Chess: the Game of our Immune System
Updated: May 29, 2021
The immune system is a pool of specialized cells that produce and function at numerous sites distributed all over the body. Thus, it is not a compact organ system per se. The field of immunology is a vast, complex, mind-numbing, and tedious work to figure out.
When I first read about our immune system, I imagined it as a game of chess. When I first saw Asterix and Obelix, I tried to match its characters with chess pieces. This led me to undertake a massive task of fabricating a dual analogy that I intend to present in this blog.
Chess is divided into three parts—opening, middle and end games. Co-incidentally, immunity is also divided into three sequential responses—innate, adaptive, and cell-mediated.
Thus, we have
Team Black - the invaders: microbes, allergens, and abiotic factors like dust and humidity; and
Team White - the immune cells
Opening Game - Innate Immune System
Whites start by moving a pawn , the weakest-yet-significant defensive wall in chess – the skin and mucous membrane. Pawns create a barrier between the invaders and the stronger pieces of the game. Blacks pawns – allergens, dust, and benign microbes–initiate their attack too.
The skin and mucous membrane continuously contact these pathogens and prevent their entry.
Skin is the biggest organ in the human body – a tough, highly efficient, keratinized layer of epithelial cells that protects it from all forms of biotic and abiotic invaders. Benign pathogens and allergens are destroyed or rendered inactive on the skin surface. Various body fluids like tears produced by eyes, or sweat produced by designated glands on the skin destroy most of the microbes by creating an unsuitable environment to thrive.
Mucus membrane protects all types of cavities – respiratory, digestive, urinary and reproductive – with the help of several other pawns – mucin (saliva), acids (stomach and vagina), tears (lacrimal glands), and defensins (sweat).
The next chess strategy is the central control of the board.
The white armoured knights – the innate immune cells and physiological responses – counteract the black knights – bacteria, viruses or protozoa that successfully breach the skin through a wound or infection.
Physiological responses like fever and inflammation provide the second line of defence, which is further re-inforced by the white blood cells (WBCs) that act as coast guards. Sweating during fever and pain felt due to injury are some reflex mechanisms that have been adopted by the human body for combating this invasion.
While these symptoms are usually associated with an illness in popular view, they are nothing but the sign of a good immune response.
The innate immune cells immediately reach the site of breach by recognising chemical signals via messenger proteins produced during fever and inflammation. These innate immune cells include phagocytes like macrophages, natural killer (NK) cells and mast cells, and lymphocytes like neutrophils, basophils and eosinophils.
Macrophages can be fixed or freely patrolling in the bloodstream, and function like a Pacman that engulfs pathogens, digests them, and excretes the waste product.
NK cells destroy infected body cells that are devoid of identifier signals that indicate their innocence – major histocompatibility complex I (MHC I). They release pore-forming perforins and apoptosis-triggering granzymes that kill infected cells systematically by signalling the activation of caspase cascade.
Mast cells release histamine during an allergic reaction and are responsible for the itch, sneeze, and asthma during anaphylaxis. Antihistamines are taken during an allergic reaction to pollen, peanuts, cat hair or any other allergen to prevent excessive inflammation and vasodilation that causes redness, rashes, and pain, an effect of mast cell-produced heparin.
Neutrophils are the suicidal time bombs, that self-destruct after devouring antigens and subsequently create a pool of dead neutrophils called pus.
In stronger innate responses, a combined inflammatory attack through activation of prostaglandins, kininogens, plasma proteins, complement and cytokines, causes swelling of blood capillaries and lymph nodes. By this time, more neutrophils circulate the bloodstream and squeeze through capillary walls to reach the site of action in a process called leukocytosis, which raises the white blood cell count manifold.
At the same time, inactive monocytes circulating in blood reach to accompany the neutrophils and convert to antigen-hungry macrophages as they reach surrounding tissues.
As an extreme response, these macrophages release pyrogens, messengers that trigger the fire alarm in hypothalamus, the biological thermostat, to raise the temperature and cause fever. Do not feel surprised when your doctor says that having a fever is a good sign because in fact, it is.
Increased body temperature increases metabolism and repair of infected cells. They also signal the liver to preserve its reserves of iron and zinc to prevent spread of bacteria.
Middle Game - Acquired or Adaptive Immune System
Next, the bishops – vaccines – come into play. These can be used to activate acquired immunity from external factors. It is a resourceful solution to prevent microbial attacks.
Vaccines are either antibodies created from an exposed source (usually blood plasma extracted from a recovered patient of the illness), inactivated parts, or whole microorganisms present in a dosage just enough to trigger an immune response but not a florid infection.
Vaccines provide passive acquired immunity. A subsequent exposure to these invaders aids in triggering the formation of antibodies (active acquired immunity) in the antibody factories: bone marrow and thymus. The secondary effect is faster and stronger than the primary.
Nevertheless, both effects create a strong synergistic bishop-pair attack that is sometimes a lifesaver.
Our body recognizes antigens by a social gathering of its own cells with them.
