FACTS, FOR CONTENT:

 

AUTOIMMUNE SCIENCE
Dr. Sarah Ballantyne, PhD

WHAT IS AUTOIMMUNE DISEASE?

• Anyof>140diseasescausedbytheimmunesystem attacking tissues in the human body

• Difficulttodiagnose
  (45% of patients later diagnosed with a serious a autoimmune disease are labeled as hypochondriacs in the early phases of their diseases)

• Chronicandlifelong(nocure)

• Medicaltreatmentsarelimited;

symptom management

• Affects~50millionAmericans

• Incidenceinincreasing

WHY FOCUS ON AUTOIMMUNE DISEASE?

• Ournation’sbiggesthealthobstacle

• Fewestavailablemedicalinterventions

• Highdirecthealthcarecosts,andevenhigherindirect health care costs

WHAT CAUSES AUTOIMMUNE DISEASE?

WHAT IS AUTOIMMUNE DISEASE?

Autoimmune Disease

COMMON AUTOIMMUNE DISEASES

• Hashimoto’s thyroiditis: up to 1 in 34
An autoimmune condition in which the thyroid
does not make enough hormones for the body's needs

• Sjögren's syndrome: up to 1 in 29
An autoimmune system disorder characterized by dry eyes and dry mouth.

• Celiac disease: up to 1 in 53
An immune reaction to eating gluten, a protein found in wheat, barley, and rye.

• Alopecia areata: up to 1 in 59
Sudden hair loss that starts with one or more circular bald patches that may overlap.

J Autoimmun. 2009 Nov–Dec; 33(3-4): 197–207.

COMMON AUTOIMMUNE DISEASES

• Psoriasis: up to 1 in 65
A condition in which skin cells build up and form scales and itchy, dry patches.

• Type 1 diabetes: up to 1 in 106
A chronic condition in which the pancreas produces little or no insulin.

• Rheumatoid arthritis: up to 1 in 123
A chronic inflammatory disorder affecting many joints, including those in the hands and feet.

• Polymyalgia rheumatic: up to 1 in 135
An inflammatory disorder causing muscle pain and stiffness around the shoulders and hips.

J Autoimmun. 2009 Nov–Dec; 33(3-4): 197–207.

COMMON AUTOIMMUNE DISEASES

• Grave’s disease: up to 1 in 160
An autoimmune disorder that results in the overproduction of thyroid hormones.

• Multiple sclerosis: up to 1 in 279
A disease in which the immune system eats away at the protective covering of nerves.

• Ulcerative colitis: up to 1 in 264
A disease that causes inflammation and sores (ulcers) in the lining of the large intestine

• Crohn’s disease: up to 1 in 444
A type of inflammatory bowel disease (IBD) that may affect any part of the gastrointestinal tract.

J Autoimmun. 2009 Nov–Dec; 33(3-4): 197–207.

FREQUENT CO-MORBIDITIES

• Cholangitis

• Chronic fatigue syndrome

(suspected autoimmune disease)

• Eczema

• Fibromyalgia

(suspected autoimmune disease)

• Polycystic ovary syndrome (PCOS)
(frequently in conjunction with autoimmune thyroid diseases)

WHAT IS AUTOIMMUNE DISEASE?

• Anyof>140diseasescausedbytheimmunesystem attacking tissues in the human body

• Difficulttodiagnose
  (45% of patients later diagnosed with a serious a autoimmune disease are labeled as hypochondriacs in the early phases of their diseases)

• Chronicandlifelong(nocure)

• Medicaltreatmentsarelimited;

symptom management

• Affects~50millionAmericans

• Incidenceinincreasing

AUTOIMMUNE DISEASE IS ON THE RISE

N Engl J Med. 2002 Sep 19;347(12):911-20.

AUTOIMMUNE DISEASE IS ON THE RISE

The net % increase/year of the incidence and prevalence of autoimmune diseases worldwide

Int. J. of Celiac Disease, 2015, Vol. 3, No. 4, 151-155.

78% OF SUFFERERS ARE WOMEN

Emerg Infect Dis. 2004 Nov; 10(11): 2005–2011.

EARLY SYMPTOMS OF AUTOIMMUNE DISEASE

• PMS
• Rashes and other skin problems • Recurrent headaches
• Resistance to weight loss
• Sleep disturbances
• Susceptibility to infections
• Swollen glands
• Thyroid problems
• Unexplained weight changes
• Yeast infections

• Allergies

• Anxiety and depression

• Blood pressure changes (usually low)

• Digestive problems

• Extreme fatigue

• Gallbladderdisease

• Low blood sugar

• Malaise

• Memory problems

• Migraines

• Muscle or joint pain

• Muscle weakness

WHAT CAUSES AUTOIMMUNE DISEASE?

