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.
10 November 2009
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.
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.
09 November 2009
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
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.
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 t
hese 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 ......
Subscribe to:
Posts (Atom)