**4. Conclusions**

502 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

effect of fish oil in the disease without significant findings. In these trials olive oil was used as a placebo again and although nonsignificant trends, toward less disability and certain improvements in quality of life, have been found the results are inconclusive (Bates et al., 1989; Weinstock-Guttman et al., 2005). However others researchers have found beneficial effects of fish oil in MS patients. Shinto et al. have reported that *n-3* fatty acids supplementation significantly decreased matrix metalloproteinase-9 (MMP-9) levels in relapsing-remitting MS. This enzyme is thought to have a significant role in the transmigration of inflammatory cells into the central nervous system by aiding in the disruption of the blood brain barrier. In this way the ability of *n-3* fatty acids to decrease the levels secreted by immune cells may be a significant observation in spite of significant

Taken over all epidemiological data, animal data and clinical trial we can confirm that PUFA, particularly *n-6* fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis. However different factors must be better controlled in the clinical trials to achieve convincing results, like trials design, sample size and the choice of an appropriate placebo. This last item is of a great important because of olive oil has been used as a placebo in most of the reviewed clinical trials, however experience of our laboratory and others clearly proved the great immunomodulator potential of this fat, usually considered relatively inert (Puertollano et al., 2004; Puertollano et al., 2010). In this way olive oil may be acting in immune system of MS patients and no significant different with *n-3* and *n-6* PUFA can be

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreatic islets. Dietary factors have been implicated in the aetiology of type 1 diabetes as well as in initiating the autoimmune process that leads to clinical disease. Macrophages and T cells, attracted to the islets, secrete soluble mediators such as oxygen free radicals, nitric oxide (NO), and the cytokines IL-1ß, interferon (IFN)-γ and TNF-α. Increasing evidence suggests that these mediators induce apoptosis, the main mode of ß-cell death in the development of T1DM. Fatty acids, because of their properties as anti-inflamatory compounds as well as cell apoptosis modulators, may be useful in the

Earlier investigations suggested that deficiency of essential fatty acids, including *n-6* and *n-3* PUFA, caused a resistance in development of the diabetes in certain animal models

However, in 2001 Krishna Mohan & Das carried out a study to evaluate the effect of supplementation of various PUFA-rich oils on the incidence of alloxan-induced diabetes in experimental animals (Krishna Mohan et al., 2001). These authors have reported that *n-3* and *n-6* fatty acids may prevent alloxan-induced diabetes in experimental animals administered before of the diabetogenic agent and this preventive action may reside in their ability to enhance antioxidant status, suppress cytokine production, and activate PPARs. These researchers have evaluated also the effect of estearic saturated FA, oleic MUFA and *n-6* AA

Recently others authors have evaluated the efficacy of a right balance *n-6*/*n-3* PUFA in diet of T1DM model NOD mice finding that low *n-6*/*n-3* ratio delays the onset of diabetes

PUFA in the same model finding that only AA was effective (Suresh et al., 2006).

changes in quality of life have not been found (Shinto et al., 2009).

**3.5 Action of dietary lipids in type 1 diabetes mellitus** 

**3.5.1 Findings from studies in animal models of type 1 diabetes** 

found.

management of T1DM.

(Lefkowith et al., 1990; Wright et al., 1995).

In the recent years the immunonutrition area has advanced significantly to elucidate the role of the diet in development and function of immune system and to prevent or ameliorate numerous diseases in which immune system is implicated like infections, cancer, inflammatory disease, allergies and autoimmune disorders. Among the diet components, fatty acids (PUFA in particular), are especially interesting by their immunomodulator and anti-inflammatory role.

Autoimmune disorders are a complex group of disease characterized by an exacerbated immune response against self structures and an elevated inflammatory state. Several investigations have shown that fatty acids and especially *n-3* PUFA act as potent antiinflammatory molecules and even induce a strong immunosupression. For this reason, the use of fatty acids has been considered a good a therapeutic strategy in prevention and treatment of these diseases.

In spite of convincing data from the several studies with animal model, clinical trials have not achieved similar results. Only clear evidence in management of rheumatoid arthritis and in remission maintenance in Crohn's disease patients justifies the use of fish oil, and perhaps in combination with olive oil. However results from studies with other diseases like ulcerative colitis, lupus and multiple sclerosis are promising. Future studies with a better control of placebo, number of enrolled patients and design are necessary to justify of use of fatty acids in this type of immune disorders.

Finally epidemiological studies report that Mediterranean countries with a traditionall diet rich in fruits and vegetables, fish oil and olive oil and poor in saturated fats, have lower levels of inflammatory disease than countries with other type of diet. In the same way countries like Japan with changes in the habitual diet to "western diet" have increased rates

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 505

Calder, P.C. (2006). N-3 Polyunsaturated Fatty Acids, Inflammation, and Inflammatory

Calder, P.C., Yaqoob, P., Thies, F., Wallace, F.A. & Miles, E.A. (2002). Fatty acids and

Camuesco, D., Galvez, J., Nieto, A., Comalada, M., Rodriguez-Cabezas, M.E., Concha, A.,

Clark, W.F., Parbtani, A., Naylor, C.D., Levinton, C.M., Muirhead, N., Spanner, E., Huff,

Cleland, L.G. & James, M.J. (2000). Fish oil and rheumatoid arthritis: antiinflammatory and

Cleland, L.G., French, J.K., Betts, W.H., Murphy, G.A. & Elliott, M.J. (1988). Clinical and

Darlington, L.G. & Stone, T.W. (2001). Antioxidants and fatty acids in the amelioration of

Duffy, E.M., Meenagh, G.K., McMillan, S.A., Strain, J.J., Hannigan, B.M. & Bell, A.L. (2004).

