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Category: Pathobiology

Pathobiology of allergy and its most severe form, anaphylaxis

When allergy season looms, some people with serious hypersensitivity to allergens tend to be apprehensive of what may come. Some would rather stay indoors than risking the odds of sucking up triggers that could instigate severe allergic reactions. Apart from triggers from the environment, other common factors for allergy include food, medication, certain toxins, venom from insect stings or bites, stress, and heredity. How does an allergy manifest? Which cells are involved in forming an allergic reaction?

 

 

 

The immune system

allergy
How does an allergy occur? The pathobiological mechanism involves several white blood cells that play a role in mounting an allergic reaction.

 

The immune system protects the body from foreign substances (generally referred to as antigens) that could pose a threat to our well-being.  It prevents harmful bacteria, viruses, parasites, etc. from invading and causing harm. The white blood cells (also called leukocytes) constantly scout for antigens in order to destroy or disable them. The white blood cells include lymphocytes, neutrophils, basophils, eosinophils, monocytes, macrophages, mast cells, and dendritic cells.

 

 

 

Allergy – overview

 

allergy pathway
The allergy pathway.
Image (by Sari Sabban) distributed under the CC 3.0 Unported license.

 

An allergy is a state of hypersensitivity of the immune system in response to an allergen (i.e. a substance capable of inciting an allergic reaction). In this regard, several white blood cells play a role in mounting an allergic reaction.

In summary, the entry of an allergen into the body triggers an antigen-presenting cell, such as a dendritic cell. The dendritic cell takes up the allergen, process it, and then present its epitopes through its MHC II receptor on its cell surface. It, then, migrates to a nearby lymph node, waiting for a T lymphocyte to recognize it.

Upon recognition, the T lymphocyte may differentiate into a Th2 cell (type 2 helper T cells), which is capable of activating B lymphocyte. B lymphocyte, when activated, matures into a plasma cell that could synthesize and release IgE antibody in the bloodstream. Some of the circulating IgE may bind to mast cell and basophil. Thus, re-entry of such allergen could incite the IgE on mast cells and basophils to recognize its epitope. In effect, this activates the mast cell or basophil to release inflammatory substances (e.g. histamine, cytokines, proteases, chemotactic factors) into the bloodstream.

 

 

 

Anaphylaxis – a dreadful allergic reaction

The allergic reaction mounted by the immune system is supposed to protect the body. However, the allergens perceived by the body as a threat are generally harmless. The body tends to overly react to the allergens, and so leads to symptoms. Histamine, for instance, brings about the common symptoms of allergy: pain, heat, swelling, erythema, and itchiness.

 

Anaphylaxis is the most severe form of allergic reaction. It can occur rapidly and it affects more than one body system, such as respiratory, cardiovascular, cutaneous, and gastrointestinal systems. It occurs as a result of the release of inflammatory substances from mast cells and basophils upon exposure to an allergen. Within minutes to an hour, symptoms could manifest as a red rash, swelling, wheezing, lowered blood pressure, and in severe cases, anaphylactic shock.

 

In the presence of breathing difficulties, racing heart, weak pulse, and/or a change in voice, the situation is precarious. It calls for an immediate medical attention.

 

Why does anaphylaxis occur? IgE-mediated anaphylaxis is the common form of anaphylaxis. Initial exposure to an allergen leads to the release of IgE so that re-exposure to the allergen leads to its identification and the eventual activation of mast cells and basophils.  Apart from immunologic factors, though, other causes of anaphylaxis are non-immunologic. For example, temperature (hot or cold), exercise, and vibration may cause anaphylaxis. In this case, IgE is not involved. Rather, these agents directly cause the mast cells and the basophils to degranulate.

 

 

 

Novel mechanism identified

Recently, a team of researchers1,2 found a novel mechanism that could explicate the hasty allergic reaction during anaphylaxis. They were first to uncover a mechanism involving the dendritic cells. Accordingly, a set of dendritic cells seem to “fish” allergens from the blood vessel using their dendrites. The dendritic cell near the blood vessel takes up the blood-borne allergen. Rather than initially processing it, and then presenting the epitope on its surface, it hands over the allergen inside a micro-vesicle to the adjacent mast cells.

 

Mast cells, unlike basophils that are in the bloodstream, are located in tissues, such as connective tissue. Thus, the question as to how the mast cells detect blood-borne allergen could be answered by the recent findings.

 

Rather than being internalized by the dendritic cells for processing, the allergen was merely taken into a micro-vesicle that budded off from the surface of dendritic cells. This, thus, saves time. It cuts the process, leading to a much rapid allergic reaction.

