Sunday, June 24, 2012

Serotonin and Neurogenesis

The Serotonin Hypothesis 

The widespread theory of depression is that depressed people have a chemical imbalance manifesting as low serotonin.  Serotonin is perceived to be ‘the happiness neurotransmitter’ so low levels would make one depressed.  There is some evidence to support this: 

  • People with depression and people who suicide have low markers of serotonin function and metabolism [1].
  • People with depression have a higher incidence of chronic pain and serotonin dampens feelings of pain [2].
  • Feeding people a tryptophan deficient diet produces serotonin depletion and may result in depression-like symptoms [3].
  • Antidepressants that increase serotonin (SSRIs, SNRIs and MAOIs) can treat depression.

However, there are a few problems: 

  • Serotonin depletion only lowers mood in people with either a family history of depression or who have previously had depression [3].
  • SSRIs take about 3-6 weeks to have much effect and up to 6-12 weeks for the patient to be in remission from depression [4].

Neurogenesis 

SSRIs have relatively immediate effects on serotonin levels, but take many weeks for noticeable effects suggesting any acute effect on mood isn’t what’s driving recovery.  Perhaps another function of serotonin has been overlooked. 

An interesting observation is that people with depression and anxiety disorders have a lower brain volume [5] and years spent with depression, but not age, is associated with greater reductions in hippocampal volume [6] and more low signal foci, which is suggestive of dysfunctional neural networks [7]. 

One of the other functions of serotonin is to stimulate the production and release of a number of growth factors such as BDNF, VEGF, IGF-1, FGF-2 and NGF which all increase neurogenesis.  Neurogenesis increases cell proliferation and survival, followed by the production of new neurons or glial cells, then increasing synaptic connections throughout the brain and neural plasticity, which can lead to a more functional reorganisation of neural networks [8]. 

Evidence that antidepressants work by increasing neurogenesis: 

  • Mice without BDNF receptors don’t respond to antidepressants [9].
  • Other treatments for depression such as NSRIs, MAOIs and electroconvulsive seizures (shock therapy) all promote neurogenesis.  Of these, the treatments that increase BDNF the most are the most clinically effective [8].
  • Antidepressant treatment increased BDNF up to normal levels within the first month, which correlated with mood improvement [10]
  • Antidepressants take 6-12 weeks likely because that’s how long it takes for the average depressed brain to increase in volume and improve its function.
  • SSRIs and growth factors like BDNF aren’t ‘happiness molecules’ as they have limited effects on mood in healthy people who have normal sized brains and functional neural networks [11].

Other things that increase neurogenesis are therapeutic for depression: 

Exercise is roughly equally as effective as SSRIs for depression and is improves anxiety disorders and bipolar disorder [12].  This effect is often explained by an increase in endorphins leading to better mood.  However, just like ideas surrounding serotonin, any acute effects on mood do not have a lasting effect on a chronic disease like depression.  Any therapeutic effect should be long-lasting and cumulative.  Just like antidepressants, exercise also increases the same growth factors that promote neurogenesis* [13]. 

Zinc supplementation to correct low zinc levels, which are often seen in depression [14], increases BDNF [15] and IGF-1 [16], is anti-inflammatory and is therapeutic for depression [17]. 

DHA increases BDNF [18], is anti-inflammatory and it is therapeutic for depression [19], although this effect may be attributed to EPA instead [20] (either way it’s LCO3).  Low plasma levels of DHA are associated with more depressive symptoms [21] and a high ratio of long chain omega 6:3s results in an excessive neuroinflammatory response [22].  During gestation and lactation, mothers who have an inadequate DHA intake may become depleted in this nutrient due to the developmental needs of the foetus/infant and DHA depletion is a likely cause of postpartum depression [23]. 

While people with depression have low serum levels of BDNF [24], their depression isn’t due to a Prozac deficiency, and the reduced brain volume is unaccounted for. 

