Abstract
The essentiality of n−6 polyunsaturated fatty acids (PUFA) is described in relation to a thymus/thymocyte accretion of arachidonic acid (20∶4n−6, AA) in early development, and the high requirement of lymphoid and other cells of the immune system for AA and linoleic acid (18∶2n−6, LA) for membrane phospholipids. Low n−6 PUFA intakes enhance whereas high intakes decrease certain immune functions. Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response. In contrast to the effects of the oxidative metabolites of AA, the longer-chain n−6 PUFA produced by γ-linolenic acid (18∶3n−6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response. The n−6 PUFA, GLA, dihomo-γ-linolenic acid (20∶3n−6, DHLA) and AA, and certain oxidative metabolites of AA can also induce T-regulatory cell activity, e.g., transforming growth factor (IGF)-β-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-α production. Low intakes of long-chain n−3 fatty acids (fish oils) enhance certain immune functions, whereas high intakes are inhibitory on a wide range of functions, e.g., antigen presentation, adhesion molecule expression, Th1 and th2 responses, proinflammatory cytokine and eicosanoid production, and they induce lymphocyte apoptosis. Vitamin E has a demonstrable critical role in long-chain n−3 PUFA interactions with immune functions, often reversing the effects of fish oil. The effect of dietary fatty acids on animal autoimmune disease models depends on both the autoimmune model and the amount and type of fatty acids fed. Diets low in fat, essential fatty acid deficient (EFAD), or high in long-chain n−3 PUFA from fish oils increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, whereas high-fat LA-rich diets increase disease severity. In experimentally induced T cell-mediated autoimmune disease, EFAD diets or diets supplemented with long-chain n−3 PUFA augment disease, whereas n−6 PUFA prevent or reduce the severity. In contrast, in both T cell- and antibody-mediated autoimmune disease, the desaturated/elongated metabolites of LA are protective. PUFA of both the n−6 and n−3 families are clinically useful in human autoimmune-inflammatory disorders, but the precise mechanisms by which these fatty acids exert their clinical effects are not well understood. Finally, the view that all n−6 PUFA are proinflammatory requires revision, in part, and their essential regulatory and developmental role in the immune system warrants appreciation.
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Abbreviations
- AA:
-
arachidonic acid
- ALA:
-
α-linolenic acid
- APC:
-
antigen-presenting cells
- CREAE:
-
chronic relapsing EAE
- DHA:
-
docosahexaenoic acid
- DHLA:
-
dihomo-γ-linolenic acid
- DTH:
-
delayed-type hypersensitivity
- EAE:
-
experimental autoimmune encephalomyelitis
- EAU:
-
experimental autoimmune uveitis
- EFAD:
-
essential fatty acid deficiency
- EPA:
-
eicosapentaenoic acid
- GLA:
-
γ-linolenic acid
- IL:
-
interleukin
- INF:
-
interferon
- LA:
-
linoleic acid
- LFA:
-
leucocyte function-associated antigen
- LT:
-
leukotriene
- MHC:
-
major histocompatibility complex
- NK:
-
natural killer
- PG:
-
prostaglandin
- PHA:
-
phytohemagglutinin
- RA:
-
rheumatoid arthritis
- ROI:
-
reactive oxygen intermediates
- SLE:
-
systemic lupus erythematosus
- TcR:
-
T cell antigen receptor
- TGF:
-
transforming growth factor
- Th:
-
T helper
- TNF:
-
tumor necrosis factor
References
Oppenheim, J.J., and Shevach, E.M. (1990) Immunophysiology, pp. 210–283, Oxford University Press, Oxford and New York.
Roitt, I., Brostoff, J., and Male, D. (1998) Immunology, 5th edn., pp. 83–198, Mosby, London.
Mosman, T.R., and Coffman, R.L. (1989) Th1 and Th2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties, Annu. Rev. Immunol. 7, 145–173.
Mosman, T.R., and Sad, S. (1996) The Expanding Universe of T-Cell Subsets: Th1, Th2 and More, Immunol. Today 17, 138–146.
Weiner, H.L. (1997) Oral Tolerance: Immune Mechanisms and the Treatment of Autoimmune Diseases, Immunol. Today 18, 335–343.
Romagnani, S. (1992) Induction of Th1 and Th2 Responses: A Key Role for the “Natural” Immune Response? Immunol. Today 13, 379–381
Vidard, L., Colarusso, L.J., and Benacerraf, B. (1995) Specific T-Cell Tolerance May Reflect Selective Activation of Lymphokine Synthesis, Proc. Nat. Acad. Sci. USA 92, 2259–2262.
Muraille, E., and Leo, O. (1998) Revisiting the Th1/Th2 Paradigm, Scand. J. Immunol. 47, 1–9.
Calder, P.C. (1998) Dietary Fatty Acids and Lymphocyte Functions, Proc. Nutr. Soc. 57, 487–502.
Harbige, L.S. (1998) Dietary n−6 and n−3 Fatty Acids in Immunity and Autoimmune Disease, Proc. Nutr. Soc. 57, 555–562.
Harbige, L.S., and Fisher, B.A.C. (2001) Dietary Fatty Acid Modulation of Mocosally-Induced Tolerogenic Immune Responses, Proc. Nutr. Soc. 60, 449–456.
Rivers, J. (1984) On the Essentiality of Omega-3 Polyunsaturated Fatty Acids, Br. J. Clin. Pract. (BJCP) 38, (Suppl. 31), 100–109.
Boissonneault, G.A., and Johnston, P.V. (1984) Humoral Immunity in Essential Fatty Acid-Deficient Rats and Mice: Effect of Route of Injection of Antigen, J. Nutr. 114, 89–94.
Jeffery, N.M., Sanderson, P., Newsholme, E.A., and Calder, P.C. (1998) Characteristics of Lipid and Lymphocytes Collected from the Lymph of Rats Fed a Low Fat Diet or High Fat Diets Rich in n−6 or n−3 Polyunsaturated Fatty Acids, Nutr. Res. 18, 299–308.
Asherson, G.L., and Stone, S.H. (1965) Selective and Specific Inhibition of 24 Hour Skin Reactions in the Guinea-Pig. I. Immune Deviation: Description of the Phenomenon and the Effect of Splenectomy, Immunology 9, 205–217.
Tanner, J.M. (1962) Growth at Adolescence, pp. 5–100, Blackwell, Oxford.
Young, J.Z. (1971) An Introduction to the Study of Man, pp. 219–225, Oxford University Press, Oxford.
Dewille, J.W., Fraker, P.J., and Romsos, D.R. (1979) Effects of Essential Fatty Acid Deficiency, and Various Levels of Dietary Polyunsaturated Fatty Acids, on Humoral Immunity in Mice, J. Nutr. 109, 1018–1027.
Erickson, K.L., Adams, D.A., and McNeil, C.J. (1983) Dietary Lipid Modulation of Immune Responsiveness, Lipids 18, 468–474.
Dvorak, B., and Stepankova, R. (1992) Effects of Dietary Essential Fatty Acid Deficiency on the Development of the Rat Thymus and Immune System, Prostaglandins Leukot. Essent. Fatty Acids 46, 183–190.
Cinader, B., Clandinin, M.T., Hosokawa, T., and Robblee, N.M. (1983) Dietary Fat Alters the Fatty Acid Composition of Lymphocyte Membranes and the Rate at Which Suppressor Capacity Is Lost, Immunol. Lett. 6, 331–337.
