Inflammation and autoimmune conditions, with Sophie Tully

Inflammation and Autoimmunity:A nutritional approach to restore inflammatory regulation

Sophie Tully BSc MSc

• Arises as a result of the body no longer recognising specific internal proteins and structures as ‘self’

• The immune system beings to ‘attack’ and destroy cells, organs and whole body systems e.g. the GI tact/CNS

• The target tissue is dependant on: genetic susceptibility, diet, lifestyle and environmental triggers

• There are over 80 classified autoimmune diseases

• As such, autoimmune disease is the 3rd biggest cause of morbidity and mortality in the western world (1st if you include CVD) www.who.com

Autoimmunity

http://www.who.com/

Autoimmune ConditionsAlopecia Coeliac

Crohn’s COPD

Dermatitis Type 1 Diabetes

Endometriosis Graves’ Disease (hyperthyroidism)

Hashimoto’s thyroiditis Arthritis (all)

Lupus Multiple Sclerosis

Polymyalgia rheumatica Psoriasis

Ulcerative Colitis Addison’s Disease (hypothyroidism)

IBD Sjögren’s Syndrome (dry eyes/mouth)

Pernicious anaemia Scleroderma (skin hardening)

Vasculitis (blood vessel inflammation) Vitiligo (skin depigmentation)

• Trigger – initiates antigen recognition of ‘self’– Viral infection – protein structure similar to our own – virus’s integral to our DNA– Bacteria/yeast infection – chronic activation of the immune response– Food sensitivities – gluten, lectins – sticky molecules that mimic internal proteins– Stress – disruption of hormone and immune regulation

• Environment– Diet affects immune and inflammatory regulation – Can cause dysbiosis, low stomach HCL and enzymes, insulin insensitivity and leaky gut =

lowered defences against ‘triggers’

• Genetics– Determines which tissues are most likely to be targeted– Increases susceptibility to triggers via environment

Biological basis of autoimmunity

Host response and autoimmunity: mechanisms that can eventually lead to autoimmunity in a susceptible individual.

Sfriso P et al. J Leukoc Biol 2010;87:385-395

©2010 by Society for Leukocyte Biology

Pathogens bear elements that are similar enough in amino acid sequence or structure to self-antigen. The immune response can eventually turn toward the self-peptide as a result of cross-reactivity, leading to the activation of naïve, autoreactive T cells specific to the corresponding self-molecule. Mφ, Macrophage.




Following tissue injury, cell death, oxidative stress, free radical production, and reparative changes, as happens in several infections, proteins that are usually recognized as self can become nonself and induce an autoimmune response.

In addition, proteins that are normally sequestered and shielded from immune recognition can be exposed to the immune system and become immunogenic. Therefore, cryptic antigens become accessible to self-reacting T lymphocytes that had escaped central and peripheral tolerance, as they had not been presented appropriately to induce tolerance.




Superantigens are proteins produced by a variety of microorganisms, especially bacteria or mycoplasmae, or virus-infected cells that can bind TCR irrespective of its antigenic specificity, resulting in the activation of a large number of T lymphocytes of different antigenic specificity, thus behaving as a potent immune-stimulating molecule.




The enhanced processing and presentation of self-antigens induce the expansion or spreading of immune response toward different self-antigens. This process, known as “epitope spreading,” has been widely involved in the pathogenesis of many systemic autoimmune diseases as well as in determining the different expression of such diseases.

• Inflammation – 1st line defence against all pathogens

• Innate non-specific immune response

• Triggers express PAMPs and DAMPs - Pathogen/damage associated

molecular proteins

• PAMPs and DAMPs are recognised by receptors expressed on immune

cells (dendrites and macrophages)

• These cells release inflammatory cytokines: TNF –α, Type 1 INF, IL-1β, IL-6,

IL-18 and INF-γ

• This initiates the inflammatory cascade

Biological basis of autoimmunity

If the antigen persists:– due to increasing stress related damage, food sensitivity, unaddressed infection …

• antigen is taken up and processed by macrophages, monocytes and B cells

• presented to Naїve CD4⁺T cells

• T cells differentiate according to trigger type and cytokine’s present

• specific T cell subtypes promote differentiation and proliferation of B cell

Cellular & Molecular Immunology (2010)

7, 182–189;

doi:10.1038/cmi.2010.22;

published online 12 April 2010

• Antigen specific antibody is produced

• Direct, prolonged and ‘remembered’ adaptive immune response

• In autoimmunity antibodies target ‘self’ proteins

• Immune system has now learnt to destroy ‘self’ whenever the trigger protein is present.

