The Skin you're in.

Hi everyone, I hope your finals went well.

I have for some time, been fascinated by the largest organ of our bodies, the skin. When I was talking with a friend of mine last week about studying for my Immunology final allergies came up and I found out something I never knew about her. I've seen her drink margaritas on more than one occasion, and so I saw surprised when she told me that she's allergic to limes. Upon further explanation she told me she can eat limes fine with no problem, but if she gets lime juice on her skin and it's exposed to sun light, her skin turns purple. My reaction... cool!

Looking further into it I found that is condition is called Phytophotodermatitis, unfortunately a non-immunological based response. But It got me thinking about people that do have allergies to sunlight, photosensitivity, and how the process works.

There are a lot of different types of photsensitivity I've found out. One in particular polymorphous light eruption (PLE) is very common and is a Type IV hypersensitivity. When our skin is exposed to UV, there is a normal increase in IL-4 neutrophils. These intern produce IL-10 and recruit Th2 cells which then go on to call in the M2 macrophages, which from class we found out are key recruiters in M2 Macrophages which help in clean up and repair. With PLE there is something blocking and or reducing this process that isn't entirely understood, although mast cells as well as Treg cells have be looked at as possible culprits because of there suppressive abilities. 

 

To the right is a diagram that helps lay out normal vs. PLE skin reactions to UVB from Wolf, Byrne and Gruber-Wackernagel 2009. 

Does anyone know of other interesting dermatology-immunology reactions that are out there? I had thought I found another one, but it turned out to be chemically related, not immunological,

Wolf P, Byrne S.N, Gruber-Wackernagel A. 2009 New insights into the mechanisms of polymorphic light eruption:resistance to ultraviolet radiation-induced immune suppression as an aetiological factor. Exp Dermatol. 18: 350-356.

The mind-body connection - a consideration for timing of your flu vaccine?

It's December 14th, which means that across the country university students are frantically studying for final exams, doing holiday shopping, arranging travel plans, writing that final term paper, blogging for the last time, etc...
Stress abound! Right?





What about getting that flu shot that you keep meaning to mark off of your to-do list? Think this frantic time is too stressful to consider being set-back by a sore arm as you have 8 more pages of a term paper to type?


Think again!  Now might just be the optimal time to roll up your sleeve and get your flu shot! At least, that what some researchers have hypothesized (Edwards et al, 2006).






While we have heard that chronic stress can induce a state of immunocompromise, could acute stress actually be "immunoenhancing"? According to a small cadre of studies related to the psychoneuroimmunology field, acute stressors have been shown to enhance antibody response. Edwards et al (2006) studied men and women under experimental conditions using the A/Panama flu strain. Subjects were randomized to one of three groups: dynamic exercise, mental stress, or control. Subjects in the intervention groups were immunized with A/Panama strain of flu vaccine immediately following their exposure to a 45-minute stress-inducing activity. A/Panama antibody titers were measured at vaccine baseline, 4 weeks post-vaccine, and 20 weeks post-vaccine. Additionally, researchers obtained serum IL-6 and cortisol levels at baseline, following the task, and after 60-minutes of recovery.

Interestingly, the Edwards et al (2006) study found the following: 

• Women in both the exercise and mental stress groups showed higher antibody titres at 4 and 20 weeks post-vaccine than those in the control group.

• Men responded similarly to women in all conditions.

• IL-6 at 60 mins into the stress recovery phase was found to be a significant predictor of subsequent antibody response in women.

  Obviously, this study was limited by its small sample size (N=60) but there's more....

But what about the flip-side of this coin? Could being un-stress / relaxed result in a diminished immune response to vaccination? Maybe yoga is contraindicated prior to vaccination?


Check out these other studies that have related but significantly different findings:

Glaser, R., Sheridan, J. F., Malarkey, W. B., MacCallum, R. C., & Kiecolt-Glaser, J. K. (2000). Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosomatic Medicine, 62, 804-807.

Glaser, R., Robles, T. F., Malarkey, W. B., Sheridan, J. F., & Kiecolt-Glaser, J. K. (2003). Mild depressive symptoms are associated with amplified and prolonged inflammatory responses following influenza vaccination in older adults. Archives of General Psychiatry, 60, 1009-1014.

