The Immune System
“The immune system is unknowable.” ~ American clinician Steven Deeks
To detect and destroy microbial invaders, an immune system covers 2 territories: cells and the extracellular pathways of the body, including the circulatory system. The pathways are patrolled by special agents of the immune system.
The human body incorporates innate immune responses evolved in the earliest multicellular organisms. Individual cells have their own defenses.
The evolution of immune systems has meant a layering of newer mechanisms on top of earlier ones. The vertebrate immune system is commonly considered bifurcated – based upon evolutionary emergence – into innate and adaptive (acquired) immunity subsystems. The significant distinction is aptitude for learning.
Innate immunity mechanisms are ever vigilant. Nonspecific antimicrobial systems are reflexive, in that their operation does not require prior contact with an infectious microbe.
Innate immunity, honed from hundreds of millions of years of evolution, requires no learning to work. That puts a quicker, though not always as effective, finger on the trigger.
In responsive flexibility, natural killer (NK) cells are the crowning achievement of the innate immune system. NK is an evolutionary bridge to adaptive immunity. NK cells are themselves adaptive: remembering their encounters and mounting pattern-sensitive (antigen-aware) secondary responses.
To keep up with evolving threats, acquired immunity gained the ability to learn and remember literally millions of new pathogens. All vertebrates have natural killer cells and acquired immunity.
Adaptive immunity is a learned response, able to ferret out pathogens that the innate system leaves alone. Adaptive response acts as a safeguard against the risk of attacking oneself, or when the innate system is not sufficiently effective in countering an attack.
Acquired immunity is layered on, and yet still dependent upon, innate immunity. Thus, the human bodily response to attack from pathogens is an interdependent orchestration of mechanisms. Almost every immune response is checked by using a dual signal code before allowing activation. A constant feedback system between the command chains and effector cells ensures an appropriate response that ends when the threat is extinguished.
“The nervous and immune systems are the two most complex systems in the body. That complexity is amplified by the fact that each influences the other, as they constantly exchange messages in response to environmental and internal cues.” ~ American science writer Richard Robinson
When the body is under attack, the immune system sends RNA-based information to the intelligence system and other parts of the body to synchronize response. This RNA influences gene expression, and so alters cellular operations.
“A belly laugh increases the ability of your immune system to fight infections.” ~ English American actress Elizabeth Taylor
Cells
The immune system amounts to a concerted set of cells with specialized roles, some of which overlap.
White blood cells (leukocytes) are a mainstay of the immune system. The number of these cells in a human body runs to the billions.
All types of leukocytes are made in bone marrow, derived from stem cells. Stem cells – found in all multicellular organism – can differentiate into different bodily cell types.
There are distinctive types of white blood cells. 50% to 60% all leukocytes are granulocytes.
Granulocytes contain granules in their cytoplasm, hence the name. There are 3 classes of granulocyte: neutrophils, eosinophils, and basophils. The granules in granulocytes carry distinct chemicals based upon cell type. Granulocyte chemicals facilitate many functions, including purging pathogens.
Neutrophils are first-responder phagocytes that attempt to engulf invaders. Phagocytes are cells that ingest foreign particles and cellular waste. Neutrophils are recruited to the site of an injury within minutes. The predominant cells of pus, neutrophils are the hallmark of acute inflammation.
Eosinophils combat infections and parasites.
Basophils release chemicals and enzymes that contribute to inflammation, speeding blood flow to an infected site.
The other white blood cells are agranulocytes: non-granular cells that comprise over a 1/3rd of the leukocytes circulating in the bloodstream. There are 2 types of agranulocyte: lymphocytes and monocytes.
Lymphocytes may be large or small. Natural killer (NK) cells, players in innate immunity, are relatively big. NK’s smaller cousins work in the department of acquired immunity: B and T cells. B cells produce antibodies: tags that stick to pathogens, marking them for destruction. Helper and killer T cells respectively coordinate and attack viral infections.
Monocytes are immune system janitors. During phagocytosis monocytes and neutrophils vacuum up after infection, clearing away foreign matter. Monocytes also present pathogen pieces to T cells so the invaders can be remembered. Monocytes that migrate from the bloodstream into tissue are called macrophages.
Monocytes and macrophages are phagocytes, which make up around 7% of all leukocytes. Phagocytes play important roles in fighting infections and maintaining health, including longevity.
Innate Immunity
Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes. ~ Dutch immunologist Marijke Keestra et al
Innate immune systems exist in all cells and organisms.
For a human with a healthy microbiome, resistance to infection is ever vigilant. Skin and cells that line entry passages deal with dirt, dust, and germs.
Commensal bacteria reside on the skin and in the mucous membranes of the eyes, nose, mouth, throat, and gastrointestinal tract. Their services include removing debris that makes a meal for a microbe, and warning of unwelcome foreigners.
There are various agents that recognize pathogens. Many are proteins but some RNA molecules also keep a lookout.
A widespread epigenetic process, RNA interference (RNAi) affects which genes are active and how active genes are. MicroRNA (miRNA) and small interfering RNA (siRNA) are active in the RNAi process.
RNAi acts as an innate antiviral defense in plants, fungi, and animals. There are also protein-based antiviral defenses. Numerous viruses have learned how to suppress these anti-viral agents.
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The skin offers the most contact area for an infection, though intact skin is impermeable to many would-be invaders. Wounds present an infection opportunity.
Many pathogenic bacteria cannot survive long on healthy skin because of direct inhibitory effects of lactic acid and fatty acids in sweat, as well as sebaceous secretions that generate an acidic environment.
Staph Infection
The grape-shaped Staphylococcus aureus, the most common cause of staph infections, is an exception to being averse to an acidic environment. About 20% of the human population carry Staph aureus for much of their lives. Staph aureus can be commensal, but can also cause a range of illnesses, from minor skin infections to life-threatening maladies such as pneumonia.
