**1. Introduction**

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

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The main role of fatty acids is focused on serving as major substrates for energy production; however, fatty acids are also involved in the formation of cellular structures as well as in the transmission of cellular signals. Among the multiple functions attributed to fatty acids are their anti-inflammatory properties. This important characteristic has been applied in the prevention, attenuation or treatment of inflammatory disorders. Based on the previous argument is obvious that several fatty acids (mainly *n*-3 polyunsaturated or *n*-9 monounsaturated fatty acids) are capable of modulating immune system functions. These fatty acids may alter immune response through different mechanisms such as alteration of membrane fluidity, eicosanoid synthesis, oxidative stress, regulation of gene expression, apoptosis or modulation of gastrointestinal microbiota.

Early studies in Greenland Eskimos determined the low prevalence of inflammatory disorders in this population (Kromann et al., 1980). Despite their beneficial effects in the reduction of inflammatory diseases, other studies have demonstrated that the administration of diets containing long-chain *n*-3 polyunsaturated fatty acids may contribute, at least in part, to the reduction of host resistance against infectious agents. In fact, epidemiological investigations described a high incidence of tuberculosis in native Eskimos (Kaplan et al., 1972), who consume a great amount of *n*-3 polyunsaturated fatty acids. These data are clearly illustrative of the potential action of certain fatty acids on the inflammatory response, and of the consequences derived from an excessive immunosuppression.

It is obvious that these fatty acids contained in the diets produce an immune status able to ameliorate inflammatory conditions. Indeed, a growing number of studies using healthy human subjects as well as animal disease models have undoubtedly demonstrated dietary fish oil or olive oil to possess anti-inflammatory properties. For this reason, polyunsaturated or monounsaturated fatty acids have showed beneficial effects in numerous inflammatory diseases characterized by a overactivation of immune system such as asthma (childhood and adult), multiple sclerosis, glomerulonephritis, inflammatory bowel disease (Crohn's disease, ulcerative colitis) and rheumatoid arthritis . Here, we summarize the involvement of fatty acids as anti-inflammatory agents and the action that these fatty acids contained in the human or animal diets exert on the prevention or treatment of autoimmune diseases.

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 493

of lymphocyte proliferation. In general, administration of high level of fatty acids, and especially *n-3* series, are related with a reduction on lymphocyte proliferation in both animals and human studies (Meydani et al., 1991; Yaqoob et al., 1994; Moussa et al., 2000). This fact can be especially interesting in the amelioration of diseases characterized by overactivation of immune response like autoimmune disorder. In addition fatty acids can

modify another lymphocyte functions like cytokine production.

 Oxidative stress Signaling transduction Gene expression Apoptosis

determining the modulation of immune system.

Eicosanoids production

Membrane fluidity and lipid rafts

Ability in antigen presentation

Table 1. Hypothetical mechanisms of dietary lipids on immune functions: factors

Modulation of gastrointestinal microbiota

Fig. 2. Schematic diagram of proposed mechanisms of action of *n-3* polyunsaturated fatty acids whereby these fatty acids are involved in the modulation of immune system functions. Abbreviations: CD14, CD14 surface receptor; COX, cyclooxygenase; EPA, eicosapentaenoic acid, IκB, NF-κB inhibitory protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; PPAR, peroxisome proliferator-activated receptor; TLR, Toll-like receptors. (Puertollano *et al.*) Several studies have demonstrated the immunomodulatory properties of polyunsaturated and monounsaturated fatty acids over reduction of pro and anti-inflammatory cytokines.

Fig. 1. Different pathways of n-3, n-6 and n-9 fatty acids synthesis. HETEs, hydroxyleicosatetraenoic acid; HPETE, hydroperoxy-eicosatetraenoic acids. (Puertollano *et al.*)

### **2. Fatty acids, inflammation and immune system**

Polyunsaturated fatty acids (PUFA) are considered essentials to mammalian cells and should be administered in the diet. These essential fatty acids are divided into two great families: *n-3* series derived from linolenic acid (LNA), and *n-6* series derived from linoleic (LA) acid. Different biochemical processes lead to the production of eicosapentanoic acid (EPA) or docohexaenoic acid (DHA) from LNA, as well as arachidonic acid (AA) from linoleic acid. Likewise, another family of non essential fatty acids such as *n-9* series derived from oleic acid, a monounsaturated fatty acid (MUFA), also seems to play an important role in the immunomodulatory process (Yaqoob, 2002) [Figure 1].

