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Introduction

In this part we will discuss some of the intricacies of the immune system specifically the innate and adaptive immune system and some of the immune cells that are involved specifically the thymus trained T Lymphocyte cells and to distinguish the difference between Th1 and Th2 Immune response, and the importance of balance between them by natural foods.


The Thymus Gland

Lymphopoiesis ( generation of lymphocytes ) refers to the creation of Immune cell Lymphocytes from stem cells located in the bone marrow.  At the moment of their creation they are undifferentiated white blood cells ( raw recruits ready to be assigned a place in their training school ( the thymus) ).  One such lymphocyte is the T cell, once born in the bone marrow it migrates to its natural ‘training ground’ the Thymus ( A gland located in the front middle part (Thorax) of the body just below the thyroid gland.  It is this gland that is most active from birth to pre adolescence that commits the naive lymphocytes to their rightful lineage. Once they arrive at the thymus, suitability selection is swift, performed by ‘nurse cells’ that verify that the new lymphocyte recruits ( Thymocytes) can recognise foreign antigens, and can exhibit self tolerance ( be able to discriminate self from non-self).    If they cannot, they are immediately destroyed and consumed (phagocytosed) by attending macrophages and then recycled.

Successful Thymic recruits

There is a >95% rejection rate of Thymocytes, so very few make it through their ‘training’, but those that do enter the next stage, where the lymphocyte recruits are repeatedly exposed to various kinds of molecules secreted by epithelial cells and progressive signalling between themselves and nurse cells until 3 types of T cells emerge.

1. The Helper T cell coordinates other immune cells during an inflammatory response.

2. The Cytotoxic killer cells possess a ‘lock and key arrangement where they have a specific antigen that is unique to each T cell bound to a MHC ( Major Histocompatibility Complex) which are cell surface proteins that are host specific ‘fingerprints’ enabling the Immune system to discriminate between host cells and foreign invaders. These cytotoxic killers lock on to the specific antigen they are programmed for and then destroy the infected cell.

3. The T Regulatory (TRegs) cells are also referred to as Suppressor T cells that are responsible for modulating the immune system ( regulating immune system response so as it does not get out of control ), and maintaining immune system tolerance both from the perspective of central tolerance; to discriminate self from nonself, and peripheral tolerance that prevents over reactivity to environmental triggers ( more on these cell types are included in a later Part ). It is estimated that some 25 million -1 billion various T cells are produced by the thymus daily, but with such a high rejection rate you can imagine how many of these cells are produced in the bone marrow.  

Thymic MHC & Antigen classification

As I mentioned in previous articles it is the MHC ( Major Histocompatibility Complex) which are cell surface proteins that each T cell is programmed with to perform this discriminatory self vs non self process. Furthermore, the T cell is also programmed with CD ( Cluster of Differentiation ) markers which in fact are glycogen protein elements of Immunoglobulins that are attached to each immune cell to steer and navigate their course of activity. Up until 2014 there were  371 CD classifications associated with immune cells, for example CD45+, CD3+, and CD4+ are CD associates of T helper cells, while CD45 is a common antigen for all Leukocyte cells and its official name is PTPRC (Protein Tyrosine Phosphatase Receptor Type).

Thymus gland health

As stated above this gland  is most active from birth to pre adolescence that commits the naive lymphocytes to their rightful lineage.  However, with good nutrition, a low stress and healthy lifestyle will keep the thymus functioning, adapting its T cell maturation process as we age and to the changing environment, despite being only a shadow of itself in old age compared to pre-adolescence.


