Important Differences Exist in the Dose–Response Relationship between Diet and Immune Cell Fatty Acids in Humans and Rodents

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are noted for their ability to diminish inflammatory and immune responses in vitro and in a variety of animal-based models of autoimmunity and inflammation. Yet, recent systematic reviews suggest that the evidence for these fatty acids having beneficial effects on inflammation or autoimmunity in humans is equivocal. A possible explanation for these disappointing and somewhat paradoxical findings emerged from the analyses described in this review. The available data on the changes in immune cell fatty acid profiles in mice, rats and humans, fed various forms and amounts of n-3 PUFA are summarized and displayed graphically. The dose–response curves generated provide new insights into the relationship between dietary n-3 PUFA and immune cell fatty acid profiles. The author suggests that the poor predictive value of most in vitro as well as many animal trials may, in part, be a consequence of the frequent adoption of experimental conditions that create differences in immune cell fatty acid profiles that far exceed what is possible in free-living humans through dietary intervention. Recommendations for improving the preclinical value of future in vitro and animal-based studies with n-3 PUFA are provided.     

Replacement of Marine Fish Oil with de novo Omega-3 Oils from Transgenic Camelina sativa in Feeds for Gilthead Sea Bream (Sparus aurata L.)

Omega‐3 (n‐3) long‐chain polyunsaturated fatty acids (LC‐PUFA) are essential components of the diet of all vertebrates. The major dietary source of n‐3 LC‐PUFA for humans has been fish and seafood but, paradoxically, farmed fish are also reliant on marine fisheries for fish meal and fish oil (FO), traditionally major ingredients of aquafeeds. Currently, the only sustainable alternatives to FO are vegetable oils, which are rich in C₁₈ PUFA, but devoid of the eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) abundant in FO. Two new n‐3 LC‐PUFA sources obtained from genetically modified (GM) Camelina sativa containing either EPA alone (ECO) or EPA and DHA (DCO) were compared to FO and wild‐type camelina oil (WCO) in juvenile sea bream. Neither ECO nor DCO had any detrimental effects on fish performance, although final weight of ECO‐fed fish (117 g) was slightly lower than that of FO‐ and DCO‐fed fish (130 and 127 g, respectively). Inclusion of the GM‐derived oils enhanced the n‐3 LC‐PUFA content in fish tissues compared to WCO, although limited biosynthesis was observed indicating accumulation of dietary fatty acids. The expression of genes involved in several lipid metabolic processes, as well as fish health and immune response, in both liver and anterior intestine were altered in fish fed the GM‐derived oils. This showed a similar pattern to that observed in WCO‐fed fish reflecting the hybrid fatty acid profile of the new oils. Overall the data indicated that the GM‐derived oils could be suitable alternatives to dietary FO in sea bream.     

Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation

The higher incidence of inflammatory diseases in Western countries might be related, in part, to a high consumption of saturated fatty acids and n−6 polyunsaturated fatty acids (PUFA) and an insufficient intake of n−3 fatty acids. The purpose of this study was to examine the effects of dietary n−3 fatty acids on innate and specific immune response and their anti-inflammatory action in models of contact and atopic dermatitis. Balb/C mice were fed for 3 wk either n−6 or n−3 PUFA-fortified diets. After inducing a contact or an atopic dermatitis, immunological parameters were analyzed to evaluate the anti-inflammatory potential of these n−3 PUFA. n−3 PUFA reduced innate and specific immune responses through inhibition of T_H1 and T_H2 responses, increase of immunomodulatory cytokines such as IL-10, and regulation of gene expression. The inhibition of both kinds of responses was confirmed by the anti-inflammatory effect observed in contact and atopic dermatitis. Reduction in weight, edema, thickness, leukocyte infiltration, and enhancement of antioxidant defenses in the inflamed ears of mice from both models along with the prevention of delayed-type hypersensitivity induced in atopic dermatitis proved n−3 PUFA efficacy. Our data suggest that dietary fish oil-derived n−3 fatty acids have immunomodulatory effects and could be useful in inflammatory disorders.     

Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host–microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.     