Pathogenic Staph infections have been a perennial problem in hospitals since the beginning of the antibiotic era. With much exposure and experience, most strains of hospital Staph aureus have acquired antibiotic resistance. A few strains can now resist all clinically useful antibiotics.
Epithelial Tissues
In traditional medical classification there are 4 basic types of animal tissue: epithelial, connective, muscle, and nervous.
Epithelial tissue lines the surfaces and cavities of body structures, including forming the structure of glands. Epithelial cells secrete, absorb, protect, sensate, and transport other cells.
Epithelial surfaces are washed by tears, saliva, and urine. Many secreted body fluids contain bactericides: acid in gastric juice, lactoperoxidase in mother’s milk, spermine and zinc in semen, and lysozyme in tears, snot, and saliva.
Mucus secreted by membranes lining the inner surfaces of the body acts to block bacteria from adhering to epithelial cells. Sticky mucus traps pathogens, which are then removed by various means, including crawling (ciliary movement), sneezing, and coughing.
The stomach is a highly acidic environment: helpful for breaking down food and killing microbes that are eaten.
The body’s gut flora assist. The contented families of commensal bacteria don’t like competition for nutrients, so friendly microbes suppress the growth of potentially pathogenic bacteria and fungi.
For example, the vagina is protected by lactic acid, which is produced by commensal microbes which metabolize glycogen. The glycogen supply is secreted as microbial food by vaginal epithelium. When protective commensals are disrupted by antibiotics, the door is opened to opportunistic pathogens such as Candida albicans and Clostridium difficile.
Endothermy
Being endothermic itself confers some innate immunity. The human body temperature, nominally 37 °C, is just warm enough to ward off fungal infection. For each 1 °C rise in body temperature, the number of fungal species that can infect an animal declines by an estimated 6%.
There is a trade-off between marginal energy consumption necessary to maintain a body temperature versus fungal protection. Mathematical modeling found 36.7 °C to be optimal for minimizing cost versus protection benefit.
251 mya, in the Great Dying, 95% of the species in the oceans and 70% of those on land were wiped out. Earth become one massive compost pile.
Microbes literally had a field day. A massive fungal bloom swept the planet. Fungi may have been a kingmaker in the species dominance that followed.
Ectotherms, such as reptiles and amphibians, are susceptible to tens of thousands of fungal infestations, whereas mammals are bothered by a few hundred. This innate mammalian immunity may have been an evolutionary edge over reptiles. Meanwhile, dinosaurs developed mesothermy, which may have been partly to ward off fungal infections.
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If a pathogen manages to penetrate the body, further innate defensive mechanisms await: bactericidal enzymes, inflammation, and phagocytosis.
Mast Cells
Mast cells are remarkably similar to basophils, which are a type of white blood cell. While mast cells play their role in innate immunity, white blood cells are a primary agent in acquired immunity.
Mast cells reside in tissues surrounding blood vessels and nerves and are particularly prominent near the boundaries between the world outside and the body within: the skin, mouth, nose, eyes, lungs, and digestive tract.
Mast cells are a key actor in inflammation, promoting wound healing and pathogen defense. Mast cells carry an arsenal of bioactive chemicals to assist healing. Mast cells also mediate allergic reaction.
Inflammation
Inflammation is complex protective and healing response by vascular tissues. The heat and extra blood flow from inflammation accelerate healing.
Wounds and infections would never heal without inflammation. Inflammation is initiated by chemical agents present in all tissues, in concert with resident phagocytes. In healthy animals, acute inflammation is a tuned response: regulated by cell-derived mediators, biochemical cascade systems, and complemented by commensal bacteria.
By contrast, chronic inflammation is a slow-burning fire, which sets in when healing cannot be completed, leading to a progressive shift in the type of cells at the inflamed site. Chronic inflammation is characterized by continued, but increasingly feeble attempts at healing, along with the destruction of formerly functional tissues.
Chronic inflammation is the result of an imbalanced immune system. The intricately interdependent immune system is amazingly robust, but can be worn down by poor lifestyle choices, and create dynamics which self-perpetuate and cascade into disease.
While mast cells in healthy individuals help heal damaged tissue, they accumulate in the fat tissue of the obese, where the mast cells dysfunction and leak molecular garbage into surrounding tissue.
From a diagnostic viewpoint, inflammation, whether acute or chronic, is a symptom of attempted healing by the body.
Many nonphagocytic cells have means to kill potential invaders. The gas nitric oxide (NO) can be formed by many cells in the body. NO serves as a key biological messenger in vertebrate, but it also acts against microbes that invade the liquid inside cells (cytosol).
Sustained levels of increased NO production damage tissue and contribute to vascular collapse. Chronically high NO is associated with a various carcinomas and inflammatory maladies, such as juvenile diabetes, arthritis, and multiple sclerosis. Carcinoma is a malignant tumor, typically arising from transformed epithelial cells.
Complements
Near the end of the 19th century Belgian immunologist Jules Bordet discovered a heat sensitivity to antimicrobial components in blood serum. A relatively heat-stable component conferred immunological protection against specific invaders, while a heat-labile component – readily damaged by heating – provided nonspecific antimicrobial defense.
The heat-labile component was named complement by German physician Paul Ehrlich in the late 1890s. The complement system was so-named because it complements the work of phagocytes and antibodies. Antibodies are large Y-shaped proteins which act as part of the immune system.
Complements comprise a complex series of over 30 proteins found in plasma and on cell surfaces. Along with blood clotting and unclotting, complement forms one of the triggered enzyme systems in plasma.
These enzymatic systems characteristically produce a rapid, highly amplified response to a triggering stimulus mediated by a cascade, where the product of one chemical reaction is the enzymic catalyst of the next. The activated proteins or other products of the cascade serve a variety of immunological functions.