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

• autoantibodies form (=autoimmunity, occurring in ~30% of us),

• the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

• the immune system is stimulated to attack, and

• enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

IMMUNE SYSTEM REVIEW

IMMUNE SYSTEM REVIEW

REGULATORY VS EFFECTOR CELLS

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

•

autoantibodies form (=autoimmunity, occurring in ~30% of us),

• the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

• the immune system is stimulated to attack, and

• enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

AUTOANTIBODY FORMATION

AUTOANTIBODY FORMATION

AUTOANTIBODIES IN CANCER

Autoimmunity Reviews, Volume 15, Issue 5, 2016, 477–483

AUTOANTIBODY FORMATION

J Clin Invest. 2015;125(6):2194-2202.

INFECTION AS A SOURCE OF AUTOANTIBODIES

• Prior infections increase risk of specific autoimmune diseases, perhaps via cross-reactive antibody formation.

• Borrelia: spirochete bacteria typically transmitted by lice and ticks.

• Lyme disease, rheumatoid arthritis, sarcoidosis, schizophrenia* and

• Chlamydophila pneumoniae: bacteria that causes pharyngitis, bronchitis, and atypical pneumonia

• Arthritis, myocarditis, Guillain-Barré syndrome, Alzheimer’s disease*, chronic fatigue syndrome*, chronic obstructive pulmonary disease*, multiple sclerosis, and Tourette syndrome

• Enterovirus: viruses of the gastrointestinal tract that cause a wide range of diseases

• Amyotrophic lateral sclerosis*, chronic fatigue syndrome*, type 1 diabetes, Guillain-Barré syndrome, and schizophrenia*

dementia*

INFECTION AS A SOURCE OF AUTOANTIBODIES

• Giardia lamblia: parasite that causes “beaver fever” or “backpacker’s diarrhea”

• multiple sclerosis, amyotrophic lateral sclerosis*, Parkinson’s disease*, chronic fatigue syndrome*, arthritis, and uveitis

• Helicobacter pylori: bacteria that causes chronic gastritis, stomach ulcers, and linked to stomach cancer

• immune thrombocytopenia, psoriasis, and sarcoidosis

• Herpesvirus: virus family causing wide range of illness, such as mononucleosis and roseola

  • Cytomegalovirus: Guillain-Barré syndrome and systemic lupus erythematosus

  • Epstein-Barr virus: dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis

  • Human herpesvirus 6: multiple sclerosis, chronic fatigue syndrome*

• Norovirus: virus causing gastroenteritis

• Crohn’s disease

INFECTION AS A SOURCE OF AUTOANTIBODIES

• Parvovirus B19: virus causes a childhood rash called fifth disease and a form of acute arthritis.

• rheumatoid arthritis, systemic lupus erythematosus and vasculitis. • Streptococcus: bacteria causing strep throat?

• Tourette syndrome
• Toxoplasma gondii: parasite causing toxoplasmosis

• Alzheimer’s disease*, Parkinson’s disease*, Tourette syndrome, antiphospholipid syndrome, systemic sclerosis, and inflammatory bowel diseases

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

• autoantibodies form (=autoimmunity, occurring in ~30% of us),

the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

•

• the immune system is stimulated to attack, and

• enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

ACTIONS OF REGULATORY T CELLS

IMMUNE HOMEOSTASIS

LOSS OF IMMUNE REGULATION

Nature Reviews Immunology 10, 849-859 (Dec 2010)

LOSS OF IMMUNE REGULATION

ROLE OF GENETICS

• RAG-1 and RAG-2

• controls receptor editing on B cells when they fail autoreactivity test

• severe combined immunodeficiency (SCID)

  • FoxP3

• intracellular molecule called regulatory T-cells

• mutations prevent regulatory T cell development

• immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).

