Over the past few decades, the prevalence of immune-related diseases, including allergies and asthma, has gradually increased. Increasing evidence suggests that environmental influences play a decisive role in shaping early immune maturation, including host responses to allergens. Therefore, increases in immune-related diseases are thought to be influenced by adverse environmental changes, including increases in harmful exposures and losses in protective exposures associated with advances in Western/industrialized/urban-related lifestyles. Rapid changes in lifestyle and environment challenge the regulatory capacity of the healthy human immune system to some extent, prompting increasing attention to the identification and evaluation of harmful and protective factors.
This review summarizes current knowledge on environmental factors with deleterious or protective effects and their different exposure pathways. In addition, a brief overview of recent findings on the interaction of environmental factors with innate and adaptive components of the immune system from in vivo studies is provided, with examples for one protective and one deleterious environmental factor.
route of exposure
The human organism is constantly exposed to various biological, chemical and physical influences from the external environment.
Conceptually, the cumulative lifetime environmental exposures and associated physiological responses are known as the human exposome that affects health, behavior, and physiology. In humans, several efficient barrier organs mediate responses to environmental exposures that enter primarily through the skin, mucosal tissues, and inhalation. Importantly, the microbiota participates in the imprinting of local immune compartments early in life, thereby promoting immune tolerance to antigens and wound healing.
skin exposure
The multiple layers and mechanical barriers of the skin control the penetration of environmental substances, thereby protecting the organism from exposure-related effects. Physical defense mechanisms, including the functional integrity of the barrier formed by hair follicles, skin glands, and blood vessels, prevent external factors from entering and affecting the body. The outermost barrier that borders the external environment, the stratum corneum, is composed of differentiated keratinocytes with tight junctions that perform first defense innate immune functions. In addition, innate and adaptive immune cells, including dermal and epidermal dendritic cells, macrophages, lymphocytes, mast cells, and complement factors, are involved in the immune response of the skin. However, absorption of skin-penetrating substances through an intact and functional dermal-epithelial barrier is possible.
Mucosal tissue exposure
Mucosal surface integrity and mucus secretion in the eyes and nose, upper respiratory tract, gastrointestinal tract (GIT), and genitourinary tract are critical to prevent diffusion and mediate elimination of invading contaminants. Dysfunctional mucosal epithelial barriers are related to antigen invasion, epithelial cell inflammation and activation, and allergic reactions leading to allergic diseases.
The gastrointestinal tract, which is exposed to the external environment through particles ingested through diet, inhalation, or other interventions, exhibits a barrier formed by tight junctional epithelial cells, lined with mucus and microbiota. However, exposure to harmful factors mediates intestinal barrier defects, leading to microbial epithelial translocation and triggering an inflammatory immune response. Mucosal tissue is further exposed to inhaled particulate matter, and substances circulating in the air are knocked by the nasal hairs and cilia in the nasal cavity to prevent deeper penetration into the trachea. Mucus secreted by goblet cells and the hair-like cilia lining the trachea and bronchi trap foreign objects and push them outward through continuous ciliary movement. Despite these efficient mechanisms, particulate matter (PM10) with a diameter of ≤10 microns reaches the upper respiratory tract, and ultrafine particles (PM0.1) can even penetrate deep into the lungs, affect alveoli and local microbiota, penetrate the lungs and cross the lung epithelial barrier and enters the systemic blood circulation. The extent of inhalation exposure depends on the size and penetration ability of the inhaled material, indoor and outdoor air quality, and initial organ damage.
Environmental factors with immune response potential
Environmental exposures that affect human organisms include small particles and chemical residues, physical impacts, microorganisms, geographic location, and lifestyle choices.
Depending on the duration, extent, and dose of exposure, environmental factors can trigger immune-enhancing or immunosuppressive responses. Importantly, environmental exposures accumulate throughout a person's life and may result in delayed reactions. Importantly, there is evidence that combinations of environmental impacts, such as wood smoke and diesel particles, will act in an additive or synergistic manner. For the sake of brevity, we review here the immune response effects of single environmental factors and will not discuss the effects of combinations of environmental influences.