* Given that much of the neural atrophy in depression is in the hippocampus, the role of the hippocampus and neurogenesis in learning and memory.  My guess is that the kinds of exercise that would most promote neurogenesis would be complex movements, engaging with the environment and sport, rather than stationary bikes and machines.

Further Reading:
(1) The chemical imbalance myth
(2) If low serotonin levels aren't responsible for depression, what is?

Sunday, June 17, 2012

Autoimmune Disease

Summary

The hygiene hypothesis suggests a lack of exposure to infections, parasites and symbiotic microorganisms (gut bacteria) predisposes one to allergies and autoimmune disease.  There are a number of observations that support the hygiene hypothesis, but some of the proposed mechanisms aren’t supported.

The story with autoimmune disease and infections is complex: some parasites and infectious agents suppress the immune system to enhance their survival, which also has the effect of protecting against autoimmune disease, asthma and allergies; while others can trigger and/or accelerate autoimmune disease due to increased immune activity and inflammation.

However, while infections can trigger an autoimmune reaction, that doesn’t explain why the immune system continues to attack the body after the pathogen has been destroyed and why the incidence of autoimmune disease increased while infectious disease has decreased.  The answer lies in the adaptive immune system.

The adaptive immune system is made up of T cells and B cells.  There are 3 main types of T cells: (1) T helper cells, which stimulate the immune response; (2) cytotoxic T cells, which kill stuff; and (3) regulatory T cells, which reduce the immune response after the infectious agent is cleared and prevent the immune system from attacking the body or harmless antigens (like in allergies).  In autoimmune disease there is an excess of T helper cells (particularly Th17 cells) and/or insufficient regulatory T cells (and often a lack of cytotoxic T cells), which creates a hyperinflammatory and poorly regulated immune response

Things that increase the Th17:Treg cell ratio
Things that decrease the Th17:Treg cell ratio
Dysbiosis and intestinal infections
Soluble fibres (and butyric acid)
Chronic inflammation
Probiotics (supplemental good bacteria)
Circadian rhythm disruption
Vitamins A and D
Chronic stress
Zinc

Estrogen tends to increase the ratio, while testosterone decreases it, which can explain the difference in rates of autoimmune disease between the sexes.  Vitamins A, vitamin D and zinc have the added bonus of also increasing the cytotoxic T cell function

Autoimmune disease requires contact with environmental antigens and intestinal permeability (leaky gut) increases exposure to environmental antigens.  Intestinal permeability is associated with autoimmune disease, asthma and allergies, precedes autoimmune disease and may be necessary for autoimmune disease to develop

It seems there are four necessary factors for autoimmune disease to develop:

1.      Genetic susceptibility
2.      Exposure to the autoimmune-inducing antigen
3.      A poorly regulated immune system (high Th17:Treg cell ratio)
4.      Intestinal permeability

While these posts were mainly about autoimmune disease it’s also relevant to allergies and asthma.  All three conditions are evidence of a dysfunctional immune system and are all associated with dysbiosis.  Autoimmune disease and food allergies are associated with intestinal permeability and other allergies may be associated with equivalent conditions elsewhere such as increased skin permeability


Some Strategies for Autoimmune Disease

This is for informational purposes only and is not meant to diagnose or treat any medical condition.

Improve Immune Regulation

Ensure good amounts of:

  • Vitamin A (liver, eggs, dairy, vegetables)
  • Vitamin D
  • Zinc (most foods, particularly animal foods and especially shellfish)
  • Sleep, while optimising circadian rhythms (sleep at night, in the dark, without much blue light or food prior to sleeping, and with light and exercise during the day.  See here)
  • Probiotics

Reduce/manage chronic stress (see Manage Your Stress) and chronic inflammation (see Causes of Inflammation).