• Sialic acid acetylesterase (SIAE)
• enzyme that decreases B cell receptor signaling required for immune

tolerance

• SIAE required to suppress autoreactive B

• present in 2% of those with autoimmune disease

• rheumatoid arthritis and type 1 diabetes

ROLE OF GENETICS

• Enzyme 3' repair exonuclease 1 (Trex1)

  • proofreading function for DNA synthesis

  • component of interferon-stimulatory response to detected viral DNA

  • Aicardi-Goutières syndrome (AGS) and chilblain

• PTPN22

  • encodes tyrosine phosphatase, nonreceptor type 22 (lymphoid)

  • affects the responsiveness of T and B cell receptors

  • R620W: type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, vitiligo, and Graves’ disease

ROLE OF GENETICS

• Methylenetetrahydrofolate reductase (MTHFR)

  • rate-limiting enzyme in the methyl cycle

  • methyl groups are used to control the activity of a huge variety of proteins through the post-translational modification methylation, cortisol, melatonin, epinephrine and serotonin

  • defects cause buildup of homocysteine, a toxic nonprotein amino acid

  • increases inflammation

  • C667T and A1298C: type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, vitiligo, multiple sclerosis Alzheimer’s disease* and schizophrenia* (also cardiovascular disease, renal disease, neurodegenerative disease, osteoporosis, and cancer).

• Human leukocyte antigen (HLA)

  • encodes many immune response genes

  • encodes the major histocompatibility complex

  • many variants linked to autoimmune disease

ROLE OF GENETICS: HLA

ROLE OF GENETICS: HLA

• HLA-B27: ankylosing spondylitis, postgonococcal arthritis, acute anterior uveitis, reactive arthritis (Reiter’s syndrome), seronegative spondyloarthropathy, iritis, psoriatic arthritis, Crohn’s disease and ulcerative colitis, and ulcerative colitis–associated spondyloarthritis

• HLA-B8: Grave’s disease

• HLA-B47: 21-hydroxylase deficiency 15

• HLA-DR2: systemic lupus erythematosus

• HLA-DR3: autoimmune hepatitis, primary Sjögren syndrome, Grave’s disease

• HLA-DR3 and HLA-DR4: type 1 diabetes mellitus, Hashimoto’s thyroiditis

• HLA-DQ2 and HLA-DQ8: celiac disease, Hashimoto’s thyroiditis, primary Sjögren syndrome

• HLA-DQ5: scleroderma

• HLA-DQ7: Hashimoto’s thyroiditis

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

• autoantibodies form (=autoimmunity, occurring in ~30% of us),

• the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

• the immune system is stimulated to attack, and

• enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

WHAT STIMULATES THE IMMUNE SYSTEM?

• Infection

• Toxinexposureand/orpoordetoxification

• Gutdysbiosis;increasedintestinalpermeability

• Stress

• Insufficientsleep

• Beingsedentaryorengaginginexhaustiveintense activity

• Nutrientdeficiencies(vitaminD,iron,zinc,etc.)

• Inflammatorydiet(sugars,sweeteners,omega-6fats, oxidized fats, processed food chemicals, preservatives, food dyes, and various inflammatory compounds in grains, legumes, dairy, nightshades)

INFECTION STIMULATES IMMUNE RESPONSES

REGULATORY VS EFFECTOR CELLS

Nature Reviews Immunology 13, 607–614 (2013)

PERSISTENT INFECTIONS

• Helicobacter pylori:
• interacts with the immune system by influencing which cytokines are

produced by macrophages, B cells, and T cells

• drives Th1 formation or Th2 formation, but usually the former, and can cause rapid switching between Th1 and Th2

• stimulates recruitment of inflammatory cells, such as neutrophils

• induce changes in gastric-acid secretion by the cells that line the stomach

and alter the secretion of mucus by the cells that line the small intestine

• chronic gastritis (inflammation of the stomach and upper digestive tract) increasing intestinal permeability (i.e., leaky gut)

• Toxoplasmosis gondii:
• 29% of healthy individuals have antibodies against T. gondii but 42% of

those with autoimmune disease do

• damages intestinal barrier and induces potent Th1 response

• inhibits macrophages and dendritic cells causing chronic secondary inflammation and immune activation

PERSISTENT INFECTIONS

• Cell wall–deficient bacteria:
• a class of antibiotic-resistant bacteria that can remain latent or slow-

growing within human cells for extended periods

• have been found in patients with sarcoidosis and systemic lupus erythematosus.

• may contribute to autoimmune disease by releasing endotoxin into phagocytes, causing release of cytokines that stimulates Th1 cells

TOXIN EXPOSURE

• Prescription drugs

• 38 drugs linked to lupus (drug-induced lupus erythematosus)

• hydralazine (a blood-pressure medication),

• procainamide (used to treat cardiac arrhythmias)

• isoniazid (an antibiotic used to treat tuberculosis)

• Pristane
• naturally occurring hydrocarbon found in petroleum that is commonly

used as a lubricant, an immunologic adjuvant, and an anticorrosion agent • rheumatoid arthritis and systemic lupus erythematosus.

