A Conceptual View of Immunology

Major rework in progress, June/August/September 2021

• Summary
• Introduction
  • Defining the Immune System
  • Immune System Goals
• Classifying the Immune System into Branches
  • The Immune System from different View Points
  • Traditional Classification: Acquired and Innate Immunity
• Mechanisms of the Immune System
  • Physical Mechanisms
  • Chemical Mechanisms
  • Biological Mechanisms
• Immune System Specificity
  • Specificity by Locations
  • Specificity by Feature Recognition
  • Cross Immune Protections
• Immune System Surveillance Methods
  • Entry Controls
  • Inspect the Transport Systems
  • Supervise the Production
• Immune System in Action: From Surveillance to Alarms to Learning to an Effector Response
  • Surveillance State
  • Alarm State
  • Learning State
  • Effector Response State
  • Immune Responses
• Variability of the Immune System
  • Factors Influencing Variability
  • Target Variability
• Immune System Members
  • Intra Cellular Immunity
  • Immune Cells
• References
  • Interspecies Transmission, Adaption & Evolution
  • Adaption of the Innate Immune System
  • References Books

Summary

Selected topics of the immune system with a focus on the principles. The immune system is viewed as the part of the homeostasis system which handles life form interactions at the molecular level.

The focus is conceptual view to understand to immune interaction with coronaviruses.

Introduction

Defining the Immune System

Defining the immune system is not straight forward. One approach is to define the immune system as the mechanisms which prevent a disease. However the immune system is involved in a disease and thus such a definition is circular (at least to some extent).

Here the immune system is defined general as mechanisms which handle life form interactions.

Immune System

The immune system denotes mechanisms which watch and regulate competitive life forms interactions at the cellular level or below. The goal is to prevent damage and this is achieved by watching interactions within or between life forms. If necessary the immune system redirects/adapts/reduces the interactions such that the interactions are not adverse or even advantageous.

Alternative Definitions of the Immune System

• Earlier the immune system was defined as “targeting things recognized to be unwanted”. To goal was to generalize the often given definition: The immune system fights pathogens or even more specific producing antibodies against pathogens.
• Sometimes in literature, the immune system was (and is) antibody centered. The reason is, the vertebrate respond to infections often involves antibodies which can easily be measured.

The Immune System in Context

• The immune system can be viewed as part of the homeostasis. The immune system handles life form interactions.
• Nearly all forms of life have some immune mechanisms. Even viruses encode proteins to reduce the hosts from interfering with their metabolism. It’s an interplay: The host immune system tries to reduce the virus metabolism and the virus immune system in turn tries the reduce the host immune system.

Specifying Life Forms Interactions

Competitive life form interactions are of the following forms:

• The interactions are competitively and if out of balance with fitness costs.
• Only regulations at the molecular or cellular level are considered to be part of the immune system. Trained neural network interaction are usually considered as not part of the immune system.
  • Molecular Interaction: Worms infecting mammals are targeted by antibodies. So, even though both are multicellular organisms, the response involves a ‘classical’ and molecular immune response.
  • Non molecular Interaction: ‘Classical’ predator-prey are competitive interactions but at the macro level. Such interaction are not considered as part of the immune system. Molecular level predator are considered immune related, e.g. cells phagocyting bacteria or viruses. Also venoms are often handled by organs of the immune system.

  As often discrete classifications in biology are approximations.

In organisms (i.e. lifeforms being composed of multiple smaller units of life) the immune system includes the interactions within a life form. The transition from ‘classical’ homeostasis to immune mechanisms is fluent. Examples:

• Cancer cells within an organism can be viewed as selfish cells that don’t respect the ‘rules of an organism’, therefore the immune system targets them. Cancer cells can be viewed as a life form within a host: They replicate without being integrated in the cellular communication of the host.
• If an organism is physically damaged, the immune system handles the displaced cells and initiates repair mechanisms.

Mindset of the Immune System

The immune system gives ‘immunity’ to damage from interactions but usually does not prevent interactions. E.g. regarding pathogen infections the immune system reduce the pathogens just enough they don’t do damage but no more or are even beneficial. There are some rare pathogens which nearly always do damage, but the vast majority of live forms interactions are only harmful in specific situations and often life forms find ways to work together for mutual benefit.