The battle map of the immune system

Innate Immune system response

Before we go any further in our discussion of Immune tolerance and regulation let us look at the immune system in action.  There are various publications that are available concerning the immune system but very few incorporate the host-microbe interaction that help coordinate and regulate the immune system in concert with our own mammalian immune system cells. They do however say that the microbiota has an immunomodulatory effect but how?.   The intelligence of the human immune system is overwhelming and to appreciate how remarkable it is, you only have to follow the functionality of a simple cut on the skin from say a nail in the dirt to ingesting contaminated food. The majority of species survive on a first line of defense in protecting themselves. It is called the Innate immune system which humans have as well, and as soon as the body becomes infiltrated by a cut or a blister that shreds the skin then the innate immune system springs into action.  If bacteria seep into the wound which is quite likely, a macrophage sentry ‘sniffs out’ the invader from its antenne designed to detect anything foreign to the body. Once the macrophage has dealt with the invader it releases chemicals to promote blood flow and pain signals so as the host is aware that there has been a breach ( although, I daresay that you would know if you cut yourself or not). To ensure a successful defense the macrophage sends cytokines (hormone like) signals to recruit more of the macrophages innate immune system team players to the wound site, but generally as you know yourselves it’s all over in a matter of days.

Adaptive Immune system response

As complex multicellular organisms the innate immune system is ineffective toward viruses when they get inside the cells ( outside of the cell they can deal with them) sneaking into our bodies, cloaking  themselves and taking over our cells using our own DNA to duplicate themselves. So we are fitted with another defense system called the Adaptive Immune system which can just about thwart any invader type ( bacteria, fungi,virus,parasite ). The adaptive immune system is all about producing antibodies for specific antigens and B memory cells that are involved as frontline battle warriors that are converted into memory modules so as the immune system can react faster without too much discomfort to the host should the same antigen storm rain down again. Antibody manufacture is a clever biochemical process since most immunologists estimate that we need around 100 million different antibodies. If we had enough genes to produce this many, which we don’t, so nature designed a system of permutation not unlike the production of many protein types from just 20 amino acids.  In the case of the B cell there are around 80 different DNA segments associated with the gene that encodes the B cell antibody. The clever part is that mature B cell clones that can be used during a microbial battle are only made on demand.   After mature B cells are produced they go into the body tissues on fishing trips to see if they can catch an antigen. Most B cells sit there forever without a ‘bite’, (e.g if the host never develops lymphoblastic leukemia then B cells that are programmed with CD19 will be fishing forever. ) but when the ‘fish’( foreign invader) takes the bait then the body begins to make multiple antibodies in preparation for the battle. This multiple manufacturing last for about a week and by the end some 20,000 B cell clones specific to this antigen would have been made.


Th1/Th2 Response

The mechanism of action is explained in more detail in the articles on the microbiome and the immune system, but suffice to say both innate and adaptive systems work together. The innate system coordinates  the ‘essential first responders’, but they are incapable of deciding the threat level, so it relies on the adaptive system to launch an all out attack where necessary.  Having said that, the innate system recognises a threat and it gathers ‘intell’ of the threat and passes it to the adaptive system as a ‘first draft battle plan, while the adaptive system is readying its arsenal and ‘troops’ This battle coordination is handled by the T Helper cell that we mentioned earlier, which also are needed for B cell and macrophage activation.

Immunology distinguishes the battle plans into Th1 response ( coordinated by Th1 Helper cells ) and Th2 response ( coordinated by Th2 Helper cells ).  The Th1 response tends to deal with a cell mediated response that respond to infections everywhere in the body including the inside of cells, the skin and the mucous membranes.  The Th2 response deals with liquids in the body (Humoral) including the bloodstream, so if the defensive firewall, our gut epithelium is breached and foreign substances including undigested food get inside the bloodstream, an inflammatory response is raised.  What is crucial here is that both Th1 and Th2 have to be balanced, and generally during gut dysbiosis they are not, where Th1 is underactive and Th2 is overactive causing chronic viral conditions including allergies, asthma, eczema, autism and autoimmune. . IT IS THE GUT FLORA THAT PLAYS THE MAJOR ROLE IN MAINTAINING BALANCE.