• Silica dust
• occupational hazard for workers in mining, stone cutting, quarrying,

blasting, road and building construction, and farming, • systemic sclerosis

• Smoking
• seropositive rheumatoid arthritis

TOXIN EXPOSURE

• Pesticides

• occupational exposure, gardening

• most are immunotoxic

• organochlorinated pesticides (mostly illegal): increase proinflammatory cytokines, decrease neutrophil and natural-killer-cell function, decrease regulatory T-cell populations, decrease cytotoxic T cell populations, alter the ratio of CD4+ and CD8+ cells, and increase autoantibody formation.

• organophosphates and carbamates (widely-used insecticides): changes the ratios of CD4+ and CD8+ T cells, including influencing Th1 versus Th2 dominance, but also inhibiting the activities of neutrophils and natural killer cells.

• tributyltin chloride (an organotin pesticide): causes thymocyte death in the thymus gland

• atrazine (an organotin pesticide): decreases natural- killer-cell activity

• propanil: decreases T cells and B cells (thymus and bone marrow); reduces natural killer cells, macrophages, and cytokine production; and causes thymic atrophy

TOXIN EXPOSURE

• Ultraviolet radiation

  • multiple sclerosis (inverse relationship, independent of vitamin D)

  • dermatomyositis

• Heavy metals

  • mercury, cadmium, lead, aluminum, and gold

  • strongly linked to autoimmune disease

• Poor detoxification (MTHFR variants)

  • methylation used in Phase 2 liver detoxification (conjugation)

  • C667T and A1298C: type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, vitiligo, multiple sclerosis Alzheimer’s disease* and schizophrenia* (also cardiovascular disease, renal disease, neurodegenerative disease, osteoporosis, and cancer).

GUT HEALTH AND THE IMMUNE SYSTEM

• Leaky gut
• considered a prerequisite for

autoimmune disease to develop
• present in every autoimmune disease that has

been tested: rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, celiac disease, multiple sclerosis, and type 1 diabetes.

• precedes disease development for celiac disease, Crohn’s disease, and
ulcerative colitis

GUT HEALTH AND THE IMMUNE SYSTEM

GUT HEALTH AND THE IMMUNE SYSTEM

• Gut microbiota

• aid digestion and increase nutrient absorption

• synthesize vitamins

• produce SCFA

• produce neurotransmitters

• regulate the immune system

• Gut dysbiosis

• any abnormality in the gut microbiota, eg. SIBO

• commonly seen in autoimmune disease

• different bacterial components modulate different aspects of the immune system

• balance Th1, Th2, and Th3 cell populations through regulation of dendritic cell activation

• stimulate the production of Th17 cells

• modulate the activation of natural killer cells

• influence the interaction between antigen receptors on the immune cell surfaces and the antigens themselves

• stimulating the production of antibodies against foreign microorganisms.

STRESS AND THE IMMUNE SYSTEM

Image credit: livelovefruit.com

STRESS AND THE IMMUNE SYSTEM

• Chronic Stress (via cortisol, cortisol resistance, CRH)

• Increases inflammation

• Affects T-cell subsets (situation dependent)

• Increases intestinal permeability

• Decreases gut motility

• Decreases mucus

production by goblet cells

• Decreases secretory IgA

• Inhibits digestion (pancreatic enzyme secretion, gall bladder function)

• Decreases intestinal blood flow

• Alters gut microbiome

• Reduces sleep quality

SLEEP AND THE IMMUNE SYSTEM

SLEEP AND THE IMMUNE SYSTEM

• Insufficient sleep

  • increases monocytes, neutrophils, and B cells in the blood

  • increases proinflammatory cytokines (including cytokines known to stimulate maturation of naïve T cells into Th1, Th2, and Th17 cells),

  • increases C-reactive protein

  • increases total cholesterol LDL.

• Non-apnea sleep disorders (eg. insomnia) increases risk of autoimmune disease by 50%

• Obstructive sleep apnea more than doubles risk of autoimmune disease

• Shift work increases risk by 50%

• Short sleep increases symptoms of many autoimmune diseases

ACTIVITY AND THE IMMUNE SYSTEM

ACTIVITY AND THE IMMUNE SYSTEM

• Exercise training reduces levels of proinflammatory cytokines in adipose tissue.

• Exercise may reduce inflammation by decreasing lipid accretion in liver and muscle.

• Lipid accumulation is linked to inflammation in a setting of nutrient overload.

• Anti-inflammatory effects may be mediated via inhibition of TLR
and IL-1 signaling.