Espersen, G.T., Grunnet, N., Lervang, H.H., Nielsen, G.L., Thomsen, B.S., Faarvang, K.L.,

Feagan, B.G., Sandborn, W.J., Mittmann, U., Bar-Meir, S., D'Haens, G., Bradette, M., Cohen,

*Association,* Vol 299, No.14, pp 1690-1697, ISSN/ISBN 1538-3598; 0098-7484.

No.4, pp 409-418, ISSN/ISBN 0029-6651; 0029-6651.

1519S, ISSN/ISBN 0002-9165; 0002-9165.

ISSN/ISBN 0007-1145; 0007-1145.

ISSN/ISBN 0022-3166; 0022-3166.

86, ISSN/ISBN 0085-2538; 0085-2538.

ISSN/ISBN 0315-162X; 0315-162X.

No.3, pp 251-269, ISSN/ISBN 0007-1145; 0007-1145.

1556, ISSN/ISBN 0315-162X; 0315-162X.

ISSN/ISBN 0770-3198; 0770-3198.

162X.

processes and rheumatoid arthritis. *The Proceedings of the Nutrition Society,* Vol 67,

Diseases. *The American Journal of Clinical Nutrition,* Vol 83, No.6 Suppl, pp 1505S-

lymphocyte functions. *The British journal of nutrition,* Vol 87 Suppl 1, pp S31-48,

Xaus, J. & Zarzuelo, A. (2005). Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, attenuates colonic inflammation in rats with DSS-induced colitis. *The Journal of nutrition,* Vol 135, No.4, pp 687-694,

M.W., Philbrick, D.J. & Holub, B.J. (1993). Fish oil in lupus nephritis: clinical findings and methodological implications. *Kidney international,* Vol 44, No.1, pp 75-

collateral health benefits. *The Journal of rheumatology,* Vol 27, No.10, pp 2305-2307,

biochemical effects of dietary fish oil supplements in rheumatoid arthritis. *The Journal of rheumatology,* Vol 15, No.10, pp 1471-1475, ISSN/ISBN 0315-162X; 0315-

rheumatoid arthritis and related disorders. *The British journal of nutrition,* Vol 85,

The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. *The Journal of rheumatology,* Vol 31, No.8, pp 1551-

Dyerberg, J. & Ernst, E. (1992). Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. *Clinical rheumatology,* Vol 11, No.3, pp 393-395,

A., Dallaire, C., Ponich, T.P., McDonald, J.W., Hebuterne, X., Pare, P., Klvana, P., Niv, Y., Ardizzone, S., Alexeeva, O., Rostom, A., Kiudelis, G., Spleiss, J., Gilgen, D., Vandervoort, M.K., Wong, C.J., Zou, G.Y., Donner, A. & Rutgeerts, P. (2008). Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. *JAMA : the journal of the American Medical* 

of inflammatory disease. In our opinion the best strategy recommending to population in general, and autoimmune disease patients in particular, is the maintenance of a healthy diet rich in naturals antioxidants (fruit, vegetables, olive oil), moderate consumption of fats and a well balanced of *n-6*/*n-3* fatty acids.

#### **5. Acknowledgements**

To Dr. José Manuel Martínez Martos and Dr. Mª Jesús Ramírez Expósito , from University of Jaén, Div. of Phisiology, for their assistance with the manuscript.

#### **6. References**


of inflammatory disease. In our opinion the best strategy recommending to population in general, and autoimmune disease patients in particular, is the maintenance of a healthy diet rich in naturals antioxidants (fruit, vegetables, olive oil), moderate consumption of fats and

To Dr. José Manuel Martínez Martos and Dr. Mª Jesús Ramírez Expósito , from University of

Adam, O., Beringer, C., Kless, T., Lemmen, C., Adam, A., Wiseman, M., Adam, P., Klimmek,

Akhtar Khan, N. (2010). Polyunsaturated fatty acids in the modulation of T-cell signalling.

Alexander, N.J., Smythe, N.L. & Jokinen, M.P. (1987). The type of dietary fat affects the

*pathology,* Vol 127, No.1, pp 106-121, ISSN/ISBN 0002-9440; 0002-9440. Andoh, A., Tsujikawa, T., Ishizuka, I., Araki, Y., Sasaki, M., Koyama, S. & Fujiyama, Y.

*medicine,* Vol 12, No.5, pp 721-725, ISSN/ISBN 1107-3756; 1107-3756. Bates, D., Cartlidge, N.E., French, J.M., Jackson, M.J., Nightingale, S., Shaw, D.A., Smith, S.,

R. & Forth, W. (2003). Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. *Rheumatology international,* Vol 23,

*Prostaglandins, leukotrienes, and essential fatty acids,* Vol 82, No.4-6, pp 179-187,

severity of autoimmune disease in NZB/NZW mice. *The American journal of* 

(2003). N-3 fatty acid-rich diet prevents early response of interleukin-6 elevation in trinitrobenzene sulfonic acid-induced enteritis. *International journal of molecular* 

