Happy Solstice, Eclipse, and New Year!

There is an eclipse of the moon tonight, but it starts at around 11:15 PM and runs until 2 AM, so good for night owls. If the sky is clear it should be spectacular.

A very happy holiday to all, and best wishes for a terrific New Year!

BCG, why still excluded in US?

This is a question I have at the end of our course: Given that the BCG is used in cancer treatment (both to boost the CTL function and increase the angry macrophages and to kill bladder tumors being the innocent bystander or battlefield), then how come it is not even included in the list of recommended childhood vaccines?
I can understand that TB is uncommon in US but since immune deficient people (eg AIDS patietnts) can develop the disease and be possible foci for its' spread, wouldn't that mean that an outbreak may occur ?

HIV trials and tribulations - a new prophylactic treatment?

I've been meaning to blog about the following for a while, and it came up in one of the past posts, but here is some information on an exciting new trial for the use of Truvada as a prophylactic measure for HIV transmission:

Recently (week of November 23rd), I read/heard on www.newyorktimes.com and NPR about a recent trial that was conducted using Truvada (a two drug combination nucleoside reverse transcriptase inhibitor) prophylactically. The article itself (on NEJM.org) gives a 44% increase in protection from HIV infection with the prophylactic use of Truvada. The other sources, where I originally heard this news, quoted other percentages, ranging from 44% to 90% efficacy, depending on the subject's reported pill use, as well as laboratory results of measured blood medication levels. I haven't had time to read the article as carefully as I would like to in order to try and discern these numbers for myself (woohoo, winter break!), but it seems like this prophylactic use of an NRTI could be promising...check out the articles below when you have time.


http://www.npr.org/blogs/health/2010/11/23/131536422/pill-cuts-hiv-infection-risk-significantly-for-a-price

http://www.nytimes.com/2010/11/24/health/research/24aids.html?_r=1&ref=research

Grant, R.M., Lama J.R., Anderson P.L., et al. (2010 November 23). Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. The New England Journal of Medicine 10 (1056). Retrieved 13 December 2010 from http://www.nejm.org/doi/full/10.1056/NEJMoa1011205#t=articleTop

Immunization vs Autism

While reading up on papers about vaccinations, I found out that some vaccines contain thimerosal which is a compound well known for its antiseptic and anti-fungal usages. Thimerosal contains toxic ethyl mercury. Thimerosal was used as a preservation component for some vaccines used for children and pharmaceutical products to avoid bacterial and fungal growth. Thimerosal has been found as a possible risk factor for autism. In the United State, the Centers for Disease Control and Prevention estimates that the current prevalence of Autism Spectrum Disease (ASD) to be 1 in 110 children (Centers for Disease Control and Prevention 2010).

In another paper I read through, a total of 109,863 children from the United Kingdom were exposed to thimerosal based on the number of DTP (diphtheria-tetanus-pertussis) and DT (diphtheria-tetanus) vaccinations. The study kept track of subjects’ gender, year of birth, month of birth, but not for other potentially confounding variables. Also, there was no apparent association seen between thimerosal and autism in the control numbers. In addition, a recent study done by Hertz-Picciotto shows that the level of mercury concentration in blood was not elevated or reduced. Therefore, there is no relationship between ASD and the mercury level in blood.

In conclusion, both studies show that thimerosal does not cause ASD or neurological disease. They do suggest that the topic requires more study in the near future. It will be interesting to see if thimerosal really does have any correlation with autism.

Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B (2004) Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 114: 584–591.

Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN (2010) Blood mercury concentrations in CHARGE. Study children with and without autism. Environ Health Perspect 118: 161–166.

TRALI – Two hits and some bad luck…

TRALI or Transfusion Related Acute Lung Injury is the most common cause of transfusion-associated death in the US. As a critical care physician, TRALI is a diagnosis we commonly consider but rarely diagnose and its pathogenesis befuddled me until now. Newly armed with new immunologic background I retackled the topic – and it is fascinating!

The clinical phenomenon

Within hours of receiving blood products, approximately one in 20,000-50,000 patients develops shortness of breath, low oxygen levels and a chest X ray with diffuse patchy consolidation (too much whiteness!). This is TRALI, a form of non-cardiogenic pulmonary edema (a life-threatening leak of fluid into the airspaces or alveoli.) Between 5-25% of patients with TRALI die as a consequence. TRALI can occur after transfusion with any product derived from blood (such as packed red cells, platelets, cryoglobulin) but risk is higher with products that contain greater proportions of plasma.

Why does TRALI occur?

TRALI appears to be due to due to donor antibodies to three major recipient leukocyte antigens. In up to 90% of cases donor antibodies to recipient MHC I, MHC II and human neutrophil antigens have been identified.
The proposed mechanisms are a bit different for each type of antigen:
• Anti-neutrophil antibodies – the donor antibody directly binds to antigen on the neutrophil surface. Activation of complement and release of neutrophil vasoactive peptides damages the pulmonary endothelium and leads to “capillary leak.”
• Anti-MHC I antibodies – the donor antibody is thought to bind to pulmonary endothelium. As neutrophils squeeze through the tiny pulmonary vessels, neutrophils bind via their Fc receptors and cross link.
• Anti-MHC II antibodies – this mechanism was a mystery until recently because neither endothelial cells nor neutrophils have MHC II! A recent article suggested the mechanism is indirect. Circulating monocytes (which do display MHC II) are activated by when bound by specific anti-MHC antibodies. The supernatant from these activated monocytes stimulates neutrophils to produce reactive oxygen species (ROS). The ROS produced by neutrophils disturbs the pulmonary endothelial barrier resulting in greater permeability and fluid leakage.