Correct dysbiosis.  Some strategies include:

  • A low FODMAP diet (which is very effective for IBS) to decrease rapidly fermentable carbohydrates that may adversely affect gut health (including intestinal permeability) and are a source of food for pathogenic bacteria [1]
  • A diet rich in soluble fibres (fruit and vegetables) to provide food for beneficial bacteria.  Resistant starch seems like an attractive therapy but can be a problem for some people, particularly in high doses and for those with SIBO (see if it works for you, but read the links before trying) [2] [3]
  • Use antibiotics only when necessary (and not for colds, which are viral infections).  Antibiotics kill both beneficial and harmful bacteria, and so can be very useful, but in doing so it creates a window for pathogens to take hold
  • Reduce alcohol.  In animal models of alcoholic liver disease there is dysbiosis, although the alcohol intake was 40% of total calories [4]

Low dose naltrexone (LDN) is a lower dose (5 mg vs. 50 mg) of the drug naltrexone, an opioid receptor blocker originally used for alcohol and opioid dependence.  LDN has been found to be quite effective for Crohn’s disease in clinical trials [5] [6] [7].  It’s thought to work by increasing opioid signalling (temporarily blocking the opioid receptor, leading to a supercompensation of opioid signalling where opioids, opioid receptors and receptor sensitivity increases) and opioids increase regulatory T cells [8] [9]

Reduce Intestinal Permeability

See this post on Suppversity for list on things that are either helpful or harmful for intestinal permeability.  Of the items on the list I would guess that gliadin (wheat), alcohol and NSAIDs would be among the more important, but also correcting dysbiosis and the stuff on the list related to gut bacteria (probiotics, butyric acid, beta-glucans)

Therapeutic Diets

On the internet you can see many people who have had success cutting out certain foods from their diet, particularly wheat, all grains, dairy, legumes, nightshades, eggs, nuts and seeds or some combination of the above.  The effectiveness of cutting out those foods seems to be somewhat variable, for example one person may find great relief from cutting out nightshades, whereas another doesn’t notice any change.  Use an elimination diet to determine the effect of foods by cutting out at least one food for a period of time (a month or so) and then reintroduce it and see how you feel.

You could try the Paleo autoimmune protocol to cut out many potentially problematic foods and reintroduce some of them progressively.  For a heavy handed approach there’s also the GAPS diet.  Both the Paleo autoimmune protocol and the GAPs diet have been designed for autoimmune disease and other gastrointestinal problems.  You’re not meant to be on either of them long term and they should be tried only if a standard, strict Paleo isn’t working.  Although most of the time, if someone is following a Paleo diet and not getting results it’s probably due to stress, sleep or some other thing being the weakest link

List of Autoimmune Diseases

The following list of autoimmune diseases comes from the American Autoimmune Related Diseases Association. (Use Control + F to find if what you’re looking for is on the list)

Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal & neuronal neuropathies, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome**, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia**, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) see Wegener's, Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpure, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Insulin-dependent diabetes (type1), Interstitial cystitis, Juvenile arthritis, Juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease (chronic), Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatic, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, Transverse myelitis, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA)

**NOTE Fibromyalgia and Chronic Fatigue are listed, not because they are autoimmune, but because many persons who suffer from them have associated autoimmune disease

Sunday, June 10, 2012

Intestinal Permeability

Even with a dysregulated immune system it’s unlikely that in real life conditions (as opposed to experimentally depleting Treg cells) one infection will produce lifelong autoimmune disease.  A healthy person may only sustain autoimmune damage while infected, whereas a person with a dysregulated immune system may have some autoimmune attacks for some time have the infection has cleared.  A lifelong autoimmune disease probably requires a dysregulated immune system and the continuous exposure to the triggering antigen, made possible by intestinal permeability [1]. 

The intestinal mucosal barrier is made up of structures to connect cells together called tight junctions to separate our body from the outside world (technically the interior of the digestive tract is not inside the body) to prevent bacteria, pathogens and toxins from entering the body.  There are a number of proteins that make up the tight junctions and keep them closed, but only one that opens them, zonulin* [2]. 