Laganiere, S., and Fernandes, G. (1991) Study on the Lipid Composition of Aging Fischer-344 Rat Lymphoid Cells: Effect of Long-Term Calorie Restriction, Lipids 26, 472–478.
Huang, S.-C., and Fritsche, K.L. (1992) Alteration in Mouse Splenic Phospholipid Fatty Acid Composition and Lymphoid Cell Populations by Dietary Fat, Lipids 27, 25–32.
Calder, P.C. (1994) Incorporation of Fatty Acids by Concanavalin A-Stimulated Lymphocytes and the Effect on Fatty Acid Composition and Membrane Fluidity, Biochem. J. 300, 509–518.
Harbige, L.S., Kone, I., Ghebremeskel, K., and Fisher, B. (2003) Membrane Phospholipid Fatty Acid Composition and Cytokine Secretion of Peripheral Blood Mononuclear Cells Obtained from Omega-6 Fatty Acid-Fed Volunteers, Immunol. Cell Biol. (in press).
Klein, A., Bruser, B., Bast, M., and Rachlis, A. (1992) Progress of HIV Infection and Changes in Lipid Membrane Structure of CD4+ Cells, AIDS 6, 332–333.
Scott, W.A., Zrike, J.M., Hamill, A.L., Kempe, J., and Cohn, Z.A. (1980) Regulation of Arachidonic Acid Metabolites in Macrophages, J. Exp. Med. 152, 324–335.
Lefkowith, J.B. (1988) Essential Fatty Acid Deficiency Inhibits the in vivo Generation of Leukotriene B4 and Suppresses Levels of Resident and Elicited Leukocytes in Acute Inflammation, J. Immunol. 140, 228–233.
Gyllenhammer, H., Palmblad, J., Ringertz, B., Hafstrom, I., and Borgeat, P. (1988) Rat Neutrophil Function and Leukotriene Generation in Essential Fatty Acid Deficiency, Lipids 23, 89–95.
Lefkowith, J., Morrison, A., Lee, V., and Rogers, M. (1990) Manipulation of the Acute Inflammatory Response by Dietary Polyunsaturated Fatty Acid Modulation, J. Immunol. 145, 1523–1529.
Rode, H.N., Szamel, M., Schneider, S., and Resch, K. (1982) Phospholipid Metabolism of Stimulated Lymphocytes. Preferential Incorporation of Polyunsaturated Fatty Acids into Plasma Membrane Phospholipid upon Stimulation with Concanavalin A, Biochim. Biophys. Acta 688, 66–74.
Endres, S., Ghorbani, R., Kelley, V.E., Georgilis, K., Lonnemann, G., van der Meer, J.M.W., Cannon, J.G., Rogers, T.S., Klemoner, M.S., Weber, P.C., et al. (1989) The Effect of Dietary Supplementation with n−3 Polyunsaturated Fatty Acids on the Synthesis of Interleukin-1 and Tumor Necrosis Factor by Mononuclear Cells, N. Engl. J. Med. 320, 265–271.
Goldyne, M.E., and Stobo, J.D. (1981) Immunoregulatory Role of Prostaglandins and Related Lipids, CRC Crit. Rev. Immunol. 2, 189–223.
Dustin, M.L., and Shaw, A.S. (1999) Costimulation: Building an Immunological Synapse, Science 283, 649–650.
Anel, A., Naval, J., Gonzalez, B., Torres, J.M., Mishal, Z., Uriel, J., and Pinerio, A. (1990) Fatty Acid Metabolism in Human Lymphocytes. I. Time-Course Changes in Fatty Acid Composition and Membrane Fluidity During Blastic Transformations of Peripheral Blood Lymphocytes, Biochim. Biophys. Acta 1044, 323–331.
Wakelam, M.J.O., and Harnett, M.M. (1998) Phospholipase A2 (EC 3.1.4.) and D (EC 3.1.4.4) Signalling in Lymphocytes, Proc. Nutr. Soc. 57, 551–554.
Sykulev, Y. (2000) From T-Cell Receptor Ligation to Effector Functions—Affinity, Kinetics and Pattern Recognition, The Immunologist 8, 51–57.
Fujikawa, M., Yamashita, N., Yamazaki, K., Sugiyama, E., Suzuki, H., and Hamazaki, T. (1992) Eicosapentaenoic Acid Inhibits Antigen-Presenting Cell Function of Murine Splenocytes, Immunology 75, 330–335.
Razin, E., Klein, B., and Globerson, A. (1981) Effects of Indomethacin Treatment on Human Peripheral Blood Monocytes, Prostaglandins Med. 6, 529–536.
Snyder, D.S., and Desforges, J.F. (1986) Lipoxgenase Metabolites of Arachidonic Acid Modulate Hematopoiesis, Blood 67, 1675–1679.
Shipman, P.M., Schmidt, R.R., and Chepenik, K.P. (1988) Relation Between Arachidonic Acid Metabolism and Development of Thymocytes in Fetal Thymic Organ Cultures, J. Immunol. 140, 2714–2720.
Calder, P.C., Bevan, S.J., and Newsholme, E.A. (1992) The Inhibition of T-lymphocyte Proliferation by Fatty Acids Is via an Eicosanoid-Independent Mechanism., Immunology 75, 108–115.
Oppenheimer-Marks, N., Kavanaugh, A.F., and Lipsky, P.E. (1994) Inhibition of the Transendothelial Migration of Human T Lymphocytes by Prostaglandin E2, J. Immunol. 152, 5703–5713.
Hopkins, J., McConnell, I., and Pearson, J.D. (1981) Lymphocyte Traffic Through Antigen-Stimulated Lymph Nodes II: Role of Prostaglandin E2 as a Mediator of Cell Shutdown, Immunology 42, 225–231.
Betz, M., and Fox, B.S. (1991) Prostaglandin E2 Inhibits Production of Th1 Lymphokines but Not of Th2 Lymphokines, J. Immunol. 146 108–113.
Phipps, R.P., Stein, S.H. and Roper, R.L. (1991) A New View of Prostaglandin E Regulation of the Immune Response, Immunol. Today 12, 349–352.
Snijdewint, F.G.M., Kalinski, P., Wierenga, E.A., Bos, J.D., and Kapsenberg, M.L. (1993) Prostaglandin E2 Differentially Modulates Cytokine Secretion Profiles of Human T Helper Lymphocytes, J. Immunol. 150, 5321–5329.
Demeure, C.E., Yang, L.P., Desjardins, C., Raynauld, P., and Delespesse, G. (1997) Prostaglandin E2 Primes Naïve T Cells for the Production of Anti-inflammatory Cytokines, Eur. J. Immunol. 12, 3526–3531.
Tripp, C.S., Wyche, A., Unanue, E.R., and Needleman, P. (1986) The Functional Significance of the Regulation of Macrophage Ia Expression by Endogenous Arachidonate Metabolites in vitro, J. Immunol. 137, 3915–3920.
Harizi, H., Juzan, M., Pitard, V., Moreau, J.F., and Gualde, N. (2002) Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions, J. Immunol. 168, 2255–2263.
Kunkel, S.L., Chensue, S.W., and Phan, S.H. (1986) Prostaglandins as Endogenous Mediators of Interleukin-1 Production, J. Immunol. 136, 186–192.
