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Introduction

 

In Part I we discussed some variants of this condition, although some are rare the American Autoimmune association has identified at least 140. The overall pathology of this condition triggers an abnormal dysfunction of the host immune system where it attacks healthy host cells as well as foreign invasive pathogens.  The National Institute of environmental health sciences has been expedient in attempting to track down its cause by identifying Adrenal dysfunction which indeed has an impact on the immune system especially Cortisol which is the bodies natural anti-inflammatory substance. However, the adrenal gland itself can become a victim of AD in a condition referred to as Addison’s disease, or primary adrenal insufficiency where the gland does not produce enough steroid hormones.   I and others believe that its gut dysfunction which is the root cause. So let us explore a little deeper in an attempt to come to a conceivable conclusion.  


The immature gut of the newborn and breast milk

 

In terms of gut health versus gut dysbiosis the most vulnerable are newborn infants. These early interactions set the tone of the mucosal and systemic immune system for the long term.   If the child is born naturally through the birth canal the baby will swallow the bacterial content of the mothers vagina which contains part of the fathers gut flora. Both bacterial flora in this area comes from the bowel, which is combined with the baby’s immature microbiome developed while in the womb ( Despite current thinking the infant is not sterile prior to birth, some bacterial strains get through the placenta to the embryo). If the mothers gut flora is dysbiotic than the baby will have a compromised gut flora as well as a compromised immune system ( it is the first 20 days of life that defines the microbiome prior to its maturation stage ). If the baby is breastfed, and despite its mother having gut dysbiosis, she will produce some antibodies that give the baby some protection. Breast milk, as nature defines the early responses to the evolving microbiota since, apart from the proteins, amino acids, and nutrients, breast milk also contains the full ‘starter kit’ for the immune system and essential probiotics that promote the expansion of microbiota constituents such as Bifidobacterium which include the following:

Growth Factors: used to mature the intestinal lining, and there are 22 in total including Tumor necrosis factor-α,Interferon-γ,Epithelial growth factor (EGF), Transforming growth factor-α (TGF-α).TGF β1,TGF-β2,Insulin-like growth factor-I (IGF-I), Insulin-like growth factor- II and Cytokines IL-2,IL-4,IL-6,IL-8,IL-10, Granulocyte-colony stimulating factor (G-CSF), Macrophage-colony stimulating factor (M-CSF), and Platelet derived growth factors (PDGF)

Full ‘starter kit’ for the immune system :  including Leukocytes (white blood cells), Phagocytes, Basophils, Neutrophils, Eosinophils, Macrophages, Lymphocytes, B lymphocytes (also known as B cells), T lymphocytes (also known as C cells), sIgA (Secretory immunoglobulin A), ,

Antimicrobial factors:  38 in total including Ribonuclease, Haemagglutinin inhibitors, Bifidus Factor (increases growth of Lactobacillus bifidus), Lactoferrin (binds to iron which prevents harmful bacteria from using the iron to grow), Lactoperoxidase, B12 binding protein


The Microbiome-Humans internal ecosystem

‘ How defined members of the microbiota interact with their host can be highly contextual with the same microbe developing as commensal or pathogenic according to nutritional. co-infection or genetic landscape of the host’   

Yasmine Belkaid/Timothy Hand ‘Role of the microbiota in immunity & inflammation 2014

Gut Flora balance

The Microbiome in the human organism is a vast ecosystem of microorganisms that live and thrive throughout the long tunnel that runs from our mouths to our anus like microbial wallpaper. Externally there are vast colonies that live on our bodies, in our mouth,on our skin, and under our arms.  The human organism cannot survive without the symbiosis between our host physiology and the microbes that live within and outside of the body. We need them ( bacteria ), and they need us (Host ). In fact if your sterilise the gut the human would not survive very long, that’s how important these  microbial communities are. Our microbial ecosystem exists to help us digest our food, regulate our immune system, protect us from harmful pathogens and manufacture essential vitamins. The composition of the gut flora ( also referred to as microbiome, or microbiota) consists of Beneficial, Opportunistic ( also referred to as Commensal bacteria) and Pathogenic flora.. The Commensal gut flora can exist as either beneficial or Pathogenic, dependent upon the healthy state of the beneficial bacteria, since a healthy gut flora keep the pathogenic and Opportunistic flora in check. When the gut flora becomes unbalanced there tends to be an overgrowth of pathogenic and/or commensal flora which take ‘centre stage’ over the beneficial flora. When this occurs the microbiota is said to be dysbiotic.

