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Immune system

Article curated by Ginny Smith

Our immune systems are vital for our survival as they protect us from bacteria, viruses and other pathogens that could cause us harm. But sometimes, they can go wrong, and cause damage to our bodies. By better understanding how our immune system works, researchers hope to support and boost the system so it can fight invaders when necessary. More information will also help us discover how to correct it when it goes wrong, and treat allergies and auto-immune diseases.

James Gathany (CDC Public Health Image library ID 11162) [Public domain], via Wikimedia Commons
Sneeze Image credit: Public domain

One way that our body has of protecting us from invaders is by forcibly expelling them, or as we call it, sneezing. Sneezing occurs when something entering our noses irritates the nose lining and triggers an electrical signal. This signal travels to the brain stem which initiates the sneeze response. While this much is understood, what scientists don't yet know is why some people tend to sneeze once, while others sneeze 2 or 3 times, and still others are plagued by bouts of many sneezes, one after the other.[1]

People who have many allergies are more likely to be multiple sneezers, particularly if they are exposed to their allergen over a long time period. It is also likely to be linked to differences in people's immune systems, and their brains, but what exactly these are, and why they cause people to sneeze differently, is yet to be discovered.

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undulatus (CC0 Public Domain) via Pixabay
Pollen is a common allergen Image credit: Public domain
One common cause of sneezing is allergies- many of us suffer the irritation of hayfever, allergies to pet hair or more serious food allergies. A report published by Sense about Science [2] shows that " the percentage of children diagnosed with allergic rhinitis and eczema have both trebled in the last 30 years" and we don't know why.

Allergies occur when the body treats something harmless, such as pollen, as a pathogen. The body mounts an immune response to the 'invader', to try and protect us from it- unfortunately this causes the common allergic symptoms of runny nose & eyes, itching and rashes. In severe cases, the body can go into anaphylaxis, even leading to death if not treated.

Allergies are, at least in part, genetic- children born to allergic parents are much more likely to suffer[3] . But this isn't enough to explain the rise that we are currently seeing. One idea for the cause of this increase is known as the 'hygiene hypothesis.' This suggests that because we now keep our homes and children so clean, they don't come into contact with the number of pathogens our ancestors were used to, so their immune systems are never 'trained' in what to respond to. As a consequence, they are activated too easily in response to things that aren't harmful[4].

Another suggestion is that a change in diet is causing the increase, however the evidence for this is limited. Other environmental factors, such as increases in pollution[5], have also been put forward, as has a link with the use of antibiotics. Determining which of these is true, or if there is another cause entirely, requires further research

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Another way in which the immune system can malfunction is in autoimmune diseases, where the body mistakenly reacts to its own tissues as if they were an invader that needs fighting off. These illnesses can affect the whole body (like in Lupus), or one specific part of it (e.g. Crohn’s disease attacks the gut lining). What causes people develop these diseases isn't known.

Genetic factors play a role, as relatives of those with an auto-immune disease are at higher risk of developing one, but environmental factors are also involved, and are thought to trigger the onset of the disease [6] . In some cases, auto-immune diseases may be triggered by infection, but some researchers think dietary factors or exposure to toxins in the environment can also be to blame. There are other factors, like sunlight, which seem to be protective. Understanding more about the causes of these illnesses may lead to improvements in their treatment, or even to measures which could prevent them.

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© Doktorinternet (own work) (CC BY-SA 4.0) via wikimedia commons
'Butterfly' rash, typically seen in around half of patients with Lupus Image credit: © Doktorinternet (own work) (CC BY-SA 4.0) via wikimedia commons 

Another mystery surrounding autoimmune diseases is why they are so much more common in women than men. In fact, women make up nearly 80 percent of those living with autoimmune diseases. Some autoimmune diseases show much stronger gender bias than others, and the bias seems to be changing in a few diseases, including MS. The severity of the disease is also affected by gender in some illnesses [7] .

One simple explanation could be that it is due to the differences in male and female immune systems- in many animals females have a more reactive immune system which could put them at risk of auto-immune diseases. Human women do produce higher levels of antibodies than men, and a stronger response to vaccinations, supporting this idea, but what mediates this difference isn't known. Some studies have suggested oestrogen has an effect on the cells of the immune system, which could explain why women of childbearing age are most often affected. However, it could equally be that androgens, found in higher levels in men, offer some protection. Differences in the genes of men & women could also play a role.

Alternatively, it may not be the reactivity of the immune system, but the ability of the organs to resist attack by it that causes the gender difference [8]. However research into other areas, such as brain injury, suggest females are better able to resist damage, so it isn't clear why they would be less resistant in this case.

Interestingly, the gender difference in MS is absent when looking at pre-pubescent patients, suggesting that something happens to girls at puberty to put them more at risk [7]. Whether this is a hormonal change or an environmental one is not clear.

Pregnancy could also be linked to the gender difference- the immune system is suppressed by the developing foetus to prevent rejection, and this causes a cascade of changes to the mother’s immune system. Some types of auto-immune disease actually tend to improve during pregnancy, but in others it can trigger the onset of the illness.

Finally, it could be a different in the levels of exposure to environmental influences, like infections or toxins, that makes women more susceptible, or a different response to exposure. All these theories need to be explored further if we are to fully understand these devastating diseases, and why they affect women more than men

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One interesting theory for the rise in both allergies and auto-immune diseases is linked to parasites [9]. Most animals in the world carry parasites- even parasites themselves! But in large portions of the world, finding a human with parasites is relatively rare. Removing parasites is seen to be a step towards improving human health, but it might also cause problems. Some people claim that our lack of internal passengers is to blame for the increase of allergic and auto-immune diseases.

