Inflammation and autoimmune conditions, with Sophie Tully

Inflammation and Autoimmunity:
A nutritional approach to restore
inflammatory regulation
Sophie Tully BSc MSc

Autoimmunity
• 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

Autoimmune Conditions
Alopecia 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)

Biological basis of autoimmunity
• 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

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.

Biological basis of autoimmunity
• 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

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.201
0.22;
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

1.Reduce exposure to the initial triggers
• 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 continued
• Leaky gut
– Elimination/rotation diet
– Gut healing formula
• Stress
– Re-evaluate priorities and values
– Mindfulness
– Active self care
– Support network

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
Inflammatory response
Eicosanoid switch Stop signal
PGE2
LTB4
Pro-inflammatory reduced
Anti-inflammatory increased
Time
Initiation Resolution Termination
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)

The omega-6 to omega-3 ratio
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
• 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
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
• 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
Cambridge • Dominating family the will medical influence innovation metabolite ‘strength’
hub for the
UK:
• 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-6
LA
Omega-6
GLA
Omega-6
DGLA
Omega-3
ALA
Omega-3
SDA
Omega-3
EPA
Omega-3
DHA
Omega-6
AA
delta-6 desaturase
(FADS2)
delta-5 desaturase
Omega-6 (FADS1) Omega-3

Anti-inflammatory
eicosanoids
Inflammatory
eicosanoids
Anti-inflammatory
eicosanoids
Anti-inflammatory
docosanoids
Series-1 prostaglandins
Series-1 thromboxanes
Series-4 leukotrienes
Hydroxy fatty acids
Series-5 leukotrienes
Hydroxy fatty acids
Resolvins
Protectins
DGLA
AA
EPA
DHA
Omega-6
Omega-3

The role of lipid mediators
 Pro-inflammatory lipid
arachidonic acid (AA)
 Anti-inflammatory/pro-resolving lipids
dihomo-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

AA to EPA ratio - biomarker of inflammatory status
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
Ratio
1.5 - 3.0
3.1 – 6.9
7.0 – 14.9
>15.0
Inflammatory status
 low
 moderate
 elevated
 high

EPA and autoimmunity
• 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 translated
• 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

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 acting
on 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

Pharmepa®
Restore & Maintain™ anti-inflammatory protocol
UK:
This unique two-step protocol is designed to:
• Restore a healthy AA:EPA ratio
• Reduce the production of pro-inflammatory products
• Increase the production of anti-inflammatory products
• Support genetic factors involved in immune regulation
• Regulate HPA-axis for improved stress perception
Suitable applications:
 Autoimmunity
 Supporting mood & psychological disorders
 Cardiovascular health
 Chronic inflammatory disorders
 AND MUCH MORE

Echiomega
Derived from Echium plantagineum, Echium seed oil (Echiomega) is a novel food
approved source of the omega-3 fatty acids SDA and ALA. SDA is the precursor to
EPA, well known for its anti-inflammatory and immune-supporting actions.
UK:
25-30% of SDA converts to EPA, compared with just 5-8% of
ALA – the principal omega-3 in most other plant-derived
oils. Echiomega, rich in SDA, is the superior choice of
omega-3 for vegetarians and vegans.
 Provides the building blocks to restore optimum omega-3
and omega-6 levels
 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

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: Studies
1. 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.

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