Title: N-3 PUFA as useful therapeutic agents in diseases characterised by immune dysregulation
Key words: polyunsaturates, polyunsaturated, cytokines, eicosanoids, inflammation, inflammatory, mediators, arthritis, rheumatoid arthritis, fatty acids, PUFA, inflammatory bowel disease, diabetes, psoriasis, asthma, allergies, dietary manipulation, arachidonic acid, prostaglandins, leukotrienes,
Date: Oct 2006
Author: Morgan, G
N-3 PUFA as useful therapeutic agents in diseases characterised by immune dysregulation
Research into the pathways of cell-mediated and humoral or acquired immunity has helped to clarify the role played by mediators such as the cytokines and eicosanoids in the inflammatory process. Eicosanoids have been extensively studied due to the fact that dietary manipulation of their substrate, the n-3 and n-6 fatty acids, have been shown to modulate certain immunological diseases such as rheumatoid arthritis. The role played by the n-3 PUFAs in this respect is commented upon here.
Key inflammatory mediators such as complement, acute phase protein, adhesion molecules, cytokines TNF-alpha and IL-1, prostaglandins of the 2-series and leukotrienes of the 4-series have been shown to be released in response to trauma, sepsis or antigenic invasion. In this response, cytokine mediators promote the differentiation of certain T lymphocytes into Th1 cells which lead to the activation and proliferation of granulocytes, macrophages and lymphocytes characteristic of the acute inflammatory response.
Such cell-mediated inflammatory markers have also been found to be present in a range of immune related diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and type 1 diabetes. They have also been found to be present in other immune diseases such as asthma and allergies characterised by a humoral response with Th2, B lymphocyte and eosinophil proliferation. It is clear that the interaction between the Th1 and Th2 mediated responses in chronic immune disorders is very close and, from studies, that this balance can be altered by dietary PUFA manipulation.
The use of n-3 PUFAs to modulate these responses is based on their ability to modify the fatty acid content of cell membranes of cells involved in the inflammatory response. Arachidonic acid, the main fatty acid present in cell membranes, serves as the main substrate in the production of the inflammatory 2-series prostaglandins and 4-series leukotrienes which are involved in cell-mediated responses. High intakes of n-3 PUFAs not only displaces arachidonic acid with ecosopentaenoic acid but also leads to the replacement of the 2- and 4- series by 3- and 5-series prostaglandins and leukotrienes which are both less biologically active and which occupy the same receptors on immunological target cells. It is for these reasons that the n-3 PUFAs have been said to be anti-inflammatory.
The close interaction of the Th1 and Th2 pathways has already been pointed out. Clinically, in ThI type disorders such as RA, anti-inflammatory cytokines characteristic of Th2 disorders and, in Th2 type disorders such as asthma, pro-inflammatory cytokines characteristic of Th1 disorders, are also found .It is true that inflammatory cytokines are associated with Th1 and anti-inflammatory cytokines with Th2 responses in general but certain cytokines such as THF, IL-1 and IL-6 are linked to both pathways. n-3 PUFAs are known to diminish the activity of antigen presenting cells which both modulate the cell-mediated response and, through T lymphocytes, the humoral response and it could be that their influence on the balance between the Th1 and Th2 pathways is effected via such cytokine mediation.
There is also evidence that immune gene expression is modified by n-3 PUFAs. In the Broughton asthma study for example (Broughton 1997) differences in responses to n-3 PUFAs were suggestive of significant genetic variance. It is known that major histocompatability class 2 expression of antigen presenting cells is diminished by n-3 PUFAs and also that apoE polymorphism is a significant modulator of n-3 PUFA efficacy in treating the atherogenic lipid profile of cardiovascular disease, a disease which is now known to have many of the features of an immune disorder (Minnihane 2000).
Such examples give some idea of the complexity of the immune system and the ways in which the n-3 PUFAs exert their effects in immune diseases.
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