Zonulin is active in the small intestine but not the large intestine.  The function of zonulin is to open up the tight junctions to move fluid, macromolecules (proteins, lipids, carbohydrates and anything larger) and leukocytes (white blood cells) between the body and small intestine.  In addition bacteria (commensal or pathogenic) and pathogens inherently stimulate the zonulin pathway so our body is protected against infection in the small intestine (which is usually sterile) [3].  When the tight junctions open, water is released into the small intestine and bacteria/pathogens/etc are flushed out of the body, causing diarrhoea* [1].

The first few steps happen to everyone

The prolamines in wheat (gliadin***), rye (secalinin) and barley (hordein) activate the zonulin pathway thereby increasing intestinal permeability and also are the trigger for coeliac disease [4].  Gluten is resistant to digestion in the stomach (acid) and small intestine (peptidases – protein digestion enzymes), increases inflammation and the reactivity of the immune system similar to LPS and promotes dysbiosis [5].  A zonulin inhibitor drug blocks increases in intestinal permeability and GI symptoms when coeliacs have gluten [6] 

Other things that can compromise barrier function and increase intestinal permeability include: small intestinal bacterial overgrowth (SIBO) [3] pro-inflammatory cytokines [7] [8], glucocorticoids, oxidative stress, NSAIDs, psychological stress and acute infections [9] [10]For a longer list on things that are either helpful or harmful for intestinal permeability see this post on Suppversity (highly recommended)

Evidence supporting the role of intestinal permeability in autoimmune disease: 

  • People with ankolosing spondylitis, asthma, coeliac disease, crohn’s disease, dermatitis herpetiformis, lupus, MS, RA and T1D tend to have elevated intestinal permeability or zonulin levels (depending on which was measured) [1] [11] [12] [13]
  • An increase in intestinal permeability following elevated zonulin levels precedes the onset of T1D by 2-3 weeks in an animal model.  Later a zonulin inhibitor drug blocked autoantibodies [1].  Also GI symptoms and elevated zonulin levels precede T1D in humans [14]
  • Intestinal permeability precedes relapse in Crohn’s disease by as much as a year, zonulin is higher in the acute phase of IBD and zonulin levels are associated with the severity of symptoms in Crohn’s disease [1]
  • In an animal model of IBD (IL-10 deficiency) intestinal permeability precedes IBD and a zonulin inhibitor reduces inflammation [15]
  • Immune activity correlates with intestinal permeability [7]
  • Healthy relatives of people with Crohn’s disease [7] and T1D [16] have elevated zonulin levels or intestinal permeability, which suggests intestinal permeability is necessary but not sufficient for autoimmunity

* V. cholerae (cholera) secretes a toxin called zonula occludens toxin (Zot), which has the same effect as zonulin 

** The appendix stores a culture of beneficial bacteria so when bacteria are flushed out of the body the colon can be repopulated. 

*** Gluten is made up of gliadin and glutenin 

Further Reading:
(1) Intestinal Zonulin: Open Sesame
(2) Leaky Gut Research

Sunday, June 3, 2012

Immune Dysfunction

The Adaptive Immune System

According to molecular mimicry and the bystander effect, once the autoimmune process is activated it becomes independent of continuous exposure to the environmental trigger, and is therefore self-perpetuating and irreversible [1].  That an adaptive immune system continues to attack the body after the pathogen has been destroyed suggests it’s not so adaptive after all.  So I think it’s fair say an immune system that produces autoimmune disease is dysfunctional. 

Our adaptive immune system has T cells and B cells.  T cells come from the thymus and include T helper (Th) cells (also called CD4+ T cells), cytotoxic T cells (also called CD8+ T cells) and T regulatory cells (Treg cells) (also called CD4+CD25+Foxp3+ T cells).