• Any exposure to original trigger antigen = antibodies liberated ready for attack

Resolution of autoimmunity - a two pronged approach:

1. Reduce exposure to the initial triggers

2. Reduce inflammation and cytokine production

• Infection – GI parasite/bacteria/infection testing– Digestive enzymes– Antimicrobials – Olive leaf, oregano oil, raw garlic, lemon

juice….

• Gut dysbiosis– Probiotics– Low carbohydrate – 100% natural organic diet

1.Reduce exposure to the initial triggers

• Leaky gut– Elimination/rotation diet– Gut healing formula

• Stress – Re-evaluate priorities and values– Mindfulness– Active self care– Support network

1.Reduce exposure to the initial triggers continued

2. Reduce inflammation and cytokine production

Inflammation, cytokines and autoimmunity

• Pro-inflammatory cytokine ‘mixture’ triggers the differentiation of T cells into specific subtypes

• Th1 – targets intracellular pathogens • Th2 - targets extracellular pathogens • Th17 – newly recognised – major contributor to autoimmunity• Treg cells – actively suppress effector cells and dampens immune

responses

• The specific T cells subtypes secrete cytokines, stimulating their own expansion and survival

Th17 and autoimmunity

• Th17 cells – now considered to regulate inflammatory and autoimmune disease

• Cytokines expressed by TH17 cells are involved in pathogenesis of numerous autoimmune diseases inc. RA, Lupus, lung and skin disorders

• BUT Th17 important in fight against infection and shown to prevent and promote cancers….double edged sword

• Reducing Th17 reduces inflammation and autoimmune disease

Th17 and autoimmunity

• Ratio of Th1 to Th17 and Treg to Th17 - important indicator of autoimmune disease

• High Th17 relative to Th1 implicated in MS, osteoporosis and IBD

• High Th17 relative to Treg contributes to the onset and progression of autoimmune disease

• High inflammation and thus high cytokines inhibit Treg cells

• Pro-inflammatory cytokine promote conversion of Tregs to Th17 cells – shifting the balance from immune regulation towards inflammation

Resoleomics - the process of inflammation resolution In

flam

mat

ory

resp

onse

Initiation Resolution Termination

PGE2

LTB4

Eicosanoid switch Stop signal

Time

Pro-inflammatory reduced

Anti-inflammatory increased

Source: Bosma-den Boer et al., 2012

The role of diet and lifestyle in modulating inflammation

• Triggers from chronic altered diet and psycho-emotional stress negatively influence the resolution step of the inflammatory response

• Failure to resolve inflammation increases susceptibility to the development of chronic, low-grade, inflammation-based diseases due to the constant activation of both the HPA-axis and innate immune system (Bosma-den Boer et al., 2012)

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The omega-6 to omega-3 ratio

• Historically, the human diet was high in omega-3 fatty acids, with a ratio of omega-6 to omega-3 fatty acids of around 1-2:1

• During the last few decades, there has been a marked increase in consumption of omega-6 and a decrease in consumption of omega-3 fatty acids

• Many modern food types are ‘new’ in regard to human evolution, rich in added omega-6 and stripped of omega-3



What is the issue?

• Omega-6 and omega-3 families share common enzymes

• Dominating family will influence metabolite ‘strength’

• Omega-6 to omega-3 ratio important but not truly reflective of health status

• How do we measure health implications of deficiency? Omega-3 index AA to EPA ratio

Omega-6LA

Omega-6GLA

Omega-6DGLA

Omega-3ALA

Omega-3EPA

Omega-3SDA

Omega-3DHA

Omega-6AA

delta-6 desaturase(FADS2)

delta-5 desaturase(FADS1)Omega-6 Omega-3

Anti-inflammatory eicosanoids

Anti-inflammatory eicosanoids

Anti-inflammatory docosanoids

Inflammatoryeicosanoids

Series-3 prostaglandinsSeries-3 thromboxanesSeries-5 leukotrienesHydroxy fatty acids

Series-1 prostaglandinsSeries-1 thromboxanes

Series-2 prostaglandinsSeries-2 thromboxanesSeries-4 leukotrienesHydroxy fatty acids

Resolvins Protectins

DGLA

EPA

DHA

AA

Omega-6

Omega-3

The role of lipid mediators

Pro-inflammatory lipidarachidonic acid (AA)

Anti-inflammatory/pro-resolving lipidsdihomo-gamma-linolenic acid (DGLA)eicosapentaenoic acid (EPA)

docosahexaenoic acid (DHA)

