Inflammation is a part of the immune response and, because of this, is a common element in a number of clinical conditions. Many of these general conditions are connected in turn to ocular ones.
This article discusses these connections, and how, in addition to treatments, lifestyle changes in the form of good diet may play a part in controlling inflammation. Inflammatory ocular conditions are summarised in Table 1.
The immune system
The immune system comprises coordinated components that combat infection by hostile pathogens, which have to be differentiated from the friendly commensal bacteria in the body – for instance the trillions of bacteria in the alimentary tract that help us to digest our food. The immune system divides broadly into innate and adaptive systems. The innate system is active against all cells not recognised as ‘self’ or ‘friendly’ on the basis of previously available information. It is a ‘fast response’ system and relatively unspecific in its response, recruiting white blood cells such as neutrophils and macrophages to the affected site. These cells engulf the foreign organism and produce reactive oxygen species such as superoxidases and hydrogen peroxide to destroy them. The adaptive system on the other hand ‘learns’ about foreign invaders through contact with them, and then manufactures a response specific with that invader or antigen. This is largely driven by lymphocytes called T-cells, which carry specific receptors for the antigen. Because the acquired response requires exposure, learning and manufacturing to become effective, it is slower to activate. Once the invader has been identified and eliminated, a small number of ‘memory cells’ are retained in the body for a considerable time. These can respond very much more quickly to a second invasion by the same hostile organism. This mechanism is the basis of immunisation, in which an attenuated or dead form of the invader is introduced into the body to provoke a response, and establish the presence of the memory cells.
The inflammation process
[CaptionComponent="1768"]Inflammation is a part of the protective immune response against pathological invading organisms. It involves identification of the affected tissue, white blood cell recruitment into the site, elimination of the invader, and subsequent tissue clean-up and repair. It can be triggered by antigens that are not infectious, such as pollen, and can cause considerable distress when the reaction is misdirected or goes into overdrive, as happens in allergies and auto-immune conditions. As with many biological systems, the body is trying to achieve a balanced and adequate defence without overdoing it. A key element is the ability for the immune system to differentiate between things that should be there, ‘self’, and foreign elements capable of producing harm, ‘non-self’. One breakdown of this ability is failure to recognise an invading organism leading to harmful progress of infection. Another is autoimmune conditions in which the system does not recognise the host’s own tissues as ‘self’, and attacks them. Regulatory T cells (Tregs) control overreaction by suppressing the production of pro-inflammatory T cells.1 Tregs are instrumental in the control of autoimmune diseases and preventing the immune system from attacking either ‘self’ tissues or ‘friendly’ bacteria.
Cytokines are chemically released messengers that summon components of the inflammatory system to the site. There are both pro-inflammatory and anti-inflammatory cytokines.2 During inflammation the capillaries in the area become dilated as the blood supply is increased, causing redness. Capillary walls become more permeable, and the area becomes oedematous, suffused with water, to allow the passage of water-borne immune components. While the underlying mechanism is defensive, the effects can be distressing – for instance with a cold or allergy, inflammation can lead to swelling that closes down the sinuses and air passages and makes breathing difficult. When the system over-reacts as happens in asthma, the consequences can be alarming and even life-threatening because air passages can become completely closed.
Inflammation and general conditions
Conditions ending in ‘-itis’ are inflammatory – colitis is the inflammation of the gut, arthritis of the joints, iritis of the iris and so on. While inflammation is common to all of these, the underlying causes can vary considerably, from infection through allergy and autoimmune conditions to a part of the wound-healing process. Treatment should be directed as far as possible to the root cause rather than the symptoms and signs. While controlling the inflammation will not necessarily eliminate the condition, it can be part of a raft of approaches that will achieve relief and is a key strategy in autoimmune conditions and allergies. Eating wisely can reduce the effects of inflammation to support administered therapies, and serve to prevent recurrence if and when the condition is cured. Many conditions that are not specifically tagged as inflammatory have an inflammatory element to them, for instance obesity, hypertension, and ocular conditions such as dry eye, where treatment of the inflammation can produce dramatic improvements in the condition.3 Chronic systemic inflammation is common in old age, termed ‘inflammaging’, and is thought to be related to life-long exposure to antigens – there is a correspondingly higher prevalence of hypertension in this age group.
Obesity and diabetes
[CaptionComponent="1769"]People with obesity often have insulin resistance and/or type 2 diabetes which has been related to an over-active inflammatory response. One theory about the cause is that expanding fat cells close off oxygen supply to the tissues, causing ischaemia and necrosis which results in the release of pro-inflammatory cytokines.4 The cytokines attract macrophages, which release further cytokines, aggravating the inflammation both locally and systemically, for instance in the liver. By contrast, macrophages which are normally resident in the tissues, as opposed to those recruited by cytokines, are inactive and non-inflammatory. Inflammation has a strong association with insulin resistance.4 Inhibition of the macrophage inflammatory pathway protects mice from obesity-induced insulin resistance, although this mechanism has not yet been demonstrated in people.
[CaptionComponent="1770"]Cardiovascular disease
Systemic low-grade inflammation in the form of raised levels of pro-inflammatory cytokines and proteins flags a higher risk of developing hypertension.5 Systemic inflammation is common in hypertensives. One potential mechanism for this is blood vessel endothelial dysfunction. The endothelium is a monolayer of cells on the inner surface of blood vessels that regulates vascular tone and therefore the diameter of the blood vessels. Sustained chronic inflammation can result in the release of reactive oxygen species at a rate faster than they can be cleared, causing oxidative stress. Oxidative stress reduces the endothelial ability to cause vasodilation, and the resultant vessel constriction can contribute to hypertension.5 Systemic inflammation and oxidative stress can cause renal dysfunction and failure. Chronic endothelial inflammation is also associated with increased adhesion of plaque to the blood vessel walls, and this can lead to atherosclerosis, aggravating blood flow restriction and increasing the potential for thrombosis.