Renz, H., Gong, J-H., Schmidt, A., Nain, M., and Gemsa, D. (1988) Release of Tumor Necrosis Factor-α from Macrophages: Enhancement and Suppression Are Dose-Dependently Regulated by Prostaglandin E2 and Cyclic Nucleotides, J. Immunol. 141, 2388–2393.
Horiguchi, J., Spriggs, D., Imamura, K., Stone, R., Luebbers, R., and Kufe, D. (1989) Role of Arachidonic Acid Metabolism in Transcriptional Induction of Tumor Necrosis Factor Gene Expression by Phorbol Ester, Mol. Cell. Biol. 9, 252–258.
Van der Pouw Kraan, T.C.T., Boeije, L.C.M., Smeenk, R.J.T., Wijdenes, J., and Aarden, L.A. (1995) Prostaglandin-E2 Is a Potent Inhibitor of Human Interleukin 12 Production, J. Exp. Med. 181, 775–779.
Fulton, A.M., and Levy, J.G. (1980) The Possible Role of Prostaglandins in Mediating Immune Suppression by Nonspecific T Suppressor Cells, Cell. Immunol. 52, 29–37.
Webb, D.R., and Nowowiejski, I. (1981) Control of Suppressor Cell Activation via Endogenous Prostaglandin Synthesis: The Role of T Cells and Macrophages, Cell. Immunol. 63, 321–328.
Fischer, A., Durandy, A., and Griscelli, C. (1981) Role of Prostaglandin E2 in the Induction of Nonspecific T Lymphocyte Suppressor Activity, J. Immunol. 126, 1452–1455.
Gualde, N., Atluru, D., and Goodwin, J.S. (1985) Effect of Lipoxygenase Metabolites of Arachidonic Acid on Proliferation of Human T Cells and T Cell Subsets, J. Immunol. 134, 1125–1129.
Rola-Pleszczynski, M. (1985) Differential Effects of Leukotriene B4 on T4+ and T8+ Lymphocyte Phenotype and Immunoregulatory Functions, J. Immunol. 135, 1357–1360.
Gualde, N., Rigaud, M., and Goodwin, J. (1985) Induction of Suppressor Cells from Peripheral Blood T Cells by 15-Hydroperoxyeicosatetraenoic Acid (15-HPETE), J. Immunol. 135, 3424–3429.
Muscoplat, C.C., Rakich, P.M., Thoen, C.O., and Johnson, D.W. (1978) Enhancement of Lymphocyte Blastogenic and Delayed Hypersensitivity Skin Response by Indomethacin, Infect. Immun. 20, 627–631.
Mertin, J., and Stackpoole, A. (1981) Anti-PGE Antibodies Inhibit in vivo Development of Cell-Mediated Immunity, Nature 294, 456–458.
Mertin, J., Stackpoole, A., and Shumway, S.J. (1984) Prostaglndins and Cell-Mediated Immunity, Transplantation 37, 396–402.
Kunkel, S.L., Fantone, J.C., Ward, P.A., and Zurier, R.B. (1981) Modulation of Inflammatory Reactions by Prostaglandins, Prog. Lipid. Res. 20, 633–640.
Abou-El-Ela, S.H., Prasse, K.W., Carroll, R., Wade, A.E., Dharwadkar, S., and Bruce, O.R. (1988) Eicosanoid Synthesis in 7,12-Dimethylbenz(a)anthracene-Induced Mammary Carcinomas in Sprague-Dawley Rats Fed Primrose Oil, Menhaden Oil or Corn Oil Diet, Lipids 23, 948–954.
Harbige, L.S., Layward, L., Morris-Downes, M.M., Dumonde, D.C., and Amor, S. (2000) The Protective Effects of Omega-6 Fatty Acids in Experimental Autoimmune Encephalomyelitis (EAE) in Relation to Transforming Growth Factor-β1 (TGF-β1) Up-Regulation and Increased Prostaglandin E2 (PGE2) Production, Clin. Exp. Immunol. 122, 445–452.
Koga, S., Luke, P.P., Specht, S.M., Rominski, B., Jaquins-Gerstl, A., Hoffman, R.A., Thomson, A.W., and Jordan, M.L. (2000) Inhibition of the Allograft Response by Donor Specific Blood Transfusion: Association with Reduced Local Th1 Cytokines and Nitric Oxide but Enhanced Prostaglandin E2 production, Transplantation 70, 1788–1796.
Goldsby, R.A., Kindt, T.J., and Osborne, B.A. (2000) Kuby Immunology, 4th edn., pp. 215–267, W.H. Freeman and Company, New York.
Kahn, D.C., and Crawford M.A. (1986) Placental Essential Fatty Acid Transport and Prostaglandin Synthesis, Prog. Lipid Res. 25, 345–353.
Crawford, M.A. (1993) The Role of Essential Fatty Acids in Neural Development: Implications for Perinatal Nutrition, Am. J. Clin. Nutr. 57 (Suppl.), 703S-710S.
Crawford, M.A. (2000) Placental Delivery of Arachidonic and Docosahexaenoic Acids: Implications for the Lipid Nutrition of Pretern Infants, Am. J. Clin. Nutr. 71 (Suppl.) 275S-284S.
Andersen, G.E., Christensen, N.C., and Johansen, K.B. (1985) Fatty Acid Changes in Plasma Lipids and Lymphocyte Phospholipids After Infusion of Intralipid to Newborns, J. Parenter. Enteral Nutr. 6, 691–694.
Phylactos, A.C., Ghebremeskel, K., Costeloe, K., Leaf, A.A., Harbige, L.S., and Crawford, M.A. (1994) Polyunsaturated Fatty Acids and Antioxidants in Early Development. Possible Prevention of Oxygen-Induced Disorders, Eur. J. Clin. Nutr. 48 (Suppl. 2), S17-S23.
Crawford, M.A., Costeloe, K., Ghebremeskel, K., Phylactos, A., Skirvin, L., and Stacey, F. (1997) Are Deficits of Arachidonic and Docosahexaenoic Acids Responsible for Neural and Vascular Complications of Preterm Babies? Am. J. Clin. Nutr. 66 (Suppl.), 1032S-1041S.
Ghebremeskel, K., Burns, L., Costeloe, K., Burden, T.J., Harbige, L., Thomas, B., and Temple, E. (1999) Plasma Vitamin A and E in Preterm Babies Fed on Breast Milk or Formula Milk With or Without Long-Chain Polyunsaturated Fatty Acids, Int. J. Vitam. Nutr. Res. 69, 83–91.
Gualde, N., Cogny van Weydevelt, F., Buffiere, F., Jauberteau, M.O., Daculsi, R., and Vaillier, D. (1991) Influence of LTB4 on CD4− CD8− Thymocytes. Evidence That LTB4 plus IL-2 Generate CD8+ Suppressor Thymocytes Involved in Tolerance to Self. Effect of LTB4 and IL-2 on Double Negative Thymocytes, Thymus 18, 111–128.
Ushikubi, F., Aiba, Y., Nakamura, K., Namba, T., Hirata, M., Mazda, O., Katsura, Y., and Narumiya, S. (1993) Thromboxane A2 Receptor Is Highly Expressed in Mouse Immature Thymocytes and Mediates DNA Fragmentation and Apoptosis, J. Exp. Med. 178, 1825–1830.
Goetzl, E.J., An, S., and Zeng, L. (1995) Specific Suppression by Prostaglandin E2 of Activation-Induced Apoptosis of Human CD4+CD8+ T Lymphoblasts, J. Immunol. 154, 1041–1047.
