Over the past several decades, many countries around the world have experienced rapid industrialization, leading to increased living standards and improved hygienic measures. While these all seem like positive changes for a society, researchers are finding that these trends have been accompanied by an increase in the prevalence of allergies and autoimmune diseases. Researchers propose that one possible explanation for this phenomenon is the hygiene hypothesis (1).
The hygiene hypothesis argues that increases in living standards and improved hygienic measures have reduced exposure to microorganisms, therefore reducing infection rates in industrialized nations. This decrease in microbial exposure has an adverse effect on the development of the immune system, and can lead to an increase in the prevalence of allergies and autoimmune diseases. What is the mechanism underlying this phenomenon? The answer is complicated, involving maternal-fetal immune interactions in utero, stimulation of the naïve immune system during infancy and how that stimulation (or lack thereof) influences immune responses throughout life.
Before diving into the complex interactions at the fetal-maternal interface (termed decidua) and their implications for immune system development, we must briefly review one important topic: cell mediated immunity and humoral immunity.
Cell-Mediated Immunity vs. Humoral Immunity
Generally speaking, the immune system is a balance between cell mediated (Th1 cell) immunity and humoral (Th2 cell) immunity, also known as the Th1/Th2 paradigm. Cell-mediated (Th1) responses are responsible for the clearing of intracellular pathogens and are generally considered pro-inflammatory responses. Th1 cell responses are characterized by production of the cytokines interleukin-2 (IL-2) and interferon gamma (IFNγ). Humoral (Th2) responses are responsible for the clearing of extracellular pathogens and requires the production of antigen-specific antibodies by B lymphocytes. Th2 responses are generally considered anti-inflammatory and are characterized by the production of IL-4, IL-5, IL-13, and IL-10. Interestingly, both Th1 and Th2 cells produce signaling molecules (IFNγ and IL-10 respectively) that upregulate the differentiation of their cell type while simultaneously suppressing differentiation of the other subtype (2). Maintaining a balance in the Th1 and Th2 paradigm is crucial for healthy immune responses. A Th1 weighted imbalance is associated with chronic inflammation (for instance, diseases like rheumatoid arthritis are considered a Th1 imbalance) which can lead to tissue damage while a Th2 weighted imbalance is associated with hypersensitivity reactions and allergies.
This is a gross oversimplification of T cell biology as ongoing research has revealed several other subsets that play important pathological roles in mediating immune responses. This simple explanation is sufficient for our purposes, however, a more in-depth review of these T-cell types can be found in our previous post or in previously published reviews (3).
Pregnancy and the Th1/Th2 Paradigm
Pregnancy presents an interesting problem for the maternal immune system. By nature of sexual reproduction, 50% of fetal DNA is derived from an allogenic source (the father) and therefore can provide a potent stimulator of the mother’s immune system. For all intents and purposes, the fetus is an allograft that the maternal immune system must tolerate for nine months until birth. This tolerance requires a drastic shift in normal immune responses in order for the fetus to be carried to term.
During a successful pregnancy, the maternal immune system becomes highly Th2 dominant as evidenced by pregnant rheumatoid arthritis (a Th1 mediated disease) patients experiencing remission (4) and the increased susceptibility to intracellular infections during pregnancy (5). This shift in favor of humoral immunity is vital for protecting the fetus during pregnancy, as a shift towards cell mediated (Th1) immunity increases the risk of spontaneous abortion (6). This bias towards Th2 immunity extends beyond fetal life, resulting in a Th2 bias in neonate immune systems (7). After birth, the neonate immune system has its first direct contact with the external environment and foreign antigens. These interactions lay the foundation for immune responses to common antigens throughout their lifetime.