A complement kills by blasting a large hole through the membrane of an invading microbe. The loss of membrane integrity ruins a pathogen’s capability to control cell fluid equilibrium, particularly salt concentration, thus slaying it.
Host cells and commensal microbes possess protein badges that identify them as friendly, inactivating any complement cascade against them. Not surprisingly, some pathogens evolved a defense strategy that presents cascade inhibitors. But most do not have this defense.
Complement is a critical part of the innate immune system. The complement system continually operates via intricately complex chemical reactions, known as pathways.
3 human complement pathways have been identified. At least 1 pathway is shared by primitive organisms that are phylogenetically distant from humans.
Complement is instrumental playing the inflammation symphony in the innate immune system orchestra. Complement facilitates phagocytosis.
The proteins and glycoproteins comprising the complement system are synthesized in the liver.
The complement system was an early immune system development and is billions of years old. Evolution added more complement artillery to early vertebrates than what invertebrates had, and even more in mammals.
In many cases, complements recognize foreign microbes directly, without the aid of antibodies, though coordinated attack with antibodies is more efficient.
span style=”font-size: 115%;”> Phagocytes
Phagocytes include monocytes and macrophages. Monocytes morph into macrophages upon leaving the circulatory system to attend to tissue damage or infection.
Phagocytes are significant throughout the animal kingdom, and quite evolved in vertebrates. A liter of human blood has about 6 billion phagocytes.
Vertebrates with jaws have 2 types of phagocyte: “professional” and “non-professional,” a distinction made by their effectiveness at phagocytosis.
Monocytes, macrophages, neutrophils, mast cells, and dendritic cells are the pros. Professional phagocytes possess surface receptors to detect pathogens, and some have the means to kill infected cells.
Phagocytic receptors involve opsonins: molecules that tag an antigen for immune response. This includes antibodies and complement.
Phagocytosis is not the principal job of the non-professionals. Most non-pro phagocytes lack pathogen receptor detectors and the oxygen guns that the pros use.
Non-professional phagocytes include epithelium, endothelium, mesenchyme, and fibroblasts. Epithelium are the cells lining the surfaces and cavities of body structures. The skin, aka epidermis, is an epithelium. Endothelial cells line the inner surface of blood vessels. Mesenchyme comprises connective tissues, such as cartilage and bone. Fibroblast cells work in wound healing.
Phagocytosis
Essential bodily cleansing at the cellular level involves various processes, covered under the general heading of phagocytosis, which involves particulate pickup, either for nutrient acquisition, debris collection, or pathogen purging. (In applying to selfsame functioning (particle pickup) for distinct reasons, the term phagocytosis is overloaded.)
Phagocytosis is a primitive biological mechanism. Protists use phagocytosis as a means for feeding, as do amoeba. In mammals, phagocytosis involves engulfing pathogens as an immune system function.
Autophagy (aka autophagocytosis) recycles cell bits for nutritional reasons, without regard to infection; providing cells with needed nutrients not otherwise immediately available.
Traumatic cell death, from injury, is necrosis. By contrast, apoptosis is programmed cell death.
Biochemical events cause cell changes which lead to natural demise. But a dying cell has reusable parts.
Apoptotic cells emit a specific “eat me” signal to which macrophages respond, processing degraded cells into useful nutrients for other cells, and for new cell production. This process is efferocytosis. One benefit of efferocytosis is avoiding toxic spills, as terminal cells are processed before leaking into surrounding tissue.
During development and throughout life, cells are eliminated by programmed cell death and rapidly cleared by phagocytes such as macrophages and glia. Failures in apoptotic cell clearance (efferocytosis) contribute to disease. ~ English immunologist Iwan Robert Evans et al
Efferocytosis triggers specific downstream intracellular activity, including signals to reduce inflammation and promote growth. Conversely, impaired efferocytosis allows tissue damage, and is a factor in autoimmune disorders.
The reason is that phagocytes are distracted from the critical tasks of fighting infections and wound repair if tissues are junked up with debris. An ineffective efferocytosis program has phagocytes clearing crud when they should be repairing infrastructure or chasing down germs.
Another aspect of phagocytosis is pathogen disposal. There are several types of specialized phagocytic cells, including macrophages and granulocytes. Phages are leukocytes, or white blood cells, of which there are several types. Macrophages recognize microbial invaders, grab them by an antibody tail sticking out, engulf them, and then destroy them with a controlled molecular explosion: releasing a respiratory burst of reactive oxygen species (ROS).
ROS are chemically reactive oxygen-bearing molecules. Besides acting as a microbial murder weapon, ROS forms as a natural byproduct of normal oxygen metabolism. ROS is also involved in intercellular signaling.
When a plant recognizes an attacking pathogen, an immediate response is rapidly producing superoxide or hydrogen peroxide to strengthen the cell wall. This prevents the pathogen from spreading to other parts of the plant. Floral ROS response essentially forms a net around the pathogen, restricting its movement and reproduction.
Macrophages also ingest free-floating antigens that have been tagged with antibodies, including toxins. Picked up particles are shunted to a lysosome: the cellular internal recycler and garbage disposal unit. Inside the lysosome membrane, digestive enzymes work at an acidic 4.5 pH: breaking down engulfed materials, which can include amino acids, sugars, and fats. The macrophage keeps what it needs and releases the rest for use by neighboring cells.
Professional phagocytes recognize the enemy using a set of pattern recognition receptors which are activated by molecular patterns specific to the surface of infectious agents. These patterns are essentially the polysaccharides and polynucleotides which are characteristic of pathogens but not found in host cells or commensal microbes.
Polysaccharides are complex polymeric carbohydrate structures. Bacteria carry a diverse range of polysaccharides, the production of which is tightly regulated and energy intensive.
