Written by: Matt Baran-Mickle
Interactions between our immune system and the environment are one of the most foundational, and, unfortunately, one of the most poorly understood aspects of an evolutionary perspective on health and disease. During my undergraduate studies I had the opportunity to complete a literature review investigating the links between diet and autoimmune disease, including as an appendix an overview of the immune system and some of the most important findings in recent immunological research, intended for an audience without a background in immunology. This and upcoming posts are drawn from my appendix and will (hopefully) help to get folks oriented in the jungle of the immune system, providing background on the immune system in our gut (the mucosal immune system), its interactions with the intestinal flora, and the immunological implications of obesity – which may hold some surprises – in the context of autoimmune disease. With luck this will help give people a clearer picture of commonly used terms and concepts like “intestinal permeability” and “systemic inflammation,” how they relate, and what in the world B and T cells have to do with anything. If you have questions regarding references, or to obtain a copy of my thesis, please email me at [email protected]. Enjoy!
The immune system lies as our primary defense against infection and disease, serving to protect us from the constant bombardment of potential pathogens that we are exposed to on a daily basis. It is necessarily complex, given the almost unlimited variety of molecules it must recognize and either ignore, or eliminate. The cells of the immune system, called white blood cells or leukocytes, originate from a common progenitor in the bone marrow and differentiate into various mature cell types in the bone marrow, the thymus (located on the midline, near the heart), the blood, or peripheral tissues. These mature cells (and the immune system in general) can be divided into two branches: those of innate immune system, and the adaptive immune system.
The innate immune system is responsible for recognizing and eliminating 99.9% of the potential pathogens that we encounter, and it does this in large part through the recognition of molecular patterns that many pathogens share. The receptors that recognize these patterns (pattern recognition receptors) are numerous but invariant, and do not change in response to infection; once a pathogen is identified through these receptors, it is destroyed through a variety of mechanisms.
The adaptive immune system, on the other hand, works to recognize most of the possible patterns present on pathogens through the production of highly variable receptors that are specific to individual parts of individual pathogens. This is accomplished, amazingly, through the shuffling and recombination of DNA, and generates essentially random mutations to these receptors, accounting for the huge variability in antigen binding capacity found in these cells (antigens are parts of pathogens that generate immune responses).
The adaptive immune system is made up of two cells types, collectively termed lymphocytes: B cells, which develop in the bone marrow, and T cells, which develop in the thymus. B cells are responsible for the production of antibodies that bind antigens in the extracellular space, permitting their clearance by cells of the innate immune system, which can recognize antigen/antibody complexes. T cells come in two varieties: those responsible for the elimination of virally infected cells (termed cytotoxic lymphocytes), and those that assist other cells in developing the appropriate response to other types of infection (termed T helper cells). All of these are important in the production of an appropriate immune response. During an infection, the recognition of a pathogen by the innate immune system induces inflammation, which is marked by the recruitment of more immune cells to the site of infection, and the production of cytokines, signaling molecules of the immune system that activate other leukocytes. Leukocyte recruitment is accompanied by swelling and occlusion of the site of infection due to the activation of clotting factors.
The inflammatory response is essential to the successful elimination of an infection, but when allowed to persist unchecked, can have a variety of consequences. The term chronic inflammation describes this self-perpetuating response, and is widely used today to describe the conditions behind many modern ailments, from asthma and allergy to heart disease and obesity. The simplest way to describe chronic inflammation is a perpetual, non-lethal low-grade activation of the immune system on a systemic level.
While chronic inflammation does not lead to acute mortality, it can cause significant, and in some cases serious, health issues. The incidence of inflammatory disease is rising rapidly in industrialized countries, and there are no easy solutions to this increasingly damaging situation.
A particularly intense manifestation of inflammatory disease are the autoimmune diseases, a wide variety of conditions that develop when the immune system attacks our own tissues instead of pathogens. Normally, checks and balances during the development of lymphocytes eliminate self-reactive cells and prevent an attack on self-tissue, but some self-reactive cells escape into the circulation. These cells are kept in check through the promotion of tolerance (non-response), primarily via regulatory T cells (Tregs) that produce suppressive cytokines when activated.
Autoimmune diseases are universally marked by a reduction in the presence and effectiveness of Treg cells, and a generally inflammatory environment, suggesting that they develop following a breakdown in tolerance. Recent estimates put the incidence of autoimmune disease (AD) at 16% in the United States, while ADs are the second-highest cause of chronic illness. The absence of AD in non-westernized cultures, however, and the increasing incidence in Western society, suggest that a difference between these may be behind the surge in disease. Because genetic evolution is a slow, generation-by-generation process, it is extremely unlikely that genetic changes are of principle importance, and more likely that a change in environment has left us vulnerable to a loss of tolerance and AD.
Nutrition is one of many environmental pressures that may contribute to the development of AD, but one that we have control over, and the differences in nutritional environment between industrialized and non-industrialized cultures are widely acknowledged. There is scant evidence, however, linking nutrition and autoimmune and inflammatory diseases specifically, so we must look to evidence for the potential impact of nutrition on inflammation, and the impact of inflammation on autoimmunity, to suggest a connection.
There are two main mechanisms that appear to play a large part in the development of inflammation and loss of tolerance that leads to AD: a breakdown in the intestinal barrier that allows the activation of potentially self-reactive lymphocytes, and metabolic disregulation in lymphocytes themselves that may also drive activation. We will address these in order.
Matt Baran-Mickle graduated from Hampshire College in 2013 with a BA in Human Physiology and Immunology, completing a senior thesis investigating the connections between nutrition and autoimmune disease from an immunological perspective. He completed pre-med requirements during his undergraduate work, and hopes to pursue a degree in Naturopathic medicine beginning in 2015. In the meantime, he eats, trains, and works in Boulder, CO.