Is one hit alone sufficient?

The above mechanisms are pretty neat, but experimentally antileukocyte antibodies alone are not sufficient to result in TRALI. For rats to develop TRALI with infusion of antileukocyte antibodies, the pulmonary endothelium must first be “primed” with lipopolysaccharide (LPS) an intensely immunogenic component of the cell wall of gram negative bacteria. This experimental data is consistent with the observation that critically ill patients appear to be at greater risk of developing TRALI than otherwise healthy patients. Presumably critical illness is associated with pulmonary microvascular injury that provides the first hit. The transfusion of antileukocyte antibodies is the second hit.

But why would blood donors have anti-MCH or anti-neutrophil antibodies anyway?

Almost always the donor has been alloimmunized during pregnancy. In recent study of 5,000 US woman, alloimmunization rates were directly correlated with parity. Antileukocyte antigens were identifiable in 1.7% of nulliparous women but rose to 29.8% among woman with three or more pregnancies.

You feeling lucky?

The bad luck part comes in receiving a blood product from a donor who has been alloimmunized by a person who has MCH or neutrophil antigens that match yours. Recall that despite the fact that antileukocyte antibodies are relatively common, TRALI is rare because the antibodies only cause disease if there is a specific cognate antigen.

What can be done to prevent TRALI?

Traditionally, blood banks have attempted to identify donor who are “responsible” for TRALI and prevent them from donating again. This means that once TRALI has occurred, blood bank staff must investigate to identify the donor. The problem with this approach is that TRALI can be difficult to identify definitively as these patients often have other reasons for having diffuse lung problems.
A more effective strategy would be to use only male donors for plasma donation. The UK implemented this approach and reports of TRALI fell by 75%. The challenge is that this is one more restriction that compromises an already stretched blood supply.

Sachs UJ, et al Mechansim of transfusion-related acute lung injury induced by HLA class II antibodies. Blood 2010 [Epub ahead of print]
Triulzi DJ. Transfusion-related Acute Lung Injury: Current concepts for the clinician. Anesthesia and Analgesia. 2009; 108: 770-6.
Stafford-Smith M. Many, but not all, outcome studies support exclusion of female plasma from the blood supply. Expert Reviews in Hematology. 2010;3:551-8.

the differences between the US and Japanese vaccination

From recent readings and news reports, it seems as though vaccinating children is more of a choice given to parents here in the United States. In Japan where I was born, it is the law that every Japanese citizen is required to have certain vaccinations. There are a few interesting differences in how the two country’s carry out their vaccination procedure/requirements. I would like to put into perspective about the differences between the US and Japanese vaccination requirements.

Hepatitis B Vaccine (HepB):

HepB vaccine is only given to certain people in Japan. For instance, people who are eligible to receive HepB in Japan are either medical practitioner or infants whose mother responsed positively to Hepatitis B surface antigen. Different from Japan, most children in the US are vaccinated with HepB sometime during their primary education.

Diphtheria, Tetanus, and Pertussis Vaccine (DTP)

Diphtheria, Tetanus toxoid, and acelluar Pertussis vaccine (DTaP):

In the US, from 0-18 months, infants and toddlers receive 4 vaccinations (2, 4, 6, 15-18 months). Another time is at the age of 4-5 years old, and at 11-12 years old. After that, it is recommended that one receive the vaccination (aka booster shot) every 10 years.

In Japan, children are immunized 3 times. The first is when they are 3-12 months old. The second shot is at 12-18 months, and the last shot is at the age of 11 and only Diphtheria and Tetanus toxoid is given at this time.

Haemophilus Influenzae type B (Hib):

Hib disease was common bacterial meningitis in child under 5 years old. The word “Influenzae” came from back in 1892, there was pandemic of influenza. During the period, Germen bacteriologist Richard Pfeiffer found Bacillus influenzae. This RNA virus was considered the cause of influenza until 1933.[Kuhnert and Christensen]

Most children in the US are usually vaccinated 4 times. Vaccination occurs at the ages of 2, 4, 6-18 months, and 4-6 years old. In Japan however, this vaccination was given to Japanese children up until 2007. Now, the vaccination is optional and is dependent on the parent as to whether or not they would like their children vaccinated.

Polio Vaccine:

There are two different ways Polio vaccination was given, Oral polio vaccine (OPV) and inactivated poliovirus vaccine (IPV). OPV is known to be able to revert to a form that can achieve neurological infection and cause paralysis. In the US, after the year 2000, four vaccinations in the form of IPV are used for Polio vaccinations. In Japan, two vaccinations of OPV are used for Polio vaccinations.