Diet-Regulating Microbiota and Host Immune System in Liver Disease

The gut microbiota has been known to modulate the immune responses in chronic liver diseases. Recent evidence suggests that effects of dietary foods on health care and human diseases are related to both the immune reaction and the microbiome. The gut-microbiome and intestinal immune system play a central role in the control of bacterial translocation-induced liver disease. Dysbiosis, small intestinal bacterial overgrowth, translocation, endotoxemia, and the direct effects of metabolites are the main events in the gut-liver axis, and immune responses act on every pathways of chronic liver disease. Microbiome-derived metabolites or bacteria themselves regulate immune cell functions such as recognition or activation of receptors, the control of gene expression by epigenetic change, activation of immune cells, and the integration of cellular metabolism. Here, we reviewed recent reports about the immunologic role of gut microbiotas in liver disease, highlighting the role of diet in chronic liver disease.     

Polyunsaturated fatty acids, inflammation, and immunity

The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n−3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n−3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n−3 PUFA in fish oil are antiinflammatory and immunomodulatory.     

Adaptive Immunity and the Risk of Autoreactivity in COVID-19

While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body’s adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection.     

The Immune System through the Lens of Alcohol Intake and Gut Microbiota

The human gut is the largest organ with immune function in our body, responsible for regulating the homeostasis of the intestinal barrier. A diverse, complex and dynamic population of microorganisms, called microbiota, which exert a significant impact on the host during homeostasis and disease, supports this role. In fact, intestinal bacteria maintain immune and metabolic homeostasis, protecting our organism against pathogens. The development of numerous inflammatory disorders and infections has been linked to altered gut bacterial composition or dysbiosis. Multiple factors contribute to the establishment of the human gut microbiota. For instance, diet is considered as one of the many drivers in shaping the gut microbiota across the lifetime. By contrast, alcohol is one of the many factors that disrupt the proper functioning of the gut, leading to a disruption of the intestinal barrier integrity that increases the permeability of the mucosa, with the final result of a disrupted mucosal immunity. This damage to the permeability of the intestinal membrane allows bacteria and their components to enter the blood tissue, reaching other organs such as the liver or the brain. Although chronic heavy drinking has harmful effects on the immune system cells at the systemic level, this review focuses on the effect produced on gut, brain and liver, because of their significance in the link between alcohol consumption, gut microbiota and the immune system.     

Significance of dietary antioxidants for health

Since evidence became available that free radicals were involved in mechanisms for the development of major diseases, including cardiovascular disease and cancer, there has been considerable research into the properties of natural dietary antioxidants. However, it has become clear that dietary antioxidants can only have beneficial effects in vivo by radical scavenging or effects on redox potential if they are present in tissues or bodily fluids at sufficient concentrations. For many dietary components, absorption is limited or metabolism into derivatives reduces the antioxidant capacity. For many dietary phytochemicals, direct antioxidant effects may be less important for health than other effects including effects on cell signalling or gene expression in vivo.     

Effects of dietary n−3 polyunsaturated fatty acids on T-Cell membrane composition and function

Dietary n−3 PUFA have been shown to attenuate T-cell-mediated inflammation, in part, by suppressing T-cell activation and proliferation. n−3 PUFA have also been shown to promote apoptosis, another important mechanism for the prevention of chronic inflammation by maintaining T-cell homeostasis through the contraction of populations of activated T cells. Recent studies have specifically examined Fas death receptor-mediated activation-induced cell death (AICD), since it is the form of apoptosis associated with peripheral T-cell deletion involved in immunological tolerance and T-cell homeostasis. Data from our laboratory indicate that n−3 PUFA promote AICD in T helper 1 polarized cells, which are the mediators of chronic inflammation. Since Fas and components of the deathinducing signaling complex are recruited to plasma membrane microdomains (rafts), the effect of dietary n−3 PUFA on raft composition and resident protein localization has been the focus of recent investigations. Indeed, there is now compelling evidence that dietary n−3 PUFA are capable of modifying the composition of T-cell membrane microdomains (rafts). Because the lipids found in membrane microdomains actively participate in signal transduction pathways, these results support the hypothesis that dietary n−3 PUFA influence signaling complexes and modulate T-cell cytokinetics in vivo by altering T-cell raft composition.     

