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Immunology

Allergies make us moody

More than a mere irritation, too much sensitivity to foods may cause anxiety

EDUARDO SANCINETTIOn the morning of July 5 last, a Tuesday, Aline looked at her mother seeking support to face a longstanding fear. At the age of 11, it was the second time in her life she had tasted cow’s milk. She cannot remember the first time, because she was only three months old. Her mother, however, has a bad memory of it. A quarter of an hour after having her bottle, which had been added to Aline’s breast feeding to help her gain weight, she became ill. Red spots appeared on her skin, she developed a hiss in her breathing and her body went limp. Only in hospital did her mother, Roselaine Aragão, discover that Aline was allergic to milk.

With medical recommendation, the bottles of milk were eliminated, but the pediatrician did not warn her that the list of prohibited products included not only milk but milk products as well. Three months later Aline had another allergy crisis after two or three spoonfuls of an infant food that, unbeknown to her mother, also contained cow’s milk. Ever since, the restrictions have been growing. No cookies, no chocolate, no ice-cream. Pizza, only without cheese. And even soap and medication require care, because they can contain milk. Roselaine started reading the package inserts of drugs and the labels of all foods, and to cook with no dairy products whatsoever. At home, not even the cat could have milk because Aline would promptly start itching. “If anybody had pizza or opened a milk carton near me, I got scared, thinking: ‘I’m going to start feeling funny’,” the girl explains. She lives in the town of Mairinque, 70 kilometers away from São Paulo, but since June she has been coming to the state capital every Tuesday for treatment that could change her life.

At the Clínicas Hospital of the University of São Paulo (USP), Aline and a limited number of people – about three a month – undergo a type of therapy known as desensitization, which tries to control the response triggered by the body’s defense system against food components. As with other allergies, the immune system of those who are hypersensitive to some food usually has an exaggerated reaction, with symptoms that range from an uncomfortable itch or a noisy sneezing attack to abdominal pain. Though rarer, there may also be an abrupt drop in blood pressure, causing dizziness or fainting; a narrowing of the respiratory paths, making breathing difficult; and, in extreme cases, the so-called anaphylactic shock, which can be fatal if the person does not get help in time.

During the treatment, conducted under the care of the allergists Fabio Morato Castro and Ariana Campos Yang, both from the Clínicas Hospital, adults and children like Aline are exposed, over the course of weeks, to the food that causes the allergy, an exaggerated reaction of the immune system, which, according to studies by São Paulo and Minas Gerais researchers, activates brain areas connected with anxiety and causes a light inflammation of fatty tissue.

Actually, it has been known for quite a while that allergy to foods is an elaborate natural cleansing mechanism that mobilizes the circulatory, gastrointestinal and respiratory system. However, only recently, as a result of animal studies, has evidence arisen indicating that the central nervous system and the endocrinal system are also involved.

040-046_Alergia_186It was the group of the immunologist Nelson Monteiro Vaz, from the Federal University of Minas Gerais, who in the 1990’s first obtained indications that the brain is affected by allergic reactions and that, in turn, it has an influence on them. Under the guidance of Vaz, immunopathologist Denise Carmona Cara developed an experimental method in which mice were exposed repeatedly to food allergens, as is the case of people who suffer from such allergies. She observed that the allergic crises affected the animals’ behavior.

After making mice sensitive to eggs, she put them in a cage with two types of beverages: pure water or sugar-sweetened water with egg albumin (the protein causing the allergy). Like all rodents, the non-allergic rodents preferred the sweetened water. The allergic ones, however, though they tried water from the two bottles, quickly gave up the sweetened water after the first signs of allergy and started having pure water. This was an indication that, somehow, the activity of the immune system was influencing the animals’ behavior – and causing them to avoid what was bad for them. Denise also managed to induce the same behavior among healthy animals by injecting them with the serum of the allergic mice.

Years later, in a series of behavior tests with mice sensitized by means of Denise’s strategy, the neuroimmunologist Alexandre Basso, then a member of the team of João Palermo Neto at the USP School of Veterinary Medicine , showed that the allergic mice were more anxious than the non-allergic ones. Analyzing the rodents’ brains, Basso found that exposure to egg albumin had activated two brain areas – the hypothalamus and the amigdala – associated with fear and aversion.

What he saw in the nervous system allowed him to explain, in part at least, the results of prior population studies conducted in other countries. These suggested that people with food allergies were more anxious and depressed than non-allergic individuals. However, the connection was incomplete.