Measles, Mumps, and Rubella (MMR) Vaccine:

In Japan, the MMR vaccine is no longer in use due to a series of health complications arising after receiving the Mumps vaccine. Since 2005, in place of the MMR vaccine, Measles and Rubella (MR) vaccine is mandatorily given. In addition, children are able to receive the Measles vaccine separate from the MR vaccine; but this is optional. In the US, Measles, Mumps, and Rubella vaccine with Varicella-zoster (Chickenpox) is still common.

Japanese encephalitis and Bacille de Calmette et Guérin (BCG) Vaccine:

In Japan, these vaccinations are mandatory. From my own experience, when I first came to the US, I had to get tested for tuberculosis by using the Mantoux test. Of course my result was positive. It was so hard to convince a doctor that I have received the BCG vaccination. There are a number of possible reasons that US is not giving Japanese encephalitis and BCG vaccinations. Both vaccinations have been proposed but none have been proven, and none can explain the lack of efficacy in both low TB burden country.

To sum it all up, it is quite interesting to see that there are some differences in how vaccinations are carried out in the US and Japan. Maybe one way worked better for an isolated island of a country, whereas the other method worked better for a larger country that is neighboring other countries. Since some of the vaccinations are mandatory in Japan, another interesting story I would like to share was when doctors and nurses from a public health department came to my elementary school to give out vaccinations. It was very random for the teacher to announce that a class was cancelled but actually, everyone in class had to head to the gym to receive a vaccination. Not only are certain vaccination requirements are different between the US and Japan, the delivery method is also a bit different in Japan as well.

Kuhnert P; Christensen H (editors). (2008). Pasteurellaceae: Biology, Genomics and Molecular Aspects. Caister Academic Press. ISBN 978-1-904455-34-9.

Centers for Disease Control and Prevention http://www.cdc.gov/vaccines/recs/schedules/default.htm

Infection Disease Surveillance Center

http://idsc.nih.go.jp/vaccine/dschedule.html

A clinical question...

I am taking care of a 6 month old boy in my clinic that has had several illnesses in his short life. Briefly, he was a full term infant with no complications. He was breastfed until about 4 months of age, then transitioned to formula. He was in daycare until 4 months of age, his 2 yo sister remains in daycare.

He has been hospitalized 3 times with respiratory illnesses, at age 2 months, 4 months and now 6 months. The first illness was a presumed viral illness. The second was again a presumed viral illness, though he was also treated with antibiotics for a potential right sided pneumonia. The third illness he was documented to have both RSV and Pertussis.

Otherwise, he has had no other significant infections (no ear, skin, urine infections, etc). He is growing and developing well. There is no family history of immunodeficiencies.

I am hoping that his difficult course has been due to "bad luck," however I think I need to screen him for immunodeficiencies at this point. I have my thoughts, but what tests would you send?

Post Ischemic Stroke Disease: Pick Your Poison

Cardiovascular disease is the number one cause of death in the United States, with stroke contributing as a major player in death caused by cardiovascular disease. Basically, a stroke is when blood and oxygen supply to any part of the brain is cut off, and an ischemic stroke in particular is where the cause of deprived blood flow is a blood clot that clogs up a blood vessel that feeds the brain. It is common knowledge that a stroke is a medical emergency that needs to be dealt with as soon as possible. Currently the best treatment for is thrombolytic therapy (clot busting drugs) which is only effective within about three hours of the clot formation. This ischemic stroke can cause permanent brain damage and even death. However, even if the person survives the ischemic stroke, there are still more fatal dangers lurking in the near future.

Although the lack of blood and oxygen to the brain causes severe damage, the negative impact of an overactive inflammatory response is responsible for much of the damage. This is because “Cerebral ischemia evokes an inflammatory response characterized by activation and release of cytokines, chemokines, endothelial-leukocyte adhesion molecules, and proteolytic enzymes that exacerbate tissue damage” and “increased levels of proinflammatory cytokines are related to a greater extent of vertebral infarct and poor clinical outcome in patients with ischemic stroke.” In experimental models, it has been shown that anti-inflammatory molecules IL-10 and IL-4 (released by lymphocytes, monocytes, and macrophages) greatly block the negative inflammatory response. In human studies it was shown that IL-10 production was increased during a stroke (most likely a countermeasure to the increase of inflammatory molecules) but more importantly, the data showed that people that naturally had a higher amount of IL-10 in their bloodstream suffered less damage from stroke. Now this is perfect, right? All that needs to be done is to undergo gene therapy to produce the IL-10 or inject exogenous IL-10….. right? Unfortunately no, the cascade of events that is initiated by IL-10 is more complex than that, and more importantly, too much anti-inflammatory can cause problems as well. [Source of information for this paragraph comes from http://stroke.ahajournals.org/cgi/content/short/34/3/671 ]

In addition to inflammation causing problems post ischemic stroke, infection also commonly causes more damage or death. Regardless of how optimal the ischemic stroke treatment is, many patients will develop a central nervous system infection shortly after. The two major theories behind this is one, that “the central nervous system and the immune system are 2 supersystems closely linked and the is functional interaction could pave the way to the appearance of immunological manifestations as the result of central nervous system injury, and vice versa” and two that “two that the emergence of systemic infection after acute brain damage could be a symptom of central nervous system-mediated decrease of immune competence”. Either way, it is saying the immune system is somewhat compromised after a stroke. Maybe this could be the IL-10 taking effect. This down regulation of the immune system can then cause an infection that can lead to death. [Source of information for this paragraph comes from http://stroke.ahajournals.org/cgi/content/abstract/38/3/1097 ]

So how do these two problems relate? Right after an acute Ischemic stroke, excess inflammation can cause greater permanent damage but too little inflammation and immune response leads to potential fatal central nervous system infections (which is likely to happen if a patient had too much IL-10 in their system). These contrasting potential actions and effects of the immune system and inflammation make post stroke therapy difficult. Treatment thus causes you to “pick your poison”, and I am assuming that physicians must closely monitor this balance of the immune system right after an acute ischemic stroke. Any thoughts?