Woo, E., Hawkins, S.A. & Millar, J.H. (1989). A double-blind controlled trial of long chain n-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. *Journal of neurology, neurosurgery, and psychiatry,* Vol 52, No.1, pp 18-22, ISSN/ISBN 0022-

acids in non-relapsing multiple sclerosis. *British medical journal,* Vol 2, No.6092, pp

enteric-coated fish-oil preparation on relapses in Crohn's disease. *The New England journal of medicine,* Vol 334, No.24, pp 1557-1560, ISSN/ISBN 0028-4793; 0028-4793. Berbert, A.A., Kondo, C.R., Almendra, C.L., Matsuo, T. & Dichi, I. (2005). Supplementation

of fish oil and olive oil in patients with rheumatoid arthritis. *Nutrition (Burbank, Los Angeles County, Calif.),* Vol 21, No.2, pp 131-136, ISSN/ISBN 0899-9007; 0899-9007. Calder, P.C. (2008a). Polyunsaturated fatty acids, inflammatory processes and inflammatory

bowel diseases. *Molecular nutrition & food research,* Vol 52, No.8, pp 885-897,

Institute Symposium on 'Nutrition and autoimmune disease' PUFA, inflammatory

Bates, D., Fawcett, P.R., Shaw, D.A. & Weightman, D. (1977). Trail of polyunsaturated fatty

Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S. & Miglioli, M. (1996). Effect of an

Calder, P.C. (2008b). Session 3: Joint Nutrition Society and Irish Nutrition and Dietetic

Jaén, Div. of Phisiology, for their assistance with the manuscript.

No.1, pp 27-36, ISSN/ISBN 0172-8172; 0172-8172.

ISSN/ISBN 1532-2823; 0952-3278.

932-933, ISSN/ISBN 0007-1447; 0007-1447.

ISSN/ISBN 1613-4133; 1613-4125.

3050; 0022-3050.

a well balanced of *n-6*/*n-3* fatty acids.

**5. Acknowledgements** 

**6. References** 

processes and rheumatoid arthritis. *The Proceedings of the Nutrition Society,* Vol 67, No.4, pp 409-418, ISSN/ISBN 0029-6651; 0029-6651.


Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 507

James, M.J., Gibson, R.A., Neumann, M.A. & Cleland, L.G. (1993). Effect of dietary

*medicine,* Vol 178, No.6, pp 2261-2265, ISSN/ISBN 0022-1007; 0022-1007. Jolly, C.A., Muthukumar, A., Avula, C.P., Troyer, D. & Fernandes, G. (2001). Life span is

Jolly, C.A. & Fernandes, G. (1999). Diet modulates Th-1 and Th-2 cytokine production in the

Kagohashi, Y., Abiru, N., Kobayashi, M., Hashimoto, M., Shido, O. & Otani, H. (2010a).

Kagohashi, Y. & Otani, H. (2010b). Diet with a low n-6/n-3 essential fatty acid ratio when

Kaplan, G.J., Fraser, R.I. & Comstock, G.W. (1972). Tuberculosis in Alaska, 1970. The

*Disease,* Vol 105, No.6, pp 920-926, ISSN/ISBN 0003-0805; 0003-0805. Kelley, D.S., Taylor, P.C., Nelson, G.J., Schmidt, P.C., Ferretti, A., Erickson, K.L., Yu, R.,

ISSN/ISBN 0022-3166; 0022-3166.

ISSN/ISBN 1741-4520; 0914-3505.

ISSN/ISBN 1741-4520; 0914-3505.

ISSN/ISBN 0022-1767; 0022-1767.

pp 172-178, ISSN/ISBN 0271-9142; 0271-9142.

supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis. *The Journal of experimental* 

prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids. *The Journal of nutrition,* Vol 131, No.10, pp 2753-2760,

peripheral blood of lupus-prone mice. *Journal of clinical immunology,* Vol 19, No.3,

Maternal dietary n-6/n-3 fatty acid ratio affects type 1 diabetes development in the offspring of non-obese diabetic mice. *Congenital anomalies,* Vol 50, No.4, pp 212-220,

started immediately after the onset of overt diabetes prolongs survival of type 1 diabetes model NOD mice. *Congenital anomalies,* Vol 50, No.4, pp 226-231,

continued decline of the tuberculosis epidemic. *The American Review of Respiratory* 

Chandra, R.K. & Mackey, B.E. (1999). Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. *Lipids,* Vol 34, No.4, pp 317-324, ISSN/ISBN 0024-4201; 0024-4201. Kelley, V.E., Ferretti, A., Izui, S. & Strom, T.B. (1985). A fish oil diet rich in eicosapentaenoic

acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. *Journal of immunology (Baltimore, Md.: 1950),* Vol 134, No.3, pp 1914-1919,

Regulatory activity of polyunsaturated fatty acids in T-cell signaling. *Progress in* 

Sherman, M. (1990). Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. *Arthritis and Rheumatism,* 

Timchalk, M., Beeler, D. & Lininger, L. (1987). Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study. *Annals of Internal Medicine,* Vol 106, No.4, pp 497-503, ISSN/ISBN 0003-4819; 0003-4819. Kremer, J.M., Bigauoette, J., Michalek, A.V., Timchalk, M.A., Lininger, L., Rynes, R.I.,

Huyck, C., Zieminski, J. & Bartholomew, L.E. (1985). Effects of manipulation of

Kim, W., Khan, N.A., McMurray, D.N., Prior, I.A., Wang, N. & Chapkin, R.S. (2010).

Kremer, J.M., Jubiz, W., Michalek, A., Rynes, R.I., Bartholomew, L.E., Bigaouette, J.,

*lipid research,* Vol 49, No.3, pp 250-261, ISSN/ISBN 1873-2194; 0163-7827. Kremer, J.M., Lawrence, D.A., Jubiz, W., DiGiacomo, R., Rynes, R., Bartholomew, L.E. &

Vol 33, No.6, pp 810-820, ISSN/ISBN 0004-3591; 0004-3591.