Bacterial polysaccharides have a variety of functions, ranging from maintaining cell wall integrity to helping bacteria survive in harsh environments, which includes being inside an animal. Pathogenic bacteria commonly produce a thick, mucous-like layer of polysaccharides to cloak antigenic proteins that would reveal their presence; but the polysaccharides can also be a tell.
Polynucleotides are biopolymer molecules comprising 13 or more nucleotide monomers covalently bonded into a chain, and intricately folded. All living organisms have polynucleotides, serving a vast variety of roles. One critical function is replication. The genome of every living organism comprises complementary pairs of enormously elongated polynucleotides wound around each other in the form of a double helix, then folded into an intricate origami. RNA and DNA are polynucleotides.
By and large phage receptors are lectin-like: binding multivalently, with considerable specificity, to polysaccharides exposed on the surface of an invading microbe. Lectin is a carbohydrate-binding protein.
Receptor engagement generates a signal through a NFĸB (nuclear factor-kappa B) transcription factor pathway. NFĸB is a protein complex that controls the movement or transcription of a polynucleotide. The signal alerts a phage, initiating phagocytosis.
Pathogen recognition stimulates a phagocyte to call for help by producing chemokines: proteins which summon other helpful cells to the infection site.
Neutrophils
Macrophages are adept at combating viruses, bacteria, and protozoa capable of living within the cells of the host. Meanwhile, neutrophils hold the fort against pyogenic (pus-forming) bacteria. It is thus no small irony that certain viruses, such as HIV, hijack macrophages for their home base.
Neutrophils tote a variety of toxic substances that kill or inhibit the growth of bacteria and fungi. Like macrophages, neutrophils pummel pathogens via ROS respiratory burst.
Neutrophils are the most abundant phagocyte, accounting for 50–60% of the total circulating leukocytes. Neutrophils are typically first on the scene at an infection.
A healthy adult produces more than 100 billion neutrophils per day. During acute inflammation, the bone marrow factory pumps out over a trillion neutrophils a day, 10 times the nominal production level.
Natural Killer Cells
NK cells possess nearly all of the features of adaptive immunity, including memory. ~ American immunologists Joseph Sun & Lewis Lanier
Viruses must hijack cells to reproduce. As part of the adaptive immune system, killer T cells recognize viruses by their memorized patterns. Natural killer (NK) cells use a more basic technique to determine a foreign invader: what isn’t displayed.
Natural killer cells are lymphocytes that recognize glycoprotein structures (MHC) on the surface of virally infected cells or tumor cells, such as cancer. These recognizable structures occur because the inhibitory receptors that prevent killer cell sanction are lost when a virus disturbs normal operation of nucleated cells.
All cells have protein-processed marker molecules called major histocompatibility complex (MHC). Class 1 MHC (MHC-1) molecules display on the surface of all body cells except mature red blood cells.
When a host cell has been virally infected, class 1 MHC molecules are modified to include viral peptides, which are a recognizable protein pattern to the acquired immunity detectives that know the distinctive mark of a virus.
To evade the wiles of acquired immunity, some viruses have learned to inhibit expression of MHC-1 on the host cell surface. This keeps telltale virus peptides from showing up on the surface. That maneuver blinds killer T cells from knowing what is going on inside a virally hijacked host cell. In the instance of viruses that take up long-term residence inside a cell, such as HIV, the result of successful concealment can be catastrophic.
NK cells are ready to kill any cell and are stopped only by one sign: an MHC-1 ID identifier. Any cell with that badge gets past a natural killer cell.
Any cell without MHC-1 display, such as tumor or virally infected cells that suppress MHC-1 expression, have a death mark by omission. As all other immune responses rely on a sign, rather than an absence of one, that is a rather ingenious mechanism.
To make the kill, NK cells attach and activate a polarization of granules that causes the target cell to spill vital contents into the space between the target and the NK cell, causing the death of the infested cell.
Natural killer cells not only lyse virally infected and tumor cells, they also play on the team fighting inflammation, as well as stimulating other responses, and modulating acquired immune response.
While NK cells do not have antigen-specific receptors, they can recognize virally infected cells that have their surfaces slathered with antibodies. NK cells recognize a specific molecular portion of an antibody.
It was long thought that only the lymphocytes of the acquired immune system retained memory of previous infections; that the innate immune system lacked the intelligence for adaptive response. Not so. Despite seemingly lacking the traditional receptors for memory, NK cells remember viral infections and more effectively respond to subsequent attacks.
Eosinophils
Helminths (parasitic worms) are too big to be phagocytosed. Eosinophil granulocytes, when released from their home in bone marrow, circulate in peripheral blood, and then traffic to tissue, particularly in the lungs and gut, which are the mucosal surfaces where helminths may reside.
Eosinophils encountering a helminth put on a fireworks show: ROS respiratory bursts to blast holes in worm cell membranes, as well as releasing cytotoxic proteins.
When not on worm duty, eosinophils fight viral infections, help deal with inflammation, and mediate allergic reactions and asthma pathogenesis. Eosinophils also get involved in many other biological processes: female breast development, the estrous cycle, allograft (transplant) rejection, neoplasia (abnormal cell growth) response, and antigen presentation, as part of the acquired immunity response.
Eosinophils are an example of an evolutionarily older mechanism being upgraded to take on additional duties in a highly coordinated and integrated system.
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Innate response is intimately linked to acquired immunity. Chronic inflammation is an example of the innate immune system adapting to systemic changes, though the adaptation appears as disease, whereas it is in fact a symptom of a more systemic problem.
All multicellular eukaryotes have a complex innate immune system. The above description merely scratches the surface of the intricate interactions involved. This relatively primeval system is an astonishing collaboration of protection. But innate immunity is just the warm-up act.
Acquired Immunity
If a pathogen makes its way past innate defenses, organisms rely upon knowledge-based adaptive immune systems. Even microbes have adaptive immunity, though their systems are distinct from those evolved by the earliest jawed vertebrates, which have been carried on in later-evolved vertebrates as a highly conserved trait.