Self medication anyone?

Cannabis, commonly known as marijuana, is a product of the cannabis sativa plant and the active compounds are collectively known as cannabinoids. Marijuana is used for all types of reasons ranging from pleasure to medicinal purposes. the discovery of cannabinoid receptors (CB1 , which is mainly expressed in the brain and CB2, which is mainly expressed in immune cells), has led to research identifying physiological functions of cannadinoids. This review looks at cannabinoids as a novel anti-inflammatory drug. cannabis has an apoptotic effect on immune cells. mice were exposed to THC and after different time points up to 72hrs lymphocytes were collected from the thymus and significant levels of THC-induced apoptosis were detected in Tcells, Bcells and macrophages were detected.

One possible mechanisms of immune control by cannabinoids during inflammation is the dys-regulation of cytokine production by immune cells and disruption of the well-regulated immune response.

Cannabinoids and MS: cannabinoids are useful in treating MS because they have neuroprotective as well as immunosuppressive properties. cannabinoids have inhibitory role on astrocytes, which secrete chemokines, cytokines, and NO.

Cannabinoids and Colitis: cannabinoids have been shown to regulate the tissue response to excessive inflammation in the colon, mediated by both dampening smooth-muscular irritation caused by inflammation and suppressing proinflammatory cytokines, thus controlling the cellular pathways leading to inflammatory responses.

Cannabinoids and liver injury: endocannabinoids and their receptors may play a critical role in regulating liver fibrogenesis; therefore, targeting the cannabinoid receptors may serve as a novel tool to prevent and treat liver injury. They also regulate liver cirrhosis by acting as mediators of vascular and cardiac functions. Endocannabinoids can trigger vasorelaxation, while an upregulated CB1-mediated cannabinoid tone causes enhanced mesenteric vasodialation leading to portal hypertension

Cannabinoids and RA: Using a non psychoactive component of cannabis, such as CBD, daily oral (5 mg/kg) or intra-peritoneal (25 mg/kg) administration of CBD inhibited disease progression.

Cannabinoids and cancers with inflammatory components: They showed that reatment with THC caused interruption of the MAPK/ERK kinase/ERK signaling module that was required for apoptotic lethality. They also reported that, in vitro, THC and other cannabinoids could induce apoptosis in transformed murine and human T cells.

seems to me as if there has been good progress in determining effects of cannabinoids as an anti-inflammatory factors, and quite frankly as more and more research is done, i wouldnt be opposed to the use of cannabinoids to treat/slow progression/eliminate symptoms of certain diseases

for more indepth mechanisms of how cannabinoids work in the various dieseases : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

A Health Happy Smile Leads to Decreased Stroke

I work as a dental assistant in the summers and winters and what stands out to me the most when I talk to patients is that they don’t floss, at least not a regular basis. Often patients think feel that toothpaste, mouthwash, or a water pick will do the job, but the dentist I work for says that those methods are like having a nasty rotten mushy apple stay on a counter top then spraying it with an antibacterial spray. Of course the millions of bacteria on the top of the mushy rotten apple will die, but you still have a nasty mess on the counter top with countless living bacteria underneath the surface. Then what is the solution then to cleaning a counter top or a tooth? Just physically wipe it off. It requires a wet rag to wipe off the mushy apple off the counter or some floss to clear out the plaque and food between teeth and under the surface of the gums. The biofilm of the early plaque is quite loosely attached to the teeth and just need some gentle physical force such as brushing and flossing can remove it. Why does the dentist tell me to stress the importance of flossing to patients? If patients don’t floss they will develop gingivitis (inflammatory gum disease), and more severe cases will develop into periodontitis (inflammatory disease of the gum and surrounding bone structure). The dentist stresses flossing so much to prevent, periodontitis is the leading cause for adult tooth loss. [Source of information from this paragraph came from Clayton Wainwright, DDS.]