Fernandez-Banares, F., Cabre, E., Gonzalez-Huix, F. & Gassull, M.A. (1994). Enteral nutrition

Galli, C. & Calder, P.C. (2009). Effects of fat and fatty acid intake on inflammatory and

Gonzalez-Huix, F., de Leon, R., Fernandez-Banares, F., Esteve, M., Cabre, E., Acero, D.,

Halade, G.V., Rahman, M.M., Bhattacharya, A., Barnes, J.L., Chandrasekar, B. & Fernandes,

Harbige, L.S. & Sharief, M.K. (2007). Polyunsaturated fatty acids in the pathogenesis and

Harbige, L.S., Layward, L., Morris-Downes, M.M., Dumonde, D.C. & Amor, S. (2000). The

Harbige, L.S., Layward, L., Morris, M. & Amor, S. (1997). Protective mechanisms by omega-

Harbige, L.S., Yeatman, N., Amor, S. & Crawford, M.A. (1995). Prevention of experimental

Hudert, C.A., Weylandt, K.H., Lu, Y., Wang, J., Hong, S., Dignass, A., Serhan, C.N. & Kang,

*America,* Vol 103, No.30, pp 11276-11281, ISSN/ISBN 0027-8424; 0027-8424. Hughes, D., Keith, A.B., Mertin, J. & Caspary, E.A. (1980). Linoleic acid therapy in severe

trial. *Gut,* Vol 34, No.6, pp 778-782, ISSN/ISBN 0017-5749; 0017-5749. Greenfield, S.M., Green, A.T., Teare, J.P., Jenkins, A.P., Punchard, N.A., Ainley, C.C. &

ISSN/ISBN 0017-5749; 0017-5749.

3, pp 123-139, ISSN/ISBN 1421-9697; 0250-6807.

159-166, ISSN/ISBN 0269-2813; 0269-2813.

S46-53, ISSN/ISBN 0007-1145; 0007-1145.

ISSN/ISBN 0300-5127; 0300-5127.

531, ISSN/ISBN 0009-9104; 0009-9104.

0007-1145; 0007-1145.

6606; 0022-1767.

0009-9104.

as primary therapy in Crohn's disease. *Gut,* Vol 35, No.1 Suppl, pp S55-9,

immune responses: a critical review. *Annals of Nutrition & Metabolism,* Vol 55, No.1-

Abad-Lacruz, A., Figa, M., Guilera, M. & Planas, R. (1993). Polymeric enteral diets as primary treatment of active Crohn's disease: a prospective steroid controlled

Thompson, R.P. (1993). A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis. *Alimentary Pharmacology & Therapeutics,* Vol 7, No.2, pp

G. (2010). Docosahexaenoic acid-enriched fish oil attenuates kidney disease and prolongs median and maximal life span of autoimmune lupus-prone mice. *Journal of immunology (Baltimore, Md.: 1950),* Vol 184, No.9, pp 5280-5286, ISSN/ISBN 1550-

treatment of multiple sclerosis. *The British journal of nutrition,* Vol 98 Suppl 1, pp

protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGFbeta1) up-regulation and increased prostaglandin E2 (PGE2) production. *Clinical and experimental immunology,* Vol 122, No.3, pp 445-452, ISSN/ISBN 0009-9104;

6 lipids in experimental autoimmune encephalomyelitis (EAE) are associated with cytokines and eicosanoids. *Biochemical Society transactions,* Vol 25, No.2, pp 342S,

autoimmune encephalomyelitis in Lewis rats by a novel fungal source of gammalinolenic acid. *The British journal of nutrition,* Vol 74, No.5, pp 701-715, ISSN/ISBN

J.X. (2006). Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. *Proceedings of the National Academy of Sciences of the United States of* 

experimental allergic encephalomyelitis in the guinea-pig: suppression by continuous treatment. *Clinical and experimental immunology,* Vol 40, No.3, pp 523-


dietary fatty acids on clinical manifestations of rheumatoid arthritis. *Lancet,* Vol 1, No.8422, pp 184-187, ISSN/ISBN 0140-6736; 0140-6736.

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 509

Matsunaga, H., Hokari, R., Kurihara, C., Okada, Y., Takebayashi, K., Okudaira, K.,

Meade, C.J., Mertin, J., Sheena, J. & Hunt, R. (1978). Reduction by linoleic acid of the severity

Miles, E.A., Thies, F., Wallace, F.A., Powell, J.R., Hurst, T.L., Newsholme, E.A. & Calder,

Millar, J.H., Zilkha, K.J., Langman, M.J., Wright, H.P., Smith, A.D., Belin, J. & Thompson,

Miller, M.R., Yin, X., Seifert, J., Clare-Salzler, M., Eisenbarth, G.S., Rewers, M. & Norris, J.M.

Moussa, M., Le Boucher, J., Garcia, J., Tkaczuk, J., Ragab, J., Dutot, G., Ohayon, E., Ghisolfi,

Nakamura, N., Kumasaka, R., Osawa, H., Yamabe, H., Shirato, K., Fujita, T., Murakami, R.,

Nieto, N., Torres, M.I., Rios, A. & Gil, A. (2002). Dietary polyunsaturated fatty acids improve

9104.

0007-1447.

555, ISSN/ISBN 0022-3166; 0022-3166.

91-100, ISSN/ISBN 0143-5221; 0143-5221.