 

Well.....no one has really studied that aspect :) But there is tons of literature related to stress and immune dysfunction! So are these conflicting reports? Or is there a "middle-ground" per se for the appropriate amount and timing of stress?






 

References
Edwards, K.M. et al (2006). Acute stress exposure prior to influenza vaccination enhances antibody response in women. Brain, Behavior, and Immunity, 20(2):159-168.

I just love this idea, so I had to share, even though it's late in the semester. Here's the article and the abstract.

Oral tolerance, food allergy, and immunotherapy: implications for future treatment.

Burks AW, Laubach S, Jones SM. J Allergy Clin Immunol. 2008 Jun;121(6):1344-50. doi: 10.1016/j.jaci.2008.02.037. Epub 2008 Apr 14.

"The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy."

Did you get your Hear Attack Vaccine yet this year?

Every fall in my workplace, the flu shot question circles the water cooler. One I’ve never heard yet is “Did you get your atherosclerosis vaccine?”. Sounds far fetched, but some researchers in La Jolla, CA might not agree. Dr. Klaus Ley has led a study which may take us closer to a vaccine for arterial plaque development or subsequent plaque rupture. Let’s work through the thought experiment with the knowledge we have gained in this course thus far. The adaptive immune system has been previously suspected of involvement with development of arterial plaque. However, there are no lymphatic draining nodes in arterial plaques, so there has been doubt that APC’s would be able to migrate to lymph nodes from arterial plaques to activate t-cells.  Dr. Ley and his team have demonstrated ex-vivo that specific types of dendritic cells and Th1 cells with certain MHC genes can have productive interactions in the plaque itself. This leads to t-cell proliferation and production of IFN-gamma. The subsequently recruited macrophages are then able to uptake circulating LDL particles and differentiate into foam cells (increases plaque formation). Dr. Ley is most excited at this discovery due to the evidence that the interaction between memory t-cells and APC’s with specific markers may be involved in aggressive plaque formation. Past studies have shown that increased levels of Treg and decreased levels of specific Th1 cells are associated with decreased plaque formation in animals models. Is it possible that plaque formation is an adaptive rather than an innate process? What if we could stimulate an appropriate innane immune response to supersede the Th1 activation? As we try to shift immunotherapy to specific antigen’s and other immunomolecules, it will become more vital to identify the specific molecules and their traits involved in immunologic interactions which give rise to adverse health conditions.I don't think the vaccine will be ready for next year...but knowing that memory t-cells play a role gives me hope that the mechanism for the vaccine exists, if we can only understand enough about the interactions...

Journal Reference:

1.      Ekaterina K. Koltsova, Zacarias Garcia, Grzegorz Chodaczek, Michael Landau, Sara McArdle, Spencer R. Scott, Sibylle von Vietinghoff, Elena Galkina, Yury I. Miller, Scott T. Acton, Klaus Ley. Dynamic T cell–APC interactions sustain chronic inflammation in atherosclerosis. Journal of Clinical Investigation, 2012; DOI: 10.1172/JCI61758

An Allergy Or Something Else?

Few years ago I had to deal with skin problems, that involved my lips, face (mostly skin around eyes), and my hands . I wonder if the symptoms were caused by the same factor.

     It all started about 7 years ago. My lips were very dry (Colorado’s fault?), I had to use chapstick (Lip smaker, no wonder I developed allergy). After using it for quite some times, I developed tingling sensation and my lips felt very uncomfortable. I switched to a different brand. Again, used it for some time… Ended up with the same symptoms. Switch brand again, symptoms developed even sooner and sooner. One time my lips swelled twice the size with yellow crust all over! Hydrocortisone 1% did the trick.  

     Meanwhile, about 3 years ago, my eyes became dry. I no long could wear contact lenses. Eye doctor proscribed me steroid drops, which work like a miracle for few days, than the nightmare began. I noticed the skin started peeling under one eye. I ignored it at first, and continued to use drops. The symptoms got worse. Skin on my cheeks and especially around eyes (crease and area under eyes) was very irritated, swollen, and kept peeling, eyes were sensitive. My lips were peeling just as much, any chapstick would give me a reaction, without chapstick there were getting super dry, painful and peeled even more. In the mean time, I got weird red dots on my heads that went away as soon as I stopped using moisturizer.