Purpose of our gut flora

Diet plays a huge part in maintaining balance or causing imbalance, as well as exogenous and endogenous toxins.   In some instances our beneficial flora innoculate or neutralize pathogens that populate the commensal flora colony. These ‘micro-creatures protect the host. Beneficial bacteria are micro-factories producing antibiotic, anti-viral, anti-fungal substances to maintain health and balance in the gut.  Bacteria give birth to many offspring to take the place of their parents who have sacrificed themselves on behalf of the host. This occurs for example when certain bacteria chelate heavy metals like mercury and arsenic, pcbs, and aluminium that have found their way into the body from, say, fish consumption or vaccines.  Since the body expels these toxic materials the bacteria also get expelled through the stool of the host. Despite government warnings to reduce fish consumption, because of our polluted bodies of water, it generally will not affect people with healthy gut floras.

Eighty % of our immune system resides on the gut wall and our beneficial flora modulate this main defense system, which is why it is so crucial that there is a working symbiotic relationship between the host and the gut bacteria. The knowledge of this partnership between host cells and bacterial flora in promoting health dates back to the time of German gynecologist Albert Doderlein in 1892.  Doderlein discovered the protective effect of beneficial bacterial species Lactobacillus which restrict the growth of pathogenic flora such as Bacteroides fragilis, Escherichia Coli (EColi), Gardnerella vaginalis, Neisseria gonorrhoeae, Staphylococcus aureus and Mobiluncus spp. Lactobacillus are considered ‘gatekeepers’ of the vaginal ecosystem. The Lactobacillus organisms achieve their protective effect by secreting Lactic acid,  Hydrogen Peroxide and antimicrobial peptides bacteriocins ( bacterial protein) such as lactocin 160 and crispasin ( a natural antibiotic..take note all you physicians reading this). A healthy microflora in general leads to a healthy vaginal microbiome preventing bacterial vaginosis, yeast infections and maintaining an acidic PH ( < 4.5) which is an environment avoided by pathogenic flora such as  Gardnerella vaginalis.  We must also never forget the groundbreaking work of Ukrainian zoologist Ilya Ilyich Mechnikov ( dubbed ‘the Father of Innate Immunity’) who discovered the phagocytic macrophage immune system cell in 1882 and upon this discovery, even Pasteur didn’t believe it ( probably because of the ‘not invented here syndrome’). Mechnikov went on to win  the 1908 nobel prize jointly with Paul Ehrlich (oddly enough Ehrlich rejected the idea of Autoimmunity calling this hypothesis“horror autotoxicus.”) . Nearing the end of his illustrious career Mechnikov began advocating the consumption of lactic acid producing bacteria as a probiotic such as yoghurt, clearly showing his knowledge of our microbial partners and their importance to us.


 

Symbiotic relationship of host and microbial flora

The central command areas, the ‘Peyer’s patches’ that are attached to the epithelium barrier  ( cells that make up the gastrointestinal (gut) wall, a defensive wall protecting the internal body space ( the lumen) from the outer area of the  internal body), which launch immune system responses recruiting T and B Lymphocyte cells, Macrophages and Dendrites. It is the beneficial bacteria species Bifidobacteria that activate the the T & B Lymphocyte cells using a secreted substance Muramyl Dipeptide.  Furthermore, our gut flora assist in our protection by destroying potential harmful bacterial species.  Even infamous pathogenic bacterial species like E.Coli produce protein based Bacteriocins (a Bacterial produced anti-biotic) to kill off competing species, thus controlling the growth of enterohemorrhagic E.Coli.  Furthermore E.Coli are one of the major Lactose digesting bacteria, and are also responsible for synthesising Vitamins K2, B1, B2,B6 and B12.  In effect E.Coli despite their reputation is a bacterial species that we cannot live without..PROVIDING YOU KEEP YOUR GUT HEALTHY.


 

Early Symbionic ‘Crosstalk between host and microbiota I

In early life of the newborn the immature immune system consist of blunted inflammatory cytokines ((biological signals that are the immune systems ‘hormones’) and skewed T & B cells giving priority to regulatory responses.  Although these temporary inactive components increase susceptibility of infection, the microbiota develops quickly without unnecessary inflammation during this colonization phase.  The neonate innate immune system, as part of its host-microbiota ‘dialog’, train the host immune macrophages and dendritic cells using proteins on their membranes called Toll-like receptors that are used to detect bacteria M(P)AMPs ( Microbial (Pathogen) Associated Molecular Patterns ) e.g using PAMPS can detect Bacterial Lipopolysaccharide ( LPS ) endotoxins found on cell membranes of gram negative bacteria, or infectious microbes like bacterial flagellin.  This function mimics what occurs in plants; being sessile organisms they are constantly under threat of attack from microbes that only want the plant nutrients. The Plants innate immune system also has the ability to recognise specific M(P)AMPS using PRRS ( Pattern recognition receptors) and when they do they quickly switch from growth and development into a defensive stance to meet the threat.