In recent years numerous investigations have examined the mechanisms of action responsible for the modulation of immune system by fatty acids and most of them are in agreement that unsaturated fatty acids are potent immunosupressor especially *n-3* PUFA (reviewed in Puertollano et al., 2008). The main mechanisms of action of fatty acids are schematized in figure 2 and include alterations of immune cells membrane fluidity, eicosanoids synthesis modifications, oxidative alteration, regulation of gene expression and apoptosis mechanisms inducement. Table 1 summarized these mechanisms of actions and others recently proposed such as modulation of gastrointestinal microbiota.

All of these mechanisms of action deal to explain the numerous effects of fatty acids on immune system. It is well known that unsaturated fatty acids are involved on the alteration

Fig. 1. Different pathways of n-3, n-6 and n-9 fatty acids synthesis. HETEs, hydroxyleicosatetraenoic acid; HPETE, hydroperoxy-eicosatetraenoic acids. (Puertollano *et al.*)

Polyunsaturated fatty acids (PUFA) are considered essentials to mammalian cells and should be administered in the diet. These essential fatty acids are divided into two great families: *n-3* series derived from linolenic acid (LNA), and *n-6* series derived from linoleic (LA) acid. Different biochemical processes lead to the production of eicosapentanoic acid (EPA) or docohexaenoic acid (DHA) from LNA, as well as arachidonic acid (AA) from linoleic acid. Likewise, another family of non essential fatty acids such as *n-9* series derived from oleic acid, a monounsaturated fatty acid (MUFA), also seems to play an important role

In recent years numerous investigations have examined the mechanisms of action responsible for the modulation of immune system by fatty acids and most of them are in agreement that unsaturated fatty acids are potent immunosupressor especially *n-3* PUFA (reviewed in Puertollano et al., 2008). The main mechanisms of action of fatty acids are schematized in figure 2 and include alterations of immune cells membrane fluidity, eicosanoids synthesis modifications, oxidative alteration, regulation of gene expression and apoptosis mechanisms inducement. Table 1 summarized these mechanisms of actions and

All of these mechanisms of action deal to explain the numerous effects of fatty acids on immune system. It is well known that unsaturated fatty acids are involved on the alteration

**2. Fatty acids, inflammation and immune system** 

in the immunomodulatory process (Yaqoob, 2002) [Figure 1].

others recently proposed such as modulation of gastrointestinal microbiota.

of lymphocyte proliferation. In general, administration of high level of fatty acids, and especially *n-3* series, are related with a reduction on lymphocyte proliferation in both animals and human studies (Meydani et al., 1991; Yaqoob et al., 1994; Moussa et al., 2000). This fact can be especially interesting in the amelioration of diseases characterized by overactivation of immune response like autoimmune disorder. In addition fatty acids can modify another lymphocyte functions like cytokine production.


Table 1. Hypothetical mechanisms of dietary lipids on immune functions: factors determining the modulation of immune system.

Fig. 2. Schematic diagram of proposed mechanisms of action of *n-3* polyunsaturated fatty acids whereby these fatty acids are involved in the modulation of immune system functions. Abbreviations: CD14, CD14 surface receptor; COX, cyclooxygenase; EPA, eicosapentaenoic acid, IκB, NF-κB inhibitory protein; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; PPAR, peroxisome proliferator-activated receptor; TLR, Toll-like receptors. (Puertollano *et al.*)

Several studies have demonstrated the immunomodulatory properties of polyunsaturated and monounsaturated fatty acids over reduction of pro and anti-inflammatory cytokines.

Role of Fatty Acids in the Resolution of Autoimmune and Inflammatory Diseases 495

Acute cardiovascular events

Asthma (childhood and adult)

Allergic disease

 Atherosclerosis Cancer cachexia

Cystic fibrosis

Multiple sclerosis

Rheumatoid arthritis

 Type 1 diabetes Type 2 diabetes

Lupus

 Obesity Psoriasis

Acute respiratory distress syndrome

Chronic obstructive pulmonary disease

Neurodegenerative disease of ageing

alphabetical order (Adapted from Calder, 2006).