Dietary Crude Lecithin Increases Systemic Availability of Dietary Docosahexaenoic Acid with Combined Intake in Rats

Crude lecithin, a mixture of mainly phospholipids, potentially helps to increase the systemic availability of dietary omega‐3 polyunsaturated fatty acids (n‐3 PUFA), such as docosahexaenoic acid (DHA). Nevertheless, no clear data exist on the effects of prolonged combined dietary supplementation of DHA and lecithin on RBC and plasma PUFA levels. In the current experiments, levels of DHA and choline, two dietary ingredients that enhance neuronal membrane formation and function, were determined in plasma and red blood cells (RBC) from rats after dietary supplementation of DHA‐containing oils with and without concomitant dietary supplementation of crude lecithin for 2–3 weeks. The aim was to provide experimental evidence for the hypothesized additive effects of dietary lecithin (not containing any DHA) on top of dietary DHA on PUFA levels in plasma and RBC. Dietary supplementation of DHA‐containing oils, either as vegetable algae oil or as fish oil, increased DHA, eicosapentaenoic acid (EPA), and total n‐3 PUFA, and decreased total omega‐6 PUFA levels in plasma and RBC, while dietary lecithin supplementation alone did not affect these levels. However, combined dietary supplementation of DHA and lecithin increased the changes induced by DHA supplementation alone. Animals receiving a lecithin‐containing diet also had a higher plasma free choline concentration as compared to controls. In conclusion, dietary DHA‐containing oils and crude lecithin have synergistic effects on increasing plasma and RBC n‐3 PUFA levels, including DHA and EPA. By increasing the systemic availability of dietary DHA, dietary lecithin may increase the efficacy of DHA supplementation when their intake is combined.     

Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease

Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD.     

An Overview of Physical,Microbiological and Immune Barriers of Oral Mucosa

The oral mucosa, which is the lining tissue of the oral cavity, is a gateway to the body and it offers first-line protection against potential pathogens, exogenous chemicals, airborne allergens, etc. by means of its physical and microbiological-immune barrier functions. For this reason, oral mucosa is considered as a mirror to the health of the individual as well as a guard or early warning system. It is organized in two main components: a physical barrier, which consists of stratified epithelial cells and cell–cell junctions, and a microbiological-immune barrier that keeps the internal environment in a condition of homeostasis. Different factors, including microorganism, saliva, proteins and immune components, have been considered to play a critical role in disruption of oral epithelial barrier. Altered mucosal structure and barrier functions results in oral pathologies as well as systemic diseases. About 700 kinds of microorganisms exist in the human mouth, constituting the oral microbiota, which plays a significant role on the induction, training and function of the host immune system. The immune system maintains the symbiotic relationship of the host with this microbiota. Crosstalk between the oral microbiota and immune system includes various interactions in homeostasis and disease. In this review, after reviewing briefly the physical barriers of oral mucosa, the fundamentals of oral microbiome and oral mucosal immunity in regard to their barrier properties will be addressed. Furthermore, their importance in development of new diagnostic, prophylactic and therapeutic strategies for certain diseases as well as in the application for personalized medicine will be discussed.     

The role of polyunsaturated fatty acid supplementation in intestinal inflammation and neonatal necrotizing enterocolitis

Dietary polyunsaturated fatty acid (PUFA) supplementation has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in a recent randomized, controlled trial. These compounds are known to modulate the inflammatory cascade and to influence intestinal health in a variety of ways. Although the pathophysiology of NEC is not well understood, recent evidence suggests that platelet-activating factor (PAF) is a key endogenous mediator of intestinal necrosis in animals. Using a neonatal rat model of NEC that includes the key risk factors of asphyxia and formula feeding, we investigated the role of dietary PUFA supplementation on the incidence and pathophysiology of NEC. Our findings suggest that PUFA reduce the incidence of NEC by modulating PAF metabolism and endotoxin translocation.     

