These fatty acids control thephysical nature (“fluidity”) of the membrane, ensuring the correct environment for the functioning of membrane proteins like receptors, channels, pumps and signaling enzymes, and influence the assembly and function of raft regions, which are involved in cell signaling. They also modify the impact of the phospholipids of which they are components in signaling processes.





Figure 2. Mechanisms by which n-6 and n-3 PUFAs can influence immune function





Fatty acids may be released from membrane phospholipids by the action of phospholipase enzymes when the cells are stimulated and the released fatty acids can have signaling actions themselves often by binding to receptors that act as transcription factors. Finally ARA, DGLA, EPA and DHA give rise to derivatives such as prostaglandins (PG), thromboxanes, lipoxins, leukotrienes (LT) and resolvins that influence the functional activities of immune cells and of other cell and tissue compartments involved in the immune and inflammatory responses.

It is this latter action of very long chain (VLC), highly unsaturated PUFAs that is the most recognised mechanism by which they can influence immune and inflammatory responses. For example, PGE2 produced from ARA exerts pro-inflammatory actions with regard to vascular permeability and pain, promotes immunoglobulin class switching in B cells towards pro-allergic IgE, and suppresses T cell proliferation, the production of the Th1-type cytokine interferon (IFN)-γ and the ability of antigen presenting cells to present antigen.

LTB4, also produced from ARA, promotes leukocyte chemotaxis, production of reactive oxygen species and other mediators from granulocytes, production of inflammatory cytokines by monocytes, and natural killer cell activity. Thus, through the actions of these types of mediators ARA may influence inflammation and immune responses, although predicting the overall impact of an alteration in ARA supply on these is not straightforward³. However, it is clear that n-6 PUFA deficiency results in loss of function of many immunologic components, that immune cells readily incorporate n-6 PUFAs including ARA, and that ARA is accumulated in the developing thymus of the mouse⁴. Thus, an appropriate supply of n-6 PUFAs, especially ARA, is probably required for optimal immune development and for mounting a good host response to infectious challenge.

Effect of dietary PUFAs on immune function

The major n-3 PUFA in the diet is α-linolenic acid (18:3n-3) which is plant derived. The metabolic derivatives of α-linolenic acid (EPA and DHA) are found in significant amounts in fish and other seafood, especially fatty fish like salmon, herring, tuna, sardines and herrings. These VLC n-3 PUFAs are also found in “fish oils”. Increased consumption of VLC n-3 PUFAs results in their incorporation into immune cells in a dose- and time-dependent manner^1-3.

This incorporation occurs largely at the expense of ARA, so decreasing the availability of the substrate for production of 2-series PGs and 4-series LTs. EPA is also a substrate for synthesis of eicosanoids, such as the 3-series PGs (e.g. PGE3) and the 5-series LTs (e.g. LTB5). These have a different structure from the eicosanoids produced from ARA, which affects their potency. In general, eicosanoids derived from EPA are less inflammatory in nature than those produced from ARA. EPA also gives rise to resolvins of the E-series while DHA gives rise to D-series resolvins, docosatrienes, and neuroprotectins⁵.

These mediators have strong anti-inflammatory effects and also affect immune functions. Through altered production of lipid mediators, altered cell signaling and altered gene expression, VLC n-3 PUFAs influence other aspects of immune function such as T cell proliferation, and production of cytokines like IFN-γ, classic inflammatory cytokines, and immunoglobulins (see 1-3).

Therapeutic possibilities

On the basis of their opposing actions it has been suggested that n-6 PUFAs predispose to, and VLC n-3 PUFAs decrease the risk of, allergic disease⁶. There is some epidemiological evidence to support a protective role of dietary VLC n-3 PUFAs⁶. Furthermore, a lower than normal content of these fatty acids is associated with allergic disease⁶.

In contrast to what is often stated, the content of ARA is also frequently lower in samples from allergic compared to non-allergic individuals. However, there is an imbalance between the n-6 and n-3 PUFAs in favour of the former. This suggests that intervention with VLC n-3 PUFAs, which can normalise this imbalance, might be of clinical benefit. Since it appears that allergic sensitisation occurs early in life, even in utero, the window of opportunity for modulation of responses by dietary PUFAs may be narrow and there is a need to focus on pregnancy and early infancy. One study has linked increased consumption of VLC n-3 PUFAs in early infancy to improved clinical outcome at 18⁷ and 36⁸ months.

Another study reported that increased maternal consumption of fish oil from week 20 of pregnancy until delivery improved the profile of cytokines in cord blood⁹, altered cord blood immune cell cytokine responses¹⁰ and improved clinical outcomes in the infants at one year of age¹⁰. The NUHEAL study investigated whether supplementation of pregnant women with the VLC n-3 PUFAs from week 22 of pregnancy until delivery alters maternal and fetal immune-related parameters. Relevant data from this study are not yet published but findings include altered cytokine profiles in maternal and cord blood.
These studies indicate that early exposure to VLC n-3 PUFAs can have immunologic consequences that might translate into improved clinical outcome. How this occurs is unclear at present. However, if early exposure to VLC n-3 PUFAs results in both immunologic changes and in clinical improvements the next challenge will be to optimise the supply and cellular contents of ARA and VLC n-3 PUFAs.

References

1. Calder P. Polyunsaturated fatty acids, inflammation and immunity. Lipids 2001;36:1007-24.
2. Calder P. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids 2003;38:342-52.
3. Calder P. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006;83:1505S-19S.
4. Harbige LS. Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids 2003;38:323-41.
5. Serhan CN, Arita M, Hong S, et al. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers. Lipids 2004;39:1125-32.
6. Calder PC, Miles EA. Fatty acids and atopic disease. Pediatric Allergy and Immunology 2000;Suppl. 13:29-36.
7. Mihrshahi S, Peat JK, et al. Marks GB. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). Journal of Allergy and Clinical Immunology 2003;111:162-8.
8. Peat JK, Mihrshahi S, Kemp AS, et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. Journal of Allergy and Clinical Immunology 2004;114: 807-13.
9. Dunstan JA, Mori TA, Barden A, et al. Maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy. Clinical and Experimental Allergy 2003;33:442-8.
10. Dunstan JA, Mori TA, Barden A, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised, controlled trial. Journal of Allergy and Clinical Immunology 2003;112:1178-84.