Th1/Th2 Balance

Dr Natasha Campbell Mcbride in her brilliant book on GAPS suggests that ‘the gut wall with its bacterial layer can be described as the right hand of the Immune system…and if there is damage to the bacterial layer then the Immune system is trying to function with its right hand tied behind its back’.  In 2004 two Japanese scientists Iwasaka & Noguchi ( study name: Th1/Th2 balance in systemic inflammatory response syndrome (SIRS)) that imbalance in the body due to infection activate a pro-inflammatory cascade ( Systemic inflammatory response syndrome ). The study Compared healthy balanced Th1/Th2 subjects with imbalanced Th1/Th2 due to a serious inflammatory response.  They found that in the unbalanced condition the Th2 humoral response dominated leading to immunosuppression.


Japanese study using yogurt and Bifidobacterium Longum

In terms of Host-microbiota interaction this crucial Th1/Th2 balance is influenced ( modulated ) by the microbiota namely Bifidobacterium Longum ( a common probiotic in yogurt) as was shown in a double blind, placebo-controlled trial based on pollen seasons 2004/2005 done by Odamaki et al 2007.  Previously a study was conducted in 2004 to analyze Bacteroides Fragilis, a common opportunistic bacterial strain, and since it likes to feed on sugar it is common in the gut of people who reside in the western world.  This strain, as I mentioned in the Microbiome articles, loves to hang around with another problematic species Clostridia to make trouble. They found wide fluctuations of Bacteroides Fragilis, in people’s gut suffering from Japanese cedar pollinosis during the pollen season, which is no surprise since this bacterial strain is associated with various infections including the lung and allergies.  By giving the trial subjects yogurt containing Bifidobacterium Longum, it suppressed the strain of Bacteroides Fragilis which again is no surprise since it balances the gut by inhibiting the overgrowth of Bacteroides Fragilis and feeding more of the beneficial bacteria stimulated growth to rebalance the gut. This was confirmed by a follow up study conducted in 2007 involving 44 allergy sufferers who received either the Bifidobacterium Longum or a placebo. Another comparison group of 14 was added, who were healthy IgE negative.  Immunoglobulin e antibody is found in excessive amounts in the blood indicating the host is battling with an allergy or an autoimmune condition.  IgE is a protein that is synthesised by blood plasma cells designed to attach themselves to foreign substances and launch a histamine offensive.  Once fecal samples were analyzed the results were the same.


Cytokines.  

From my earlier articles on the Microbiome I have recreated and modified  the following text.  Cytokines ( taken from the Greek words meaning ‘Cell Movement’) although similar in functionality to endocrine hormones, are small protein signaling molecules that form a field communication network where various immune cells chemically communicate with each other.  Cytokines tend to be pleiotropic ( multiple activations from one signal ) as opposed to hormones that circulate in less variable concentrations which are made by more specific cells. The question is how does the Th1 and Th2 Helper T cells know what cytokines to produce ?.  The Dendritic cell is the immune systems surveillance arm that provides the ‘Intel’ of an invasion. The Intelligence report delivered by the dendritic cell to the T Helper cell contains the identification of the microbial invader, provided by the PPRs (Pattern Recognition Receptors) located on the membrane of the dendritic cell ( as discussed in the previous article ( part II), and the location of the invasion picked up by other cytokine transmissions coming from skin or other tissue cells. Once the T Helper cells are in possession of this report Th1 Helper cells secrete TNF, IFN-γ and IL2 and Th2 Helper cells secrete IL-4,IL-5, IL-10 and IL-13.  The ‘IL’ refers to Interleukin that are glycoproteins used to regulate immune system response.   What is the function of these various Cytokines ?:

Th1 T Helper cell cytokines

TNF = Activates Macrophages and Natural Killer Cells (NKT)

IFN-γ = Since Macrophages have a voracious appetite, feeding on all this microbial debris makes them tired so they need some encouragement to stay in the ‘battle of the pathogens’ so this cytokine acts as a ‘prod’ to maintain their involvement. This cytokine also has stimulatory influence of B cells to produce IgG3 antibodies used to opsonize(Greek word for ‘prepare to be eaten’)  viruses and bacteria ( The target cell is coated in Opsonins  which are protein ‘sprinkles’ ), compliments of the Complement arm of the immune system, where the cell is marked or made more ‘delicious’ to wet the phagocytic appetite.