**3. Fatty acids and autoimmune disorders** 

**3.1 Fatty acids and inflammatory bowel disease** 

Inflammatory bowel disease (Crohn's disease, ulcerative colitis)

Systemic inflammatory response to surgery, trauma and critical illness

autoimmune disorder where fatty acids have shown to exert beneficial effects.

eicosanoids like LTB4 are actively produced in situ (Sharon et al., 1984).

Table 2. Inflammatory disorder where fatty acids could be useful. Diseases are listed in an

Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in immune responses against its own cells and tissues. Autoimmunity involves an inflammatory response against own tissues which are implicated different mechanisms like autoantibodies production, immunocomplex formation and lymphocytes T reactivity. Recently, an important investigation about the implication of fatty acids and dietary lipids in the amelioration of autoimmune diseases has been carried out because of their anti-inflammatory properties (Linos et al., 1999). Below we will summarize the main

Inflammatory bowel disease (IBD) includes Cronh´s disease and ulcerative colitis which are autoimmune disorders characterized by an exacerbated inflammatory response against innocuous stimulus in gastrointestinal tract. Their pathogenesis is considered to include disorders of the immunomodulation of the bowel mucosa which results in lesions of the epithelium tissue layer caused by activated T cells, mononuclear cells and macrophages. In Crohn's disease the mucosa of the whole alimentary tract from the mouth to the anus can be affected, with maximal manifestation in the ileum and colon, while in ulcerative colitis the mucosa of the colon is mainly affected. In both diseases inflammatory cytokines and

The gastrointestinal system is subjected to sustained exposure to ingested foods throughout the whole life, and this gives rise to interactions between food components and gastrointestinal mucosal cells. Interactions with transporters and transcription factors contribute to the modulation of various responses, including those of cells involved in

In this context interesting investigations indicates that *n-3* PUFA exert a significant inhibition of Th1-type cytokines, whereas they have little effects on Th2-type cytokines (Wallace et al., 2001). In spite of olive oil diets are involved in the reduction of cytokine secretion, their immunosupressant effects are not as potent as those exerted by the administration of a fish oil diet (Puertollano et al., 2004). Fatty acids are able to modify the natural killer (NK) cells activity too. Finally recent studies have proved the action of fatty acids in the expression of adhesion molecules like lymphocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) (Sanderson et al., 1995; Miles et al., 2001). These facts have been shown in preliminary studies in animal models but it is necessary to confirm it in human studies.

#### **2.1 Dietary lipids and inflammatory response**

Inflammation is part of immune response and is a complex process affected by different factors, included mediators generated from fatty acids. Eicosanoids from *n-6* series fatty acids (like prostaglandine E2 (PGE2) and leukotriene B4 (LTB4) among others) are considered pro-inflammatory mediators while molecules from *n-3* series (like PGE3 and LTB5) generally are endowed with lower bioactivity. It is necessary to keep an optimal *n-6*/*n-3* balance to achieve a healthy inflammatory state.

Numerous researches have demonstrated that fish oil rich diet promotes a decrease on inflammatory ecoisanoids production from *n-6* PUFA because of the competition between the two metabolic pathways. In this way *n-3* PUFA supplementation of the human diet is able to decrease production of inflammatory eicosanoids like PGE2, LTB4 and thromboxane B2 (TXB2) by inflammatory cells (Meydani et al., 1991; Kelley et al., 1999; Trebble et al., 2003; Rees et al., 2006). In addition *n-3* PUFA have other effects over inflammatory response. One of the most important is the generation of resolvins, a group of mediators derived from EPA and DHA that appear to exert potent anti-inflammatory actions (Calder, 2008a). Decreasing antigen presentation via major histocompatibility complex class II (MHC II), inhibiting Tcell reactivity and diminishing inflammatory cytokine production (Calder et al., 2002; Akhtar Khan, 2010; Kim et al., 2010) are others of the anti-inflammatory effects of *n-3* fatty acids. Autoimmunity can be considered as an exacerbated inflammatory response against self structures; therefore *n-3* long chain fatty acids can be useful in the treatment of these diseases.