The immune system is pragmatic and efficiency focused:

• the immune system usually is minimalist and does just as much to prevent harm but no more.
• the immune system can redirect interactions to mutual benefits.

Else life forms on todays earth would be busy fighting and couldn’t spend time on cooperating and creating.

Nearly all life forms on todays earth create and cooperate in a variety of forms, which indicates an evolutionary advantage of these behaviors.

Interactions are often beneficial to learn and evolve.

Immune System Goals

Homeostasis provides optimal conditions for in the different compartments of a life form. The immune system viewed as part of the overall homeostasis system has the task to prevent damage resulting from interactions with life forms.

• Some compartments of a life form are more susceptible than others, the immune protects these compartments especially well.
• Keep all parts working is important too since these all parts of a life form have their functions.

In organisms are grouped into different compartments and they have different cell populations. The cell populations vary in function and susceptibility to homeostasis changes including infections. In the case of vertebrates, the most susceptible cell populations are within the bones: stem cells and neurons. The immune system protects these cell populations with a high priority.

Life is all about homeostasis. Provide a good and suitable environment to live and replicate regardless whatever the environment is. Homeostasis is a constant and ubiquitous task, also in day to day life: If there’s not enough water in the blood we get thirsty, if it’s too hot we sweat and if it’s too cold some specialized cells warm the body.

Classifying the Immune System into Branches

The Immune System from different View Points

Immune mechanism can be viewed from different perspectives and accordingly be classified:

• Immune System Mechanisms: Physical, chemical and biological mechanism are used.
• Immune System Specificity: Is the targeting broad or narrow? Which substances are recognized and targeted. Substances that are ignored.
• Variability of the Immune System. How and which capabilities of the immune system adapt. Sometimes only the strength of a response is changed, sometimes the mode of response and sometimes the target capabilities. Changing the target capabilities throughout lifetime is known as acquired immunity
• Protection Locations: Local or systemic (global). At frequent foreign substances entry points many local protection mechanism are in place.

Traditional Classification: Acquired and Innate Immunity

Historically the immune system was divided into two arms, the first arm being antibody related and the second arm all other cellular responses. The antibody related arm turned out to be very specific and lifetime acquired. Lifetime acquired was termed adaptive, acquired or learned. So the traditional classifications is as follows:

• Specific Immunity = Acquired Immunity = Adaptive Immunity in the sense only one species is targeted = Acquired Immunity/Adaptive Immunity: Very specific and lifetime acquired: Antibody: Humoral = systemic
• Unspecific Immunity in the sense multiple species are targeted = Innate Immunity: Anything except Antibodies/ T Cells

Mechanisms of the Immune System

At a broad level, the immune system can be view to use physical, chemical or biological mechanisms. However the classification as often falls short: e.g. fever = rising the temperature is a physical mechanisms though it effects chemical and biological reactions and fever is accompanied by chemical and biological mechanisms.

Some notes on the relations between Physics, Chemistry and Biology are in Biology, Chemistry and Physics.

Physical Mechanisms

Physical mechanisms are mainly used as entry control.

• protecting layers: dead cells on the epithelium (e.g. skin)(The outer layer of the body = the surface of the body = anything that can be reached while the body) is not injured - is called epithelial layer and the cells epithelial cells i.e. the cells on the surface. This layer has often various protections e.g. dead cells (which is the case for the skin)
• Mucus clearance:
  • middle and upper respiratory tract
  • many parts of the alimentary tract

Chemical Mechanisms

Chemical mechanisms are often used to disinfect fluids e.g. the stomach content or the content of vacuoles within cells.

Examples of chemical mechanisms in use are:

• change of pH e.g. acidic fluids (e.g. stomach acid) or alkaline environment (e.g. small intestine)
• degradation of substances by hydrogen peroxide

Biological Mechanisms

Unlike chemical and physical mechanisms, biological mechanism can specifically recognize substances and thereby distinguish different life forms and even self and non self. Often the recognizing part is carried out by biological mechanisms which allow specific target recognition and the elimination part is then chemical or physical.