However the dentist also stresses gum and surrounding bone hygiene for the health of internal organs and overall systemic health. That’s right; a health smile leads to an overall healthier body. The gums and jaw has constant blood circulation, just like your ear for example. If you get a chronic ear infection, it is quite obvious to get to the doctor clear the infection. The infection is sending harmful pathogens and inflammatory cytokines into your circulatory system. However if you have a chronic gum and surrounding bone infection it might not be as obvious to quickly go to the dentist clear the infection. Like the ear or any chronic infection, it is important to clear periodontal infection as soon as possible. In fact, the dentist receives many patients from general surgeons who will not operate on the patient until after all the oral infections are dealt with. [Source from Dr. Wainwright]

The link between oral health and system health is a current hot area of research, and one fine example is the correlation between periodontitis and stroke. The basic flow chart is that microbes cause dental caries and periodontal disease; which lead to bacteremia (bacteria in the blood) and systemic inflammation; which lead to atherosclerosis and thrombosis; which lead to coronary heart disease and cardiovascular disease, such as stroke. Several of these negative inflammatory cytokines connected to periodontal disease are such as IL-1 and TNF. Animal studies have shown that inducing periodontal disease in rabbits leads to the accumulation of coronary artery disease. In addition, several human studies such as the NHANESIII or a study in the Annals of Neurology demonstrate that periodontitis (not gingivitis) had a correlation with increased risk of stroke. Although more large scale studies are needed, the current evidence supports that periodontitis can increase the chance of having a stroke. [Sources from Ray Wagner MD, MS, FAAP; and articles found on http://d2l.ltc.arizona.edu/d2l/orgTools/ouHome/ouHome.asp?ou=167152 and http://d2l.ltc.arizona.edu/d2l/orgTools/ouHome/ouHome.asp?ou=167152]

Preventing periodontitis is quite easy with proper dental hygiene and regular trips to see the dentist. What is sad is that now around 75% of Americans adults are affected by some stage of periodontitis and the future adults don’t look so great with early childhood carries, aka ECC or child tooth decay, being the leading chronic disease among school aged children. So when I tell the patients at the dental office that flossing necessary to keep your teeth, I can also now tell them that flossing can help prevent stroke and other cardiovascular diseases. Any thoughts?

Celiac Disease: Pathology through leaky guts.

Celiac disease is one of the few autoimmune disorders that we can treat effectively and with few side-effects; however, our understanding of its pathogenesis is, as it is for most autoimmune disorders, lacking. Although the DQ2 and DQ8 HLA-class II types, the same ones related to Type-I Diabetes predisposition, contribute approximately 40% of the susceptibility for this disorder (I really don’t understand how statisticians get these numbers, but there is an apparent consensus on this one) and other, known gene loci may contribute another 2-3% of the risk, the majority of the susceptibility for this disorder appears to be environmentally-related (1). *I think I should point out – in TIDM, very specific alleles with HLA-DQ and –DR have been identified related to this disease, however this is not the case with Celiac. We still aren’t sure which specific alleles with DQ and DR are important in Celiac, or if that matters at all.

Environmental factors that may contribute include the amount and quality of gluten fed to babies early in life. Babies that are fed high-gluten diets during and after weaning are more likely to develop Celiac, especially if the grains they are fed contain more of the “toxic” epitopes related to autoimmunity (2). Furthermore, breastfeeding has (again) been shown to be extremely beneficial by promoting the growth of benevolent “friends” in the duodenum and jejunum, who help to process large carbohydrates as well as to keep mean bacteria out. You can almost think of them as bouncers for your tight-junctions!

What a segue – genes related to tight-junction regulation are emerging as a potentially crucial factor in Celiac development (2). In particular is the protein Zonulin, which was discovered as an analog to the Vibrio cholerae enterotoxin Zot. This protein reversibly permeabilizes the tight junctions between intestinal epithelial cells (IECs) via cytoskeletal rearrangements, allowing luminal antigen to bypass transcytosis and cross into the lamina propria, where antigens such as gluten can be altered into immunogens. In vitro experiments using cultured biopsies from Celiac patients showed sustained, rather than transient, increases in zonulin production compared to normal controls when the tissues were exposed to gliadin peptides. [Type-I Diabetics also have elevated levels of serum zonulin, and it appears to be a major player in the autoimmunity seen in Bio-Breeding Diabetic-Prone rats] (2).

Furthermore, zonulin-expression appears to be mediated by innate chemokine receptors on the luminal, not basolateral, side of the intestinal epithelium, in particular the receptor CXCR3. In patients with Celiac, CXCR3 appears to be activated by luminal gluten, which then leads to zonulin production via the MyD88 pathway. This may cause a sustained increase in intestinal permeability, which leads to the inflammatory destruction characteristic Celiac Disease. The zonulin pathway may also be a major player in Type-I Diabetes and other inflammatory bowel diseases, however the genetic and environmental modulators that cause differential development of these disorders is still not understood.

Citations:

1. Barisani, D et al Celiac Disease: From Pathogenesis to Novel Therapies. Gastroenterology 2009;137:1912-33
2. Fasano, A et al Tight Junctions, Intestinal Permeability, and Autoimmunity: Celiac Disease and Type I Diabetes Paradigms. Ann NY Acad Sci 2009 May;1165:195-205

Cross-Tolerance

Here is the second question: Is there spreading of tolerance just like epitope spreading in immune responsiveness?

I have been wondering about this for very long because of an unusual observation in my research.

The term “Cross-Tolerance” I will refer to here is the one suggested by two investigators working in transplant immunology from Harvard and Beth Israel Deaconess medical center (1) and specifically means that “T cell tolerance to one set of antigens would result in the development of tolerance to other unrelated antigens due to cross-reactivity” (1). In the literature there is some reference to cross-tolerance in the context that DC can either do cross-presentation to cross-prime T cells (I posted before) or cross-tolerize T cells (which is when self antigens are cross-presented in which case those T cells that recognize such antigens will be deleted, this is different from what I am referring to here where cells becoming tolerant to one antigen (be itself or not) develop an unexpected tolerance to another unrelated antigen).