AA and EPA are the significant eicosanoid precursors

AA to EPA ratio is a direct biomarker of inflammatory status

• PUFAs are incorporated into ALL cell membranes – inc. immune cells

• Released by Phospholipase A2 enzyme and converted to eicosanoids

• Phospholipase A2 stimulated by inflammatory signals – releases AA

• Cyclooxygenase 2 (COX-2) and Lipoxygenase (LOX) enzymes convert AA to pro-inflammatory

- Prostaglandins- Leukotrienes- Thromboxanes

• EPA directly displaces AA from cell membrane- Reduced substrate for pro-inflammatory

eicosanoids

• EPA switches off Phospholipase A2- Less AA release into circulation

• EPA inhibits AA metabolism • EPA decreases expression of COX-2

- Less pro-inflammatory eicosanoids produced

The key to regulating inflammation is through the modulation of eicosanoids:

• pro-inflammatory eicosanoids from AA drive the immune and inflammatory processes

• anti-inflammatory eicosanoids from EPA act to end the process through resolution

• Reduce pro-inflammatory product production and increase anti-inflammatory (pro-resolving) products

The AA to EPA ratio is an indication of the balance between pro-inflammatory and anti-inflammatory eicosanoids

High AA and low EPA levels will drive the inflammatory response and the subsequent failure to resolve inflammation may increase susceptibility to the development of chronic, low-grade, inflammation-based diseases

AA to EPA ratio - biomarker of inflammatory status

Ratio1.5 - 3.03.1 – 6.9

7.0 – 14.9>15.0

Inflammatory status low moderate elevated high

• EPA directly competes with AA for COX and LOX capacity– leads to greater production of anti-inflammatory eicosanoids and reduced

production of pro-inflammatory eicosanoids

• EPA eicosanoids considerably less ‘sticky’ than AA derivatives – reduces leukocyte adhesion and chemotaxis – major factor that drives

autoimmune pathogenesis

• Omega-3s:– suppress monocyte synthesis of cytokines at genetic level (mRNA)– reduce phagocytic activity of immune cells– reduce antigen presenting cells ability to present antigens to T and B cells.

EPA and autoimmunity

• Increasing EPA reduces AA stimulation of white blood cells – important for preventing unwanted antibody production

• PPARγ, a nuclear receptor involved in metabolism and immune regulation is expressed by Treg cells– Synthetic PAPR γ activators (agonists) were able to inhibit immune

response in a rat model of autoimmune disease

– EPA activates PAPR γ – subsequently inducing Treg cell immune regulation

EPA and autoimmunity

• Increasing EPA levels reduces inflammatory cytokine load preventing risk of triggers inducing full immune response

• EPA supresses immune activation of white blood cells – preventing production of ‘self’ targeted antibodies

• EPA competes with AA to reduce production of pro-inflammatory signals and subsequent release of immune factors that contribute to the initiation, progression and severity of organ specific autoimmunity

EPA and autoimmunity translated

• EPA the most potent omega-3 suppressor of TNF- α and IL-6 production– key drivers of Th17 differentiation

• EPA reduces immune cell destructive activity and antigen recognition

• EPA directly alters genetic expression of cytokines

• EPA stimulates important genetic factors involved in the regulation and resolution of inflammatory disease

EPA and autoimmunity translated

Stress and inflammation - a double edged sword

• Stress triggers inflammation and autoimmune disease• High inflammation increases stress perception and psychological

distress

• Reducing inflammation directly reduces stress • Reducing chronic stress prevents high inflammation

– both protect against subsequent disease risk

– Serum PUFAs levels - specifically EPA - directly predict inflammation and stress risk

– Inflammatory cytokine levels and the AA:EPA ratio - correlate with risk and severity of depression

– 1g pure EPA daily significantly improves severity of clinical depression

(Lotrich et al., 2012., Sublette et al., 2012 Mozaffari-Khosravi et al., 2012)

EPA and autoimmune disease studies

Effects of eicosapentaenoic acid supplementation on immunoglobulin A nephropathy. Uchiyama-Tanaka, Y. and Y. Mori 2010

• EPA reportedly improves renal survival in patients with immunoglobulin (Ig)A nephropathy• Eighteen biopsy-confirmed IgA nephropathy patients (aged 31 +/- 3 years) were enrolled. Five

biopsy-confirmed IgA nephropathy patients were enrolled as control subjects.• EPA was administered at 1.8 g/day for 12 months. Administration of other drugs used to treat IgA

nephropathy was not changed. • The estimated creatinine clearance (eCCr), serum creatinine (Cr) concentration, urinary protein

creatinine ratio (U/P), and other clinical parameters were checked. • In the EPA group, values Cr and U/P tended to improve, with no adverse effects from the EPA. • eCCr improved significantly (P = 0.001) in the EPA group, but not in the control group (P > 0.05). • The effect of EPA in patients with IgA nephropathy is not pronounced, but these results suggest

that EPA is a safe and worthwhile supplement to the drugs used to treat this disease.

