Inflammation and autoimmunity


Immune Defense

The immune system is a complex and tightly regulated system designed to protect the body from all invading pathogens.

The immune system is a complex and tightly regulated system designed to protect the body from all invading pathogens and repair damage caused to cells by injury, infection and stressors. The correct functioning of this extremely precise process is dependent on numerous factors including diet, stress and sleep – each of these factors has the capacity to disrupt the process and create systemic havoc!

Autoimmunity is a huge burden in the western world; the third biggest cause of morbidity and mortality, it is the clinical manifestation of an immune system so overwhelmed that it goes into overdrive and begins to attack cells and systems of the body, causing diseases such as type 1 diabetes, arthritis, lupus, multiple sclerosis and hyper/hypo-thyroidism, to name but a few of the 80+ classified autoimmune conditions. Autoimmunity arises with the established presence of three key factors:

  • First there must be a trigger which switches on the immune system – for example, chronic stress, viral infection or food sensitivities.
  • Then the environment must allow the immune system to remain consistently overwhelmed until it begins to lose control. ’Environment’ refers to the state of the body. Poor diet, gut dysbiosis, intestinal permeability and high physical or mental stress all reduce the ability of the body to naturally deal with the trigger and control the immune system.
  • There must be genetic susceptibility present, determined by single nucleotide polymorphisms (SNPs) in an individual’s genetic code, which results in one or several organs being the specific target for the rogue immune cells.

Once the immune system has been triggered, and the environment allows for its continuous activation, the chemical signals that would normally govern the process of ‘search and destroy’, to identify and eliminate pathogens, fail to effectively halt this process and begin to specifically seek out structures similar to the original trigger/s or those involved in the immune response and are thus elevated to unusually high levels. The first port of call for the immune system in dealing with a ‘trigger’ is the inflammatory response. An invading molecule or a cell damaged by injury or stress expresses specific molecular proteins, known and PAMPs or DAMPs. Immune cells recognise these triggers and engulf the pathogen, which triggers the release of numerous inflammatory cytokines. These signals alert the rest of the immune system that it needs to become active in order to eliminate the harmful invader. Cells such as leukocytes, monocytes and phagocytes migrate to the area of damage or infection from the lymph and blood vessels in close proximity, a process facilitated by vessel membranes becoming more permeable and the expression of adhesion molecules. The sudden influx of immune cells, chemicals and additional fluids results in the classic symptoms of inflammation – swelling, pain, redness and heat. If the initial inflammatory response cannot deal with the pathogen or the pathogen is consistently present, as in the case of triggers, monocytes and dendrites will ‘present’ the antigen to naïve T cells. The type of PAMP or DAMP presented to the T cells triggers the release of specific cytokines, subsequently stimulating the differentiation of the naïve T cells into more specific subtypes, each uniquely poised to stimulate a full blown immune response to the specific antigen type. The T cell subtypes themselves secrete further cytokines – specific to them, which subsequently triggers the differentiation of B cells – the cells responsible for producing antibodies. It is at this point, once the B cells have been triggered and the production of antibodies is in full swing, that the body has now ‘learnt’ to attack and destroy any object expressing the structures and proteins similar to those of the initial trigger and full blown autoimmune disease is in progress. The specific T cell subtypes now understood to play a key role in the onset and progression of autoimmune disease is known as Th17. This subtype and its cytokines IL-17 and IL-22 have been found to be elevated in multiple sclerosis, type 1 diabetes, Crohn’s, psoriasis and rheumatoid arthritis. Autoimmunity and its severity appear to be dependent on the balance between Th17 cells and two other subtypes: 1) Th1 – important for driving the immune response towards targeting intracellular pathogens and thus keeping the immune system focused on targeting harmful ‘invaders’; 2) Treg cells, a unique subtype of T cell crucial for the regulation of the immune response. A high level of Th17 affects the Th1 cell’s ability to focus on invading molecules and also directly inhibits the immune suppressor activity of Tregs. In addition, high levels of Th17 can stimulate Tregs to convert to Th17, further driving the immune response towards inflammation. Resolution and prevention of autoimmune disease is a two-pronged approach: first the initial trigger must be eliminated to prevent immune and antibody stimulation; secondly, the body’s ability to control and resolve inflammation and consequently reducing the cytokine load must also be addressed. In order to remove triggers and reduce their autoimmune potential, the following steps must be taken:

