The Immune System: Oh What a Tangled Web

December 5, 2018

 

   The immune system is a remarkably complex and interwoven system of various cells that serve either as action heroes, checks, and balances, the vast majority of these are classified together as the family of white blood cells. All components are essential to achieve health. Too much or too little of any can result in severe disease. The primary diseases that the immune system is involved in can be categorized globally into exogenous proliferative invaders, foreign invaders (infections); endogenous proliferative invaders, rebels (malignancies, cancer); and self-destructive actions, excess friendly fire (autoimmune diseases, GDD).

 

     In many respects it may be useful to think of the immune system as a military organization, where you have advance troops (early action) , main armed force (subacute action), and occupying force (chronic disease)..

 

Three Battle Forces 

 

1- Advance Troops

The main components of the advance troops are B-cells (B-lymphocytes) that elaborate antibodies (analogous to guided missiles from jets), and polymorphonuclear cells (PMNs) grouped into neutrophils, eosinophils, basophils and mast cells. Neutrophils are the most common of all the white cells and can directly kill entities (cytodestruction by phagocytosis - directly eating the invader). Eosinophils, basophils and mast cells release a number of chemicals locally (histamine, heparin, main components) in concept similar to soldier releasing a blast of agent orange surrounding themselves. The advance troops primarily deal with foreign invaders (infections), and their imbalance results in allergies/asthma..

 

2- Main Armed Force

Whereas neutrophils are the main warriors in the advance troops, monocytes/macrophages  together with T-cells (including natural killer T cells, great name) and natural killer cells (my favorite name) are the main combatants in the subacute group. The macrophages directly eat their enemies. Natural killer cells and T-cells are generally cytotoxic (inject their enemies with poison). The main armed force primarily deals with malignancies/cancer , but some infections (fungi, Tb), imbalance results in autoimmune disease and GDD.

 

3- Occupying Force

Bone marrow derived cells - the most well known being the circulating fibrocyte, with the subtype CD34+ being familiar as it is associated with NSF. This is a chronic response of the immune system. These are the least well understood components of the immune system. In conjunction with the Main force they have many of the same functions (cytokine release), but in combatting problem enemies, they resort to processes to wall them off. In the medium time-frame this is designed to prevent imminent death (and usually successful). but which generally cause long term problems. Autoimmune disease with excess fibrosis (scleroderma), aggressive fibromatosis, and NSF reflects imbalance of the chronic immune system. This is also the circumstance with chronic progressive GDD.

 

Weapons

 

Complement System/Complement Cascade: There are at least 30 different proteins and protein fragments that form the complement system. They can be thought of as a full variety of different fire-arms; hand-guns, machine guns, bazookas. They are produced in the liver and circulate in the blood system in inactive state (that become activated by an inflammatory condition). This system is especially important with exogeneous proliferative invaders (infections).

Antibodies: IgA, IgE, IgG, IgM. Antibodies are like missiles that are shot out by B-cells. Their main function is to hit the cell membrane of invaders, as markers so killer cells can identify them and then eliminate them. IgG is the commonest, and is the antibody that best serves for identification and killing of invaders. IgE is associated with allergies and anaphylaxis reactions (second strike recognition). IgM is associated with anaphylactoid reactions (first strike recognition - many severe acute contrast reactions in Radiology).

 

Leukotrienes: fat based mediators that signal it is time for war, and are produced by white blood cells. There are in excess of 30 types of leukotrienes. They identify when it is time to fight, and call the troops to battle, also involved in the clean up: signaling to clear the battle field.

These are important also in allergies and asthma, reflecting abnormal excessive release.

 

Cytokines: Small proteins. They serve as communication devices like cell phones and walkie talkies to guide the course of battle: increase or decrease humoral immunity (local chemical release, antibodies) and cell mediated immunity (eg:macrophages).

There are in excess of 30 types of cytokines. Many of the white cells can release these communication proteins, but primarily neutrophils, macrophages, B-cells, T-cells, and circulating fibrocytes.

Imbalance of cytokines is a principle factor of autoimmune diseases and GDD.

 

 

Checks and Balances

 

T-cells: There is no better illustration among checks and balances than T-cells. I think when I was in medical school there was 1 T-cell that was recognized; now there are maybe 30, which I take to mean there are probably 1,000. There are T-cells that specifically respond  to the class of infective organisms: virus, bacteria, fungi and protozoa. There likely is even much greater subspecialization to subtypes of these infective organisms. So T-cells include not only natural killer T-cells, but a large category of helper T-cells (primarily helping to neutralize invaders), but the important group of suppresser T-cells, which signal to the immune system to settle down and stop the killing rampage. Suppressor T cells are crucial in the checking of immune reaction.

 

B-cells: Antibodies are primarily designed to attack foreign invaders, but also are involved in allergies (as discussed above). As with T-cells it is now becoming understood that there are checks to antibodies. To control overproduction of antibodies and the creation of diseases like autoimmune disease, there appear to be antibodies designed to attack the primary antibodies. In fact to take it one step further in the balance, there may be antibodies to the antibodies to the antibodies.

 

Anti-oxidants:  Anti-oxidants represent an excellent example to illustrate the complexity of the immune system and how achieving the correct balance is essential for health. Oxidation is a common cell function, and we commonly recognize oxidation as a major problem in aging and abnormal aging in cells, and damage from radiation such as sunlight and also x-rays (and cancer risk). Oxidation is however an important weapon that the immune system uses to kill infective organisms and malignancy (eg:cancer) cells. Studies in rodents have shown that excess levels of anti-oxidants increases the risk of infection and cancers. In essence this illustrates a major theme of mine which is : everything in moderation. 

 

Cytokine proper balance. The exact same reasoning is important when considering cytokines. These are responsible for autoimmune disease and GDD, but suppress them too much and it puts the host at risk for infection and cancer.

 

Summary

 

The immune system is an incredibly complex system composed of many elements, a number of which appear to have similar functions, although different entities (leukotrienes and cytokines), others the same type of cell, but with varying, including exact opposite, functioning (T-cells). I have used an analogy to a military organization and campaign to make it more accessible to the lay reader. I hope this has been effective. If despite this, and attempting to simplify the description (hopefully not making things too incorrect in the simplification), it still appears very complex: that may then also accurately reflect the situation. Although I describe 3 different forces, advance, main, and occupying, it does not step so uniformly through these phases, and they can all coexist at the same time (which is also the case in a military campaign).

It is critical to understand that cells and chemical weapons, expressions, and messengers, are in a critical balance of action and inaction. This understanding then becomes very challenging for medical management to attempt to achieve the right balance to be sufficient to treat disease but not too much to damage or kill the host. 

     Even in this brief overview one can appreciate that there are atleast 1,000 moving parts, many with intentional redundancy, intentional synergy, and intentional activation order. The redundancy helps limit the shut down of the entire system if one or so pathways is somewhat aberrant, but at the same time there are numerous, in the hundreds, of ways that things can go wrong. Considering there are so many moving parts that are working together it shows how one drug which is designed to achieve one action (kill a type of bacteria) can easily fail. That is why the present and future direction of most treatments (certainly cancer treatment has evolved in this fashion) is to arm up the existing immune system, as the native immune system has fundamentally many tools to deal with enemies, not just one - but the system needs quite often to be trained to recognize who is the enemy (to attack it) and who is the friend (to leave it alone).

 

A future blog will look at the balancing of treatment drugs, immune system assistance, supplements and other measures. 

 

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