Special cells, called memory cells, receive pathogens or pathogenic proteins, and if deemed ‘eligible’ to be considered antigenic, are ‘remembered’ by the adaptive immune cells.
Adaptive immunity is different from innate immunity because it can specifically remember pathogens and can create a memory of its own. It can provide a slow but sustained immune response upon encountering the same pathogens later, unlike the innate cells that provide aggressive response irrespective of the pathogen. This is like a skilled chess player who knows when and how to build his strategy.
Black bishops – potent bacteria, viruses, fungi, toxins (proteins or compounds that create toxicity of any kind) or infected cells – start roaming around in bloodstream and infected tissues.
The rooks – dendritic cells, antigen presenting cells (APCs), and B-lymphocytes – dominate the middle game in chess.
Wounded macrophages release messenger proteins to activate the dendritic cells. Dendritic cells specialize in collecting pathogen carcass and present it as membrane proteins on their outer surface. Thus, they become antigen presenting cells (APCs).
Castling, whether king’s side or queen’s side, is an important defensive strategy. Analogously, APCs tend to call for either anti-viral or anti-bacterial forces. In the case of former, the usual response is to destroy the infected cells without harming the healthy ones, while in latter, APCs themselves travel to the closest lymph node in a day to activate helper and killer T cells that initiate the endgame of cell-mediated immunity.
B-lymphocytes originate and mature in the bone marrow (although they are named so because they were found in the butt of birds called Bursa of Fabricius), unlike other white blood cells that mature at the site of action. Each B cell has about 10,000 special protein receptors that are made of membrane bound antibodies, the structure of which is unique to the B cell.
Beside immune competency, B cells also practise self-tolerance policy and ignore APCs that present antigens of own cells. In contrast if they encounter a foreign antigen, they start cloning themselves, producing antigen-specific antibody receptors. Some of these clones form effector B-cells that immediately start battling, while others form memory B cells that preserve the genetic code for the specific antibody receptor.
Effector B cells, also known as plasma cells, have a highly dense rough endoplasmic reticulum (RER) and can mass produce antibodies at the rate of about 2000 per second for a duration of 4-5 days.
Antibodies are the freely floating counterparts of the membrane-bound antibodies located on the plasma cells. They can bind to the antigens and mark them for death via opsonization, physically block binding sites on the viruses or bacterial toxins via neutralization, or aggregate antigens through cross-connection of antibodies at multiple binding sites via agglutination.
A form of passive humoral immunity is observed in babies when they receive endogenous antibodies from the mother through placenta before birth, and breast milk after birth. However, these antibodies die before converting to memory cells and hence cannot provide long lasting immunity. The process of vaccination for various diseases after birth is thus an essential step in life.
End Game - Cell-mediated Immune System
Endgame is mostly dominated by the queen - T-lymphocytes. Black queen – incurable viruses, lethal bacteria, and non-viruses – can breach the cell barrier and enter the healthy cells. The recent corona virus and AIDS virus come in this category. This triggers the cell-to-cell combat mode or cell-mediated immune response.
Just like the queen’s development supported by knights and bishops, cell-mediated immune response is supported by the APCs and B cells. APCs present broken bits of endogenous proteins (MHC I) from infected cells on their outer membrane or the phagocytes (macrophages, dendritic cells) and B cells that present the exogenous proteins (MHC II) from pathogens.
T-lymphocytes have numerous functions. They are responsible for inflammation, activation of macrophages and other T cells, or regulation of the immune response.
In the absence of T cells, the immune system may go rogue and start attacking its own healthy cells, a phenomenon known as an autoimmune response.
T cells are of several types, each of which performs a specific set of functions. The naïve (virgin) helper T cell binds only to a specific combination of MHC II and antigen to get activated into a specific helper T cell. This helper T cell then activates a helper T stem cell to convert to a fully functional helper T cell of the same type, which further augments its functionality by cloning and multiplying either into more helper T cells or regulatory T cells. Just like an offensive attack backed-up by the queen, the helper T cells raise an attack alarm of cytokines to activate cytotoxic (or killer) T cells that euthanize weakened infected body cells via apoptosis. The helper T cell also causes cytotoxic T cells to multiply and attack with full strength to checkmate the enemy.
Without killer T cells, there will be no adaptive immune response, a situation occurring in immunodeficiencies, e.g. AIDS. Human immunodeficiency virus (HIV) specifically attacks helper T cells and alters their capacity to redirect and activate multiplication of the cytotoxic T cells. In the absence of perfectly functional helper T cells, the killer B cells remain untrained, and can randomly form effector and memory B cells without perceiving the antigen as self or foreign. At this point, regulatory T cells prevent the immune system from going berserk with its immune response and try to protect healthy cells from harm. But in immunodeficiencies, even these regulatory cells are rendered inactive. This is like the stalemate situation where the immune system becomes hyperactive and causes autoimmune diseases like multiple sclerosis or type 1 diabetes.
This concludes the entire immune response from the perspective of a chess strategist. I hope the mind-numbing complexity of the immune system has been simplified a little with this dual analogy. Cheers to our immunity !