Systemic lupus erythematosus and rheumatoid arthritis
Systemic lupus erythematosus is an auto-immune condition in which antibodies are produced against the person’s own tissues. Rheumatoid arthritis is more specific than this in that the synovial membranes in the joints are attacked with accompanying inflammation and pain. In both cases there can be associated oral and ocular dryness symptoms 7,8 that in combination with other signs and symptoms can be associated with Sjögren’s syndrome (Figure 3).
[CaptionComponent="1771"]Psychological stress
Real or perceived threats, often arising from a modern lifestyle, can cause psychological stress, which in turn triggers the release of pro-inflammatory cytokines 11 and oxidative stress. These are associated with recurrent depressive episodes.12,13,14 As they have a common cause in inflammation, depression can occur in combination with inflammation-triggered physical conditions such as arthritis and asthma.
Nutritional contributors to inflammation
From the above discussion, there seem to be three significant contributors to inflammation – obesity, oxidative stress and balancing the immune system to provide a controlled response to antigens, and not to overreact. All of these factors are well known within the healthcare community, but for them to be effective, they need to be understood and acted upon within the wider general population. As hospitals normally only see people once conditions are established, primary healthcare providers can assume an educational role in addition to their normal clinical activities, aimed at preventive education in addition to disease identification and referral. This imparts a need for primary care practitioners to have a better understanding of nutrition and its impact in the community.
Nutritional approaches to reducing inflammation
Obesity has been discussed in an earlier article 15 and, in view of its increased prevalence and impact on other conditions including inflammation, needs to be addressed early and on a continual basis. This can happen both at a daily level with basic nutritional advice in practice, and at a more advanced level in co-ordination with GPs and nutritionists. The neutralisation of oxidative stress requires consumption of anti-oxidants, found largely in fresh fruit and vegetables. ‘Five a day’ is a standard minimum recommendation, and this should be increased where inflammation is already established.
Omega fatty acid intake needs to be balanced. Omega 6 fatty acids have a predominantly pro-inflammatory, and omega 3 fatty acids an anti-inflammatory role. They compete for digestion, so that absorption and use is proportional to intake. The evolutionary proportion of these in our diets is about one to one. The current western diet contains a much higher proportion of omega 6, sometimes 20 or more to one, which increases the activity of the inflammatory system. Re-balancing this intake with increased consumption of oily fish such as herring, mackerel or salmon and vegetable sources such as linseed have been shown to be beneficial for people suffering from inflammatory and auto-immune diseases.16 A large Danish study found that a 30g per day increased intake of oily fish was associated with a 49 per cent reduction in the risk of rheumatoid arthritis.17
Diet may play a role in the development of rheumatoid arthritis, with lower risks associated with increased consumption of olive oil, fatty fish and fruit and vegetables.18 Switching to a Mediterranean diet which is high in these results in a reduction of symptoms.19
Some gut bacteria have roles to play in controlling immune system behaviour.20 For instance, a correlation has been found between early use of antibiotics and later development of asthma. Dietary fibre has been shown to play a role in controlling inflammatory conditions.20 Removal of selected bacterial populations results in a reduction of the Tregs that allow them to co-exist in the gut. Bacteria that live adjacent to the gut lining specialise in digesting fibre and produce metabolites that induce Treg formation. Reduced nutrition from fibre will potentially therefore reduce Treg presence and result in increased inflammatory activity. Insufficient fibre for nutrition can cause the bacteria to switch to sugars in the mucosal lining, which can increase its permeability to antigens, allowing them to reach the bloodstream.21
This in turn can result in allergies.22-24 Dietary fibre therefore has a dual role to play in both weight control and in mediating the inflammatory response.
Conclusion
Inflammation is a common element to many modern diseases of affluence and ageing, both developing factors in modern society. Conditions which are associated with inflammation such as arthritis, cardiovascular disease and diabetes are on the increase, with a 60 per cent increase in the latter in the UK in the last decade.25 Primary care practitioners such as optometrists, opticians, dentists and others, because of their more regular and routine contact with a wide range of the population, are in an excellent position to contribute to preventative education of the public. To do this, they need to understand the impact of diet on general and ocular health.
Ocular clinical refresher — diabetes
Diabetes manifests early through retinal microaneurysms. Vessel blockage causes ischaemia which can lead to new vessel proliferation, with dot and blot haemorrhages and exudates in the retina. Advanced proliferative retinopathy can result in a cycle of bleeding into the vitreous and scar formation, with scar contraction causing further bleeding (Figure 3). Traction on the retina from scarring can lead to detachment. Osmotic imbalance from higher concentrations of sugar can lead to crystalline lens changes and corresponding changes in refraction including cataract development. There is an increased risk of glaucoma.
Ocular clinical refresher — Hypertension
Ocular manifestations of hypertension include flame-shaped haemorrhages in the superficial layers of the retina and cotton wool patches caused by occlusion of the pre-capillary arterioles. Long-standing hypertension leads to arteriosclerotic vascular changes such as copper or silver-wiring and nipping or humping of veins at artero-venous crossings. Swelling of the optic disc is a sign of malignant hypertension, and requires immediate treatment to reduce risks of heart and renal failure, stroke and permanent loss of vision.6
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Ross Grant is an optometrist and co-founder of Toolbox Training and Consultancy