Other tests conducted more recently together with the group of Momtchilo Russo, from the USP Institute for Biomedical Sciences, showed that the activation of the hypothalamus and the amigdala is mediated by antibodies. These components of the immune system, by activating the mast cells that lie near the nerves, cause information about the organism’s defense to reach the brain. “We showed that this behavioral change is a physiological response that enables the animal to react quickly to early signs of allergy and to avoid food that is bad for it,” explains Russo. Once activated, the brain sends orders to the circulatory, gastrointestinal, respiratory and immune systems to control the allergic reactions. “It’s an integrated response,” he adds.

Still, the brain can easily be fooled. Allergic animals are capable of stuffing themselves with egg albumin, provided it is offered in a palatable form. For mice, this means lots of sugar. Luciana Mirotti, a member of Russo’s team, sweetened the water with egg albumin more heavily and observed that the rodents consumed an amount of the allergen equal to their own weight over 24 hours. “The sugar must activate a reward mechanism in the nervous system that allows the animal to withstand the discomfort of the allergy,” says Luciana. This unnatural behavior helps one to understand why sometimes humans continue to consume a food that is bad for them, even when the body is sending them signals to avoid it.

art4485img2EDUARDO SANCINETTIAlmost two decades after perceiving the behavior changes induced by the allergy, Denise, now with the student Luana Dourado, identified a new phenomenon. In a paper published this year in Cellular Immunology, these researchers showed that prolonged exposure to the food allergens causes a light inflammation of the adipose tissue, similar to what happens to the obese. “We haven’t yet found out whether this inflammation is temporary,” Denise tells us. “If it disappears quickly, it might help the body to get rid of whatever is causing the allergy. However if it persists, it might change the metabolism of fat.”

High risk
As there are no allergy curing drugs – medication can only control the symptoms – the solution for the serious cases is to desensitize the organism. This forces it, little by little, to adapt to the compounds, generally proteins, that it recognizes at first as something alien to the body and potentially noxious, even when these compounds are within foodstuffs. When the desensitizing works – and it has worked in almost all cases treated at the Clínicas hospital – the body stops fighting these compounds and the person is then able to coexist peacefully with moderate portions of the food.

However, the procedure is risky and requires monitoring by a physician. “We only do it in cases in which the risk of the person having accidental contact with the food and dying is greater than the risk of having an allergic reaction during the treatment,” states Ariana, the coordinator of the USP Food Allergy Ambulatory Clinic, where the treatment is conducted on an experimental basis, even though it is available in American, European and Brazilian clinics.

Therefore, before beginning the treatment, which takes two to three months, the physicians investigate by means of skin tests and blood tests the maximum concentration of a given foodstuff – the most common ones are milk, eggs, wheat and soy – that the organism is likely to come into contact with without unleashing an allergic reaction. They then dilute it further. The daily doses of the solution only start being ingested after an antiallergic drug has been taken, to further reduce the risk of an immune system reaction.

Aline began her desensitizing treatment in June, having milk drops in water that was still transparent, as the solution was diluted. One month later, she was already having pure milk, though only in minute amounts: just two drops (0.1 milliliter) that her mother put in her mouth every hour with a syringe. As the body’s tolerance increases, the doses become more concentrated until the end of the sensitizing procedure, dubbed D-day, when the person should be able to consume a medium-sized portion of the food. Aline’s target is to get to 150 ml of milk (almost a glass) in two months, without getting ill, and to therefore enjoy a less troubled life. Thereafter, however, she will have to consume milk on a regular basis to make sure the allergy does not come back. “No, she isn?t afraid any longer when I prepare her milk, nor is she afraid of children that are running around holding a glass of milk during the school break,” Roselaine tells us.

More common among children, food allergies affect a larger portion of the adult population than previously imagined. The data are scarce, but surveys in the United States and in Europe suggest that the world is becoming more allergic. In a little more than one decade, the proportion of adults with food allergies rose from 1% to 2% and then to the current 4%. Among children, who are more inclined to allergies, the rate varies between 8% and 11%. However, the most common types of allergy, i.e., the respiratory ones, affect 30% of the population.

EDUARDO SANCINETTIA study on 38.4 thousand American children published in July in the journal Pediatrics showed that 8% of them were allergic to a food and that, among the allergic children, 39% had already experienced severe reactions. Though children are the most frequent victims, it is the parents that complain about the deterioration of the quality of life. In England, researchers from the University of Nottingham and the University of Derby have compared the quality of life of families with children with food allergies to those that have allergy-free children. Evaluated with questionnaires, the quality of life of the children in the two groups was essentially the same. However the restrictions imposed upon the allergic children affected the parents? day-to-day life, in particular when it came to social relations, according to the research, soon to be published in Appetite. “These children’s parents live with the imminent feeling that they can lose control over their child’s health,” Ariana tells us. “And the fear increases when the children start school, because the capacity to refuse food will then depend on the child’s level of maturity.”