Some environmental factors have beneficial effects on immune initiation and function as well as disease prevention, such as plant-based bioaerosols and dust. Specifically, farm-related exposures induce anti-inflammatory immune responses, mitigate allergic and autoimmune responses, and may reduce the risk of autoimmune diseases if they occur prenatally or early in life. Other naturally occurring bioactive compounds with beneficial immunomodulatory properties include polyphenols, which are subdivided into flavonoids and non-flavonoids and have shown anti-neuroinflammatory potential and reduce symptoms of inflammation-related depression.
In contrast, air pollutants such as PM (a complex air suspension composed of solid and liquid, organic and inorganic particles) and nanoparticles (environmental pollutants of small size (1-100 nm)) are immune Negative effects on activity and functionality. In mice, chronic ultrafine suspended particulate matter (PM2.5), diesel engine exhaust particles, and engineered nanoparticles induced systemic and neuroinflammatory immune responses. In humans, maternal exposure to traffic-related air pollutants, such as nitrogen oxides, PM, and ozone (O3), is associated with elevated levels of inflammatory cytokines in newborns and impairs immune system development and postpartum immune function. Other immunoreactive airborne agents potentially inflammatory include cigarette smoke, organic agricultural dust, and microplastics. Chemicals detected in human serum, namely polyfluoroalkyl substances and perfluoroalkyl substances (PFAS), have been associated with impaired vaccine-induced antibody responses. However, the authors of a recent review article on immunomodulatory effects of PFAS and exposure concluded that more evidence is needed due to inconsistent results on the immunomodulatory effects of PFAS exposure. Additionally, prenatal exposure to phthalates, which are endocrine disruptors, is associated with male reproductive impairment in mice. Few clinical studies have shown that phthalate metabolites can cross the placental barrier and subsequently impair genital development in human male fetuses. Additionally, exposure to environmental phthalates in children has been associated with allergic symptoms such as atopic dermatitis, asthma, and allergic rhinitis. Chemical exposure also affects microbiota that are critical for intact host immune function. In children, chemical exposure is associated with alterations in microbiota development early in life, potentially favoring changes in immune function and associated diseases later in life, such as asthma. Overall, environmental exposures are particularly important during vulnerable developmental periods, and in utero or in the newborn, environmental exposures can alter immune maturation, function, and development.
Effects of environmental factors on innate and adaptive immune responses
Due to the variability of environmental factors, the following paragraphs are intended to focus, by way of example, on one of each of the protective and deleterious factors of asthma and allergic disease. Regarding protection, multiple epidemiological studies around the world have shown that children raised on farms have significantly reduced prevalence of asthma and allergic diseases, a phenomenon known as the “protective farm effect.” Among these, contact with livestock and feed, consumption of raw milk and microbial diversity are crucial. Environmentally mediated protection against allergy and asthma was robust among Amish children compared with Hutterite children (asthma prevalence 5.2% and 21.3%, respectively). Despite similar geographical and genetic backgrounds, the two groups differ in their agricultural lifestyles, with the Amish practicing traditional agriculture and the Hutterites employing highly industrialized practices. The protective capacity of these rural agricultural environments has been linked to multiple immune components. Regarding the innate part of the immune system, farm exposure is associated with changes in the functional properties of dendritic cells (DCs), the cells that are first exposed to environmental factors and thus influence T cell responses. Immunomodulatory effects by reducing the proportion of myeloid dendritic cells (mDCs) associated with an agricultural lifestyle are consistent with significantly elevated expression of pathogen-sensing innate immune receptors, such as Toll-like receptors (TLR) 2, TLR7 , TLR8 and differentiation clusters.