The terms acquired immunity and adaptive immunity are used interchangeably. In vertebrates, adaptive response is activated by the innate immune system.
Living a short life can be advantageous if you are pathogen – but only if you produce offspring.
Innumerable pathogens evolved strategies to evade the innate immune system. Disguises and subterfuges are picked up from surrounding cellular material and incorporated into the next generation. Many micro-marauders can shape their exteriors to completely avoid complement activation. These are not random acts by lucky microbes. This is intelligence at work in a life form with no recognized brain, doing what parents everywhere do: try to make a better life for their offspring.
An antibody is a protein that remembers past encounters with pathogens. The remembered molecular pattern is an antigen, short for antibody generator.
An antigen is a memory molecule which can provoke an immune system response, except in the case of self-antigens. A self-antigen is a molecule of cellular self-recognition.
An antibody recognizes a pathogen upon contact, without mistakenly targeting the body’s own cells or friendly microbes. It attaches itself to the ne’er-do-well and calls for reinforcements, including the complement system and phagocytes.
Specialized lymphocytes – B & T cells – are the front-line warriors of the adaptive immune system. Some of the lymphocytes that win the war against an infection transform into historians. These memory cells pass on the tale of past battles so that an immune response can be faster and more effective the next time.
Somatic Hypermutation
The adaptive immune system can evolve at microbial speed via somatic hypermutation (SHM). As a learning process, SHM diversifies the recognition receptors used by lymphocytes to recognize foreign elements (antigens), thus allowing adaptive response to new threats. Antigens are usually proteins or polysaccharides.
This learning process is encoded in antibody genes. These genes can rearrange themselves to form a vast array of antibodies: well over 100 million distinct types.
SHM affects only immune cells. Somatic mutation is different than germline mutation. Somatic mutations are essentially disease memory, typically not passed on to offspring. In contrast, germline mutations are part of the heredity system that provides adaptations from one generation to the next.
Clearinghouses
As blood and lymph pass through the spleen and lymph nodes, contents are trapped and examined. Recognized cellular matter passes by. Foreign matter is assailed.
The body has a single spleen: an organ found in all vertebrates. The spleen has several functions. One is removing aged or dead red blood cells and recovering the iron from the hemoglobin within a cell. Parts of the spleen act like a supersized lymph node.
There are hundreds of small lymph nodes, scattered throughout the body. Lymph nodes are distributed intelligence centers for the adaptive immune system. Lymph nodes act as customs agents for the body, inspecting blood and lymph cargo.
B and T cells do the inspecting. Anything that is “self” is allowed through. This includes commensal microbiota, which the immune system learns in infancy to accept as part of oneself.
Foreigners set off alarms, activating attack. Infection can come in the form of a virus, bacterium, parasite, or tumor that has infiltrated tissues.
Lymphocytes pick up on chemical signals in the bloodstream. While a body’s own cells commonly call for help, warning signals are sometimes put out by commensal microbes as an assist.
Individual cells and commensal microbes throughout the body, not just lymphocytes, know their neighbors and communicate with each other. Further, cells know not only their own assignments but also the roles of neighboring cells. This extensive distributed knowledge is necessary for a body to function.
Host cells and commensal microbes raise a fuss if an invader is found in the neighborhood. A pathogen is assaulted by a dazzling array of lymphocytes, each lymphocyte bearing a single antibody. An antibody-antigen fit to the right lymphocyte causes the lymphocyte to swell and proliferate.
Adaptive Lymphocytes
Though they have learning ability, natural killer (NK) cells are conventionally designated as innate immunity lymphocytes. The adaptive immunity system designates 2 lymphocyte cell types: B & T.
T cells take their title from the thymus gland in the neck where these cells mature. In birds B cells mature in a lymphoid organ called the bursa of Fabricus; hence their designation (from where they were discovered). Only birds have a bursa. Mammalian B cells arise from the stem cells which give rise to all types of blood cells.
All lymphocytes are born in bone marrow. T lymphocytes travel to the thymus to mature.
During fetal development, mammalian B cells mature in the liver. After birth, some B cells mature in bone marrow, while others travel to mucous membranes, particularly the gut and lungs, to mature.
B cells surveil for infection by looking for foreign organic substances. This requires knowing what is native (versus foreign). Thus arises the problem of self-tolerance: not mistaking beneficent cells for malignant ones. This takes training. In bone marrow, which is sterile, the investigative receptors of B cells are edited by self-antigens to recognize the body’s own cells.
Then there is the issue of not having B cells attack the friendly bacteria that belong to the body’s microbiome. Hence B cells are sent to mucous membranes, where they are trained with antigens from resident microbes, to recognize the little critters as compatriots, not pathogens.
After T and B lymphocytes mature, they migrate to the lymph nodes and spleen, where they take up residence.
The different types of lymphocytes have different life spans. B cells live a week. T cell life span varies considerably, though typically a week or 2. Serving in the line of duty shortens a T cell’s life expectancy.
T Cells
T cells surveil the RNA of bodily cells, looking for molecular patterns that are characteristic of viruses. Like telltale fingerprints, viral manipulation of RNA leaves traces that T cells can sense. Some savvy viruses wipe away giveaway fragments. Others place decoys that confound the immune system. Adept practitioners of stealth, viruses are especially difficult to detect.
There are 4 types of T cells: killer (cytotoxic), helper, memory, and regulatory.
Killer T cells destroy virally infected cells and tumor cells.
Helper T assist both B cells and killer T in their jobs. Helper T cells also play a role in the education of killer T. Helper T cells are the invasion target of HIV, the AIDS virus.
Memory T cells are antigen-specific T historians: T cells that persist after an infection; old soldiers that remember the war. If re-exposed to their cognate antigen, memory T proliferate to T cells that can fight again.