Duchen, K., Yu, G., and Bjorksten, B. (1998) Atopic Sensitization During the First Year of Life in Relation to Long Chain Polyunsaturated Fatty Acid Levels in Human Milk, Pediatr. Res. 44, 478–484.
Willis, A.L., and Smith, J.B. (1981) Some Perspectives on Platelets and Prostaglandins, Prog. Lipid. Res. 20, 381–406.
O'Flaherty, J.T., Bass, D., Thomas, M., Dechatelet, L., Waite, M., and McCall, C. (1981) Role of Arachidonic Acid in Neutrophil Aggregation, Prog. Lipid Res. 20, 671–676.
Higgs, G.A. (1986) The Role of Eicosanoids in Inflammation, Prog. Lipid Res. 25, 555–561.
Crawford, M.A., and Harbige, L.S. (1988) n-3 Fatty Acids and the Evolution of the Brain, Clin. Biol. Res. 282, 336–354.
Horton, J. and Ratcliffe, N. (1998) Evolution of Immunity, in Immunology, 5th edn. (Roitt, I., Brostoff, J., and Male, D., eds.), pp. 199–220, Mosby, London.
Morley, J. (1974) Prostaglandins and Lymphokines in Arthritis, Prostaglandins 25, 315–326.
Alleva, D.G., Burger, C.J., and Elgert, K.D. (1994) Tumor-Induced Regulation of Suppressor Macrophage Nitric Oxide and TNF-α Production. Role of Tumor-Derived IL-10, TGF-β, and Prostaglandin E2, J. Immunol. 153, 1674–1686.
Young, M.R., Wright, M.A., Lozano, Y., Matthews, J.P., Benefield, J., and Prechel, M.M. (1996) Mechanisms of Immune Suppression in Patients with Head and Neck Cancer: Influence on the Immune Infiltrate of the Cancer, Int. J. Cancer 67, 333–338.
Kucharzik, T., Lugering, N., Winde, G., Domschke, W., and Stoll, R. (1997) Colon Carcinoma Cell Lines Stimulate Monocytes and Lamina Propria Mononuclear Cells to Produce IL-10, Clin. Exp. Immunol. 110, 296–302.
Calder, P.C. (1996) Immunomodulatory and Anti-inflammatory Effects of n−3 Polyunsaturated Fatty Acids, Proc. Nutr. Soc. 55, 737–774.
Santoli, D., and Zurier, R.B. (1989) Prostaglandin E Precursor Fatty Acids Inhibit Human IL-2 Production by a Prostaglandin E-Independent Mechanism, J. Immunol. 143, 1303–1309.
Madhavi, N., Das, U.N., Surya Prabha, P., Sravan Kumar, P., Koratkar, R., and Sangeeta Sagar, P. (1994) Suppression of Human T-Cell Growth in vitro by cis-Unsaturated Fatty Acids: Relationship to Free Radicals and Lipid Peroxidation, Prostaglandins Leukot. Essent. Fatty Acids 51, 33–40.
Chow, S.C., Sisfontes, L., Bjorkhem, I., and Jondal, M. (1989) Suppression of Growth in a Leukemic T Cell Line by n−3 and n−6 Polyunsaturated Fatty Acids, Lipids 24, 700–708.
Dornand, J., and Gerber, M. (1989) Inhibition of Murine T-Cell Responses by Anti-Oxidants: The Targets of Lipo-Oxygenase Pathway Inhibitors, Immunology 68, 384–391.
Calder, P.C. (1995) Fatty Acids, Dietary Lipids and Lymphocyte Functions, Trans. Biochem. Soc. 25, 302–309.
Kollmorgen, G.M., Sansing, W.A., Lehman, A.A., Fischer, G., Longley, R.E., Alexander, S.S., King, M.M., and McCay, P.B. (1979) Inhibition of Lymphocyte Function in Rats Fed High-Fat Diets, Cancer Res. 39, 3458–3462.
Meydani, S.N., Nicolosi, R.J., and Hayes, K.C. (1985) Effects of Long-Term Feeding of Corn Oil or Coconut Oil Diets on Immune Response and Prostaglandin E2 Synthesis of Squirrel and Cebus Monkeys, Nutr. Res. 5, 993–1002.
Young, M.R., Ellis, N.K., Young, M.E., and Wepsic, H.T. (1987) Stimulation of Hematopoiesis and Bone Marrow Suppressor Cells by the Subcutaneous Injection of Linoleic Acid, Cell. Immunol. 107, 238–248.
Yaqoob, P., Newsholme, E.A., and Calder, P.C. (1994) The Effect of Dietary Lipid Manipulation on Rat Lymphocyte Subsets and Proliferation, Immunology 82, 603–610.
Harbige, L.S., Yeatman, N., Amor, S., and Crawford, M.A. (1995) Prevention of Experimental Autoimmune Encephalomyelitis in Lewis Rats by a Novel Source of γ-Linolenic Acid, Br. J. Nutr. 74, 701–715.
De Deckere, E.M., Verplanke, C.J., Blonk, C.G., and Van Nielen, W.G. (1988) Effect of Type and Amount of Dietary Fat on Rabbit and Rat Lymphocyte Proliferation in vitro, J. Nutr. 118, 11–18.
Kelley, D.S., Nelson, G.J., Serrato, C.M., Schmidt, P.C., and Branch, L.B. (1988) Effects of Type of Dietary Fat on Indices of Immune Status in Rabbits, J. Nutr. 118, 1376–1384.
Friend, J.V., Lock, S.O., Gurr, M.I., and Parish, W.E. (1980) Effect of Different Dietary Lipids on the Immune Response of Hartley Strain Guinea-Pigs, Intern. Arch. Allergy Appl. Immunol. 62, 292–301.
Crevel, R.W.R., Friend, J.V., Goodwin, B.F.J., and Parish, W.E. (1992) High-Fat Diets and the Immune response of C57 B1 Mice, Br. J. Nutr. 67, 17–26.
Yamada, K., Hung, P., Yoshimura, K., Taniguchi, S., Lim, B.O., and Sugano, M. (1996) Effect of Unsaturated Fatty Acids and Antioxidants on Immunoglobulin Production by Mesenteric Lymph Node Lymphocytes of Sprague-Dawley Rats, J. Biochem. 120, 138–144.
Medawar, P.B., Hunt, R., and Mertin, J. (1979) An Influence of Diet on Transplantation Immunity, Proc. R. Soc. B 206, 265–280.
Otto, D.A., Kahn, D.R., Hamm, M.W., Hamazaki, T., Forrest, D.E., Wooten, J.T., and Grant, E. (1993) n−3 Polyunsaturated Fatty Acids as a Potential Adjuvant Therapy for Acute Rejection Following Cardiac Transplantation, in Essential Fatty Acids and Eicosanoids: Selected Papers from the 3rd International Congress (Sinclair, A., and Gibson, R., eds.) pp. 396–401, AOCS Press, Champaign.
Rossetti, R.G., Seiler, C.M., DeLuca, P., Laposata, M., and Zurier, R.M. (1997) Oral Administration of Unsaturated Fatty Acids: Effects on Human Peripheral Blood T Lymphocyte Proliferation, J. Leukoc. Biol. 62, 438–443.
Fisher, B.A.C., and Harbige, L.S. (1997) Effect of Omega-6 Lipid-Rich Borage Oil Feeding on Immune Function in Healthy Volunteers, Trans. Biochem. Soc. 25, 343S.