In 2002, a study by Dr. Maria Yazdanbakhs linked an intestinal parasite with protection against allergies. The hypothesis is that our immune systems evolved in tandem with parasites which produced factors to damp it down, in order to avoid being flushed out by the body. Without these factors, our immune systems are on overdrive leading them to respond to harmless invaders like pollen, causing allergies, or even to our own cells, causing auto-immune diseases. Some people think that that infection during childhood is enough to provide these protective effects, even if the infection is later cleared. However evidence to support this claim is inconsistent. Some trials have found that those with the highest parasite load show the lowest level of allergic reactions, while others have suggested infection may actually induce allergies and asthma.

Even if we do find a strong link between parasites and protection against these illnesses, there is still a lot of work to be done. Parasites themselves are a crude tool- it may be that they produce some factors that reduce the immune system’s response but others that stimulate it. Some researchers are trying to isolate the important factors so they can be trialled alone- the idea of taking a pill containing a chemical originally discovered in an intestinal worm is much more appealing to most of us than purposefully infecting ourselves with the worm! Whether this will be possible, however, remains to be seen.

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Jarmoluk (CC0 Public Domain) via Pixabay
Hangover Image credit: Public domain
As well as allergies and auto-immune diseases, there may be another effect of our immune system that causes suffering to a huge number of people- hangovers. Scientists don't fully understand hangovers- while it is known that consuming large amounts of alcohol causes dehydration, low blood sugar and changes in hormone levels the next day, why these should lead to the specific symptoms of a hangover isn't clear.

Now, some scientists are suggesting that it might be our immune system that is to blame. A study found that the day after a binge, the concentration of immune system messengers called cytokines found in the blood increases. If these same molecules are injected into healthy people, they cause hangover-like symptoms. [9]. The theory is that our immune systems try to fight the alcohol in our blood stream, thinking it is an infection, and this is what causes the headaches, nausea and fatigue the following day. It will be a while before we know whether this will lead to an effective treatment for hangovers- for now, drinking plenty of water and taking some painkillers is still the best cure- apart from not drinking of course!

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Animal immune systems

Mikakaptur (CC0 Public Domain) via Pixabay
Dolphin Image credit: Public domain

Not all animals have identical immune systems, but one group of mammals has a mutation that makes it stand out from the others- the toothed whales. Recent research has discovered that these whales have a mutation in the Mx genes, which are responsible for producing virus fighting proteins, meaning they can't produce these proteins[10]. . How they have survived without them is unclear, as the proteins are thought to be vital in fighting off illnesses like HIV and Flu.

Baleen whales share a common ancestor with toothed whales, and they retain functional copies of the Mx genes, which suggests the toothed whales lost the gene since diverging from their common ancestor. The senior investigator on the study that discovered this difference, Gill Bejerano, thinks that the common ancestor may have been exposed to a virus that forced the loss of Mx gene function in order to survive. This is supported by the findings that some viruses today may exploit Mx gene function for individual gain. In order to avoid being wiped out by these viruses, the whales must have evolved compensatory mechanisms, but we don't know what these are. What we do know is it means their immune systems are very different to our own, which could open up fascinating areas of future research.

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This article was written by the Things We Don’t Know editorial team, with contributions from Ellen Moran, Ginny Smith, Johanna Blee, Rowena Fletcher-Wood, and Joshua Fleming.

References
why don’t all references have links?

[1] Erickson, M,H., (1940) The Appearance in Three Generations of an Atypical Pattern of the Sneezing Reflex The Pedagogical Seminary and Journal of Genetic Psychology 56(2):455-459 DOI: 10.1080/08856559.1940.10534512
[2] Sense About Science (2015) Making Sense of Allergies http://senseaboutscience.org/wp-content/uploads/2016/09/Making-Sense-of-Allergies-1.pdf [3] Gough, H., et al., (2015) Allergic multimorbidity of asthma, rhinitis and eczema over 20 years in the German birth cohort MAS Pediatric Allergy and Immunology 26(5):431-437 DOI: 10.1111/pai.12410
[4] Kramer, A., et al., (2013) Maintaining health by balancing microbial exposure and prevention of infection: the hygiene hypothesis versus the hypothesis of early immune challenge Journal of Hospital Infection 83:S29-S34 DOI: 10.1016/S0195-6701(13)60007-9
[5] Penard-Morand, C., et al., (2010) Long-term exposure to close-proximity air pollution and asthma and allergies in urban children European Respiratory Journal 36(1):33-40 DOI: 10.1183/09031936.00116109
[6] Baumgart, D,C., Sandborn, W,J., (2012) Crohn's disease The Lancet 380(9853):1590-1605 DOI: 10.1016/S0140-6736(12)60026-9
[7] Ngoa, S.T., Steyna, F.J. and McCombeb, P.A., (2014) Gender differences in autoimmune disease Frontiers in Neuroendocrinology 3/ 35:347-369 DOI: 10.1016/j.yfrne.2014.04.004
[8] Dai, C., et al., (2014) Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage Current Opinion in Immunology 31:87-96 DOI: 10.1016/j.coi.2014.10.004
[9] Okada, H., et al., (2010) The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update Clinical & Experimental Immunology 160(1):1-9 DOI: 10.1111/j.1365-2249.2010.04139.x
[10] Kim, D., et al., (2003) Effects of alcohol hangover on cytokine production in healthy subjects Alcohol 31(3):167-170 DOI: 10.1016/j.alcohol.2003.09.003
[11] Braun, B., et al., (2015) Mx1 and Mx2 key antiviral proteins are surprisingly lost in toothed whales Proceedings of the National Academy of Sciences 112.26:8036-8040 DOI: 10.1073/pnas.1501844112



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