  • T helper cells secrete various cytokines to increase the activity of B cells, cytotoxic T cells and phagocytes (cells that ingest harmful stuff, such as macrophages), depending on the immune response required
  • Cytotoxic T cells kill infected and cancerous cells (the innate immune system has different cells that perform a similar function which are called natural killer cells (NK cells)
  • Treg cells decrease the immune response once the infection has cleared and are crucial for maintaining immunological tolerance (not attacking harmless antigens or self-antigens)* 

B cells come from bone marrow and are mainly made up of plasma B cells that produce antibodies, which are proteins that bind to antigens (like a receptor for antibodies) and help the immune system identify what to target. 

There are also memory T cells and memory B cells that were antibody producers but weren’t used during a previous infection so as to mount a faster and stronger immune response if infected again.  Memory T and B cells are the reason why vaccinations are effective. 

In autoimmune disease there tends to be high levels of T helper 17 (Th17) cells and low levels of Treg cells, which suggests a highly inflammatory and poorly regulated immune system and is what you would expect [2] [3].  Experimental manipulation of the balance between Th17 and Treg cells can strongly influence the autoimmune process: 

  • Germ-free mice have no resident bacteria so they produce very few Th17 cells, which protects them from autoimmune disease.  They also have low numbers of Treg cells.  If exposed to segmented filamentous bacteria to increase Th17 cells (but not Treg cells), they develop autoimmune diseases such as RA and experimental autoimmune encephalomyelitis (EAE), an animal model of MS [4] [5].
  • Thymectomy (surgically removing the thymus) leads to a deficiency in Treg cells and then autoimmune diseases such as Hashimoto’s thyroiditis and T1D [6]
  • Deletion (genetic mutations) or depletion of Treg cells results in widespread autoimmune disease [2] [3]
  • Inflammatory responses in autoimmune diseases is promoted by Th17 cells and inhibited by Treg cells [2] [4] [6]

* B cells and T cells are continually making antibodies at random.  Some of these will be effective against infections and others not so much, but some will bind to self-antigens and will need to be destroyed.  Treg cells are needed to suppress any auto-reactive cells that make it out of the thymus. 

Influencing the Th17:Treg Cell Ratio 

Perhaps the major factor behind immune dysfunction is an unhealthy gut bacteria (dysbiosis).  Under normal circumstances ATP generated from gut bacteria* can be used to produce Th17 cells and beneficial bacteria increase Treg cells to protect themselves from immune attacks [2].  So a more pathogenic gut flora will trend towards inflammation and poor immune regulation, while a healthy gut flora will trend towards appropriate immune regulation. 

Dysbiosis is associated with RA, T1D, IBD (includes Crohn’s disease, ulcerative colitis and others), asthma and allergies [4] [7] [8].  The ‘altered microflora hypothesis’ suggests that recent environmental changes such as diet, antibiotics, etc negatively alter gut bacteria, which can lead to immune dysfunction and is responsible for the increasing incidence of autoimmune diseases, allergies and asthma** [8]. 

Some factors involved in dysbiosis are difficult to change.  Natural birth and breastfeeding provides beneficial bacteria to outcompete any pathogens and are associated with a reduced risk of autoimmune disease.  Getting a caesarean or formula deprives the baby of the beneficial bacteria they would ordinarily get [9] [7].  Previous antibiotic use can eliminate bacterial species and provides an opportunity for antibiotic resistant bacteria and fungal infections to gain a foothold [8].  Being raised in an indoor environment surprisingly increases bacterial diversity, but increases pathogenic bacteria at the expense of beneficial bacteria [9]. 