Regulatory T are the maintainers of immunological tolerance: keeping the immune system from attacking self-antigens. (Regulatory T cells were formerly known as suppressor T cells.) Regulatory T cells shut down T cell immune response once an infection is defeated. Regulatory T also suppress auto-reactive T cells that fail T cell training in the thymus.
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The thymus is a specialized immune system organ. The only known function of the thymus is educating and producing T cells. The thymus is a T cell’s college.
The thymus does most of its work early in life. The thymus is largest and most active during neonatal and pre-adolescence, reaching its maximal size during adolescence, typically by the early teens, and gradually declining in size thereafter.
T cell maturation involves learning to distinguish between foreign matter and cells of the self, including the microbiome. This schooling is called tolerance induction, This educational process not well understood.
There are several mechanisms that induce tolerance, which involve a sophisticated complex of sequenced communications and responses that must be learned and passed on to the next generation of immune system cells.
Immature lymphocytes are tested for self-recognition. Cells that bind too strongly to self-antigens, and thus would signal attack on the body’s own cells, are alternately not allowed to mature, edited for other functioning, or deleted.
98% of thymus T cells (thymocytes) fail the tests: either not recognizing enemy microbes or considering friendlies as unfriendly. The remaining 2% survive to serve active duty.
Helper T display on their surface copies of a single protein chain called CD4, and so are sometimes referred to as CD4 T. Killer T display the dimeric (doubled) CD8, hence CD8 T. Immature T cells arrive in the thymus uncommitted to a career as helper or killer. That decision is made during maturation.
B Cells
Long-term protection against infectious diseases requires the production of highly potent antibodies by B cells. ~ English immunologist Katelyn Spillane
B cells are white blood cells (plasma cells). The role of B cells is to produce antibodies that bind to antigens.
Antibodies can take 2 physical forms. One is soluble: secreted by a B cell, floating freely in blood plasma. This type of antibody attaches to any correspondent antigen that it finds and calls for help.
Depending on the antigen, the binding may impede the disease-causing agent. Regardless, macrophages respond to the altercation.
Soluble antibodies are good for mopping up, but they don’t provide for an ongoing war against an infection. Thus, the other type of antibody binds to the surface of a B cell and alerts its owner once it comes into contact with an antigen.
B cell responses start when they encounter foreign antigens on the surfaces of a type of immune cell called antigen-presenting cells. The B cell and the antigen-presenting cell form a tight contact, known as an immune synapse, from which the B cell can acquire the antigen for processing and presentation to helper T cells so it can be destroyed. ~ Katelyn Spillane
Antigen recognition has at least 3 aspects: physical shape congruence, electrical attraction, and lipophilic interaction (chemical bonding of cell membranes).
Once activated, a B cell literally rips an antigen off the cell to which it is attached. This physical encounter allows the B cell to better sensitize itself to the antigen, and so produce more potent antibodies. If physical force does not work, the B cell employs an enzyme to peel the antigen off.
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When a B encounters an antigen, it usually is not completely activated by it. Full B activation typically requires an assist from a helper T.
In certain situations, B cells may activate themselves to produce antibodies without T help by using a pattern match between a B-cell pattern recognition receptor (PRR) and a pathogen-associated molecular pattern (PAMP). This T-less antibody activation is much faster, but also somewhat indiscriminate, as it does not represent activation by a specific antigen.
Any and all B lymphocytes contacting these PAMPs via their PRRs will start their antibody factory, regardless of whether those particular antibodies are needed to fight the infection. This can be wasteful, but the urgent response may make the difference in the body gaining a quick upper hand on an infection.
B solo initiatives are not necessarily productive, so self-activated B cells do not go on to be memory cells. Such an episode is forgotten.
Antibodies
An antibody is a Y-shaped protein with each fork of the Y specifically shaped (a paratope) to lock onto a specific antigen (an epitope, equivalent to a key). This binding allows an antibody to tag a microbe or infected cell for other immune system actors to kill, or, alternately, neutralize the target, by blocking a part of a microbe essential for survival or invasion. Each B cell is programmed to make one, and only one, specific antibody.
Antibodies are manufactured by plasma cells derived from B lymphocytes that have transformed. T cells don’t make antibodies, but they help B cells do so.
A single B cell can produce more than 10 million antibodies in an hour and can make variations capable of tagging a remembered antigen that may have varied somewhat.
Manufactured antibodies are secreted: circulating in search of the antigen that triggered their formation. Antibodies work their way out of the bloodstream, settling in among other cells throughout the body, such as the digestive tract, where they tag swallowed germs. Antibodies are plentiful in saliva, and in mother’s milk, as well as other bodily fluid secretions.
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B cells and T cells differ in their activation via antigen reception. B cells produce and release copies of the antibody they display on their surface. These antibodies flow through the body, looking to attach to an antigen in circulation.
T cells do not distribute antibodies. Instead, they set out on patrol, using their surface antigen receptors as eyes, looking for an invader.
B battle bacteria found in body fluids, while T vex viral infection, as well as other pathogens that take up resi-dence inside of host cells, using the machinery within to reproduce.
T tackle intracellular parasites, which fall into 2 cate-gories: facultative and obligate.
Facultative pathogens are versatile: they can replicate on their own but prefer the intracellular life because of the protection it affords. Macrophages are a popular home site. Facultative pathogens include Mycobacteria, which causes tuberculosis, and Leishmania, a protozoan parasite carried by sandflies, which bite and infect humans, caus-ing skin sores and other maladies.
Obligate intracellular pathogens must employ host cells to replicate. Viruses are obligate parasites.
Dendritic Cells
Potentially interesting substances are also brought to lymph nodes and the spleen by dendritic cells. Dendritic cells act as messengers between innate and adaptive immunity. Their job is presenting antigens. Dendritic cells uptake various possible protein antigens and process them into peptides (protein fragments) on their surface.
