity.

Not all data indicates that sex hormones play an important role in autoimmunity. Female patients with rheumatoid arthritis often experience remission during pregnancy when estrogen levels are at their peak. In fact, another reason that gender may influence the induction of autoimmunity is a process called X chromosome inactivation.

To maintain appropriate levels of gene expression, females inactivate one of their two X chromosomes. Normally this happens in about 50% of the female’s paternal and maternal cells resulting in a mosaic expression of paternal and maternal genes on X chromosomes. However, cases of skewed silencing (greater than 75% inactivation of one allele) occur. These women have a large population of cells with one X chromosome inactivated and small population of cells with the other X chromosome inactivated. Some cells from the small population may not be represented in the bone marrow and thymus, explaining a possible mechanism of autoimmunity. Of note, bias in X chromosome inactivation has been observed in Juvenile Rhuematoid Arthritis.

In sum, having a more active immune system or two copies of X chromosome alleles cuts both ways: increased resistance to infection but greater propensity to develop autoimmunity.

The Role of Astrocytes in HIV Neuropathogenesis

A new study suggests that HIV infection of astrocytes may be extensive in individuals that suffer from HIV-associated dementia (HAD). Until now, it was thought that astrocyte infection in HIV was rare. Previous studies had shown that only 1-3% of astrocytes were infected in individuals with HAD. The new data suggest that infection may be greater than earlier thought; specifically, 16-19% of the perivascular astrocyte population may be infected (1). Astrocytes make up a large amount of the cells in the brain and are important in maintaining normal functioning neurons. Some of these functions include neurotransmitter uptake, ion concentration maintenance, neurovascular coupling, structural support, and the formation of the blood brain barrier among other things. As such, a reduction in the proper functioning of the astrocyte may result in dramatic changes in brain function. Such is the case in HAD and HIVE (HIV encephalitis).

HIV does not directly damage neurons in the brain, rather it does so indirectly through nearby cells: astrocytes, macrophages and microglia. Some mechanisms have been described. Specifically, the release of neurotoxic mediators by activated macrophages/microglia (M/M). To enter the central nervous system, HIV must cross the blood brain barrier (BBB). It does this via infected monocytes. Infected monocytes cross into the central nervous system, activating astrocytes and the M/M response in the neuronal tissue. Once there, the macrophages and microglia not only damage surrounding neurons, but help to induce a greater monocyte response. The release of chemotactic substances attracts additional monocytes, effectively amplifying the overall response (2). Again, neuronal damage is indirect, resulting from the activation of local macrophages and microglia in addition to the breakdown of normal astrocyte function.

Interestingly, astrocytes do not actively make new virus when infected with HIV. Rather, they are latently infected as the transcription and translation processes are altered and no new viral proteins are produced. It is unknown how latent infection results in the compromise of astrocyte function and ultimately HAD. However, one study suggested the role of cytokine release from HIV infected brain macrophages and microglia. In this particular model, astrocytes infected with HIV have altered gene expression, specifically the Fas is upregulated, making them particularly susceptible to apoptosis. Astrocytes become stimulated by surrounding macrophages and microglia via cytokines and other factors. This stimulation is said to result in apoptosis (3). The details of these specific pathways in this form of astrocyte death, and ultimately HAD, remain to be elucidated.

Of particular significance, with regards to this new study, is that astrocyte infection frequency correlated with HIVE severity, particularly in the perivascular regions (1). This is thought to occur through increased movement of infected monocytes into the brain. With the aforementioned mechanisms of central nervous system HIV infection in mind, this makes sense. The upregulation of chemokines released by infected monocytes and microglia results in subsequent amplification of the pro-inflammatory response resulting in HIVE. Interestingly though, this study also suggests that there is a release of cytokines from infected astrocytes as well. Accordingly, the greater the number of astrocytes infected, the greater the severity of HIVE. Applying these findings may hold particular significance for how the treatment for HAD should be approached. Current therapy, highly active antiretroviral therapy (HAART), only targets replicating virus. As such, only infected macrophages are targeted in the brain. Infected astrocytes, which do not have actively replicating virus, are not targeted by HAART. Knowing that astrocyte infection may now be more extensive than earlier thought, it may be important to consider its role carefully when treating HIV individuals for HAD and HIVE.


Churchill, Melissa J., Steven L. Wesselingh, Daniel Cowley, Justin C. McArthur, and Bruce J. Brew. "Extensive Astrocyte Infection Is Prominent In Human Immunodeficiency Virus-Associated Dementia." Annals of Neurology 66.2 (2009): 253-58.

Gorry, Paul R., Chi Ong, Janine Thorpe, Sylvie Bannwarth, Katherine A. Thompson, Anne Gatignol, Steven L. Wesselingh, and Damian FJ Purcell. "Astrocyte Infection by HIV-1: Mechanisms of Restricted Virus Replication, and Role in Pathogenesis of HIV-1 Associated Dementia." Current HIV Research 1.4 (2003): 463-74.