 

However, these findings were observed in mouse models. Therefore, the researchers have yet to observe if this novel mechanism also holds true on humans. If so, this could lead to possible therapeutic regulation of allergies, especially the most dreadful form, anaphylaxis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Choi, H.W., Suwanpradid, J. Il, Kim, H., Staats, H. F., Haniffa, M., MacLeod, A.S., & Abraham, S. N.. (2018). Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesiclesScience 362 (6415): eaao0666 DOI: 1126/science.aao0666
2 Duke University Medical Center. (2018, November 8). Using mice, researchers identify how allergic shock occurs so quickly: A newly identified immune cell mines the blood for allergens to directly trigger inflammation. ScienceDaily. Retrieved November 22, 2018 from www.sciencedaily.com/releases/2018/11/181108142440.htm

 

First Video Proof That Could Explain Antibiotic-Resistant Superbug Bacteria

Amidst the battle for supremacy, our army of immune cells relentlessly wages war against various pathogens, especially superbug bacteria. Despite the pool of ample winnings, our body still experiences defeat from time to time. We succumb to diseases as the war reels its favor towards the tenacious pathogens. Of course, we cannot allow our immune defense to be utterly defeated. Otherwise, we’d be dead. As bacteria advance by taking over much space and nutrients inside our body, we get external help through antimicrobial chemicals that scientists continue to contrive.  Unfortunately, antibiotic resistance has surfaced and turned certain strains of bacteria into a superbug – one that has become resistant to the effects of antibiotics.

 

 

 

Chemical warfare prior to the rise of a superbug

Antimicrobial chemicals, particularly antibiotics, came into existence as chemicals that were strategically designed and produced with the intent of killing pesky bacteria. In 1928, penicillin was discovered, which led to its use as the first natural antibiotic capable of undermining a spectrum of bacteria, if not by killing, by inhibiting their growth. Its role as a wonder drug against various bacteria caused Alexander Fleming to receive a duly recognition by winning a Nobel prize award for its discovery. Soon, more antibacterial agents came up to our defense. Antibiotics, such as penicillin and cephalosporin, destroy bacterial cell wall whereas polymyxins target bacterial cell membrane. Rifamycin, quinolones, sulfonamides, and the likes interfere with the enzymes essential to bacteria. Once again, we gained an upper hand.

 

 

 

Bacteria resisting: the rise of a superbug

A Scanning Electron Microscope (SEM) image of cells of the bacteria Vibrio tasmaniensis(Credit: Lewis Lab at Northeastern University. Image created by Anthony D’Onofrio, William H. Fowle, Eric J. Stewart and Kim Lewis)

 

While we thought we finally came up with a powerful weapon, the bacteria conjured up an amazing strategy to work in their favour — antibiotic resistance. Some of them started to morph. They evolved and mutated into new strains referred to as superbug. They became capable of resisting the drugs’ antimicrobial effects. One of their strategies is to produce β-lactamases that destroy the structure of β-lactam antibiotics (e.g. penicillin and cephalosporin). The bacteria that evolved into superbug organisms did not just live; they thrived. They multiplied and passed on to the next generation the features that could withstand a number of antibiotics.

 

 

 

DNA uptake by superbug bacteria

Apart from the vertical gene transfer of genes, antibiotic resistance could also be transferred through horizontal gene transfer. It is a mechanism whereby genes are taken up or transposed from one species to another, and one of the possible explanations for the rise of superbug bacteria. DNA uptake by a bacterial cell was captured for the first time in a video by a team of scientists from Indiana University. In the video1, it shows how a bacterial cell takes up DNA fragments from dead bacterial cells through its pilus. Like a harpoon, the pilus was used by the bacterium, Vibrio cholera, to catch and reel a stray DNA fragment, and then bring it inside the bacterial cell via the same pore on its cell wall. It, then, incorporates the DNA into its own genome. Accordingly, this is probably one of the mechanisms for a bacterium to turn into a superbug.

First video evidence of DNA uptake by Vibrio cholera.
(Video credit: Ankur Dalia, Indiana University, uploaded on YouTube by Group IU Biology News)

 

A researcher from the team, Courtney Ellison, recounted, “The size of the hole in the outer membrane is almost the exact width of a DNA helix bent in half… If there weren’t a pilus to guide it, the chance the DNA would hit the pore at just the right angle to pass into the cell is basically zero.” It appears that the pilus takes a crucial role in horizontal gene transfer. If left to chance the DNA fragment would not easily get inside the cell since the pore was too small for it to fit. Through horizontal gene transfer, those that were once sensitive to the antibiotic could later become superbug bacteria as well. As Ankur Dalia, another researcher from the same team, pointed out, “Horizontal gene transfer is an important way that antibiotic resistance moves between bacterial species….” The video that the research team captured for the first time could explain how antibiotic resistance can be acquired from one superbug bacterial species to another.