There are 2 pathways that dendritic cells use to present antigens to T cells: one for CD4 (helper) T cells, and one for CD8 (killer) T cells.
Dendritic cells are part of the mammalian immune system. Dendritic cells are present in tissues exposed to the outside, such as skin, nose, lungs, stomach, and intestines. Once activated by pattern recognition receptors, dendritic cells migrate to the lymph nodes, bearing bad tidings.
Major Histocompatibility Complex
Almost all human cells have protein-processed marker molecules called major histocompatibility complex (MHC). There are 2 classes of MHC molecule.
Class 1 MHC molecules are on all body cells except mature red blood cells. Class 2 MHC molecules are present only on certain cells, including macrophages, B cells, and dendritic cells. CD8 (killer T) cells bind to class 1 MHC, while CD4 (helper T) cells bind to class 2 MHC.
Helper T tag and flag infected cells for others to kill. Killer T directly attach to infected cells and kill them.
Each cell in the body comprises a network of microcanals (endoplasmic reticulum (ER)) that connect the cell cytoplasm and nucleus. Chromosomes inside the nucleus generate MHC molecules that range the ER and make it to the cell surface, acting as a signpost of self.
An invaded cell will display peptides attached to class 1 MHC that include processed pathogen proteins (proteasomes).
Both classes of MHC possess polymorphism: the ability to change shape. The number of forms that MHC proteins can take in humans runs to the hundreds. But an individual will have only a few types of class 1 or 2 MHC present on cells, and each cell has identical MHC types. MHC proteins are therefore a marker of individuality. That is why tissue transplants are so problematic.
T cells cannot recognize free-floating antigens. They can only recognize antigens when held by MHC molecules on the surfaces of other cells.
Use of MHC to identify fragments of foreign material allows T cells to identify pathogens that have altered their antigenic profile, and thus were able to slip past antibody identification. In the process of regenerating themselves, pathogens lose peptide particles which are picked up by MHC molecules and put on a T cell surface for identification.
T cell receptors are constructed by putting together several peptides, plus a few amino acid sequences. This combination allows the immune system to generate an almost infinite variety of receptors, capable of recognizing almost any potential invader.
Interaction between T and MHC is crucial for adaptive immune defense and has a long heritage: the same T–MHC mechanism is 450 million years old, developed in the common ancestor to frogs, trout, sharks, and people.
Viral Infection
A viral infection begins with a jump into a cellular driver’s seat. To evade detection, that happens very quickly.
Virus try to minimize time in blood or lymph, where they are readily tagged. To do so they take 1 of 2 stratagems.
The 1st is to live awhile in a cell, replicating by hijacking cell machinery. When the virus has met its production quota, it causes the cell to burst open, releasing the next generation of hatchlings to find a new home. This is lysis.
The 2nd technique is for homebodies who take up residence inside a host cell, without killing it. They release offspring from the cell surface without damaging the cell: lysogeny.
Freshly secreted viruses make for a nearby cell to infect. T cells are specialists in detecting viruses hidden within.
Researchers once thought that the AIDS virus was slow on the draw because it took years, even a decade, before symptoms showed. Instead, the long latency is full of furtive activity. The virus is constantly cleared, but, absent a strong immune system or helpful drugs, viral production eventually overwhelms response.
Because T cells are specialized to act against cells bearing pathogens within, T only recognize an antigen derived from these microbes when it appears on the surface of a host cell. T surface receptors, which are similar but not identical to B antibodies, must recognize an antigen plus an alien MHC surface marker that tells the T cell that it is making contact with a foreigner.
Intracellular pathogens only survive inside invaded macrophages by being able to subvert the innate killing mechanisms of these cells. Disabled phages can fight back. An invaded microphage is savvy enough to steal an antigenic fragment from its invader and hoist it to the surface, raising the alarm.
Helper Ts assuredly recognize a virally infected macrophage via a double check. A helper T is first attracted to the ubiquitous class 1 MHC antigens that signal infestation.
The class 2 MHC molecules that phages have are designed to uptake foreign peptides shed by microbes nestled inside pockets within phagocytic cells (vesicles). While the class 2 MHC antigens attracts attention, an infected cell also signals via a surface molecule picked up by another protein on the helper T surface.
This 2-step validation mobilizes T response. Note the neat evolution that macrophages, themselves subject to viral infection, possess such a double-signal system.
Based upon this double check, a helper T produces various cell signaling proteins called cytokines. Cytokines bind to other cells that have matching receptors. That connection influences the behavior and activity of the contacted cell. Some cytokines help B cells make antibodies, while others rouse the hostage macrophage with activating factors that switch on the previously suppressed microbiocidal mechanisms within the phage, thereby killing the invader.
Once a killer T comes into intimate contact with a failing phage it confirms by MHC 1 identification, then delivers the kiss of apoptotic death.
Apoptosis is programmed cell death, commenced by chemical communiqué. A dying cell breaks into smaller pieces, called apobodies (apoptotic bodies), that surrounding cells engulf and digest, preventing what otherwise could be a toxic spill of cell contents.
Veteran lymphocytes become memory cells, thus allowing the body to remember past incursions, and so be better prepared for the next time. Active cell transformation to memory retention is a key mechanism of adaptive immunity.
Pathogen Alert
Becoming alert to a pathogen requires massing troops to eliminate a rapidly reproducing infection. Because a body can make a hundred million or more different antibodies, carrying inventory is infeasible. The only way to combat an infection is to reproduce the right antibody for lymphocytes quickly and massively.
This multiplication miracle is accomplished by clonal selection: lymphocytes that come into contact with an antigen are triggered to undergo successive waves of self-cloning. This is how the immune system solves the problem of allowing many different antibody-specific lymphocytes to cruise the body, yet effectively counter an invasion by massive response.