    There was no way cover all that peeling and swollen “beauty”, since makeup only made things worse. Dermatologist didn’t do much but proscribing topical steroids that only provided short term relief. Once I stop taking them, symptoms come back. Then I tired doxycycline for two weeks, not much difference either. Finally, I went to a cosmetologist, she gave facial creams, all natural, and with time I started getting better. I don’t know if it facial cream that helped, but the symptoms were slowly disappearing, the skin was getting better and better.

    Now, few years later, the only minor issue remaining is my lips. All I use is pure petroleum jelly, few times a day. If I won’t moisturize them, it will get sore and uncomfortable. On rare occasions I use lipstick and it doesn’t irritate but I don’t know what will happen if I will use it on daily basis. 

Am I Delusional?

In my attempt to find something even Dr. Cohen has not heard of I started exploring this new sub-specialty of neuroimmunology.  I cam across an article on PubMed describing the features of anti-NMDA receptor encephalitis, which seems to be correlated to antibodies neuronal cell membrane antigens such as VGKC, NMDAR, and AMPA receptor.  This interesting disease is typically diagnosed in psychiatric hospitals because of the severe schizophrenic symptoms including hallucinations.  With the broadening realization of neuroimmunology researchers and physicians are realizing the implications immunopathology can cause psychiatric symptoms. 

Antibodies to these antigens are tested in CSF serum and are usually in correlation with younger women diagnosed with ovarian teratoma.   Along with hallucinations which is often seen in schizophrenia paranoid subtype, anti-NMDA has co-occurring symptoms often not seen between schizophrenic subtypes such as flat affect, catatonia, and seizures.  Based on prior knowledge with psychiatry, specialists speculate the cause of these symptoms may be due to the inhibition of NMDAR causing a reduction of GABA release. 

The use of corticosteroids and immunoglobulins have been used for treatment along with psychiatric medications.  This poses an interesting questions if more psychiatric disorders are link to immunopathology as well as could treatments come from immunological drugs?  Not to mention in this particular incidence because schizophrenia has long been misdiagnosed is there a chance that many of those in history fall more into a category of anti-NMDA receptor encephalitis? 

The field of combining neurology, psychiatry and immunology may prove to be more relevant than originally thought.

Lizuka, T.  Unique clinical features and pathophysiology of anti-NMDA receptor encephalitis.  Rinsho Shinkeigaku.  2009.  Vol 49(11).  Pg 774-778.

Waas, JA. & Storm, AH.  Anti- NMDA- receptor encephalitis; a neuropsychiatric illness requiring further study.  Tijdschr Psychiatry.  2012.  Vol 54(3).  Pg 279-283.

Evolutionary Chase: The Red Queen Hypothesis

Remember the book Alice in Wonderland. So if you remember there is a character called the Red Queen. The Red Queen said, “It takes all the running you can do, to keep in the same place.”
The idea was Alice and the Red Queen were constantly running in the same place but getting nowhere. This concept can be applied to evolutionary fitness. Hypothesized by Lee Van Valen in
According to the hypothesis, there is a sort of evolutionary arms race. Selection pressures by organisms force other organisms to evolve to keep up, like host parasite, predator prey, ect. Sexual reproduction may allow for a species to evolve fast enough to maintain an ecological niche in their ecosystem.