Yadav, A., and R. G. Collman. "CNS Inflammation and Macrophage/Microglial Biology Associated with HIV-1 Infection." Nal of Neuroimmune Pharmacology 4.4 (2009): 430-47 http://www.ncbi.nlm.nih.gov/pubmed/19768553

Duke Transplant Error

In February 2003, a transplant that occurred at Duke resulted in the death of a young immigrant patient who received a set of ABO incompatible heart and lungs. Jesica Santillan was a young girl with severe, congenital restrictive cardiomyopathy whose family had illegally immigrated to the US to pursue the only possible treatment, a rare heart double-lung transplant. The family begged for money to pay for the treatment and were later helped by a wealthy North Carolina businessman who began a charity for Jesica. Once the money was raised, a pediatric transplant surgeon at Duke procured organs for Jesica after deciding they were not appropriate for the two patients listed on the UNOS (United Network for Organ Sharing) match list. After more phone calls, the surgeon was given permission to use the organs for Jesica. Tragically, after the organs had been transplanted and perfused, the surgical team received news that the organs were from a Type A donor and Jesica was Type O.

For 30 minutes after transplantation, Jesica's new organs functioned well, but then rejection set in. With Type O blood, Jesica's plasma contained both anti-A and anti-B antibodies, resulting in the rapid rejection of the transplanted organs, which contained blood with Type A antigens. Due to pre-existing antibodies, the humoral-mediated immune response in ABO incompatibility cases is both rapid and severe. Jesica was immediately treated using plasmapheresis, which is used to remove antibodies from the blood in the hope of reducing the severity of rejection. Jesica was also treated with high-dose immunosuppressants to reduce her immune system's attack on the new organs. Two weeks after the initial, mismatched transplant a second transplant surgery was performed using organs from a Type O donor.

Shortly after the second surgery Jesica suffered severe and irreversible brain damage from brain swelling and intracranial bleeding. Neurological tests showed she was brain dead and scans showed there was no brain activity or perfusion. During transplant surgery, patients are put on a machine that circulates their blood, but the anticoagulant drugs used to prevent clotting in the machine increase the risk of bleeding in and around the brain. That afternoon, Jesica was taken off life support and died.

This serious error in the transplant process raised many questions for the agencies, practitioners and hospitals involved. Although the transplant surgeon remembered talking about other compatibility factors, he could not remember talking about blood type, which is the primary requirement for an organ match. Additionally, Duke kept the initial error quiet and out of the media for one week after the inappropriate transplant. Furthermore, the issue of medical care and illegal residency was raised as Jesica's family were illegal immigrants receiving care at one of the top American institutions.

Regardless of the controversial ethical and patient safety concerns raised by this error, the importance of even simple immunology such as blood type can be seen in this case. The advances in treatment that allowed Jesica to survive until the second surgery show the progress of medicine in the field of immunology, but illustrate the importance of simple principles first and foremost. The lessons learned? Always double check important criteria, even if it seems so basic that someone else should have already confirmed it. And the basic principles of immunology do not lose significance at any level of science or medicine, even as our knowledge of immunology increases and reveals new levels of complexity.

T cells and immunosuppression after organ transplantation - Post II

As promised in the last post, in this post I shall further delve into the pharmacodynamics of immunosuppressants that interact with cellular immunophilins and are used as primary immunosuppressants in clinic. Broadly there are two drug types in this category, first is the calcineurin inhibitors and second is the mTOR (mammalian target of rapamycin) inhibitors. In context of T cells these inhibitors hinder the proliferation signal as well as proliferation of T cells. Here we can think of immunosuppression as basically inhibiting proliferation of immune system cells so as to inhibit an immune response.

Calcineurin is a phosphoprotein serine/threonine phosphatase. In T cells this is involved in calcium dependent immunogenic pathway which is activated when APC interacts with a T cell receptor, resulting in an increase of calcium in T cell cytoplasm. Protein calmodulin binds calcium, then binds calcineurin which activates calcineurin. Activated calcineurin (http://cgap.nci.nih.gov/Pathways/BioCarta/h_calcineurinPathway) then dephosphorylates NFATs (Nuclear factor for activated T cells) which are now able to get inside the nucleus and induce different transcription factors that help in expression of IL-2 genes. Recall IL-2 is a short range lymphokine that effects the behavior of same or another cell. Here it can be T cells as well B cells. Once secreted IL-2 signal activates Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling in the target cell by interacting with IL-2 receptor on target cell surface. The PI 3-kinase/Akt patwhway activates mTOR, a very important serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription (http://www.biocarta.com/pathfiles/h_mtorPathway.asp). As you can already imagine inhibiting either calcineurin or mTOR can have very negative effect on cell growth. With calcineurin specifically on various types of T-cell's cell growth, differentiation and multiplication. mTOR has an overall effect on cell growth of all cell types in humans, that's why mTOR inhibitors have another prominent use of being anti-cancer drugs besides being immuosuppressants.