 

 

 

The battle is far from over. The antibiotic resistance already raised global concerns as it has rendered certain antibiotics ineffective. Pathogenic superbug bacteria have successfully armed themselves with genes that could neutralize antibiotic effects. Fortunately, scientists do not waver in determining the strategies that superbug bacteria exploit.  The recent discovery of the way by which bacteria employ to make them antibiotic-resistant superbug strains could lead to better therapeutic strikes that could counter them, hopefully, with ample success.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Indiana University. (2018). IU scientists watch bacteria ‘harpoon’ DNA to speed their evolution. Retrieved from https://news.iu.edu/stories/2018/06/iub/releases/11-scientists-watch-bacteria-harpoon-dna-to-speed-their-evolution.html

Pathobiology Of Broken Heart Syndrome

When someone says “I could die of a broken heart…”, chances are, that person may be truly risking life from a broken heart – a condition referred to as broken heart syndrome. The emotional agony can be likened to a physical pain. Apparently, it was only recently that it gained stalwart attention from researchers as they began to probe the pathobiology behind a broken heart syndrome.

 

 

 

Broken heart syndrome – overview

Hearing stories of a person in severe emotional distraught from a loved one’s death and then died not long after is not uncommon. How much of losing a loved one, a gut-wrenching rejection, or an austere betrayal could lead to death no longer surprise us. Deep sorrow certainly takes a toll. Death is inevitable but dying from a broken heart syndrome is something that is treatable and preventable, thus, is escapable. Inopportunely, the pathobiological aspect of a broken heart syndrome has not been fully unmasked. What is known about it so far is the fact that severe emotional stress is capable of triggering the transient weakening of the heart muscle, turning the latter fatally dysfunctional.

 

 

 

Pathology of Broken heart syndrome

An illustration of left ventriculogram in (A) broken heart syndrome (arrow) and (B) normal.

(Credit: JHeuser, WikiMedia Commons under GNU Free Documentation License)

 

The medical term for broken heart syndrome is takotsubo cardiomyopathy. The condition was first described in Japan in 19901 and the name is derived from”takotsubo“, which when translated means an “octopus trap“. It is so because the left ventricle of the heart of a person with broken heart syndrome is shaped like a contraption pot used for catching octopuses. Its apex balloons or bulges out while its base remains as is. As a result, the heart with temporarily enlarged apical ventricle cannot function as it should. Consequently, blood is not pumped properly and this leads to angina (chest pain) and shortness of breath, which are symptoms typical of a heart attack. Because of this, broken heart syndrome can be easily mistaken as a heart attack. The difference lies in the arteries. A true heart attack is due to an occlusion in the artery. In broken heart syndrome, arteries are not obstructed. Also, the ventricle is only temporary dysfunctional and therefore may normalize again if given enough time to rest and recuperate.

 

 

 

Biology of a broken heart syndrome

Unraveling the mysteries of broken heart syndrome is a recent biological pursuit. Consequently, the precise mechanism is not yet clear. Experts presume a surge in adrenaline and other stress hormones since the condition is often associated with emotional stressful events (n.b. it has also been reported to happen during euphoric events, e.g. winning a lottery). The overwhelming presence of these hormones might have stunned the heart and triggered structural changes in the myocytes and/or the coronary blood vessels.2 In a study published in Psychoneuroendocrinology, researchers found that bereaved individuals have higher levels of pro-inflammatory cytokines.3

 

 

 

A person who went through a broken heart syndrome and survived it could attest how the struggle had been real. Having to go through an intensely stressful event could plausibly cloud one’s drive and enthusiasm for life. Research on the pathobiology behind broken heart syndrome is understandably new, and as such inadequate for now.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Akashi, Y.J., Nef, H.M,, Möllmann, H., & Ueyama, T. (2010). “Stress cardiomyopathy”. Annu. Rev. Med. 61: 271–86. Doi:10.1146/annurev.med.041908.191750
2 Harvard Women’s Health Watch. (2018). Takotsubo cardiomyopathy (broken-heart syndrome). Retrieved from https://www.health.harvard.edu/heart-health/takotsubo-cardiomyopathy-broken-heart-syndrome.
3 Fagundes, C.P., Murdock, K.W., LeRoy, A., Baameur, F., Thayer, J.F., & Heijnen, C. (2018). Spousal bereavement is associated with more pronounced ex vivo cytokine production and lower heart rate variability: Mechanisms underlying cardiovascular risk? Psychoneuroendocrinology 93:65-71. doi: 10.1016/j.psyneuen.2018.04.010.

