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.

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