*diabetes,* ISSN/ISBN 1399-5448; 1399-543X.

pp 49-54, ISSN/ISBN 0261-5614; 0261-5614.

pp 879-882, ISSN/ISBN 0258-851X; 0258-851X.

Watanabe, C., Komoto, S., Nakamura, M., Tsuzuki, Y., Kawaguchi, A., Nagao, S. & Miura, S. (2009). Omega-3 polyunsaturated fatty acids ameliorate the severity of ileitis in the senescence accelerated mice (SAM)P1/Yit mice model. *Clinical and experimental immunology,* Vol 158, No.3, pp 325-333, ISSN/ISBN 1365-2249; 0009-

of experimental allergic encephalomyelitis in the guinea pig. *Journal of the neurological sciences,* Vol 35, No.2-3, pp 291-308, ISSN/ISBN 0022-510X; 0022-510X. Meydani, S.N., Endres, S., Woods, M.M., Goldin, B.R., Soo, C., Morrill-Labrode, A.,

Dinarello, C.A. & Gorbach, S.L. (1991). Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. *The Journal of nutrition,* Vol 121, No.4, pp 547-

P.C. (2001). Influence of age and dietary fish oil on plasma soluble adhesion molecule concentrations. *Clinical science (London, England : 1979),* Vol 100, No.1, pp

R.H. (1973). Double-blind trial of linoleate supplementation of the diet in multiple sclerosis. *British medical journal,* Vol 1, No.5856, pp 765-768, ISSN/ISBN 0007-1447;

(2011). Erythrocyte membrane omega-3 fatty acid levels and omega-3 fatty acid intake are not associated with conversion to type 1 diabetes in children with islet autoimmunity: The Diabetes Autoimmunity Study in the Young (DAISY). *Pediatric* 

J. & Thouvenot, J.P. (2000). In vivo effects of olive oil-based lipid emulsion on lymphocyte activation in rats. *Clinical nutrition (Edinburgh, Scotland),* Vol 19, No.1,

Shimada, M., Nakamura, M., Okumura, K., Hamazaki, K. & Hamazaki, T. (2005). Effects of eicosapentaenoic acids on oxidative stress and plasma fatty acid composition in patients with lupus nephritis. *In vivo (Athens, Greece),* Vol 19, No.5,

histological and biochemical alterations in rats with experimental ulcerative colitis. *The Journal of nutrition,* Vol 132, No.1, pp 11-19, ISSN/ISBN 0022-3166; 0022-3166. Norris, J.M., Yin, X., Lamb, M.M., Barriga, K., Seifert, J., Hoffman, M., Orton, H.D., Baron,

A.E., Clare-Salzler, M., Chase, H.P., Szabo, N.J., Erlich, H., Eisenbarth, G.S. & Rewers, M. (2007). Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. *JAMA : the journal of* 


Krishna Mohan, I. & Das, U.N. (2001). Prevention of chemically induced diabetes mellitus in

Lefkowith, J., Schreiner, G., Cormier, J., Handler, E.S., Driscoll, H.K., Greiner, D., Mordes,

Leslie, C.A., Gonnerman, W.A., Ullman, M.D., Hayes, K.C., Franzblau, C. & Cathcart, E.S.

Linos, A., Kaklamani, V.G., Kaklamani, E., Koumantaki, Y., Giziaki, E., Papazoglou, S. &

Linos, A., Kaklamanis, E., Kontomerkos, A., Koumantaki, Y., Gazi, S., Vaiopoulos, G.,

Loeschke, K., Ueberschaer, B., Pietsch, A., Gruber, E., Ewe, K., Wiebecke, B., Heldwein, W. &

Lorenz, R., Weber, P.C., Szimnau, P., Heldwein, W., Strasser, T. & Loeschke, K. (1989).

Lorenz-Meyer, H., Bauer, P., Nicolay, C., Schulz, B., Purrmann, J., Fleig, W.E., Scheurlen, C.,

Martinez-Dominguez, E., de la Puerta, R. & Ruiz-Gutierrez, V. (2001). Protective effects

*Society ...[et al.],* Vol 50, No.2, pp 102-106, ISSN/ISBN 1023-3830; 1023-3830.

No.8422, pp 184-187, ISSN/ISBN 0140-6736; 0140-6736.

Vol 208, No.5, pp 401-406, ISSN/ISBN 0001-6101; 0001-6101.

1349, ISSN/ISBN 0022-1007; 0022-1007.

No.6, pp 1077-1082, ISSN/ISBN 0002-9165; 0002-9165.

Vol 20, No.6, pp 419-426, ISSN/ISBN 0300-9742; 0300-9742.

0022-1007.

0163-2116; 0163-2116.

5521; 0036-5521.

dietary fatty acids on clinical manifestations of rheumatoid arthritis. *Lancet,* Vol 1,

experimental animals by polyunsaturated fatty acids. *Nutrition (Burbank, Los Angeles County, Calif.),* Vol 17, No.2, pp 126-151, ISSN/ISBN 0899-9007; 0899-9007. Kromann, N. & Green, A. (1980). Epidemiological studies in the Upernavik district,

Greenland. Incidence of some chronic diseases 1950-1974. *Acta Medica Scandinavica,* 

J.P. & Rossini, A.A. (1990). Prevention of diabetes in the BB rat by essential fatty acid deficiency. Relationship between physiological and biochemical changes. *The Journal of experimental medicine,* Vol 171, No.3, pp 729-743, ISSN/ISBN 0022-1007;

(1985). Dietary fish oil modulates macrophage fatty acids and decreases arthritis susceptibility in mice. *The Journal of experimental medicine,* Vol 162, No.4, pp 1336-

Mantzoros, C.S. (1999). Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables? *The American Journal of Clinical Nutrition,* Vol 70,

Tsokos, G.C. & Kaklamanis, P. (1991). The effect of olive oil and fish consumption on rheumatoid arthritis--a case control study. *Scandinavian journal of rheumatology,* 

Lorenz, R. (1996). N-3 Fatty Acids Only Delay Early Relapse of Ulcerative Colitis in Remission. *Digestive diseases and sciences,* Vol 41, No.10, pp 2087-2094, ISSN/ISBN

Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease--a randomized, placebo-controlled, double-blind cross-over trial. *Journal of internal medicine.Supplement,* Vol 731, pp 225-232, ISSN/ISBN 0955-7873; 0955-7873.