Epstein-Barr Virus – It’s More Than Just The Kiss

Epstein-Barr virus — the virus causing the kissing disease or mononucleosis — is eyed as a risk factor for contracting seven other major diseases. This is what the research team at Cincinnati Children’s Hospital Medical Center reported. The Epstein-Barr virus is contracted by kissing or by the oral transfer of saliva. Apparently, once the Epstein-Barr virus infects the body it stays there forever.

 

 

 

Epstein-Barr virus and mononucleosis

Epstein-Barr virus illustration. (Credit: Vix Maria, ©Biology-Online.org)

 

The Epstein-Barr virus belongs to the herpes family, Herpesviridae. It contains DNA that bears 85 genes and is surrounded by a nucleocapsid. Apart from the nucleocapsid, the virus is further bounded by a protein tegument and an outermost layer of a lipid envelope. The envelope has glycoprotein projections, which are crucial for the virus during its infection of the host cell.1 B cells, the immune cells producing antibodies, are ought to destroy them. However, the Epstein-Barr virus can outwit them by a slick mechanism. The virus invades the B cell, reprograms it, and makes it “follow” its “commands”. The virus is known for causing mononucleosis or the kissing disease. The common symptoms include fever, fatigue, sore throat, rash, and swollen lymph nodes, especially in the neck.

 

 

 

Epstein-Barr virus and the seven major diseases

According to the study led by three scientists, John Harley, Leah Kottyan, and Matthew Weirauch, the Epstein-Barr virus infection has been implicated to seven unrelated serious diseases.2 Previous studies by Dr. Harley and his team have already connected Epstein-Barr virus with the increased risk of developing systemic lupus erythematosus years ago. Recently, however, they found that the virus could also augment the risk of developing other serious diseases, such as multiple sclerosis, type 1 diabetes, inflammatory bowel disease, celiac disease, rheumatoid arthritis, and juvenile idiopathic arthritis.3 A person contracting the Epstein-Barr virus has a greater risk of developing them. This is because the virus produces a protein, Epstein–Barr virus nuclear antigen 2 (EBNA-2), that interacts with the human DNA, especially at genetic risk variants. 2 A genetic risk variant pertains to a variant in the DNA genome that has a potential to cause disease(s).

 

 

 

Epstein-Barr virus and future research

Epstein-Barr virus, known for causing kissing disease or mononucleosis, is linked to other serious diseases.

 

Dr. Harley and his team suspect that the EBNA2 protein from the Epstein-Barr affects a set of transcription factors. Accordingly, what the seven seemingly unrelated diseases share in common is a set of dysfunctional transcription factors, each affected by the EBNA2 protein.2 When the activity of transcription factors deviate from what they are supposed to do, the host cell (such as B cell) would not be able to carry out its normal function. This, in turn, could progress to certain diseases. With their recent finding, Dr. Harley and his team are optimistic that further intensive research could direct to finding better therapies and preventive methods such as vaccines against Epstein-Barr virus infection.

 

 

 

This recent finding suggests that contracting Epstein-Barr virus can lead to multiple diseases apart from mononucleosis. Therefore, this calls for more studies that aim at finding better cures and preventive measures. Currently, there is no vaccine against Epstein-Barr virus; being able to boost our immunity against the virus may help mitigate the risk to many other diseases, such as those mentioned above.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1Odumade, O.A., Hogquist, K.A., & Balfour Jr., H.H. (2011). “Progress and Problems in Understanding and Managing Primary Epstein–Barr Virus Infections”. American Society for Microbiology. 24 (1): 193–209. doi:10.1128/CMR.00044-10
2 Harley, J.B., Chen, X., Pujato, M., Miller, D., Maddox, A., Forney, C., Magnusen, A.F., Lynch, A., Chetal, K., Yukawa, M., Barski, A., Salomonis, N., Kaufman, K.M., Kottyan, L.C., & Weirauch, M.T. (2018). “Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity.” Nature Genetics. DOI: 10.1038/s41588-018-0102-3
3 Cincinnati Children’s Hospital Medical Center. (2018). ‘Mono’ Virus Linked to Seven Serious Diseases. Retrieved from https://www.cincinnatichildrens.org/news/release/2018/mono-virus.