The calcineurin inhibitors were found earlier compared to mTOR inhibitors and other drugs and still remain the primary immunosuppressants post transplantation. However they have low therapeutic index and in long term use they are highly toxic to the body, specially to the kidney. In these type of long term toxic drug therapy cases, the strategy is to have a synergistic drug partner that can enhance drug effect (possibly by suppressing the target biochemical pathway via a different effector) and at the same time reduce the drug dose which is causing the toxicity. This way lesser drug toxicity with different side effect spectrum is achieved. This is where mTOR inhibitors come in picture after sirolimus was discovered. The calcineurin and mTOR inhibitors such as cyclosporine A and sirolimus/everolimus respectively don't bind these targets by themselvs. They first need binding parter which can then enable them to bind to calcineurin and mTOR. Calcineurin inhibitors cyclosporine A and tacrolimus bind immunophilins cyclophilin A and FKBP 12 (FK506 (tacrolimus) Binding Protein) respectively. Sirolimus/everolimus also bind to FKBP12 but due to combined structural difference they form complex with mTOR and thus inhibit its activity. Here is a representation of this (click to enlarge).

It was found out after several clinical trials that sirolimus enhances nephrotoxicity by an unexplained mechanism but some studies have found out that sirolimus actually increases blood and tissue concentration of calcineurin inhibitors there by increasing the overall toxicity. Brain has notably high levels of Calcineurine, and no surprise cyclosporine A has a serious side effect of neurotoxicity in long term treatment. Although tacrolimus has a different binding parter the toxicity profile is quite similar to that of cyclosporine. Side effects of mTOR inhibitors are those associated with depleted cell growth and divison such as thrombocytopenia. the focus of concern about toxicity related to these drugs is more on possible drug interaction or any other synergistic negative effects which remain unexplained. Why these drugs negatively effect kidney the most, is not yet known, but a possible involvement of mitochondrial dysfucntion due to calcium imbalance is being considered by several groups.

Thanks for reading this post !! until the next one ......

Another Reason to Floss

I found an interesting article which described a possible link between arthritis and oral health. Apparently, two studies were conducted and presented just this summer in Denmark at a medical conference. Two major observations were elucidated from this research:

1) 56 percent of the patients surveyed who had pre-existing rheumatoid arthritis also had inflamed gums, a condition referred to as periodontitis. Furthermore, these people also possessed more plaque, looser teeth, and fewer teeth than their arthritis-free counterparts.

2) Non-smokers who were afflicted with moderate to severe periodontitis are potentially more vulnerable to acquiring rheumatoid arthritis.

The article then includes a glimpse of hope. A regulated anti-TNF therapy has proven to be an effective strategy for treating the oral disease in patients with rheumatoid arthritis, as 80% of the patients analyzed yielded positive results. I am curious how an anti-IL-1 therapy would fare, as a few of the articles we read in class deemed that to be more beneficial in slowing the progression of arthritis overall.

Also a quick side note in case you were wondering what this periodontitis is all about. You can think of it as an aggravated or a later stage of gingivitis. While gingivitis is generally defined as inflammation of gum caused by plaque, periodontitis involves inflammation of gum, alveolar bone, ligaments, and other structures near the tooth.

My oral hygienist consistently reminds me of a connection that has been discovered between poor gum health and an increased risk of heart disease. Add to that this newfound information concerning the palliative effect of healthy mouth care on arthritis, and I suppose I have one more reason to start flossing regularly!


Source:
Durning, Marijke. "Interesting Connection: Teeth & Arthritis." .

H1N1 and Rheumatoid arthritis

We know from talking about arthritis the past couple of weeks that Rheumatoid arthritis (RA) is a type of inflammatory arthritis and Osteoarthritis (OA) is not. So I was wondering, since getting a H1N1 flu shot is a very popular subject right now, does it even work for people with Rheumatoid arthritis who have problems with their immune system and are probably taking medication that suppresses their immune system. Well, the CDC does recommend that people with inflammatory arthritis get flu shots. They also recommend that they do not get the nasal-spray, since it contains live, but weakened flu viruses. They recommend the flu shot since it contains flu viruses that have been killed, so it is safer for people who have weaker immune systems. The CDC only had recommendations so I looked further and found a study published in the Annals of Rheumatic Diseases that showed proof that people with rheumatoid arthritis who were taking immunosuppressant drugs were able to respond to the flu shot. Their responses were not strong, but at least the flu vaccine was making the infections milder, making it worth getting.