Koop, I., Pudel, V. & Carr, L. (1996). Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group). *Scandinavian journal of gastroenterology,* Vol 31, No.8, pp 778-785, ISSN/ISBN 0036-

upon experimental inflammation models of a polyphenol-supplemented virgin olive oil diet. *Inflammation research : official journal of the European Histamine Research* 


*the American Medical Association,* Vol 298, No.12, pp 1420-1428, ISSN/ISBN 1538- 3598; 0098-7484.

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 511

Romano, C., Cucchiara, S., Barabino, A., Annese, V. & Sferlazzas, C. (2005). Usefulness of

Sanchez-Fidalgo, S., Villegas, I., Cardeno, A., Talero, E., Sanchez-Hidalgo, M., Motilva, V. &

Sano, H., Hla, T., Maier, J.A., Crofford, L.J., Case, J.P., Maciag, T. & Wilder, R.L. (1992). In

Sharon, P. & Stenson, W.F. (1984). Enhanced synthesis of leukotriene B4 by colonic mucosa

Shinto, L., Marracci, G., Baldauf-Wagner, S., Strehlow, A., Yadav, V., Stuber, L. &

Shoda, R., Matsueda, K., Yamato, S. & Umeda, N. (1996). Epidemiologic analysis of Crohn

Shoda, R., Matsueda, K., Yamato, S. & Umeda, N. (1995). Therapeutic efficacy of N-3

*gastroenterology,* Vol 30 Suppl 8, pp 98-101, ISSN/ISBN 0944-1174; 0944-1174. Simopoulos, A.P. (2002). Omega-3 fatty acids in inflammation and autoimmune diseases.

Sperling, R.I. (1995). Eicosanoids in rheumatoid arthritis. *Rheumatic diseases clinics of North America,* Vol 21, No.3, pp 741-758, ISSN/ISBN 0889-857X; 0889-857X. Sperling, R.I., Weinblatt, M., Robin, J.L., Ravalese, J.,3rd, Hoover, R.L., House, F., Coblyn,

*Scotland),* Vol 29, No.5, pp 663-673, ISSN/ISBN 1532-1983; 0261-5614. Sanderson, P., Yaqoob, P. & Calder, P.C. (1995). Effects of dietary lipid manipulation upon

29, No.4, pp 539-546, ISSN/ISBN 0004-3591; 0004-3591.

No.2, pp 240-247, ISSN/ISBN 0008-8749; 0008-8749.

7121, ISSN/ISBN 1007-9327; 1007-9327.

0021-9738; 0021-9738.

9165; 0002-9165.

0731-5724; 0731-5724.

ISSN/ISBN 0016-5085; 0016-5085.

ISSN/ISBN 0952-3278; 0952-3278.

and delays renal disease in BXSB and MRL/1 strains. *Arthritis and Rheumatism,* Vol

omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn's disease: a double-blind, randomized, placebocontrolled study. *World journal of gastroenterology : WJG,* Vol 11, No.45, pp 7118-

Alarcon de la Lastra, C. (2010). Extra-virgin olive oil-enriched diet modulates DSScolitis-associated colon carcinogenesis in mice. *Clinical nutrition (Edinburgh,* 

graft vs host and host vs graft responses in the rat. *Cellular immunology,* Vol 164,

vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. *The Journal of clinical investigation,* Vol 89, No.1, pp 97-108, ISSN/ISBN

in inflammatory bowel disease. *Gastroenterology,* Vol 86, No.3, pp 453-460,

Bourdette, D. (2009). Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis. *Prostaglandins, leukotrienes, and essential fatty acids,* Vol 80, No.2-3, pp 131-136,

disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. *The American Journal of Clinical Nutrition,* Vol 63, No.5, pp 741-745, ISSN/ISBN 0002-

polyunsaturated fatty acid in experimental Crohn's disease. *Journal of* 

*Journal of the American College of Nutrition,* Vol 21, No.6, pp 495-505, ISSN/ISBN

J.S., Fraser, P.A., Spur, B.W. & Robinson, D.R. (1987). Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and


Owen, R.W., Mier, W., Giacosa, A., Hull, W.E., Spiegelhalder, B. & Bartsch, H. (2000).

Pattison, D.J., Symmons, D.P. & Young, A. (2004). Does diet have a role in the aetiology of

Paty, D.W., Cousin, H.K., Read, S. & Adlakha, K. (1978). Linoleic acid in multiple sclerosis:

Pestka, J.J. (2010). N-3 Polyunsaturated Fatty Acids and Autoimmune-Mediated

Prickett, J.D., Robinson, D.R. & Steinberg, A.D. (1983). Effects of dietary enrichment with

Prickett, J.D., Robinson, D.R. & Steinberg, A.D. (1982). A diet enriched with

Prickett, J.D., Robinson, D.R. & Steinberg, A.D. (1981). Dietary enrichment with the

Puertollano, M.A., Puertollano, E. & de Pablo, M.A. (2010). Host Immune Resistance and

Puertollano, M.A., Puertollano, E., Alvarez de Cienfuegos, G. & de Pablo, M.A. (2008).