Note that in epitope/ antigen spreading of immune response this is based on that the disease process/ tissue damage will result in exposure of new epitopes/ antigens to which another immune response will develop. So, cross immune tolerance is not the reverse of epitope spreading because it is , as suggested by the investigators in this recent article about cross-tolerance(1), an issue of cross-reactivity of the TCR (they refer to “TCR plasticity”). I would also quote this: “structural criteria rather than primary sequences may dictate the TCR recognition of different antigenic epitopes, which makes it exceedingly difficult to predict the crossreactive nature of TCRs” (1). This is something we did discuss in class in the context of development of immune response to graft antigens because of the cross-reactivity of the TCR and JJ Cohen had his nice live models of the two apples and the dishes to clarify that. Here, this is extended to the development of tolerance not just responsiveness. I think that because it is a cross-reactivity issue, I would not expect it to have a specific marching sequence of spread the way epitope spreading is.

However, it is of note that the paper presents a “suggested mechanism and definition” not results of a specific study.

So what, why should this matter?

1. Ofcourse for me it does because I had a kind of a persistent finding of what I assume is some form of tolerance to a one specific control antigen and disappearance of this once immune responsiveness is being restored. A weared observation that had no explanation so far.

2. There is a long discussion in the paper about the implications of this in transplant immunology: for example, would inducing tolerance of T cells to specific antigens related to the graft result in loss of important protective responses to some pathogens?, so would it be best to choose a graft with minimal cross-reactivity with those of the recipient not only to reduce the chance of rejection but the possible harms of cross-tolerance upon tolerance induction and therefore, the chance of viral and other infections to follow. I think this is a fine line though still going in the same direction.

Does anyone have any experience with this? Any comments/ suggestions?

I am sorry if this post comes late in the course, I just found this last week.

(1)Zhao Y and Li X. Cross-Immune Tolerance: conception and its’ potential significance on transplantation tolerance. Cellular and Molecular Immunology. 2010; 7: 20-25.

HIV/AIDS, TB, and malaria vaccine trials in Africa

Throughout human history many diseases and epidemics have affected large populations for centuries. However one particular region of the world has had to bear a heavy burden over the past few decades; Africa has had its population decimated by epidemics for many years. Currently they face three dreadful diseases: HIV/AIDS, tuberculosis (TB), and malaria. There are 22 million people living with HIV in sub-Saharan Africa (UNAIDS 2008), an estimated 9.27 million new cases of TB (WHO 2009), and in 2006, there were an estimated 247 million episodes of malaria and an estimated 881,000 malaria deaths (WHO 2009). Given the grave conditions in Africa it has been proposed to begin vaccination trials on the populations in multiple developing countries; however this has raised many ethical issues: Is it right use these populations as test subjects? Or should the vaccines be tested and developed outside of Africa then provided to the populace once they are known to be effective?
In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009 (Mamotte et al.). The five major ethical issues discussed at this conference were community engagement, ancillary care obligation, care and treatment, informed consent, and resource sharing. Addressing community engagement there has been a wide spread effort to inform the people of HIV/AIDS spread and treatment as opposed to TB and malaria. Ancillary care refers to treating other health issues the patients may have while participating in the vaccine trials; these individuals could have multiple medical problems that require medical attention. Moreover, the treatment and care debate is extremely important: treatment for malaria or TB is not too expensive and is available, however HIV/AIDS treatment is much more extensive and expensive as well; thus it has been hard defining a standard level of treatment and care to all participants enrolled in these vaccine trials. Informed consent is also a difficult issue because many of patients needing to seek treatment do not understand their conditions or they have misconceptions about the treatment they will receive. This is largely due to illiteracy and lack of education. Finally, resource sharing between researchers working on each individual disease in the past has been poor. To combat this, many are pushing to have more of a collaborative effort in order to successfully resolve these pressing ethical issues. Overall it boils down to two main ideals, do these desperate times call for desperate measures or with the ability to treat these diseases should we uphold a high ethical standard while it could cost lives in the meantime?

Delicious worms

I saw this posted on CNN today and recalled our discussion of parasites in relation to the immune system in class. Worms elicit a strong Th2 response to ward off the parasite and/or it's eggs by macrophages encapsulating the offenders to prevent further insult. Considering the evolution of our society and sanitation, we are no longer regularly infected with worms. Evolutionarily speaking, we are in a disequilibrium in regards to these mechanisms and many autoimmune diseases, including ulcerative colitis, have been implicated as a result. The Th2 response is less inflammatory than other processes and as a result CD4+ and CD25+ T-cells produce more inhibitory cytokines to regulate the aggressive proinflammatory cells. One needs only consult that episode of Futurama to determine whether worms are the right treatment for him/her.

http://www.cnn.com/2010/HEALTH/12/09/worms.health/index.html

Cross-presentaion, cross-priming

I have recently found some interesting information in relation two questions that have been ringing in my mind for a while and I’ll post each separately to avoid a long post:

First Question: Isn’t it likely that the Dendritic cell (DC) will be killed by CTL when it cross-presents antigens with MHC classI?