Dysbiosis may emerge later in life from other factors besides antibiotics:

  • Inflammatory substances such as alcohol promote dysbiosis [10], which makes sense as pathogens can use inflammation to kill commensal species.
  • Unabsorbed carbohydrates (FODMAPs) give pathogenic bacteria have an easy food source for rapid fermentation and division.  The resulting bacterial overgrowth increases endotoxins/inflammation and intestinal permeability [11].
  • A lack of soluble fibre.  Fermentation of soluble fibre (prebiotics) into butyric acid supports good bacteria and the butyric acid decreases pro-inflammatory cytokines, increases anti-inflammatory cytokines (such as IL-10, the interleukin of Treg cells) [12], decreases intestinal permeability [13] and supplementation is therapeutic for IBD [14] [15].  Also, probiotic supplementation increases Treg cells [16]

There are other factors involved besides dysbiosis.  TGFβ and pro-inflammatory cytokines such as IL-1, IL-6 and IL-21 are required for Th17 cell development and IL-17 production (a pro-inflammatory cytokine secreted by Th17 cells) [2].  Elevated pro-inflammatory cytokines from other sources of inflammation and other factors can therefore overexcite the immune system, potentially creating an immune profile conducive to autoimmunity.  For example, people with IBD tend to have higher serum levels of endotoxins (a highly inflammatory substance) and endotoxin levels correlate with disease activity [17].  (See Causes of Inflammation)

The development of Treg cells requires TGFβ and retinoic acid (derivative of retinol/vitamin A) [2].  Supplementing retinoic acid increased Treg cells, decreased IL-6 and Th17 cells and halted the progression of an animal model of RA [18].  Vitamin D increases IL-10 (an anti-inflammatory cytokine secreted by Treg cells) and reduces inflammation [19].  Serum 25-hydroxyvitamin D correlates with Treg cell function [20] and sunlight/vitamin D is often associated with a reduced incidence of autoimmune disease [21]. 

Vitamins A and D also increase the cytotoxic T cells, which has the effect of better controlling infections.  This allows vitamins A and D to increase immune function in regards to infection and cancer, while being effective against autoimmunity.  People with autoimmune disease tend to have a high CD4+:CD8+ cell ratio (helper:cytotoxic) with high levels of T helper cells and low or deficient levels of cytotoxic T cells [22] [23]. 

Other things that may unfavourably affect immune regulation include:

  • Female sex.  Women have a higher incidence of autoimmune disease than men [24] and have a higher CD4+:CD8+ cell ratio [22]  Testosterone increases Treg cells [25] and estrogen promotes immune activity when its high but suppresses immune activity when its low [26]. 
  • Low zinc levels.  Zinc is quite for immune function and low zinc levels are associated with an increased CD4+:CD8+ cell ratio, higher IL-6 and impaired immunity [27]
  • Circadian rhythm disruption.  Shift work and jet lag are associated with inflammatory diseases and disrupting the circadian rhythm increases Th17 cells in mice [28]
  • Last, but certainly not least is chronic stress.  Stress is a probable trigger for many incidences of autoimmune disease [29] and can trigger asthma in animal models [30].  I'm aware of a few mechanisms by which stress unfavourably affects immune regulation: glucocorticoid resistance [31] [32]; dysbiosis [33]; prolactin [34] [35]; and substance P [36].  (See Inflammation and Neurodegeneration and Prolactin and Stress)

* Microbes reside in many part of the body include skin, mouth and the lower GI tract, which has the greatest density and diversity.  There are roughly 100 trillion bacterial cells which combined have 150 times our genetic material.  Humans collectively carry roughly 1,000 bacterial species and about 160 in each person [2].  The gut microbiota prevents pathogen colonisation and assist in immune development and homeostasis, T cell differentiation, inflammation, repair and angiogenesis [9].  Bacterial species compete over our GI tract.  Beneficial bacteria assist in the immune response against pathogens and some pathogenic bacteria trigger inflammation to kill commensal species [2] 

** I prefer the altered the altered microflora hypothesis over the hygiene hypothesis

*** Cortisone is often used as the drug treatment for autoimmune diseases because it is immunosuppressive.  Cortisone is prescribed on the assumption that the immune system of an autoimmune disease patient is overactive, but it might be more accurate to say that it’s under-regulated.

**** It's ironic that stress, which is meant to suppress immunity and be anti-inflammatory, can create pro-inflammatory immune system and trigger autoimmune disease.  Perhaps this is due to the acute stress vs. chronic stress dichotomy.