One of the difficulties in dealing with food allergies, according to experts, is its unpredictability. Although the allergies mostly do not lead to problems more severe than passing discomfort, the sensitivity level can vary widely so that it is not always possible to forecast it with blood tests or skin reaction tests. The sensitivity depends on three factors: the characteristics of the individual’sdefense system; the properties of the allergen; and the frequency and means of exposure to it. These factors vary a great deal and independently, which is why those who produce a high number of antibodies against the allergen of a food may not be those with the most severe clinical reactions when consuming it. For the same reason, a history of light allergic reactions (spots on the skin and itching) does not guarantee that something more serious will not happen.

Year ago, Richard Pumphrey, from the Royal British Infirmary, tracked deaths from food allergies in the United Kingdom from 1999 to 2006 and found that more than half of the people who died after eating the food to which they were allergic had never had severe reactions previously. Perhaps for this reason, Pumphrey suggests, their doctors had not recommended that they carry an adrenalin applicator. “As one doesn’t know ahead of time how strong a reaction each person will have, we treat all of them as severe cases,” Ariana says.

Only eight foods account for almost 90% of allergy cases. Cow’s milk tops the list, followed by fish, other seafood, eggs, peanuts, nuts, wheat and soy. It is estimated that 2.5% of children are allergic to milk and that 1% of them are allergic to eggs, problems that tend to disappear naturally by the age of five. As for allergies to shrimp, shellfish, sardines, peanuts and various kinds of nuts, they tend to arise later and often last for a lifetime.

Furthermore, there is talk about an increase of allergy to foods that in the past seemed harmless: carrots, peaches, apples, pears and kiwifruit. The most surprising and unexpected case may be that of an allergy to manioc, which, whether boiled or cooked, is a source of carbohydrates for more than 800 million people in South America, Africa and Asia. Domesticated thousands of years ago, possibly by South-American natives, manioc is an ingredient in various processed foods because it leaves no strong flavor or taste and, until recently, was considered low in allergenics. All of this, however, will have to be reviewed.

art4485img4EDUARDO SANCINETTIIn 2004, Castro’s team described two Brazilian cases of allergy to manioc that are among the first to be identified in the world. At the Occupational Allergy Ambulatory Clinic at the Clinicas Hospital, the physician Clóvis Galvão, in just over a month, attended to two women with sensitivity to latex that were complaining that they had had an allergic crisis after eating manioc. Galvão took these cases to Castro, the coordinator of the allergy group of the Immunology Investigation Group, headed by the immunologist Jorge Kalil, for them to start, jointly, a more detailed investigation of the issue.

Immunological tests confirmed that the organism of those who had an allergy to latex, common among physicians, nurses and cleaning staff, produced antibodies that could recognize the manioc allergens. This is an example of crossed allergy, but it was still necessary to identify which allergens and how many of them were involved. Using antibodies from the blood of the first patients and from nine further cases recorded since, the immunologist Keity Santos identified five proteins capable of causing allergies. She then isolated and characterized one of them. During a period she spent at the Laboratory of Diagnosis and Treatment of Allergy at the University of Salzburg in Austria, coordinated by the Brazilian scientist Fátima Ferreira, she synthesized this protein and showed, in in vitro tests, that it was rendered inactive by the antibodies produced against the latex proteins.

This protein – Man e 5, a name formed from the scientific name of manioc (Manihot esculenta) – has a similar structure to that of one of the 14 allergens of latex, produced from the rubber tree sap. This was described by the researchers in an article soon to be published in the Journal of Allergy and Clinical Immunology. “Now that we know that these manioc proteins cause allergies, Keity can try to develop a way of detecting them or destroying them, making it possible to produce allergen-free starch,” says Fátima, who in recent years has described allergic reactions to apples, walnuts, hazelnuts, celery and carrots in people who are sensitive to the pollen of the birch tree, which is common in Europe.

Two hypotheses try to explain the growth of food allergies. The first is easy access to exotic foods. It has never been as easy and as fast to travel from one point of the world to another, which has certainly contributed to the internationalization of diets previously limited to a few regions. The time it took for these changes to occur, however, may have been insufficient for the human body, used to eating a limited variety of foods for hundreds of thousands of years, to adapt to the new allergens.