Having read through few articles on the subject, here is the scenario I would put:

· If an APC is virally infected (ie with viral replication inside it), then one would expect it to present some of the virally derived antigens in association with MHCI and I suppose that if the CTL delivers an apoptotic signal to the APC after Ag recognition then this would be beneficial.

· In case of tumors not invading into the APC’s or viruses that do not infect the APC’s (ie. extracellular antigens) then only through cross-presentation would it possible to excite a CTL response (ie dendritic cells (DC) would ingest this extracellular antigen, process it and present it in association with MHC I). So, this is also cross-priming. The question becomes: wouldn’t this be detrimental as CTL activation would mean death to the DC? Here is the issue: Only certain subsets of DC in the lymph nodes are capable of cross-presentation (these are well characterized by surface markers in mice but not in humans yet) and I would quote this from a recent review paper published in nature immunology reviews (1):” During a systemic infection, all DCs might be killed if they all could cross-present. Although DCs possess mechanisms to avoid CTL-mediated killing to some degree, it is clear that cross-presenting DCs can be effectively killed during viral infections. However, this killing does not seem to affect the ensuing immune response as CTLs need less than one day of antigen presentation by DCs for activation and a little longer for developing cytolytic functionality, and they can then carry out their tasks without continual stimulation, at least for some days” (1)

· Now the question becomes: how then could a DC activate CD4-helper T cells in case of an intracellularly derived antigen which is usually presented with class I MHC but not class II ? I just found talk about “Autophagy pathway” in DC’s in which intracellular antigens can be taken into autophagosomes, degraded in lysosomes and presented in association with MHC class II (2).

So it seems that within the DC’s, the pathways of Ag-presentation in association with MHC classes I or II complement each other as needed.

Question: Relevance and application of cross-priming??

I hope you can see that it is of value to combat viral infections in which DC’s are not infected and also to combat tumors. There is beautiful discussion in the paper of Kurtis et al. about the application of this in cancer therapy: for example, not removing draining lymph nodes even when negative for any tumor spread (contrary to current strategies), and the use of the tumor as its’ own vaccine.

(1) Kurtis C, Robinson BWS and Knolle PA. Cross-priming in health and disease. Nature reviews/ immunology. June 2010; 10: 403-414.

(2) Li Y, Wang L, Pang P, Twitty C, Fox BA, Aung,S, UrbaWJ and Hu H. Cross-presentation of tumor associated antigens through tumor-derived autophagosomes. Autophagy. 2009; 5(4): 576-577.

Acupuncture Anatomy and the Placebo Effect

In Dr. Zoe Cohen’s class we recently talked about anti-inflammatories and had a large focus on acupuncture. One of the basic articles we looked over studied the anti-inflammatory affects scupuncture had on rheumatoid arthritis (RA). The class as a whole did find several flaws and questionable portions of the paper, and we did chuckle at the fact that the scientists were performing acupuncture on a rat and how do we know if rat have similar acupoints. Furthermore, we questioned if the acupoint on a human had any anatomical basis to the nerves, cardiovascular system, etc. I did a bit of research about acupuncture on the National Oriental Medicine Accreditation Agency’s website and found that they do study the deep and superficial blood circulation as well as nerves, and so there is supposed to be some correlation between acupoints and nervous anatomy. (http://www.nomaa.org/Documents/NOMAA_Institutional_Self_Study_Guide.pdf pages 13 and 14). However I am still truly skeptical on how an acupoint in an ear can somehow pinpoint a specific internal organ to influence. Peripheral nerves lead to the central nervous system, not to specific organs.

Also in class we talked about acupuncture being a placebo effect. The issue we discussed in class was how to make an adequate placebo for acupuncture as puncturing an ear is easily felt. I mentioned that maybe some kind of local or topical anesthetic could be used so the patient wouldn’t be able to tell whether the needle pierced the skin on the ear or not. I did some lay article research on acupuncture and I found and interesting article on http://www.acupuncture.com/education/theory/placebo.htm. Apparently, using placebos in randomized clinical trials is horrible; since the placebo effect is inherent in the treatment option, we can’t use derived data from treatment group; and efficacy apparently should not be based on statistics like “the distancing and neutrality requirement of randomization, blinding and p values” but rather on a “a self-selected, biased, individual person and has nothing to do with generalizability and replicability”. Ok then….. that throws out pretty much everything we use to support that a treatment has a significant effect and throws out that there could be a general treatment for diseases. I’m not buying one bit of it. If stats don’t matter in acupuncture, then why was the stats taken to support acupuncture in the first paper that talked about acupuncture, RA, and rats? The journal it is published in is called the “Evidence-Based” Complementary and Alternative Medicine. And yes I understand that this acupuncture.com article is just a lay article. Any thoughts?

