Abstract

During the last decades, the world has witnessed a dramatic increase in allergy prevalence. Epidemiological evidence shows that growing up on a farm is a protective factor, which is partly explained by the consumption of raw cow’s milk. Indeed, recent studies show inverse associations between raw cow’s milk consumption in early life and asthma, hay fever, and rhinitis. A similar association of raw cow’s milk consumption with respiratory tract infections is recently found. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections. However, for ethical reasons, it is not possible to conduct controlled studies with raw cow’s milk in infants, so formal proof is lacking to date. Because viral respiratory tract infections and aeroallergen exposure in children may be causally linked to the development of asthma, it is of interest to investigate whether cow’s milk components can modulate human immune function in the respiratory tract and via which mechanisms. Inhaled allergens and viruses trigger local immune responses in the upper airways in both nasal and oral lymphoid tissue. The components present in raw cow’s milk are able to promote a local microenvironment in which mucosal immune responses are modified and the epithelial barrier is enforced. In addition, such responses may also be triggered in the gut after exposure to allergens and viruses in the nasal cavity that become available in the GI tract after swallowing. However, these immune cells that come into contact with cow’s milk components in the gut must recirculate into the blood and home to the (upper and lower) respiratory tract to regulate immune responses locally. Expression of the tissue homing-associated markers α4β7 and CCR9 or CCR10 on lymphocytes can be influenced by vitamin A and vitamin D3, respectively. Since both vitamins are present in milk, we speculate that raw milk may influence homing of lymphocytes to the upper respiratory tract. This review focuses on potential mechanisms via which cow’s milk or its components can influence immune function in the intestine and the upper respiratory tract. Unraveling these complex mechanisms may contribute to the development of novel dietary approaches in allergy and asthma prevention.

Introduction

In the Western world, the prevalence of chronic inflammatory diseases, including allergies, has increased dramatically in the last few decades, while the number of serious infectious diseases has declined rapidly (1). An inverse correlation, indicating a “protective effect” of infectious diseases against chronic inflammatory diseases (e.g., allergy and asthma), was postulated in 1989 by Strachan, who formulated the hygiene hypothesis (2). The hygiene hypothesis suggests that the exposure to viruses and bacteria is essential to induce a T-helper (Th)1 response, which balances the immune system and protects against Th2-mediated diseases. With the discovery of additional T cell subsets such as Th17 cells and regulatory T cells (Tregs), this paradigm had to be revised. For example, it was demonstrated that suppressive dendritic cells (DCs) induced by helminths restored the disturbed Th1/Th2 balance by induction of Tregs (3). The immune education of DCs was suggested to be an important step toward understanding the complex relation between infectious diseases and allergies (4). Th2 responses are now known to be enhanced by the production of type 2 cytokines (e.g., TSLP, IL-25, IL-33) secreted by group 2 innate lymphoid cells and epithelial cells (5, 6). Thus, different cell types are responsible for Th2-mediated diseases such as allergies. Allergy is initiated as an aberrant immune response towards a harmless antigen (allergen). Via activation of Th2 cells, the allergen triggers the production of allergen-specific IgE by B cells that binds to high-affinity FcεR1 on effector cells like mast cells and basophils. Effector cells release soluble factors (e.g. histamine) upon secondary exposure to the allergen that cause immediate type I allergic symptoms. The term “atopic march” refers to the sequence of IgE responses and clinical symptoms initiated in early life (7).