Harbige, L.S., Layward, L., Marris, M., and Amor, S. (1997) Cytokine Secretion by Human T Cell Clones Is Differentially Regulated by Eicosanoids, Trans. Biochem. Soc. 25, 347S.
Watanabe, S., Yssel, H., Harada, Y., and Arai, K. (1994) Effects of Prostaglandin E2 on Th0-Type Human T Cell Clones: Modulation of Functions of Nuclear Proteins Involved in Cytokine Production, Int. Immunol. 6, 523–532.
DeLuca, P., Rossetti, R.G., Alavian, C., Karim, C., and Zurier, R.B. (1999) Effects of γ-Linolenic Acid on Interleukin-1β and Tumor Necrosis Factor-α Secretion: Studies in vitro and in vivo, J. Investig. Med. 47, 246–250.
Fernandes, G. (1994) Dietary Lipids and Risk of Autoimmune Disease, Clin. Immunol. Immunopathol. 72, 193–197.
Kennedy, M.K., Torrance, D.S., Picha, K.S., and Mohler, K.M. (1992) Analysis of Cytokine mRNA Expression in the Central Nervous System of Mice with Experimental Autoimmune Encephalomyelitis Reveals That IL-10 mRNA Expression Correlates with Recovery, J. Immunol. 149, 2496–2505.
Khoury, S.J., Hancock, W.W., and Weiner, H.L. (1992) Oral Tolerance to Myelin Basic Protein and Natural Recovery from Experimental Autoimmune Encephalomyelitis Are Associated with Downregulation of Inflammatory Cytokines and Differential Upregulation of Transforming Growth Factor β. Interleukin 4, and Prostaglandin E Expression in the Brain, J. Exp. Med. 176, 1355–1364.
Liblau, R.S., Singer, S.M., and McDevitt, H.O. (1995) Th1 and Th2 CD4+ T Cells in the Pathogenesis of Organ-Specific Autoimmune Diseases, Immunol. Today 16, 34–38.
Levy, J.A., Ibrahim, A.B., Shirai, T., Ohta, K., Nagasawa, R., Yoshida, H., Estes, J., and Gardner, M. (1982) Dietary Fat Affects Immune Response, Production of Antiviral Factors, and Immune Complex Disease in NZB/NZW Mice, Proc. Natl. Acad. Sci. USA 79 1974–1978.
Lin, B., Huang, C., Chiang, B., and Jeng, S. (1996) Dietary Fat Influences Ia Antigen Expression, Cytokines and Prostaglandin E2 Production of Immune Cells in Autoimmune-Prone NZB × NZW F1 Mice, Br. J. Nutr. 75, 711–722.
Hurd, E.R., Johnston, J.M., Okita, J.R., MacDonald, P.C., Ziff, M., and Gilliam, J.M. (1981) Prevention of Glomerulonephritis and Prolonged Survival in New Zeland Black/New Zealand White F1 Hybrid Mice Fed an Essential Fatty Acid-Deficient Diet, J. Clin. Investig. 67, 478–485.
Kelley, V.E., Ferretti, A., Izui, S., and Strom, T.B. (1985) A Fish Oil Diet Rich in Eicosapentaenoic Acid Reduces Cyclooxygenase Metabolites, and Suppresses Lupus in MRL-1pr Mice, J. Immunol. 134, 1914–1919.
Morrow, W.J.W., Homsy, J., Swanson, C.A., Ohashi, Y., Estes, J., and Levy, A. (1986) Dietary Fat Influences the Expression of Autoimmune Disease in MRL/lpr/lpr Mice, Immunology 59, 439–443.
Godfrey, D.G., Stimson, W.H., Watson, R.R., Belch, J.J., and Sturrock, D. (1986) The Modulation of Autoimmunity in the MRL-mp-lpr/lpr Mouse by Dietary Fatty Acid Supplementation, Prog. Lipid Res. 25, 288–293.
Lin, B., Jeng, S., Chiang, B., and Huang, C. (1997) Dietary Fat Affects Lipids and Anti-Cardiolipin Antibody Levels in Autoimmune-Prone NZB/W F1 Mice, Br. J. Nutr. 77, 657–669.
Whiston, R., Stanford, M., Wallace, G., and Harbige, L.S. (1997) Effect of Borage Oil Feeding in Experimental Autoimmune Uveitis (EAU), Immunology 92 (Suppl. 1), 93 (Abstr).
Adda, D.H., Beraud, E., and Depieds, R. (1977) Evidence for Suppressor Cells in Lewis Rats' Experimental Allergic Encephalomyelitis, Eur. J. Immunol. 7, 620–623.
Karpus, W.J., and Swanborg, R.H. (1991) CD4+ Suppressor Cells Inhibit the Function of Effector Cells of Experimental Autoimmune Encephalomyelitis Through a Mechanism Involving Transforming Growth Factor-β, J. Immunol. 146, 1163–1168.
Hughes, D.A. (1998) In vitro and in vivo Effects of n−3 Polyunsaturated Fatty Acids on Human Monocyte Function, Proc. Nutr. Soc. 57, 521–525.
Sanderson, P., MacPherson, G.G., Jenkins, C.H., and Calder, P.C. (1997) Dietary Fish Oil Diminshes the Antigen Presentation Activity of Rat Dendritic Cells, J. Leukoc. Biol. 62, 771–777.
Pullman-Mooar, S., Laposata, M., Lem, D., Holman, R.T., Leventhal, L.J., Demarco, D., and Zurier, R.B. (1990) Alteration of the Cellular Fatty Acid Profile and the Production of Eicosanoids in Human Monocytes by γ-Linolenic Acid, Arthritis Rheum. 33, 1526–1533.
Fan, Y., and Chapkin, R.S. (1992) Mouse Peritoneal Macrophage Prostaglandin E1 Synthesis Is Altered by Dietary γ-Linolenic Acid, J. Nutr. 122, 1600–1606.
Tate, G., Mandell, B.F., Laposata, M., Ohliger, D., Baker, D.G., Schumacher, R.H., and Zurier, R.B. (1989) Suppression of Acute and Chronic Inflammation by Dietary γ-Linolenic Acid, J. Rheumatol. 16, 729–733.
Clausen, J., and Moller, J. (1967) Allergic Encephalomyelitis Induced by Brain Antigen After Deficiency in Polyunsaturated Fatty Acids During Myelination, Acta Neurol. Scand. 43, 375–388.
Abbas, A.K., Lichtman, A.H., and Pober, J.S. (1997) Cellular and Molecular Immunology, 3rd edn., pp. 424–438, W.B. Saunders Company, Philadelphia.
Yaqoob, P., and Calder, P. (1995) Effects of Dietary Lipid Manipulation upon Inflammatory Mediator Production by Murine Macrophages, Cell. Immunol. 163, 120–128.
Hiraoka, K., Sasaguri, Y., Komiya, S., Zenmyo, M., Inoue, A., and Morimatsu, M. (1993) Effects of Lipid Peroxide on Production of Matrix Metalloproteinase 1 (Tissue Collagenase) and 3 (Stromelysin) and Tissue Inhibitor Metalloproteinase 1 by Human Rheumatoid Synovial Fibroblasts, Exp. Mol. Pathol. 59, 169–176.
Hennig, B., Toborek, M., McClain, C.J., and Diana, J.C. (1996) Nutritional Implications in Vascular Endothelial Cell Metabolism, J. Am. Coll. Nutr. 15, 345–358.