Exercise as an Anti-Inflammatory Treatment

As we all know, exercise is one of the healthiest things you can do for your body, and is particularly effective against cardiovascular disease and type 2 diabetes. CVD, type 2 diabetes, obesity, and metabolic syndrome are typically associated with low levels of chronic inflammation, which can be counteracted by exercise. Exercise stimulates muscle fibers to produce IL-6, which causes the release of other anti-inflammatory cytokines, inhibits TNF-alpha, and stimulates lypolysis and fat oxidation. TNF-alpha plays a role in insulin resistance, which is a characteristic of metabolic syndrome and diabetes. During exercise TNF-alpha is not released, and plasma IL-6 levels increase 20-fold. This paper focused on acute exercise’s influence on inflammation, and said that the long-term benefits of exercise have not been proven, which I found interesting. The paper mainly subscribed long-term exercise’s effectiveness as many acute bouts of exercise, and each individual workout had positive effects on inflammation. Moral of the story: exercise is good for keeping chronic inflammation at bay and preventing and/or treating CVD, type 2 diabetes, and metabolic syndrome. It’s also great stress relief during finals!

Peterson AMW, Pedersen BK. "The anti-inflammatory effect of exercise." J Appl Physiol 98: 1154-1162, 2005.

Chicken Soup Benefits

The idea that chicken soup is the remedy to the common cold may not be as much of a placebo effect as some may imagine. Although it is not a complete cure to your winter woes, chicken soup is seen, with scientific backing, to improve hydration and nutritional health in an individual, increase the clearance of mucus, and even possibly reduce the strength of the inflammatory response that comes hand-in-hand with viral infections.

A study done by B. Rennard et al looks at the ability of chicken soup to inhibit neutrophil chemotaxis in vitro. This study compared different dilutions of a traditional chicken soup recipe, different stages of preparation and isolation of different ingredients in that same recipe, and various commercially available chicken soup recipes in comparison to the main control. The soup significantly inhibited the migration of neutrophils, and the concentration of the soup was very influential in the effect of inhibition. Early stages of the soup preparation revealed little activity of inhibition, but as time progressed and more ingredients were added to the mixture, an increase in inhibition of neutrophil chemotaxis occurred. Also, when regarded separately, all the ingredients of the traditional chicken soup were seen to all have inhibitory effects. Lastly, thirteen different chicken soup recipes were tested against the "traditional" chicken soup recipe used in the previous experiments. Five of these recipes actually had higher levels of inhibition, while two of the recipes had no activity.

It is stressed in the study that this was performed in vitro, so limited evidence could be obtained about anti-inflammatory activity of chicken soup. But there are effects that have been observed with in vivo use of chicken soup, including stimulation of nasal clearance and improvement of upper respiratory tract symptoms. All in all, its not just a coincidence that chicken soup has been thought to be the "cure-all" for the common cold for centuries, so listen to your grandma and drink up!

Tolerance versus Activation based on the duration of T cell-APC contact

It seems we know a lot about T cell activation and central tolerance but somehow little when it comes to rules and mechanisms of peripheral tolerance, although in my opinion the latter is essential to understand and manage autoimmunity/ development of malignancy and even chronic infections.

A group from the University of California at San Francisco in collaboration with scientists from Stanford (1) did fabulous work to look into what drives CD4+ T cell tolerance versus activation to a systemic self antigen(sOVA) in two transgenic mice models (one that is lymphocyte deficient [sOVA-Tg/Rag-/-] and one that is lymphocyte sufficient sOVA-Tg). They examined both cytokine and activation/proliferation markers. They also used two-photon laser scanning microscopy to examine polyclonal and antigen-specific T cells in an inguinal lymph node from the mice and acquired 4D images (using a special software).

They found a prolonged activation of NF-κB in the lymphopenic host (in whom autoimmunity would develop) but a shorter-lasting activation in the immunocompetent host (by 8-hour posttransfer). Looking into the T cell-APC interaction, they found a significant decrease in the movement velocity of Ag-specific T cells in both hosts at 4 hours posttransfer, indicating that even in conditions of tolerance (in the lymphocyte-sufficient host) Ag recognition is needed but that rather a stop-signal is delivered. The striking difference was the duration of interaction with the APC: continuing for 18-hours in the host to develop autoimmunity while in the Ag-tolerant host, the Ag-specific T cells had regained their motility and moved away by this time. Therefore, indicating that the duration of this interaction is important in determining the fate of TCR signaling.

My comments :

· Do you notice the association between lymphopenia and autoimmunity? I must say, I used to think of it otherwise (mistaken) but I had the chance to see a patient with T cell deficiency and multiple endocrinopathies (diabetes and thyroid disease). Notice that this is not primarily due to depletion of T regs [actually in this paper they have treated the lymphopenic mice with anti-CD25 and found the same results. The authors propose reduced competence for DC and cytokines in cases of lymphopenia as a possible mechanism].

· Imaging in Immunology is a nice point here: They used Two-Photon laser scanning microscopy (TPLSM) to visualize and quantify the movement and interaction between APC-T cell. I had a discussion with the responsible person in the core microscopy about it (Radu Moldoven) and this modality is available and can be used to visualize anything bigger than 350nm but the tracking software is still unavailable at our university.

· Q: what happens next after Tcell-APC interaction in conditions of tolerance?

I hope you find this post useful

Thanks

(1) Katzmana SD, O’Gormanb WE, Villarinoa AV, Galloa E, Friedmana RS, Krummela MF, Nolan GP and Abbas AK. Duration of antigen receptor signaling determines T-cell tolerance or activation. PNAS. 2010; 107 (42): 18085-18090.