Puertollano, M.A., de Pablo, M.A. & Alvarez de Cienfuegos, G. (2004). Olive oil and

Rees, D., Miles, E.A., Banerjee, T., Wells, S.J., Roynette, C.E., Wahle, K.W. & Calder, P.C.

3598; 0098-7484.

143, ISSN/ISBN 0029-6651; 0029-6651.

ISSN/ISBN 0066-9458; 0066-9458.

*aceites,* No.55, pp 42-51.

pp 53-58, ISSN/ISBN 0001-6314; 0001-6314.

No.4-6, pp 251-258, ISSN/ISBN 1532-2823; 0952-3278.

No.2, pp 556-559, ISSN/ISBN 0021-9738; 0021-9738.

Preedy (Ed.), pp. 131-153, Humana Press Springer, NY.

*Nutritional Therapy and Metabolism,* Vol 26, No.3, pp 97-108.

6915.

3591.

*the American Medical Association,* Vol 298, No.12, pp 1420-1428, ISSN/ISBN 1538-

Phenolic compounds and squalene in olive oils: the concentration and antioxidant potential of total phenols, simple phenols, secoiridoids, lignansand squalene. *Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association,* Vol 38, No.8, pp 647-659, ISSN/ISBN 0278-6915; 0278-

rheumatoid arthritis? *The Proceedings of the Nutrition Society,* Vol 63, No.1, pp 137-

failure to show any therapeutic benefit. *Acta Neurologica Scandinavica,* Vol 58, No.1,

Glomerulonephritis. *Prostaglandins, leukotrienes, and essential fatty acids,* Vol 82,

eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice. *Arthritis and Rheumatism,* Vol 26, No.2, pp 133-139, ISSN/ISBN 0004-3591; 0004-

eicosapentaenoic acid suppresses autoimmune nephritis in female (NZB x NZW) F1 mice. *Transactions of the Association of American Physicians,* Vol 95, pp 145-154,

polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB x NZW F1 mice. *The Journal of clinical investigation,* Vol 68,

Dietary Lipids, In: *Dietary Components and Immune Function* Watson, Zibadi &

Dietary lipids, modulation of immune functions and susceptibility to infection.

immune system functions: potential involvement in immunonutrition. *Grasas y* 

(2006). Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. *The American Journal of Clinical Nutrition,* Vol 83, No.2, pp 331-342, ISSN/ISBN 0002-9165; 0002-9165. Robinson, D.R., Prickett, J.D., Makoul, G.T., Steinberg, A.D. & Colvin, R.B. (1986). Dietary

fish oil reduces progression of established renal disease in (NZB x NZW)F1 mice

and delays renal disease in BXSB and MRL/1 strains. *Arthritis and Rheumatism,* Vol 29, No.4, pp 539-546, ISSN/ISBN 0004-3591; 0004-3591.


function in rheumatoid arthritis. *Arthritis and Rheumatism,* Vol 30, No.9, pp 988-997, ISSN/ISBN 0004-3591; 0004-3591.

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 513

Vilaseca, J., Salas, A., Guarner, F., Rodriguez, R., Martinez, M. & Malagelada, J.R. (1990).

Volker, D.H., FitzGerald, P.E. & Garg, M.L. (2000). The eicosapentaenoic to

Wallace, F.A., Miles, E.A., Evans, C., Stock, T.E., Yaqoob, P. & Calder, P.C. (2001).

Walton, A.J., Snaith, M.L., Locniskar, M., Cumberland, A.G., Morrow, W.J. & Isenberg, D.A.

Weinstock-Guttman, B., Baier, M., Park, Y., Feichter, J., Lee-Kwen, P., Gallagher, E.,

Westberg, G. & Tarkowski, A. (1990). Effect of MaxEPA in patients with SLE. A double-

Whiting, C.V., Bland, P.W. & Tarlton, J.F. (2005). Dietary n-3 polyunsaturated fatty acids

Wright, J.R.,Jr, Fraser, R.B., Kapoor, S. & Cook, H.W. (1995). Essential fatty acid deficiency

Wright, S.A., O'Prey, F.M., McHenry, M.T., Leahey, W.J., Devine, A.B., Duffy,

Yaqoob, P. (2002). Monounsaturated fatty acids and immune function. *European* 

0017-5749.

0741-5400.

0998.

2060; 0003-4967.

0954-3007.

0022-3166; 0022-3166.

ISSN/ISBN 0003-4967; 0003-4967.

ISSN/ISBN 0952-3278; 0952-3278.

143, ISSN/ISBN 0300-9742; 0300-9742.

pp 125-130, ISSN/ISBN 0940-5429; 0940-5429.

Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis. *Gut,* Vol 31, No.5, pp 539-544, ISSN/ISBN 0017-5749;

docosahexaenoic acid ratio of diets affects the pathogenesis of arthritis in Lew/SSN rats. *The Journal of nutrition,* Vol 130, No.3, pp 559-565, ISSN/ISBN

Dietary fatty acids influence the production of Th1- but not Th2-type cytokines. *Journal of leukocyte biology,* Vol 69, No.3, pp 449-457, ISSN/ISBN 0741-5400;

(1991). Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. *Annals of the Rheumatic Diseases,* Vol 50, No.7, pp 463-466,

Venkatraman, J., Meksawan, K., Deinehert, S., Pendergast, D., Awad, A.B., Ramanathan, M., Munschauer, F. & Rudick, R. (2005). Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. *Prostaglandins, leukotrienes, and essential fatty acids,* Vol 73, No.5, pp 397-404,

blind, crossover study. *Scandinavian journal of rheumatology,* Vol 19, No.2, pp 137-

reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. *Inflammatory bowel diseases,* Vol 11, No.4, pp 340-349, ISSN/ISBN 1078-0998; 1078-

prevents multiple low-dose streptozotocin-induced diabetes in naive and cyclosporin-treated low-responder murine strains. *Acta Diabetologica,* Vol 32, No.2,

E.M., Johnston, D.G., Finch, M.B., Bell, A.L. & McVeigh, G.E. (2008). A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus. *Annals of the Rheumatic Diseases,* Vol 67, No.6, pp 841-848, ISSN/ISBN 1468-

*journal of clinical nutrition,* Vol 56 Suppl 3, pp S9-S13, ISSN/ISBN 0954-3007;


Spurney, R.F., Ruiz, P., Albrightson, C.R., Pisetsky, D.S. & Coffman, T.M. (1994).

Stene, L.C., Joner, G. & Norwegian Childhood Diabetes Study Group. (2003). Use of cod

Stulnig, T.M. (2003). Immunomodulation by polyunsaturated fatty acids: mechanisms and

Suresh, Y. & Das, U.N. (2006). Differential effect of saturated, monounsaturated, and

Swank, R.L. (1950). Multiple sclerosis; a correlation of its incidence with dietary fat. *The* 

Trebble, T.M., Stroud, M.A., Wootton, S.A., Calder, P.C., Fine, D.R., Mullee, M.A.,

Trebble, T.M., Wootton, S.A., Miles, E.A., Mullee, M., Arden, N.K., Ballinger, A.B., Stroud,

Tulleken, J.E., Limburg, P.C., Muskiet, F.A. & van Rijswijk, M.H. (1990). Vitamin E

van der Tempel, H., Tulleken, J.E., Limburg, P.C., Muskiet, F.A. & van Rijswijk,

Venkatraman, J.T. & Chu, W.C. (1999). Effects of dietary omega-3 and omega-6

ISSN/ISBN 0004-3591; 0004-3591.

ISSN/ISBN 1018-2438; 1018-2438.

0002-9165; 0002-9165.

6980.

0952-3278.

1145.

9629; 0002-9629.

9165; 0002-9165.

0004-3591.

0731-5724.

4967.

function in rheumatoid arthritis. *Arthritis and Rheumatism,* Vol 30, No.9, pp 988-997,

Fish oil feeding modulates leukotriene production in murine lupus nephritis. *Prostaglandins,* Vol 48, No.5, pp 331-348, ISSN/ISBN 0090-6980; 0090-

liver oil during the first year of life is associated with lower risk of childhoodonset type 1 diabetes: a large, population-based, case-control study. *The American Journal of Clinical Nutrition,* Vol 78, No.6, pp 1128-1134, ISSN/ISBN

effects. *International archives of allergy and immunology,* Vol 132, No.4, pp 310-321,

polyunsaturated fatty acids on alloxan-induced diabetes mellitus. *Prostaglandins, leukotrienes, and essential fatty acids,* Vol 74, No.3, pp 199-213, ISSN/ISBN 0952-3278;

*American Journal of the Medical Sciences,* Vol 220, No.4, pp 421-430, ISSN/ISBN 0002-

Moniz, C. & Arden, N.K. (2005). High-dose fish oil and antioxidants in Crohn's disease and the response of bone turnover: a randomised controlled trial. *The British journal of nutrition,* Vol 94, No.2, pp 253-261, ISSN/ISBN 0007-1145; 0007-

M.A., Burdge, G.C. & Calder, P.C. (2003). Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant cosupplementation. *The American Journal of Clinical Nutrition,* Vol 78, No.3, pp 376-382, ISSN/ISBN 0002-

status during dietary fish oil supplementation in rheumatoid arthritis. *Arthritis and Rheumatism,* Vol 33, No.9, pp 1416-1419, ISSN/ISBN 0004-3591;

M.H. (1990). Effects of fish oil supplementation in rheumatoid arthritis. *Annals of the Rheumatic Diseases,* Vol 49, No.2, pp 76-80, ISSN/ISBN 0003-4967; 0003-

lipids and vitamin E on serum cytokines, lipid mediators and anti-DNA antibodies in a mouse model for rheumatoid arthritis. *Journal of the American College of Nutrition,* Vol 18, No.6, pp 602-613, ISSN/ISBN 0731-5724;


Yaqoob, P., Newsholme, E.A. & Calder, P.C. (1994). Inhibition of natural killer cell activity by dietary lipids. *Immunology letters,* Vol 41, No.2-3, pp 241-247, ISSN/ISBN 0165- 2478; 0165-2478.

**Part 5** 

**Other Conceptual Advances & New Insights** 

Yuceyar, H., Ozutemiz, O., Huseyinov, A., Saruc, M., Alkanat, M., Bor, S., Coker, I. & Batur, Y. (1999). Is administration of n-3 fatty acids by mucosal enema protective against trinitrobenzene-induced colitis in rats? *Prostaglandins, leukotrienes, and essential fatty acids,* Vol 61, No.6, pp 339-345, ISSN/ISBN 0952- 3278; 0952-3278.
