CHRONIC INFLAMMATION & AUTOIMMUNITY
Inflammation is a critical biological response to physical injury, damage or infection and is vital to health. It is part of the body's defence mechanism when there is a threat present.
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Acute Inflammation
Acute inflammation is the immediate response which starts rapidly, becomes severe in a short period and symptoms such as swelling or pain may last a few days. The immune system recognises and promptly removes harmful and foreign stimuli and begins the repair of any damaged tissue. By design, inflammation is a finite process with resolution once the threat disappears.
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Failure of the resolution phase may lead to chronic inflammation.
The diagram below describes the activation, peak and resolution phases in the inflammatory response. The resolution phase is essential to control inflammation and restore tissue homeostasis once the danger signal has gone.
What stops an effective resolution phase?
(i) genetic factors coding for exaggerated immune responses (e.g., HLA-B27 in arthritis).
(ii) mechanisms that promote the development of Autoimmunity (e.g., citrullinated protein antibodies in arthritis).
(iii) processes leading to impaired epithelial barrier surfaces (e.g. leaky gut) leading to prolonged microbial exposure.
Inflammation Resolution
Diagram below describes the activation, resolution, and process leading to chronicity of inflammation. The timeline of the inflammatory response involves an activation phase, peak phase, and resolution phase.
Reference: (Schett, G., Neurath, M.F., 2018)
Inflammatory Mechanisms (the science stuff)
An inflammatory response involves complex cell interactions between the immune system, the vascular system and the tissue. The body initiates a chemical signalling cascade, these signals activate leukocytes (white blood cells) from general circulation to sites of damage. These activated leukocytes produce cytokines (signalling molecules) that initiate inflammatory responses. Inflammatory response processes all share a common mechanism:
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1) Cell surface pattern receptors recognise foreign stimuli
PAMPS (bacteria or virus are known as 'pathogen-associated molecular patterns') and DAMPS (non infectious tissue or cell damage known as 'danger-associated molecular patterns') can trigger the inflammatory response through activation of pattern-recognition receptors (PRRs) expressed on both immune and nonimmune cells (eg TLR-4).
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2) Inflammatory pathways are activated
Receptor stimulation activates important intra-cellular signalling pathways that play very important roles in inflammation and immune response. These include NF-kB, STAT and MAPK pathways. If these become dysregulated, there is a higher risk of inflammatory and autoimmune diseases occurring.
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3) Inflammatory markers are released
The inflammatory pathways regulate pro- and anti-inflammatory cytokines (signalling molecules) to be released from immune cells and facilitate and inhibit inflammation. Inflammatory cytokines such as: IL-1, IL-6, IFNg, TNFa, are produced by cells primarily to recruit leukocytes to the site of infection or injury. Excessive inflammatory cytokine production can lead to chronic inflammation.
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4) Inflammatory cells are recruited.
Neutrophils (innate immune cells) are the first immune cells that swarm to sites of damage. Resolution of acute inflammation depends on effectively stopping neutrophil recruitment. Neutrophils die (apoptosis) when engulfed by macrophages. This is an essential anti-inflammatory and pro-resolving mechanism.
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Neutrophils are followed by monocytes (which turn into macrophages), lymphocytes (natural killer cells, T cells an B cells) and dendritic cells which play a role in the antigen presenting process to activate the adaptive immune response. Any dysregulation of the complex immune cell communication and recruitment process can lead to chronic inflammation and disease.
Pro-inflammatory signalling mechanisms
'Classical inflammation is a complex process that involves the recognition of harmful stimuli (pathogens, irritants, etc.) by immune cells, triggering the release of proinflammatory cytokines that will result in the clearance of infectious agents and reestablishment of healthy tissue'.
Reference: (RaquelEspin-Palazon, BartWeijts, VictorMulero, DavidTraver, 2018)
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Chronic Inflammation
Chronic inflammation is a slow, long-term inflammation lasting for a prolonged period of several months to years, it is present in virtually all inflammatory diseases and can be co-existent with Autoimmune conditions.
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Symptoms of Chronic Inflammation:
Body pain
Chronic fatigue
Insomnia
Depression, anxiety and mood disorders
Gastrointestinal complications like constipation, diarrhoea, and acid reflux
Weight gain or weight loss
Frequent infections
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Consequences of Chronic Inflammation
Can prevent the gut from absorbing nutrients
Can prevent the brain from responding to neuro rehabilitation
Can prevent kidneys and liver from detoxifying properly
Can prevent lungs, intestines and sinuses from healing mucosal linings.
Can prevent the Endocrine system from signaling properly
Can cause patients to lose cognitive function
Causes of Chronic inflammation:
Failure of eliminating the agent causing an acute inflammation such as infectious organisms including bacteria, fungi and other parasites that resist host defences and remain in the tissue for an extended period.
Exposure to a low level of a particular irritant or foreign material that cannot be eliminated by enzymatic breakdown or phagocytosis in the body including industrial chemicals.
An autoimmune disorder where the immune system recognises body tissue as a foreign antigen, and attacks.
A defect in the cells responsible for mediating inflammation.
Recurrent episodes of acute inflammation.
Inflammatory and biochemical inducers causing oxidative stress and mitochondrial dysfunction.
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Risk Factors Associated with Chronic Inflammation:
Several risk factors are known to promote a low-level inflammatory response. These include:
Age: The age-associated increase in inflammatory molecules may be due to mitochondrial dysfunction or free radical accumulation over time and other age-related factors like an increase in visceral body fat.
Obesity: Many studies have reported that fat tissue is an endocrine organ, secreting multiple adipokines and other inflammatory mediators.
Diet: saturated fat, trans-fats and refined sugar are associated with pro-inflammatory molecules.
Smoking: is associated with lowering the production of anti-inflammatory molecules and inducing inflammation.
Low Sex Hormones: Studies show that sex hormones like testosterone and oestrogen can suppress the production and secretion of several pro-inflammatory markers.
Stress and Sleep Disorders: Both are associated with inflammatory cytokine release.
Causes & Consequences of low grade Systemic Chronic Inflammation (SCI)
Reference: (Furman, D., Campisi, J., Verdin, E. et al. 2019)