Harbige, L.S., Crawford, M.A., Jones, J., Preece, A.W., and Forti, A. (1986) Dietary Intervention Studies on the Phosphoglyceride Fatty Acids and Electrophoretic Mobility of Erythrocytes in Multiple Sclerosis, Prog. Lipid Res. 25, 243–248.
Harbige, L.S., Ghebremeskel, K., Williams, G., and Summers, P. (1990) n−3 and n−6 Phosphoglyceride Fatty Acids in Relation to Hydrogen Peroxide Induced in vitro Erythrocyte Haemolysis in Captive Marmosets (Callithrix jacchus), Comp. Biochem. Physiol. 97B, 167–170.
Witting, L.A. (1972) The Role of Polyunsaturated Fatty Acids in Determining Vitamin E Requirement, Ann. N.Y. Acad. Sci. 203, 192–198.
Dworkin, R.H., Bates, D., Millar, J.H.D., and Paty, D.W. (1984) Linoleic Acid and Multiple Sclerosis: A Reanalysis of Three Double-Blind Trials, Neurology 34, 1441–1445.
Burton, J.L. (1989) Dietary Fatty Acids and Inflammatory Skin Disease, Lancet i, 27–31.
Belch, J.J.F., and Muir, A. (1998) n−6 and n−3 Essential Fatty Acids in Rheumatoid Arthritis and Other Rheumatic Conditions, Proc. Nutr. Soc. 57, 563–569.
Leventhal, L.J., Boyce, E.G., and Zurier, R.B. (1993) Treatment of Rheumatoid Arthritis with γ-Linolenic Acid, Ann. Intern. Med. 119, 867–873.
Zurier, R.B., Rossetti, R.G., Jacobson, E.W., Demarco, D.H., Liu, N.Y., Temming, J.E., White, B.M., and Laposata, M. (1996) γ-Linolenic Acid Treatment of Rheumatoid Arthritis, Arthritis Rheum. 39, 1808–1817.
Melnik, B.C., and Plewig, G. (1989) Is the Origin of Atopy Linked to Deficient Conversion of n−6 Fatty Acids to Prostaglandin E1?. J. Am. Acad. Dermatol. 21, 557–563.
Mertin, J., and Meade, C.J. (1977) Relevance of Fatty Acids in Multiple Sclerosis, Br. Med. Bull. 33, 67–71.
Meade, C.J., Mertin, J., Sheena, J., and Hunt, R. (1978) Reduction by Linoleic Acid of the Severity of Experimental Allergic Encephalomyelitis in the Guinea Pig, J. Neurol. Sci. 35, 291–308.
Navarro, X., and Segura, R. (1988) Plasma Lipids and Their Fatty Acid Composition in Multiple Sclerosis, Acta Neurol. Scand. 78, 152–157.
Bruderlein, H., Daniel, R., Boismenu, D., Julien, N., and Couture, F. (1981) Fatty Acid Profiles of Serum Phospholipids in Patients Suffering Rheumatoid Arthritis, Prog. Lipid Res. 20, 625–631.
Johansson, U., Portinsson, S., Akesson, A., Svantesson, H., and Akesson, B. (1986) Fatty Acid Composition of Plasma Phosphatidylcholine and Erythrocyte Lipids and Dietary Fat Intake in Juvenile Chronic Arthritis, Prog. Lipid Res. 25, 579–582.
Haugen, M.A., Kjeldsen-Kragh, J., Bjerve, K., Hostmark, A.T., and Forre, O. (1994) Changes in Plasma Phospholipid Fatty Acids and Their Relationship to Disease Activity in Rheumatoid Arthritis Patients Treated with a Vegetarian Diet, Br. J. Nutr. 72, 555–566.
McCowen, K.C., Ling, P.R., and Bistrian, B.R. (2000) Arachidonic Acid Concentrations in Patients with Crohn Disease, Am. J. Clin. Nutr. 71, 1008–1009.
Hassam, A.G., Rivers, J.P.W., and Crawford, M.A. (1977) Metabolism of γ-Linolenic Acid in Essential Fatty Acid-Deficient Rats, J. Nutr. 107, 519–524.
Phylactos, A.C., Harbige, L.S., and Crawford, M.A. (1994) Essential Fatty Acids Alter the Activity of Manganese-Superoxide Dismutase in Rat Heart, Lipids 29, 111–115.
Hinds, A., and Sanders, T.A.B. (1993) The Effect of Increasing Levels of Dietary Fish Oil Rich in Eicosapentaenoic and Docosahexaenoic Acids on Lymphocyte Phospholipid Fatty Acid Composition and Cell-Mediated Immunity in the Mouse, Br. J. Nutr. 69, 423–429.
Cantillon, D.M., Morrissey, P.A., O'Connor, T.P., and Flynn, A. (1990) Effect of Dietary Fish Oil on Rat Lymphocyte Proliferation in vitro, Proc. Nutr. Soc. 49, 113A.
Wu, D., Meydani, S.N., Meydani, M., Hayek, M.G., Huth, P., and Nicolosi, R.J. (1996) Immunologic Effects of Marine- and Plant-Derived n−3 Polyunsaturated Fatty Acids in Nonhuman Primates, Am. J. Clin. Nutr. 63, 273–280.
Harbige, L.S. (1996) Nutrition and Immunity with Emphasis on Infection and Autoimmune Disease, Nutr. Health 10, 285–312.
Meydani, S.N., Lichtenstein, A.H., Cornwall, S., Meydani, M., Goldin, B.R., Rasmussen, H., Dinarello, C.A., and Schaefer, E.J. (1993) Immunologic Effects of National Cholesterol Education Panel Step-2 Diets With and Without Fish-Derived n−3 Fatty Acid Enrichment, J. Clin. Investing. 92, 105–113.
Bell, S.J., Chavali, S., Bistrian, B.R., Connolly, C.A., Utsunomiya, T., and Forse, R.A. (1996) Dietary Fish Oil and Cytokine and Eicosanoid Production During Human Immunodeficiency Virus Infection, J. Parenter. Enteral Nutr. 20, 43–49.
Prickett, J.D., Robinson, D.R., and Bloch, K.J. (1982) Enhanced Production of IgE and IgG Antibodies Associated with a Diet Enriched in Eicosapentaenoic Acid, Immunology 46, 819–826.
de Caterina, R., Cybulsky, M.A., Clinton, S.K., Gimbrone, M.A., and Libby, P. (1995) Omega-3 Fatty Acids and Endothelial Leukocyte Adhesion Molecules, Prostaglandins Leukot. Essent. Fatty Acids 52, 191–195.
Khalfoun, B., Bardos, P., and Lebranchu, Y. (1996) In vitro Effects of Docosahexaenoic and Eicosapentaenoic Acids on Human Endothelial Cell Production of Interleukin-6 and Lymphocyte-Endothelial Cell Interactions, in Omega-3, Lipoproteins and Atherosclerosis (Davignon, J., Fruchart, J.C., and Ordovas, J.M., eds.), pp. 65–81, John Libbey Eurotext, Paris.
Khalfoun, B., Sibue, D., Bardos, P., and Lebranchu, Y. (1998) Docosahexaenoic and Eicosapentaenoic Acids Inhibit the CD28-Lymphocyte Activation Pathway in vitro, Transplant. Proc. 30, 3978–3979.