Food allergy (FA) is a public health issue gaining worldwide attention [1–9]. While the overall prevalence of food allergy has been estimated to be approximately 7%, only 3–4% of adults and 5–6% of children have received a physician-confirmed food allergy diagnosis [10–12]. A metaanalysis published in 2007 suggested that the prevalence of food allergy ranges from 3 to 35%, and one Australian study suggested that more than 10% of 1  year olds had a challenge-proven egg allergy [1, 13]. This wide range is a reflection of the varying definition of food allergy (i.e. self-report versus a requirement for symptoms compatible with an IgE-mediated reaction and confirmatory testing), non-reporting of incidents, and respondent bias [1, 14]. Studies suggest that food allergens are the primary cause of anaphylaxis [15–19]. There are about 7% of Canadians with food allergies—among all Canadian children, 1.7% specifically have peanut allergies [14], of which 90% have experienced a severe reaction [14]. A number of US studies have suggested that the incidence of anaphylaxis is increasing and is perhaps as high as 49.8 per 100,000 person-years [15, 20–24]. Additionally, within the last decade, US hospitalizations secondary to food-induced anaphylaxis increased by 350% [25]. Similarly, a study by Ben-Shoshan et  al. has revealed that in at least one emergency department in Quebec, Canada, the rate of emergency department visits for anaphylaxis doubled over a 4 year period [26]. There is no cure for food allergy and, thus, strict avoidance of allergenic foods is paramount in symptom prevention [7]. Food allergen labeling is an internationally recognized risk management tool and regulatory policies are being developed to lower food allergen exposure risk for individuals with food allergies [7]. In 2008, the Canadian Minister of Health announced new labeling requirements for food allergens and intolerances contained in pre-packaged foods. A regulatory update was released in August 2012 noting the requirement to list all food allergens, gluten sources, and sulphites in the ingredient lists or in a precautionary statement [27]. Despite the increasing public health concern surrounding food allergies and the recent update in Canadian food allergen labeling regulations, there is scarce information regarding the best way to present allergen information to consumers [28]. Knowledge about consumers’ use of allergen labels may inform regulatory agencies about the appropriate packaging of foods and design of food labels to reduce risk of exposure to food allergens [29–33]. The objective of this study was to use a stated choice experiment to evaluate Canadians’ preferences for different types of food allergen-related information on food labels, and to determine if there are differences in preferences across different types of respondents.

The American Academy of Sleep Medicine recommends that adults sleep 7 to 8 hours for optimal health and performance1 ; however, only 65% of adults in the United States adhere to this recommendation, with an even lower prevalence of 54% among African Americans.2 Caregivers tend to have shorter sleep duration, poorer sleep quality, and a higher prevalence of sleep disturbances compared with noncaregivers.3–7 Short sleep duration and disturbed sleep are associated with mood, accidents, and negative health outcomes including obesity, hypertension, diabetes, cardiovascular disease, and all-cause mortality.8,9 It is important to identify the factors contributing to poor sleep among caregivers to improve their quality of life. Caring for a child with asthma or a chronic illness is associated with a higher exposure to psychosocial stressors (depression) and poor health,10,11 which is associated with poor sleep.12–14 To our knowledge, few studies have specifically focused on the sleep of caregivers of children with asthma.6,15,16 Caregivers of children with chronic illnesses such as asthma may have disturbed sleep due to nocturnal caregiving or stress due to the challenges of caregiving,6,15,16 which may be influenced by stressors that are due to socioeconomic status (SES).17,18 However, these factors are understudied. Another limitation of this literature is that the vast majority of the prior studies were conducted among non-Hispanic White populations.6,15 Associations may be different in African Americans given the high prevalence of poor sleep,19 the greater exposure to psychosocial stressors, and the likelihood of living in low-socioeconomic environments.12,19–23 Prior studies have shown that psychosocial stressors and neighborhood factors contribute to poor sleep, particularly among African Americans.12,22,24 For example, in a study of African American adults, participants with higher stress slept on average 33 minutes less than those reporting less stress.12 The prior study focused on general stressors, as opposed to understanding the influence of specific stressors such as anxiety, worry, or depressive symptoms. Additionally, asthma is a highly prevalent condition among African American children, with striking racial disparities in morbidity and mortality.25 As a result of the higher prevalence of asthma among African American children,26 psychosocial factors may be particularly pertinent to African American caregivers and may help to identify a population that may be at increased risk for poor sleep.