Oleic acid is the main fatty acid contained in olive oil. Olive oil has traditionally been used as a placebo in the studies investigating the potential action of other dietary lipids on the modulation of immune functions. Thus, MUFA that constitute olive oil were initially considered as neutral fatty acids. Nevertheless different studies demonstrated that olive oil is clearly involved in anti-inflammatory activities and in the modulation of immune response (reviewed in Puertollano et al., 2010). The anti-inflammatory activity of olive oil appears to be associated with the production of the metabolite eicosatrienoic acid from oleic acid (20:3 *n-9*), which is a potent inhibitor of LTB4 (James et al., 1993). In addition it is possible that beneficial effects of olive oil may be in part due to the presence of natural antioxidants, contributing to an increase in the stability of oil (Linos et al., 1999).

Taken together there is evidence that both *n-3* PUFA and *n-9* MUFA can be useful in treatment of inflammatory disorders associated with autoimmune disease. Table 2 summarizes a list of some of the diseases and conditions with an inflammatory component that could be beneficially affected by *n- 3* and *n-9* series fatty acids.


In this context interesting investigations indicates that *n-3* PUFA exert a significant inhibition of Th1-type cytokines, whereas they have little effects on Th2-type cytokines (Wallace et al., 2001). In spite of olive oil diets are involved in the reduction of cytokine secretion, their immunosupressant effects are not as potent as those exerted by the administration of a fish oil diet (Puertollano et al., 2004). Fatty acids are able to modify the natural killer (NK) cells activity too. Finally recent studies have proved the action of fatty acids in the expression of adhesion molecules like lymphocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) (Sanderson et al., 1995; Miles et al., 2001). These facts have been shown in preliminary studies in animal models but it is necessary

Inflammation is part of immune response and is a complex process affected by different factors, included mediators generated from fatty acids. Eicosanoids from *n-6* series fatty acids (like prostaglandine E2 (PGE2) and leukotriene B4 (LTB4) among others) are considered pro-inflammatory mediators while molecules from *n-3* series (like PGE3 and LTB5) generally are endowed with lower bioactivity. It is necessary to keep an optimal *n-6*/*n-3* balance to

Numerous researches have demonstrated that fish oil rich diet promotes a decrease on inflammatory ecoisanoids production from *n-6* PUFA because of the competition between the two metabolic pathways. In this way *n-3* PUFA supplementation of the human diet is able to decrease production of inflammatory eicosanoids like PGE2, LTB4 and thromboxane B2 (TXB2) by inflammatory cells (Meydani et al., 1991; Kelley et al., 1999; Trebble et al., 2003; Rees et al., 2006). In addition *n-3* PUFA have other effects over inflammatory response. One of the most important is the generation of resolvins, a group of mediators derived from EPA and DHA that appear to exert potent anti-inflammatory actions (Calder, 2008a). Decreasing antigen presentation via major histocompatibility complex class II (MHC II), inhibiting Tcell reactivity and diminishing inflammatory cytokine production (Calder et al., 2002; Akhtar Khan, 2010; Kim et al., 2010) are others of the anti-inflammatory effects of *n-3* fatty acids. Autoimmunity can be considered as an exacerbated inflammatory response against self structures; therefore *n-3* long chain fatty acids can be useful in the treatment of these

Oleic acid is the main fatty acid contained in olive oil. Olive oil has traditionally been used as a placebo in the studies investigating the potential action of other dietary lipids on the modulation of immune functions. Thus, MUFA that constitute olive oil were initially considered as neutral fatty acids. Nevertheless different studies demonstrated that olive oil is clearly involved in anti-inflammatory activities and in the modulation of immune response (reviewed in Puertollano et al., 2010). The anti-inflammatory activity of olive oil appears to be associated with the production of the metabolite eicosatrienoic acid from oleic acid (20:3 *n-9*), which is a potent inhibitor of LTB4 (James et al., 1993). In addition it is possible that beneficial effects of olive oil may be in part due to the presence of natural

Taken together there is evidence that both *n-3* PUFA and *n-9* MUFA can be useful in treatment of inflammatory disorders associated with autoimmune disease. Table 2 summarizes a list of some of the diseases and conditions with an inflammatory component

antioxidants, contributing to an increase in the stability of oil (Linos et al., 1999).

that could be beneficially affected by *n- 3* and *n-9* series fatty acids.

to confirm it in human studies.

achieve a healthy inflammatory state.

diseases.

**2.1 Dietary lipids and inflammatory response** 


Table 2. Inflammatory disorder where fatty acids could be useful. Diseases are listed in an alphabetical order (Adapted from Calder, 2006).