Eicosapentaenoic acid attenuates arthritis-induced muscle wasting actingon atrogin-1 and on myogenic regulatory factors Castillero, 2009

• The aim of this work was to elucidate whether EPA administration is able to prevent an arthritis-induced decrease in body weight and muscle wasting in rats.

• Arthritis was induced by intradermal injection of Freund’s adjuvant; 3 days later, nine rats received 1 g/kg EPA or coconut oil daily.

• EPA administration decreased the external signs of arthritis and paw volume as well as liver TNF-α mRNA.

• EPA did not modify arthritis-induced decrease in food intake or body weight gain. • However, EPA treatment prevented arthritis-induced increase in muscle TNF- α and atrogin-1,

whereas it attenuated the decrease in gastrocnemius weight and the increase in MuRF1 (ligase protein involved in muscle degradation) mRNA. In the control rats, EPA administration increased PCNA (proliferating cell nuclear antigen) and MyoD (human myogenic differentiation) mRNA and protein.

• The results suggest that in experimental arthritis, in addition to its anti-inflammatory effect, EPA treatment attenuates muscle wasting by decreasing atrogin-1 and MuRF1 gene expression and increasing the transcription factors that regulate myogenesis.

Alterations in circulating fatty acid composition in patients with systemic lupus erythematosus: a pilot study Aghdassi et al., 2011• INTRODUCTION: Circulating fatty acids (FAs) may play a role in the disease pathogenesis of patients with

systemic lupus erythematosus (SLE).

• OBJECTIVES: To compare red blood cell (RBC) and plasma FA composition: (1) between female SLE patients and age-matched healthy female (HF) controls and in SLE with history of cardiovascular disease (CVD) and those with no history (SLE+CVD vs SLE-CVD); and (2) between SLE patients who were or were not receiving prednisone treatment at the time of blood sampling.

• METHODS: This cross-sectional study consisted of 33 female patients with SLE (11 SLE+CVD, 22 SLE-CVD) and 20 HF controls. Demographics, CVD risk, medication profile, blood biochemistry, and FA composition of RBC and plasma total lipids were determined.

• RESULTS: RBC FA composition showed lower eicosapentaenoic acid (EPA, omega-3 active metabolite) and omega-3 index (EPA+ docosahexaenoic acid) in SLE patients compared with HF controls. The ratio of the RBC inflammatory metabolite, arachidonic acid, to the anti-inflammatory metabolite EPA was also significantly higher in SLE patients than in HF controls.

• CONCLUSION: SLE patients, regardless of their history of CVD, have altered plasma and RBC FA composition favouring inflammation.

Ethyl-eicosapentaenoic acid ameliorates the clinical course of experimental allergic encephalomyelitis induced in dark agouti rats Salvati et al., 2013

• We investigated the effects of EPA in an established animal model for multiple sclerosis (MS): experimental autoimmune encephalomyelitis (EAE) induced in dark agouti rats.

• Diets supplemented either with 0.2% or 0.4% of EPA were administrated daily from the day of induction until the end of experiment. One group of rats received diet supplemented with 0.2% of EPA 10 days before induction. The control group (immunized rats) was fed with chow diet.

• The animals were analyzed at two different stages of the disease: during the acute phase (14 d.p.i.) and during the recovery phase (32 d.p.i.).

• We showed a delayed onset of clinical severity of disease in all groups of rats fed EPA-supplemented diets. This effect was associated to an increased expression of myelin proteins and an improved integrity of the myelin sheath as well as an up-regulation of FoxP3 expression in the central nervous system during the acute phase of EAE.

• No significant changes in T cell subsets were noted at the periphery. On the contrary, during the recovery phase of EAE, in animals assuming EPA-supplemented diet, an increase of CD4+CD25+ and CD4+CD25+FoxP3+ in peripheral lymphocytes was noted.

• Our results indicate that EPA-supplemented diets may provide benefits to MS patients.

Effects of Combination Therapy with Renin-Angiotensin System Inhibitors and Eicosapentaenoic Acid on IgA Nephropathy Moriyama et al., 2013• OBJECTIVE: The beneficial effects of renin-angiotensin-aldosterone system inhibitors (RASI) and the

omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on IgA nephropathy (IgAN) have been reported. However, it is unknown whether these agents have any synergistic interactions.