In infants, both atopic and non-atopic individuals have been shown to express a slightly Th2 biased (due to deficiencies in IFNγ production) response to aeroallergens (8). As infants age, non-atopic individuals have a down-regulation of this Th2 response to aeroallergens while atopic individuals consolidate these Th2 responses to memory T cells that are responsible for the hypersensitivity reactions later in life (9). In response to inhaled allergens (house dust mite, pet dander, pollen, etc.), atopic adults express a cytokine profile more closely resembling Th2 (humoral) immunity while non-atopic individuals express a cytokine profile more closely resembling Th1 (cell-mediated) immunity (9).
Education of Neonatal Immune System
What causes the Th2 bias exhibited in utero and during infancy to consolidate into memory T cells that cause hypersensitivity reactions in atopic adults? The underlying mechanisms are nuanced and not fully understood, but it seems that stimulation of the neonate immune system by bacterial components and parasites has a protective role against allergy development (10-14). Chronic stimulation of the naïve immune system by bacterial components, notably stimulation by Mycobacterium tuberculosis (14) and activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (10), plays a role in the development of Th1 cells and production of their associated cytokines. Without stimluation by antigens that can evoke a Th1 response, the neonate immune system remains biased towards Th2 immunity. Therefore, if an infant is chronically exposed to aeroallergens before significant Th1 cell activity has been stimulated by microbial components, it would seem that their immune system can only respond with Th2 mediated immune responses. If there continues to be a lack of microbial stimulation that develops Th1 responses during a person’s formative years, then it is plausible that the Th2 responses to common aeroallergens will consolidate to memory T cells, priming the individual for hypersensitivity reactions to those aeroallergens in the future.
Even without an in-depth understanding of human biochemistry and immunology, the hygiene hypothesis makes sense. The human immune system has co-evolved with a myriad of microorganisms over thousands of years to reach a state of relative equilibrium. However, within the last two hundred and fifty years (since the first industrial revolution in England in the 1760s) humans have begun to reduce their microbial exposure in an attempt to lead a healthier life. In the last one hundred years especially, the environment in which we live has rapidly transformed, upsetting the equilibrium that had developed. One hundred years (or two hundred and fifty years for that matter) simply isn’t enough time for the new evolutionary pressures put in motion by rapid industrialization and mass sanitation to appreciably affect population genetics. Essentially, our bodies are still adapted to life hundreds, if not thousands, of years ago while people in industrialized nations live in an environment with vastly different immune system stimuli. The hygiene hypothesis argues that this incongruence is what is leading to the rise in allergic and autoimmune diseases in industrialized nations.
Implications of Hygiene Hypothesis on Treatment Options
In an attempt to rectify this incongruence, researchers and doctors are developing treatments that aim to educate the immune system or provide the “proper” stimuli (i.e. stimuli that more closely resembles what our ancestors experienced). Doctors are using fecal transplants to correct intestinal flora as a therapy for inflammatory bowel disease (15), parents are exposing children to peanuts at an earlier age to prevent peanut allergies (16), and the FDA has just approved a new therapy, Odactra, to treat allergic symptoms caused by house dust mite (HDM) (17).
Conventional methods for managing allergic diseases rely on curtailing symptoms once they arise or using long-term corticosteroids to help reduce the severity and incidence of allergic inflammation. Odactra, on the other hand, is a tablet composed of extract from the two most common species of HDM: Dermatophagoides farinae and Dermatophagoides pteronyssinus. The pill is taken daily and administered sublingually (under the tongue) where it dissolves rapidly. By chronically challenging the immune system with HDM extract, doctors hope to train the immune system to become more tolerant of HDM antigens, gradually lessening the allergic reactions HDM induces in sufferers. However, the exact mechanisms underlying sublingual immunotherapy have yet to be elucidated, but they appear to be similar to the mechanisms involved in subcutaneous immunotherapy (18).
This type of treatment is representative of a larger shift in Westernized medicine over the last couple of decades to utilize treatments that work with a patient’s immune system to fight disease. Odactra and other therapies like it that seek to educate the immune system and/or restore its previous stimulation patterns could be an answer for the rise in allergic and autoimmune diseases in industrialized nations.