Blok, W.L., Katan, M.B., and van der Meer, J.W.M. (1996) Modulation of Inflammation and Cytokine Production by Dietary n−3 Fatty Acids, J. Nutr. 126, 1515–1533.
Barnes, P.J., and Liew, F.Y. (1995) Nitric Oxide and Asthmatic Inflammation, Immunol. Today 16, 128–130.
Robinson, D.R., Colvin, R.B., Hirai, A., and Steinberg, A.D. (1986) Dietary Marine Lipids Modify Autoimmune Diseases, in Health Effects of Polyunsaturated Fatty Acids in Seafoods, pp. 247–259, Academic Press, Orlando.
Fernandes, G., Bysani, C., Venkatraman, J.T., Tomar, V., and Zhao, W. (1994) Increased TGF-β and Decreased Oncogene Expression by ω-3 Fatty Acids in the Spleen Delays Onset of Autoimmune Disease in B/W Mice, J. Immunol. 152, 5979–5987.
Chandrasekar, B., Troyer, D.A>, Venkatraman, J.T., and Fernandes, G. (1995) Dietary Omega-3 Lipids Delay the Onset and Progression of Autoimmune Lupus Nephritis by Inhibiting Transforming Growth Factor-β mRNA and Protein Expression, J. Autoimmun. 8, 381–393.
Fernandes, G., Chandrasekar, B., Luan, X., and Troyer, D.A. (1996) Modulation of Antioxidant Enzymes and Programmed Cell Death by n−3 Fatty Acids, Lipids 31 (Suppl.) S91-S96.
Avula, C.P., Zaman, A.K., Lawrence, R., and Fernandes, G. (1999) Induction of Apoptosis and Apoptotic Mediators in Balb/C Splenic Lymphocytes by Dietary n−3 and n−6 Fatty Acids, Lipids 34, 921–927.
Venkatraman, J.T., and Chu, W.C. (1999) Effects of Dietary Omega-3 and Omega-6 Lipids and Vitamin E on Serum Cytokines, Lipid Mediators and Anti-DNA Antibodies in a Mouse Model for Rheumatoid Arthritis, J. Am. Coll. Nutr. 18, 602–613.
Mosconi, C., Colli, S., Medini, L., Stragliotto, E., Maderna, P., Tremoli, E., and Galli, C. (1988) Vitamin E Influences the Effects of Fish Oil on Fatty Acids and Eicosanoid Production in Plasma and Circulating Cells in the Rat, Biochem. Pharmacol. 37, 3415–3421.
Leslie, C.A., Gonnerman, W.A., Ullman, M.D., Hayes, K.C., Franzblau, C., and Cathcart, E.S. (1985) Dietary Fish Oil Modulates Macrophage Fatty Acids and Decreases Arthritis Susceptibility in Mice, J. Exp. Med. 162, 1336–1349.
Prickett, J.D., Trentham, D.E., and Robinson, D.R. (1984) Dietary Fish Oil Augments the Induction of Arthritis in Rats Immunized with Type II Collagen, J. Immunol. 132, 725–729.
Harbige, L.S. (1993) Essential Fatty Acids, Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis, Ph.D. Thesis, Brunel University, Uxbridge, London, pp. 76–86.
Mertin, J. (1983) Omega-6 and Omega-3 Polyunsaturates and the Immune System, Br. J. Clin. Pract. (Suppl.) 31, 111–114.
Grimm, H., Grimminger, F., Korom, S., and Seeger, W. (1998) Use of Fish Oil to Prevent Graft Rejection, Proc. Nutr. Soc. 57, 577–585.
Chang, H.R., Dullon, A.G., Vladoianu, I.R., Piguet, P.F., Arsenijevic, D., Girardier, L., and Pechere, J.C. (1992) Fish Oil Decreases Natural Resistance to Infection with Salmonella typhimurium, Metabolism 41, 1–2.
D'Ambola, J.B., Aeberhard, L.M., Trang, N., Gaffar, S., Barrett, C.T., and Sherman, M.P. (1991) Effect of Dietary n−3 and n−6 Fatty Acids on in vivo Pulmonary Bacterial Clearance by Neonatal Rabbits, J. Nutr. 121, 1262–1269.
Mayatepek, E., Paul, K., Leichsenring, M., Pfisterer, M., Wagner, D., Domann, N., Sonntag, H.G., and Bremer, H.J. (1994) Influence of Dietary n−3 Polyunsaturated Fatty Acids on Leukotriene B4 and Prostaglandin E2 Synthesis and Course of Experimental Tuberculosis in Guinea Pigs, Infection 22, 106–112.
Fritsche, K.L., Shahbazian, L.M., Feng, C., and Berg, J.N. (1997) Dietary Fish Oil Reduces Survival and Impairs Bacterial Clearance in C3H/Hen Mice Challenged with Listeria monocytogenes, Clin. Sci. 92, 95–101.
Byleveld, P.M., Pang, G.T., Clancy, R.L., and Roberts, D.C.K. (1999) Fish Oil Feeding Delays Influenza Virus Clearance and Impairs Production of Interferon-γ and Virus-Specific Immunoglobulin A in the Lungs of Mice, J. Nutr. 129, 328–335.
Fritsche, K.L., Byrge, M., and Feng, C. (1999) Dietary Omega-3 Polyunsaturated Fatty Acids from Fish Oil Reduce Interleukin-12 and Interferon-Gamma Production in Mice, Immunol. Lett. 65, 167–173.
Blok, W.L., Vogels, M.T., Curfs, J.H., Eling, W.M., Buurman, W.A., and van der Meer, J.W. (1992) Dietary Fish-Oil Supplementation in Experimental Gram-Negative Infection and in Cerebral Malaria in Mice, J. Infect. Dis. 165, 898–903.
Bjornsson, S., Hardardottir, I., Gunnarsson, E., and Haraldsson, A. (1997) Dietary Fish Oil Supplementation Increases Survival in Mice Following Klebsiella pneumoniae Infection, Scand. J. Infect. Dis. 29, 491–493.
Fernandes, G., Tomar, V., Venkatraman, M.N., and Venkatraman, J.T. (1992) Potential of Diet Therapy on Murine AIDS, J. Nutr. 122, 716–722.
Godfrey, D.G. (1957) Antiparasitic Action of Dietary Cod Liver Oil upon Plasmodium berghei and Its Reversal by Vitamin E, Exp. Parasitol. 6, 555–565.
Levander, O.A., Ager, A.L., and Beck, M.A. (1995) Vitamin E and Selenium: Contrasting and Interacting Nutritional Determinants of Host Resistance to Parasitic and Viral Infections, Proc. Nutr. Soc. 54, 475–487.
Mascioli, E., Leader, L., Flores, E., Trimbo, S., Bistrian, B., and Blackburn, G. (1988) Enhanced Survival to Endotoxin in Guinea Pigs Fed IV Fish Oil Emulsion, Lipids 23, 623–625.
Terano, T., Salmon, J.A., and Moncada, S. (1984) Effect of Orally Administered Eicosapentaenoic Acid (EPA) on the Formation of Leukotriene B4 and Leukotriene B5 by Rat Leukocytes, Biochem. Pharmacol. 33, 3071–3076.
Leitch, G.A., Lee, T.H., Ringel, E.W., Prickett, J.D., Robinson, D.R., Pyne, S.G., Corey, E.J., Drazen, J.M., Austen, K.F., and Lewis, R.A. (1984) Immunologically Induced Generation of Tetraene and Pentaene Leukotrienes in the Peritoneal Cavities of Menhaden-Fed Rats, J. Immunol. 132, 2556–2565.