IL2 = . Killing and devouring is tiring work so like the macrophage, the NKT’s also becomes fatigued after chasing down and  killing 3 or 4 targets within the space of 16 hours so IL2 recharges them to kill more. IL2 also serves as a Growth factor for CTLs (Cytotoxic T Lymphocyte cells). If you have read the article ‘Microbiome and the Immune system’ you may remember that the pharmaceutical industry is incorporating IL2 into protein therapeutic drugs in an attempt to kill cancer cells..do they really think that cancer cells ( our own stem cells ) are so stupid that they are going to fall for that one ?.

Th2 T Helper cell cytokines

IL-4 = Proliferation growth factor for other T Helper cells expressing the Th2 profile

IL-5 = Stimulates B cells to secrete Immunoglobulin A ( IgA) 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 mentioned in Part II.

IL-10 = This is somewhat of a mystery since IL-10 exerts a suppressive action on immune cells residing in both the Lamina propria and the epithelium. Actually  IL10 is critical to maintain immune quiescence which should be reserved for TRegs as a regulatory action since IL-10 is also secreted by the regulator T cells as you would expect.

IL-13 = Stimulates the production of mucous in the intestines to shore up protection against pathogenic bacteria breaching the intestinal wall.

There is third T-Helper cell TH17 which the immune system invokes to tackle a fungal invasion such as in the vaginal canal. Possibly more may be discovered in the future.

 

Conclusions

I have not included a discussion on all immune system cells ( you can learn more from the articles on the microbiome) but to highlight some of the triggers that can ignite autoimmune conditions.  In this part we have discussed one of these triggers, Th1/Th2 imbalance which can be reversed by the intake of beneficial bacteria such as Bifidobacterium Longum, as described above. In the next part we will discuss more studies involving the microbiota and revealing more on the how autoimmune conditions are initiated.  We will also discuss Leukotrienes and Prostaglandins, how they are produced and their purpose as inflammatory stimulators.

“Osmosis Jones to dispatch. We got multiple germs – I repeat, multiple germs – comin’ down the windpipe, and if these bad boys hit the blood stream, we’re gonna be illin’! I’m talkin’ nose-drippin’, chicken soup-drinkin’, rectal thermometer-stickin’ illin’!”

Quote Osmosis Jones Movie 2001


Check out the previous articles :

Autoimmune Disease I

Autoimmune Disease II (Gut Flora Balance, Gut Symbiosis)


References/Acknowledgments :

    1. Gut and Psychology Syndrome Book 2010 Dr Natasha Campbell Mcbride
    2. How the immune system works Lauren Sompayrac Book 2012
    3. Lymphopoiesis, Immune Tolerance,  Autoimmune disease, Cluster of Differentiation Wikipedia
    4. Microbiome and the Immune system 2017 Article Eric Malouin Dr John Bergman Owners guide for humans website
    5. Function of T cells in the Thymus gland Carolyn Csanyl 2017 Sciencing
    6. Asthma in patients with Japanese Cedar Pollinosis Akihiko Tanaka et al 2012 World allergy organisation
    7. Influence of Bifidobacterium longum BB536 intake on faecal microbiota in individuals with Japanese cedar pollinosis during the pollen season Odamaki et al 2007 NCBI
    8. Th1/Th2 balance in systemic inflammatory response syndrome (SIRS)  Iwasaka & Noguchi 2004 NCBI
    9. Movie quote Osmosis Jones 2001  IMDB

Author : Eric Malouin

 

 

 

 

 

 

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