The second hypothesis proposes that, underlying this hypersensitivity, there might be some forms of interference of the human being with his own body – more specifically, with his digestion. The main doorway for human contact with the external world is not the skin, as many people may think, but the intestines. If the skin were detached from the body and opened over a flat surface, it would cover no more than a mere two square meters, whereas the intestines would cover an area 200 times larger, more or less two tennis courts. It is largely through the intestines that elements that are alien to the organism gain access to the body. As soon as they go through the delicate intestinal membrane, the components of foods and the infectious agents run into an army of immune system cells, ready to recognize what is part of the organism and can be incorporated into it and what is alien and must therefore be eliminated.

Along the path from the mouth to the blood, food is crushed, mashed and gets a bath of acids and digestive salts, while also undergoing an enzyme attack. What is left is so small that it mostly escapes the radar of the immune system. The proteins, which at first may contain 200 or more amino acids, are disassembled into sequences of only half a dozen or so. However, if something in the digestion is not performing properly, bigger fragments can get to the blood and draw the attention of a special group of defense cells that, in turn, mobilize toxins and antibody producing cells.

Stuck on the membrane of the mast cells, which are crucial for allergic reactions, antibodies work like the trigger of a gun, ready to shoot. As soon as the antibodies come into contact with the alien protein again, the mast cells release powerful compounds (histamine, heparin, leukotriene and others) that cause blood vessels to dilate, blood pressure to drop and the smooth muscles of the respiratory pathways to contract. Four to six hours later, cells recruited from within the bones get to the area and start a new attack, helping to eliminate the external agents but reviving the allergy symptoms.

A recently completed study by Castro’s group strengthens the notion that among adults, the food allergy increase is tied to a loss of the capacity to digest proteins, caused by the disseminated use of medication of the omeprazole class, the so-called proton pump inhibitors.

In Salzburg, Keity submitted the allergenic manioc proteins to digestion in a solution with normal stomach acidity and in another one, 100 times less acid, such as that found in the stomach of people who use medication for inflammation and gastric ulcers. In the first case, the digestive enzymes broke down the proteins into pieces that were small enough to be absorbed by the intestines and to circulate in the blood without activating the defense cells. However, in the less acid solution, the protein was not digested properly and there were fragments left over that were large enough to unleash an allergic reaction.

“Manioc has been consumed for thousands of years and there has never been any suspicion that it caused allergy,” says Castro. “‘What could have changed recently?” The most perceptible change pointed out by some researchers is the proton pump inhibitors, introduced in the late 1980’s and now among the world’s best selling drugs.

To test whether this might explain the rise of allergies to manioc, the physicist Hyun Mo Yang, from the State University of Campinas, developed for Castro a mathematical model that allows one to estimate how long it would take for the first cases to appear among a population that used the medicine. The result? About 10 years. “This is almost the amount of time that has elapsed since the introduction of omeprazole in Brazil and the identification of the earliest cases,” Castro comments, who created, in 2008, the Group of Studies of New Regional Allergens, to investigate the allergenic proteins in Brazilian plants and insects.

“We still have no clear explanations for what we’re seeing at the clinic,” says Jorge Kalil, who, in addition to his work at the Institute of Immunology Research, also heads the Laboratory of Immunology of the Instituto do Coração, heart institute, and the Butantan Institute. “Allergy induction might be an unforeseen effect of this kind of drug.” If it is confirmed in connection with manioc, this effect might explain what happens with some of the other 475 allergenic proteins found in food that, along with another almost one thousand, are being catalogued by the bioinformatician Helen Arcuri from Allergennet, an online data base that brings together information on the characteristics of these proteins, the clinical symptoms that they cause and the tests that detect them.

Until there is any new information, the only solution is to stay away from foods that might unleash an allergy and to try, as appropriate, to desensitize patients such as Aline, who, actually, has drawn up a list of what she wants to try when she becomes free to consume milk. Cookies, cake, brigadeiro, a chocolate sweet, ice-cream and pizza. This time, with a lot of cheese on it.

The project
Institute for Investigation in Immunology (nº 2008/57881); Type Thematic Project/INCT; Coordinator Jorge Kalil – FM/USP; Investment R$ 2,909,938.18 (FAPESP) R$ 3,554,319.49 (CNPq)

Scientific articles
SANTOS, K.S. et al. Allergic reactions to manioc (Manihot esculenta Crantz): Identification of novel allergens with potential involvement in latex-fruit syndrome. Journal of Allergy and Clinical Immunology. Forthcoming.
MIROTTI, L. et al. Neural pathways in allergic inflammation. Journal of Allergy. Feb. 9, 2011.

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