• METHODS: We divided 38 IgAN patients into two groups: an EPA group (n=18) treated with RASI plus EPA and a DILAZEP group (n=20) treated with RASI plus dilazep dihydrochloride. We analyzed the clinical and histological background of each patient, any relevant clinical findings obtained one year after treatment and any factors significantly related to decreases in proteinuria.

• RESULTS: At one year after treatment, the EPA group demonstrated a significantly decreased mean blood pressure (from 94.7+/-9.0 to 86.4+/-7.2 mmHg, p=0.0007) and a significantly decreased median level of proteinuria (from 0.80 to 0.41 g/g creatinine, p<0.001). In the DILAZEP group, the mean blood pressure significantly decreased (from 95.2+/-13.2 to 88.1+/-7.7 mmHg, p<0.001) without any significant decrease in the median level of proteinuria (from 0.88 to 0.60 g/g creatinine).

• According to a multivariate logistic analysis, EPA was found to be the only independent factor related to decreases in proteinuria (odds ratio = 5.073, 95% CI: 1.18-26.7, p=0.0285).

• CONCLUSION: We conclude that EPA accelerates the effects of RASI and thus decreases the proteinuria observed in patients with IgAN.

Conclusion

• EPA directly reduces inflammation and inflammatory stimuli leading to auto immunity

• EPA positively impacts immune response ‘course’ to control and resolve inflammation

• EPA acts to reduce immune mechanisms associated with organ specific autoimmune disease

• EPA acts via numerous mechanisms to reverse and resolve clinical manifestations of autoimmune disease

• 1.5-3g EPA optimal for management and resolution of Inflammatory disease



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Favourable omega-6 to omega-3 ratio of 1:1.8 Naturally high in SDA and GLA Vegetarian precursor to EPA Supports immune function Naturally anti-inflammatory Supports cardiovascular health

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References: Inflammation, Autoimmunity and EPA science• Calder, P.C., Marine omega-3 fatty acids and inflammatory processes: Effects,

mechanisms and clinical relevance. Biochim Biophys Acta, 2014.• Simopoulos, A.P., Omega-3 fatty acids in inflammation and autoimmune diseases. J

Am Coll Nutr, 2002. 21(6): p. 495-505.• Singh, R.P., et al., Th17 cells in inflammation and autoimmunity. Autoimmun Rev,

2014.• Leung, S., et al., The cytokine milieu in the interplay of pathogenic Th1/Th17 cells

and regulatory T cells in autoimmune disease. Cell Mol Immunol, 2010. 7(3): p. 182-9.

• Iwami, D., et al., Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells. Int Immunopharmacol, 2011. 11(3): p. 384-9.

• Yokota, S., et al., Pathogenesis of systemic inflammatory diseases in childhood: "Lessons from clinical trials of anti-cytokine monoclonal antibodies for Kawasaki disease, systemic onset juvenile idiopathic arthritis, and cryopyrin-associated periodic fever syndrome". Mod Rheumatol, 2014: p. 1-10.

References: Studies1. Lotrich, F.E., B. Sears, and R.K. McNamara, Elevated ratio of arachidonic acid to long-chain omega-3

fatty acids predicts depression development following interferon-alpha treatment: relationship with interleukin-6. Brain Behav Immun, 2013. 31: p. 48-53.

2. Sublette, M.E., et al., Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry, 2011. 72(12): p. 1577-84.

3. Mozaffari-Khosravi, H., et al., Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: a randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol, 2013. 23(7): p. 636-44.

4. Uchiyama-Tanaka, Y. and Y. Mori, Effects of eicosapentaenoic acid supplementation on immunoglobulin A nephropathy. Ther Apher Dial, 2010. 14(3): p. 303-7.

5. Castillero, E., et al., Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors. Am J Physiol Regul Integr Comp Physiol, 2009. 297(5): p. R1322-31.Aghdassi, E., et al., Alterations in circulating fatty acid composition in patients with systemic lupus erythematosus: a pilot study. JPEN J Parenter Enteral Nutr, 2011. 35(2): p. 198-208.

6. Salvati, S., et al., Ethyl-eicosapentaenoic acid ameliorates the clinical course of experimental allergic encephalomyelitis induced in dark agouti rats. J Nutr Biochem, 2013. 24(9): p. 1645-54.

7. Moriyama, T., et al., Effects of combination therapy with renin-angiotensin system inhibitors and eicosapentaenoic acid on IgA nephropathy. Intern Med, 2013. 52(2): p. 193-9.

Inflammation and autoimmune conditions, with Sophie Tully

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