Lokesh, B.R., Black, J.M., German, J.B., and Kinsella, J.E. (1988) Docosahexaenoic Acid and Other Dietary Polyunsaturated Fatty Acids Suppress Leukotriene Synthesis by Mouse Peritoneal Macrophages, Lipids 23, 968–972.
Schmidt, E.B., and Dyerberg, J. (1989) n−3 Fatty Acids and Leucocytes, J. Intern. Med. 225 (Suppl. 1), 151–158.
Kremer, J.M., Jubiz, W., Michalek, A., Rynes, R.I., Bartholomew, L.E., Bigaouette, J., Timchalk, M., Beeler, D., and Lininger, L. (1987) Fish-Oil Fatty Acid Supplementation in Active Rheumatoid Arthritis: A Double-Blinded. Controlled, Crossover Study, Ann. Intern. Med. 106, 497–502.
Cleland, L.G., French, J.K., Betts, W.H., Murphy, G.A., and Elliott, M.J. (1988) Clinical and Biochemical Effects of Dietary Fish Oil Supplements in Rheumatoid Arthritis, J. Rheumatol. 15, 1471–1475.
Kremer, J.M., Bigauoette, J., Michalek, A.V., Timchalk, M.A., Lininger, L., Rynes, R.I., Huyck, C., Zieminski, J., and Bartholomew, L.E. (1985) Effects of Manipulation of Dietary Fatty Acids on Clinical Manifestestations of Rheumatoid Arthritis, Lancet, i, 184–187.
Sperling, R.I. (1998) The Effects of Dietary n−3 Polyunsaturated Fatty Acids on Neutrophils, Proc. Nutr. Soc. 57, 527–534.
Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., and Miglioli, M. (1996) Effect of an Enteric-Coated Fish-Oil Preparation on Relapses in Crohn's Disease, N. Engl. J. Med. 334, 1557–1560.
Donadio, J.V., Jr., Bergstralh, E.J., Offord, K.P., Spencer, D.C., and Holley, K.E. (1994) A Controlled Trial of Fish Oil in IgA Nephropathy, N. Engl. J. Med. 331, 1194–1199.
Bjorneboe, A., Soyland, E., Bjorneboe, G.-E.A., Rajka, G., and Drevon, C.A. (1987) Effect of Dietary Supplementation with Eicosapentaenoic Acid in the Treatment of Atopic Dermatitis, Br. J. Dermatol. 117, 463–469.
Bittiner, S.B., Tucker, W.F.G., Cartwright, I., and Bleehen, S.S. (1988) A Double Blind Randomised Placebo-Controlled Trial of Fish Oil in Psoriasis, Lancet i, 378–380.
Walton, A.J.E., Snaith, M.L., Locniskar, M., Cumberland, A.G., Morrow, W.J.W., and Isenberg, D.A. (1991) Dietary Fish Oil and the Severity of Symptoms in Patients with Systemic Lupus Erythematosus, Ann. Rheum. Dis. 50, 463–466.
Greenwood, B.M. (1968) Autoimmune Disease and Parasitic Infections in Nigerians, Lancet i, 380–382.
Lee, S.L., and Siegel, M. (1976) Systemic Lupus Erythematosus: Epidemiological Clues to Pathogenesis, in Infection and Immunology in the Rheumatic Diseases (Dumonde, D., ed.), pp. 307–317, Blackwell, Oxford.
Agranoff, B.W., and Goldberg, D. (1974) Diet and the Geographical Distribution of Multiple Sclerosis, Lancet ii, 1061–1066.
Esparza, M.L., Sasaki, S., and Kesteloot, H. (1995) Nutrition, Latitude, and Multiple Sclerosis Mortality: An Ecologic Study, Am. J. Epidemiol. 142, 733–737.
Linos, A., Kaklamanis, E., Kontomerkos, A., Koumantaki, Y., Gazi, S., Vaiopoulos, G., Tsokos, G.C., and Kaklamanis, P. (1991) The Effect of Olive Oil and Fish Consumption on Rheumatoid Arthritis—A Case Control Study, Scand. J. Rheumatol. 20, 419–426.
Heliovaara, M., Knekt, P., Aho, K., Aaran, R.-K., Alfthan, G., and Aromaa, A. (1994) Serum Antioxidants and Risk of Rheumatoid Arthritis, Ann. Rheum. Dis. 53, 51–53.
Kromann, N., and Green, A. (1980) Epidemiological Studies in the Upernavik District. Greenland, Acta Med. Scand. 208, 401–406.
Ross, R. (1999) Atherosclerosis—An Inflammatory Disease, N. Engl. J. Med. 340, 115–126.
Murasko, D.M., Weiner, P., and Kaye, D. (1987) Decline in Mitogen-Induced Proliferation of Lymphocytes with Increasing Age, Clin. Exp. Immunol. 70, 440–448.
Manoussaki, M.N., Tzioufas, A.G., Silis, P.J.E., Pange, J., Goudevenos, J., and Moutsopoulos, H.M. (1987) High Prevalence of Anti-cardiolipin and Other Autoantibodies in a Healthy Elderly Population, Clin. Exp. Immunol. 69, 557–565.
Mariotti, S., Sansoni, P., Barbesino, G., Caturegli, P., Monti, D., Cossarizza, A., Giacomelli, T., Passeri, G., Fagiolo, U., Pinchera, A., et al. (1992) Thyroid and Other Organ-Specific Autoantibodies in Healthy Centenarians, Lancet 339, 1506–1508.
Lesourd, B. (1999) Immune Response During Disease and Recovery in the Elderly, Proc. Nutr. Soc. 58, 85–98.
Bruunsgaard, H., Pedersen, A.N., Shroll, M., Skinhoj, P., and Pederson, B.K. (2000) Prohterative Responses of Blood Mononuclear Cells (PBMC) in a Cohort of Elderly Humans: Role of Lymphocyte Phenotype and Cytokine Production, Clin. Exp. Immunol. 119, 433–440.
Consolini, R., Legitimo, A., Calleri, A., and Milani, M. (2000) Distribution of Age-Related Thymulin Titres in Normal Subjects Through the Course of Life, Clin. Exp. Immunol. 121, 444–447.
Sakata-Kaneko, S., Wakatsuki, Y., Matsunaga, Y., Usui, T., and Kita, T. (2000) Altered Th1/Th2 Commitment in Human CD4+ T Cells with Ageing, Clin. Exp. Immunol. 120, 267–273.
Huber, L.A., Xu, Q.-B., Jurgens, G., Bock, G., Buhler, E., Gey, K.F., Schonitzer, D., Traill, K.N., and Wick, G. (1991) Gorrelation of Lymphocyte Lipid Composition Membrane Microviscosity and Mitogen Response in the Aged, Eur. J. Immunol. 21, 2761–2765.
Stulnig T.M., Buhler, E., Bock, G., Kirchebner, C., Schonitzer, D., and Wick, G. (1995) Altered Switch in Lipid Composition During T Cell Blast Transformation in the Healthy Elderly, J. Gerontol. 50A, B383-B390.
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Harbige, L.S. Fatty acids, the immune response, and autoimmunity: A question of n−6 essentiality and the balance between n−6 and n−3. Lipids 38, 323–341 (2003). https://doi.org/10.1007/s11745-003-1067-z
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DOI: https://doi.org/10.1007/s11745-003-1067-z