Armed to the Teeth—The Oral Mucosa Immunity System and Microbiota

The oral cavity is inhabited by a wide spectrum of microbial species, and their colonization is mostly based on commensalism. These microbes are part of the normal oral flora, but there are also opportunistic species that can cause oral and systemic diseases. Although there is a strong exposure to various microorganisms, the oral mucosa reduces the colonization of microorganisms with high rotation and secretion of various types of cytokines and antimicrobial proteins such as defensins. In some circumstances, the imbalance between normal oral flora and pathogenic flora may lead to a change in the ratio of commensalism to parasitism. Healthy oral mucosa has many important functions. Thanks to its integrity, it is impermeable to most microorganisms and constitutes a mechanical barrier against their penetration into tissues. Our study aims to present the role and composition of the oral cavity microbiota as well as defense mechanisms within the oral mucosa which allow for maintaining a balance between such numerous species of microorganisms. We highlight the specific aspects of the oral mucosa protecting barrier and discuss up-to-date information on the immune cell system that ensures microbiota balance. This study presents the latest data on specific tissue stimuli in the regulation of the immune system with particular emphasis on the resistance of the gingival barrier. Despite advances in understanding the mechanisms regulating the balance on the microorganism/host axis, more research is still needed on how the combination of these diverse signals is involved in the regulation of immunity at the oral mucosa barrier.     

Immunomodulation by polyunsaturated fatty acids: Impact on T-cell signaling

In recent years the potential application of the immunomodulatory effects of polyunsaturated FA (PUFA), particularly those of the n−3 series, in a variety of inflammatory disorders has been of considerable interest. However, the mechanisms underlying inhibition of T-cell activation have so far been unclear. In this short review we summarize possible mechanisms for the modulation of immune responses by PUFA. Effects of PUFA on T-cell signal transduction pathways and underlying molecular mechanisms are described in detail. These recent results add considerably to the understanding of mechanisms of PUFA actions, but their relevance in the in vivo situation must still be elucidated.     

Effects of dietary polyunsaturated fatty acids on neuronal function

Diets deficient in linoleic acid (18∶2n−6), or that have unusual ratios of linoleic acid to α-linolenic acid (18∶3n−3) induce changes in the polyunsaturated fatty acid (PUFA) composition of neuronal and glial membranes. Such changes have been linked to alterations in retina and brain function. These functional effects are presumed to follow from the biochemical consequences of modifying membrane PUFA content; known effects include modifications in membrane fludity, in the activities of membrane-associated, functional proteins (transporters, receptors, enzymes), and in the production of important signaling molecules from oxygenated linoleic and α-linolenic acid derivatives. However, despite the demonstration that central nervous system function changes when dietary PUFA intake is altered, and that in general, membrane PUFA content influences membrane functions, little work has focused specifically on brain and retina to reveal the underlying biochemical bases for such effects. This review examines this issue, looking at known effects of dietary PUFA on neurons in both the central and peripheral nervous systems, and attempts to identify some approaches that might promote productive investigation into the underlying mechanisms relating changes in dietary PUFA intake to alterations in neuronal and overall nervous system functioning.     

n−3 Polyunsaturated fatty acids and inflammation: From molecular biology to the clinic

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n−3 FA. However, n−3 FA have a number of other effects that might occur down-stream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n−3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.     

Leptin in Dental Pulp and Periapical Tissues: A Narrative Review

Leptin is a non-glycosylated 16 kDa protein synthesized mainly in adipose cells. The main function of leptin is to regulate energy homeostasis and weight control in a central manner. There is increasing evidence that leptin also has systemic effects, acting as a link between innate and acquired immune responses. The expression of leptin and its receptor in human dental pulp and periradicular tissues have already been described, as well as several stimulatory effects of leptin protein expression in dental and periodontal tissues. The aim of this paper was to review and to compile the reported scientific literature on the role and effects of leptin in the dental pulp and periapical tissues. Twelve articles accomplished the inclusion criteria, and a comprehensive narrative review was carried out. Review of the available scientific literature concluded that leptin has the following effects on pulpal and periapical physiology: 1) Stimulates odontogenic differentiation of dental pulp stem cells (DPSCs), 2) Increases the expression of dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1), odontoblastic proteins involved in odontoblastic differentiation and dentin mineralization, 3) Stimulates vascular endothelial growth factor (VEGF) expression in human dental pulp tissue and primary cultured cells of human dental pulp (hDPCs), 4) Stimulates angiogenesis in rat dental pulp cells, and 5) Induces the expression of interleucinas 6 and 8 in human periodontal ligament cells (hPDLCs). There is evidence which suggests that leptin is implicated in the dentin mineralization process and in pulpal and periapical inflammatory and reparative responses.     

Fatty acids,the immune response,and autoimmunity: A question of n−6 essentiality and the balance between n−6 and n−3

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.