This idea is relevant to immunology because the Red Queen hypothesis may explain the rate of evolution for genes in immunoglobulin and certain protein kinases. Think about the way we mix maternal and paternal genes HLA determination or MHC, or the hypervariable regions in immunoglobulin. Essentially sexual reproduction is worth the cost because of genetic variation, at least in some environments. Parasites and bacteria are constantly evolving to keep evade our drugs and so our genetic diversity may help us keep up with them. However there are some pitfalls to this hypothesis in immunology, we have not evolved fast enough to keep up with HIV or certain cancers.



http://www.factfixx.com/2011/12/06/the-red-queen-hypothesis/
 Kuma, K.; Iwabe, N.; Miyata, T. (1995). "Functional constraints against variations on molecules from the tissue-level - slowly evolving brain-specific genes demonstrated by protein-kinase and immunoglobulin supergene families". Molecular Biology and Evolution 12 (1): 123–130. PMID 7877487
http://www.pbs.org/wgbh/evolution/library/01/5/l_015_03.html

Autoimmunity in women

I study MS, a disease with a predisposition towards women. While doing the reading for this course, I noticed that many other autoimmune diseases (i.e. SLE, Sjogren's syndrome, thyroid disease, and myasthenia gravis, to name a few) appear to be more prevalent in women. Another interesting tidbit that I picked up while reading about this is that while women are more likely to experience autoimmune disease, when men do experience autoimmune disease, the symptoms are often more severe. We didn't really discuss basic differences between the male and female immune systems during the course, so I will present some ideas here based on this review: Sex Differences in Autoimmune Disease, Caroline Whitacre, 2001.

Some facts:

-after immunization, female rats produce more antibody and more vigorous T-cell activation that male mice (human data contradicting). 

-women have higher CD4+ lymphocytes than men.

-higher production of Th1 cytokines in women.

-cytokine production is enhanced in vitro in the presence of estrogen.

Studies have focused mainly on the following sex hormones: estrogen, progesterone, and testosterone. Along these lines, there huge increase in estrogen and progesterone production during 3rd trimester of pregnancy. In MS and RA, disease activity decreases during pregnancy but moreso during the 3rd trimester. There is then a post-pardum "flare" that is often seen when estrogen and progesterone levels fall. These hormones could alter the balance of Th responses, with estrogen and progesterone pushing towards more Th2. 

Overall, there appear to be major differences between male and female immune systems, and these differences influence the frequency of autoimmunity in females greater than males. There seems to be an effect from sex hormones, but genetic differences are likely as well. Perhaps lifestyle differences between genders could also affect immune system function? Understanding the link between sex differences in immunity and autoimmunity will provide novel insight into how we think about these diseases and how we prevent and treat them.

Strategies for vaccination against Malaria

In reading about Malaria and the struggle to create a vaccine against it I came across this article/chart about promising strategies to create a vaccine. The parasites, of the Plasmodium genus, that causes Malaria in humans has been around for hundreds to even thousands of years. This disease has no vaccine but lots of research is being done to find one. There are three strategies that are seen as promising in possible vaccination. 

The first is to grow genetically modified or irradiate immature parasites in mosquitoes, extract them and then inject fragments into a previously uninfected human. This would trigger an immune response in the human and lead to the creation of anti-body against the parasite. With anti-body, IgE is the class of anti-body that fights parasites, present and memory cells developed if the person were to be infected with the parasite again hopefully Malaria would not develop and the parasite would be killed quickly.

The next strategy is similar to the first strategy but instead of altering the parasite, healthy parasite surface proteins are taken and coupled with an adjuvant. The adjuvant will elicit an increased immune response to the antigen, the foreign parasite surface proteins. This would be followed up by a booster shot about two years later. This would also lead to memory cell formation.

A vaccine for the mosquito itself would prevent the transmission from person to person. How it is suppose to work is by creating a human antibody against an enzyme in the mosquito critical to the proliferation of the parasites. Taking parts of the enzyme aminopeptidase and injecting them into a human would lead to the creation of anti-bodies against the enzyme. When the immunized human is then bitten by a mosquito not only would the mosquito ingest blood, but also antibody. This antibody would then bind to aminopeptidase prohibiting the enzyme from performing its proper function in the proliferation of Malaria causing parasites.

Each of these are very novel ways to try and vaccinate against Malaria and hopefully one day soon they will be given to eradicate this disease that has been around for so long. To combine a vaccination that not only treats the human but also prevents transmission by, in a round-a-bout way, immunizing the mosquito as well seems like an excellent way to not only protect humans but maybe one day eliminate the parasite all together.   

http://www.scientificamerican.com/article.cfm?id=malaria-vaccine-strategies