Trends in Immunology Volume 35, Issue 6, p262–269, June 2014

NUTRIENT DEFICIENCY AND THE IMMUNE SYSTEM

• Vitamin A: immune regulator, differentiation

• Vitamin D: immune regulator, Treg cells

• Vitamin E: antioxidant

• Vitamin K2: antioxidant

• Vitamin B6: methylation

• Vitamin B9 (folate): methylation

• Vitamin B12: cell production, methylation

• Vitamin C: antioxidant

• Zinc: T-cell development and activation, cytokines

• Selenium: antioxidant, cell function and activation

• Iodine: phagocyte health

• Iron: antioxidant enzymes

• Magnesium: thymus gland

• Copper: cytokine production, cell proliferation

• Phytochemicals: antioxidants

• Omega 3 fats: phagocytes

NUTRIENT DEFICIENCY AND THE IMMUNE SYSTEM

• Vitamin A: alopecia areata, multiple sclerosis, and autoimmune hepatitis

• Vitamin D: systemic lupus erythematosus, type 1 diabetes, autoimmune interstitial lung disease, multiple sclerosis, rheumatoid arthritis, celiac disease, psoriasis, and inflammatory bowel disease

• Vitamin E: psoriasis, vitiligo, alopecia areata, and rheumatoid arthritis

• Vitamin K2: supplementation beneficial in an animal model of multiple

• Vitamin B6: type 1 diabetes

• Vitamin B9: cerebral folate deficiency syndrome, rheumatoid arthritis, Sjogren's syndrome, celiac disease, Crohn's disease and ulcerative colitis

• Vitamin B12: multiple sclerosis, celiac disease, Sjogren's syndrome, Crohn's disease, ulcerative colitis, autoimmune atrophic gastritis, alopecia areata and type 1 diabetes

• Vitamin C: lichen planus, and idiopathic thrombocytopenic purpura

• Zinc: rheumatoid arthritis, multiple sclerosis, pemphigus vulgaris, Alzeimer’s disease, autoimmune hepatitis, primary biliary cirrhosis, autoimmune thyroid disease, systemic lupus erythematosus, celiac disease and type 1 diabetes

NUTRIENT DEFICIENCY AND THE IMMUNE SYSTEM

• Selenium: Hashimoto’s thyroiditis, Grave’s disease, pemphigus vulgaris and lichen planus

• Iodine: Hashimoto’s thyroiditis, Grave’s disease

• Iron: rheumatoid arthritis, autoimmune gastritis, systemic lupus

erythematosus, Sjogren's syndrome and celiac disease

• Magnesium: systemic lupus erythematosus

• Copper: rheumatoid arthritis and pemphigus vulgaris

• Phytochemicals: supplementation beneficial in autoimmune thyroiditis, type 1 diabetes, and rheumatoid arthritis

• Omega 3 fats: supplementation beneficial in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, autoimmune-mediated glomerulonephritis

INFLAMMATORY DIETS

• Prolamins: increase intestinal permeability, feed bacterial overgrowth in the gut, and stimulate the immune system

• Agglutinins: increase intestinal permeability, feed bacterial overgrowth in the gut, and stimulate the immune system

• Saponins/Glycoalkaloids: increase intestinal permeability and significantly stimulate the immune system

• Antinutrients: causes increased intestinal permeability, feed gut dysbiosis, and cause inflammation

• Digestive Enzyme Inhibitors: increase intestinal permeability, feed bacterial overgrowth in the gut, and cause inflammation.

• Processed food chemicals: causes increased intestinal permeability, feed gut dysbiosis, and cause inflammation

INFLAMMATORY DIETS

• Sugar and sweeteners: increase intestinal permeability, causes inflammation, and causes hormone dysregulation

• High Omega-6 relative to Omega-3 fatty acids: cause inflammation and gut dysbiosis

• Alcohol: increased intestinal permeability, damages the gut, feeds bacterial overgrowth in the gut, and stimulates inflammation

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

• autoantibodies form (=autoimmunity, occurring in ~30% of us),

• the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

• the immune system is stimulated to attack,

and

• enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

WHAT CAUSES AUTOIMMUNE DISEASE?

• Geneticsusceptibility(1/3ofyourriskfor autoimmune disease)

• Infection,environmentaltriggers,orbadluck • Dietandlifestyle

Immune Dysregulation (the body attacks itself)

THE IMMUNE SYSTEM IN AUTOIMMUNE DISEASE

Autoimmune disease occurs when:

and

•

• autoantibodies form (=autoimmunity, occurring in ~30% of us),

• the body’s natural backup system for eliminating/regulating cells that produce autoantibodies fails,

• the immune system is stimulated to attack,

enough damage occurs to cells or tissues within the body to manifest as symptoms of a disease.

AUTOIMMUNE DISEASE

Autoimmune Disease