Even in the neonate gastrointestinal tract the immune system has already formed Gut Associated Lymphoid tissue (GALT) containing the Peyer’s patches and lymphoid follicles where activation of antigen primed T&B cells occurs. I have recreated the following diagram taken from my early work on the microbiome that shows this arrangement.  Once the T&B cells are activated by the beneficial bacterial species Bifidobacteria as mentioned earlier, they then migrate into the Lamina Propria where further protective immune response activity occurs.

 


 

‘Keep your friends close, but keep your (potential) enemies closer’

Again to call upon my earlier work on the microbiome  the symbiotic relationship between the microbiome and the host immune system in terms of pathogenic bacteria control is the immune systems ability to trigger a response from either an inbound foreign microbe or a pathogen  derived from the commensal colony of the microbiome. Furthermore, the mechanism to maintain the relationship with the microbiome also applies to the containment of a potential pathogens. This is why the GI Tract and the skin have the most dense number of immune cells near the colonies of commensal flora; analogous to the proverb ‘Keep your friends close, but keep your (potential) enemies closer’. To maintain their ecological niche the microbiome exercise a dominant position over the immune system to maintain the epithelial barrier integrity and the containment of their own colonies. On the other hand to ensure the state of homeostasis the immune system minimises microbial contact with this mucosal ‘firewall’ to reduce inflammation and microbial translocation. This is achieved by the mucosa proper, and the secretion of immunoglobulin A ( IgA) secreted by Lymphocytes to neutralise antibodies to protect the mucosal membranes located in all breathing orifices,bladder,saliva, tear ducts, sweat glands , including the epithelial surface protecting it from pathogenic attachment.  In addition, use is made of antimicrobial peptides ( such as Reg IIIγ) secreted by the epithelium to create a segregation or ‘demilitarised zone’ between the microbiome, the host intestine and immune cells. It is of interest to note that the Mucosal IgA does not possess any memory capabilities but IgA secretion produce clones that contend with the potential changes that occur within the microbiota.


Conclusions

In this part we have discussed the developing immune system of a child, the purpose of the gut flora and why it needs to be balanced. I have also touched upon the Symbiotic relationship of host and microbial flora, and Symbionic ‘Crosstalk between host and microbiota. In the next part we will discuss  the role of the thymus gland where important immune system cells called the Helper T cells (Th1 &Th2) receive their training and development, and how crucial this gland is during the neonatal and pre-adolescent period of life. In addition we will take a cursory look at the battle map of the immune system and how crucial it is to maintain Th1 and Th2 balance.

Bruiser: What’s so funny?

Joe Cramp: I don’t know.

Thrax: They’re making this too easy! Hahaha! You know, in all of the bodies I’ve been in no one has ever gotten wise to me and now, for the first time, an immunity cell has figured out everything and they don’t believe him!

[Bruiser and Joe Cramp laugh]

Thrax: Can you taste the irony in that?

[Bruiser and Joe Cramp laugh again]

Thrax: SHUT UP! What are you two laughing at? Alright, we’re back on schedule.

Bruiser: But, boss. We are the only ones left. Maybe we should incubate for a while?

Thrax: You incubate! I said forty eight hours, I’m going to make my deadline.

[Thrax kills both germs and destroys the gas station off-screen]

Thrax: Medical books aren’t written about losers!

Quote from Osmosis Jones 2001


Check out the previous article:

Autoimmune Disease I


References/Acknowledgments:

    1. Gut and Psychology Syndrome Book 2010 Dr Natasha Campbell Mcbride Role of the Microbiota in Immunity & Inflammation 2014 NCBI Yasmine Belkaid & Timothy Hand
    2. Vaginal flora, Colicin Wikipedia
    3. Microbiome and the Immune system 2017 Article Eric Malouin Dr John Bergman Owners guide for humans website
    4. Movie quote Osmosis Jones 2001  IMDB

Author : Eric Malouin

 

 

 

 

 

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