Additionally, gene-environment interaction of the single nucleotide polymorphism rs2230626 in the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene may be associated with protective effects against asthma and allergy in children raised in farm-related environments. Regarding the adaptive branch of the immune system, farm children had reduced lymphocyte proliferation and a positive correlation between early (in utero) exposure to an agricultural lifestyle and regulatory T lymphocyte (Treg) numbers and Treg function. However, immune switching resulted in lower Treg levels in school-age farm children, suggesting the existence of a critical window in early healthy immune maturation, both in terms of flexibility and variability, and in immune timing. Furthermore, farm exposure was associated with a T helper lymphocyte (TH)1-dominated cytokine profile, with elevated levels of interleukin (IL)-12, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) , while reducing levels of the TH2 cytokine IL-5.
Therefore, the rapid increase in the prevalence of asthma in recent decades may be partly due to the increasing dominance of urban lifestyles and the increasing trend of exposure to harmful environmental factors that may play a causal role in the development of the disease, resulting in a lack of Protective environment associated with the farm. Epidemiological data released by the World Health Organization (WHO) in a 2018 update indicate that 90% of people are exposed to air containing high concentrations of indoor and outdoor pollutants. Additionally, more than 80% of urban residents breathe air with levels of pollutants that exceed World Health Organization guidelines. Therefore, increased asthma risk in children may be related to prenatal harmful environmental exposures, namely cigarette smoke, accompanied by an impaired TH1 response toward a TH2 dominant phenotype and increased pro-inflammatory conditions (secretion of IL17A, IL-8, IL-1). 6. TNF-α). However, some believe there is a causal link between asthma and air pollution (not just cigarette smoke). Regarding the innate branch of the immune system, plasmacytoid dendritic cell (pDC) numbers increased and mDC and natural killer (NK) cell numbers decreased after in utero exposure to air pollution.
Furthermore, in a human study of 118 healthy asthmatic patients, PM10 and PM2.5 exposure was positively associated with innate lymphocyte type 2 (ILC2) frequency, cells that function similarly to asthma- and allergy-mediated TH2 lymphocytes. Furthermore, PM10 exposure in patients with severe asthma was associated with increased frequency of ILC2 compared with patients with mild asthma, and PM10 exposure acts in a rather chronic manner, as ILC2 levels are highly correlated with exposure levels. This correlation between PM2.5 and patients with severe asthma cannot be described. ILC1 cells were shown to be associated with O3, NO2, and carbon monoxide (CO) exposure, but not PM. Concerning the adaptive branch of the immune system, recent publications describe, albeit contradictory, disturbances in lymphocyte distribution following in utero exposure to air pollutants, including PM2.5, PM10, NO2 or SO2. Martins Costa Gomes and colleagues described a decrease in the number of CD4+ and an increase in the number of CD8+ cells after exposure to SO2, while Garcia-Serna and colleagues reported a decrease in the number of CD8+ T cells, a decrease in the number of Treg cells, and an increase in the number of TH1 cells. Exposure to PM during pregnancy. Additionally, exposure to traffic-related air pollution (TRAP; a mixture of NO2, PM2.5, PM10, O3) during pregnancy has also been shown to increase pro-inflammatory (IL-1β and IL-6), TH2-related (IL- 13) and immunoregulatory (IL-10) cytokines in neonatal offspring. In contrast, Hahn and colleagues found that the production of IL-6, TNF-α, and IL-10 in cord blood mononuclear cells (CBMC) of children born to mothers exposed to higher levels of PM2.5 during pregnancy reduce. In addition to the in vivo data, which is the focus of this review, Deckers et al. and Krusher et al. Recent findings on mechanisms that protect against asthma and allergy are described, including mouse and in vitro studies.
in conclusion
Various environmental factors, classified as protective or deleterious, interact with the innate and adaptive parts of the human immune system and its functions through different exposure pathways to modulate its function. Here, early life represents a critical window of opportunity, but also vulnerabilities that influence the subsequent development of the child's immune system. Prenatal and postnatal environmental exposures shape the still developing immune system by modulating innate and adaptive cell differentiation, (im)balancing T cell responses, and modulating cytokine secretion. However, the exact cellular mechanisms by which these harmful or protective environmental factors contribute to disease prevention and/or disease exacerbation, including asthma and allergic diseases, still require further investigation. This is critical for future prevention strategies and effective consultation with governments and authorities.