Infection counteraction usually takes several days to produce a large enough concentration of antibodies. At the same time, the bug is rapidly reproducing.
Let’s go back to the point that the body can remember a 100 million antibody patterns. The actionable implication is that a 2nd or subsequent attack by the same infectious agent produces a quicker response than initial exposure. That is why vaccines work. A 1st-time reaction may take several days to have an effect, but a subsequent adaptive reaction can happen in a very few days.
The immune system functions as a network of shared information, regulated by interactions between lymphocytes and their secreted molecules. The immune system is not only a breakneck munitions factory, it’s a voluminous library. This knowledge is acquired through the education of the lymphatic system during early development, reaching back to the fetal stage.
Self-Tolerance
A loss of tolerance in discriminating between cells of the self and nonself can lead to antibody synthesis against the body’s own cells or commensal microbes, resulting in autoimmune disease.
Circulating body components in a fetus that reach the lymphoid system are remembered as “self,” creating a permanent unresponsiveness to these protein patterns. This self-tolerance is not absolute. Autoimmune disorders may have many causes and conditions (multifactorial etiology).
Genetic predispositions facilitate onset of autoimmune diseases, but even good genes can succumb to neglect by a body’s occupant. Diabetes and arthritis are autoimmune diseases. A healthy body keeps potentially harmful anti-self lymphocytes in check.
Mitosis
A bone marrow transplant is done by injecting stem cells from a donor into the blood stream of a recipient. These injected stem cells mysteriously find their way to the marrow where they make their home.
Stem cells are unspecialized mother cells found in all multicellular organisms. Stem cells divide through mitosis, a complex and highly regulated process: splitting into 2 by making a copy of the many various parts of a eukaryotic cell, including the nucleus, cytoplasm, organelles, and membrane.
A daughter cell can differentiate from the mother cell, becoming more specialized, and thereby taking on roles which the mother cell never had. Differentiation can dramatically alter a cell’s size, shape, membrane potential, metabolic activity, and response to communications from other cells.
Energetically regulated, differentiation physically expresses via tightly controlled modifications in gene expression. Although there are exceptions, where genetic material itself is rearranged, typically the DNA sequence itself remains the same during differentiation. Genetic expression is an intricate process, where a reproduced daughter cell takes on different physical characteristics as well as different behaviors, despite ostensibly having the same genome.
By this inheritance process new cells can be born that take on a new template of existence. Cellular inheritance includes selectively passing on the memories from the previous generation of cell, mother to daughter.
Fetal Development
A developing fetus is a foreign body to its mother, but the mother’s immune system has an immunological tolerance to it. Conversely, the human fetal immune system, which develops at about 10 weeks, recognizes and tolerates non-inherited maternal material.
Blood is produced in waves during fetal development; each wave generating distinct populations of T cells that coexist for some duration, with tutoring so that the young T cells learn from their elders. The development of the human immune system is a tiered process.
Early in development, T cells come from the liver, and are biased toward immune tolerance. Later, hematopoiesis switches to fetal bone marrow. The ratio of T cells gradually moves from a higher population of regulatory T cells to a ratio of regulator/enforcer T cells found in adults.
There is hazard in the fetal immune system bias toward tolerance during its formative education. Exposure of a fetus to malaria in utero, though the placenta, results in an expansion in regulatory T cells that are malaria specific. That is why children infected from placental malaria are more susceptible to malaria later in life.
Vaccines
Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known. ~ Italian medical biologist Maria Vono et al
Vaccines put weak and dead viruses into the system, to be carted off and dissected. But there are only so many anti-bug bureaucrats.
More than 1 or 2 strains of a virus in a vaccine overloads the local lymph nodes that serve as police stations. This problem can be ameliorated by injecting different strains into different parts of the body, so different lymph nodes look at different suspects.
Any 1 of 4 strains of virus can cause dengue fever. Injecting the 4 strains in a single vaccine isn’t effective. One lymph node can only do so much at one time.
Instead injecting individual strains into different areas of the body eliminates local lymph node competition in figuring which strain to watch for, and is effective vaccination; though that too takes time: a few days for T cells from local nodes to circulate through the body, spreading the proverbial word.
Vaccines have limits. It has long been known that getting a flu shot one year can make you more susceptible the next year, as T cells are looking for last year’s model. But the rapid turnover in viral cells means rapid adaptation to changing conditions. As to pathogens, what doesn’t kill you makes you stronger.
The human immune system uses inflammation as a healing response: to focus forces to counter pathogens. But too much inflammation can be harmful. So immune cells signal to limit inflammation. To do so, they need a microbial assist.
Exposure to pathogens can strengthen child immune systems. When children are deprived of a healthy microbiome their immune systems get a poor education.
Untutored immune cells can unleash a tumult of inflammation. Instead of selectively killing off invaders, they damage their host.
The efficaciousness of vaccines rests upon their quality and administration protocol. There are many variables that determine whether a vaccine is worthwhile.
But there is one certainty. The pharmaceutical companies that manufacture vaccines are in the business of pushing their products. Profit only comes from volume sales.
Product quality is by no means assured. Testing can be cursory, or even manipulative, so to present positive results. Government oversight is scant. That makes the safety of vaccines something of a shot in the dark.
Fighting for Survival
Fighting an infection is a symphonic stimulation, requiring an orchestra of players: certain cells send signals that other receive, others mop up the chemicals used in sending signals; production of some cells accelerate, while others are deprived. Commensal microbes are in the thick of it: fighting those of their kind, albeit to save their own proverbial skin.
In the struggle to survive hostile microbes, adaptive immunity does not supersede innate immunity. By itself, acquired immunity affords little protection. The great advantage of adaptive immunity is that it coheres the immune response, driving innate immune mechanisms to efficacies that otherwise cannot be attained.