  • identify and treat infection
  • restore gut biosis and repair intestinal permeability
  • switch to a natural, organic, grass-fed (if meat is consumed) diet, high in quality proteins, fats and vegetables
  • address stress – emotional, physical and environmental

The body’s ability to control and regulate inflammation is dependent on the specific balance of those eicosanoids which are derived from polyunsaturated fatty acids. Of particular importance are the omega-6 arachidonic acid and the omega-3 eicosapentaenoic acid. Arachidonic acid is the precursor to the major pro-inflammatory eicosanoids: series-2 prostaglandins, series-2 thromboxanes, series-4 leukotrienes and hydroxy fatty acids. Whilst EPA is the precursor to the same types of eicosanoids, they are of different series which renders them much less potent on the inflammatory scale; instead, they are actively involved in the resolution of the inflammatory process. Whilst other PUFAs including DHA, GLA and DGLA are involved in the inflammatory response, only EPA is directly able to compete with and oppose the pro-inflammatory actions of AA; optimising EPA levels is therefore vital in determining the body’s ability to switch off the inflammatory process. Fatty acids are incorporated into our cell membranes following ingestion in the diet. In the presence of inflammatory signals the phospholipase A2 enzyme releases AA, which is then converted to its pro-inflammatory eicosanoids by the cyclooxygenase (COX) or lipoxygenase (LOX) enzymes. EPA acts to oppose or counter the pro-inflammatory impact of AA via numerous mechanisms:

  • Direct displacement of AA from cell membranes
  • Switching off the activity of phospholipase A2
  • Inhibiting AA metabolism by competing for COX and LOX activity
  • Decreasing expression of the COX-2

An ideal AA to EPA ratio is between 1.5 to 3 AA for every EPA molecule, but due to our consumption of refined, processed and grain-based diets high in total omega-6 and pre-formed AA, this ratio is often greater than 15 to 1 in developed countries. In addition to its important role in the regulation of inflammation, EPA also helps to prevent the onset and progression of autoimmunity via the following mechanisms:

  • reducing leukocyte adhesion and chemotaxis – major factors that drive autoimmune pathogenesis
  • suppression of monocyte synthesis of cytokines at the genetic level (mRNA)
  • reducing phagocytic activity of immune cells
  • reducing the ability of antigen presenting cells to present antigens to T and B cells
  • reduced stimulation of white blood cells – important for preventing unwanted antibody production
  • activation of PPARγ, a nuclear receptor expressed by Treg cells and involved in metabolism and immune regulation
  • stimulation of genetic factors promoting the repair, replacement and protection of cells targeted by the immune system in autoimmunity

Studies continue to unpick the mechanisms by which EPA contributes to the prevention and resolution of autoimmunity and a wealth of animal and human studies are showing considerable improvement to both the onset and progression of autoimmunity with EPA therapy. Whilst the area of EPA is still in its relative infancy, with the broad ranging actions of EPA, both in the prevention and resolution of the inflammatory response and in subsequent immune control, it is clear that high-dose EPA has an important role to play in dealing with the huge burden of autoimmune disease.

References

  1. Calder, P.C., Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta, 2014.
  2. Simopoulos, A.P., Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr, 2002. 21(6): p. 495-505.
  3. Singh, R.P., et al., Th17 cells in inflammation and autoimmunity. Autoimmun Rev, 2014.
  4. Leung, S., et al., The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol, 2010. 7(3): p. 182-9.
  5. Iwami, D., et al., Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells. Int Immunopharmacol, 2011. 11(3): p. 384-9.
  6. Yokota, S., et al., Pathogenesis of systemic inflammatory diseases in childhood: “Lessons from clinical trials of anti-cytokine monoclonal antibodies for Kawasaki disease, systemic onset juvenile idiopathic arthritis, and cryopyrin-associated periodic fever syndrome”. Mod Rheumatol, 2014: p. 1-10.
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Sophie Tully

About Sophie Tully

A trained pharmacologist, Sophie pursued her passion for health and nutrition by completing a master’s degree in Clinical & Public Health Nutrition at UCL, London. Sophie balances her Igennus role with her own private nutrition and health consultancy business working with elite athletes and the general public to achieve optimal health through lifestyle and dietary interventions. Sophie’s main research interests lie in the role of nutrition and lifestyle in inflammation, psychology and immunology. Sophie also lectures at the College of Naturopathic Medicine.