Immune System Specificity

To some extent all parts of the immune system are specific:

• wanted things: Healthy self cells in healthy tissues shouldn’t be attacked by the immune system since this would disrupt the homeostasis.
• possible dangers: things learned or associated to disruption of the homeostasis e.g. pathogens doing damage.

To specify the targets the location, feature recognition and mostly a combination of location and features are used:

• Specificity by Locations
  • Most life forms have an outer shell (e.g. skin, fur, chitin) to mechanically shield large of their bodies.
  • Most life forms have different shells. Examples
    • In vertebrate the bone marrow and the brain are shielded by bones.
    • In eukaryotes the DNA is within a nucleus inside the cells.
  • The sites of frequent interaction with outside are especially well supervised by the immune system.
    • Stomach acid in the stomach.
    • Mucus layer, particle filtering and strong immune cells in the respiratory tract.
• Specificity by Feature Recognition
  • Antibodies target very specific molecule structures
  • RNAi silences RNAs with a specific sequence
• Specificity by Feature Recognition and Location.
  • Filter by Size: The respiratory tract has evolved to block most particles except small molecules (02, CO2, H2O) from reaching/leaving the lungs.
  • Sites where the immune surveillance sounds an alarm (e.g. pathogen entry is detected) are put into an alert state by inflammation. At these sites the immune system acts much more aggressive.

Specificity by Locations

Immune responses can be global (affecting the entire body), local for some tissue or even inside single cells:

• entire body (e.g. fever, circulating antibodies or the skin)
• tissue specific (e.g. local inflammation, Tissue resident cells e.g. T cells)
• cell intern (intra cellular processes). The oldest form of protection that developed already in prokaryotes.

Specificity by Feature Recognition

The range of specificity is huge and not discrete, so the following categories are just a coarse approximation.

No or very Broad Recognition

Mechanisms relying mostly and the location often lack a fine grained feature recognition. Examples:

• skin: keep everything out
• some immune cells such as neutrophil granulocytes can induce a local shutdown of all living things
• stomach acid

Semi Specific Recognition

Examples

• Receptors from double stranded DNA based lifeforms targeting single stranded DNA
• Semipermeable-Membranes (e.g. Cell membranes, nucleus membrane, blood brain barrier): only permeable for specific substances

Specific Recognition

These mechanism target usually exactly one molecular structure. The recognition is so specific that often only a single species or even individual of a species is targeted.

Examples:

• RNA pieces silencing other RNAs [to check whether this can’t be adapted, probably unused DNA is used produce some silence RNA so the overall possibilities would be constant but what is in used would be adaptable]
• Antibodies target specific biological substances (mostly proteins). Antibodies are an example of theLifetime Acquired Immune System.

Cross Immune Protections

All form of life on earth share common molecular patterns. The more genetically related the forms, the more genes and corresponding proteins are similar. Some elements are more conserved and are possible targets to develop cross protections either by the immune system or artificial medications.

Cross Immune Protection by the Specific Immunity

• Van der Hoek et al. observed that some serum conversions against one coronaviruses are not followed by serum conversion against another coronavirus as follows:
  • OC43 -protects-> HKU1 (only unidirectional, both OC43 and HKU1 are betacoronaviruses)
  • NL63 -protects-> 229E (only unidirectional)
• Han et al showed that calves innoculated with HECV-4408 get immune protection against the BCoV strain DB2. HECV-4408 is a BCoV strain that has been observed to cause diarrhea in humans.

Feature Recognition Mechanisms

Detecting Protein Structures

Antibody

Antibodies are molecules produced by the immune system (by plasma cells = activated B cells) which bind to specific substances are called antibodies.

Mostly antibody target foreign things e.g. worms. Likely this inspired the name anti-(foreign)-bodies.

Antigen

Particles for which the immune system can produce antibodies are called antigens.

Most antigens are foreign substances. Antigens first were observed against such foreign substances, this may have inspired the name: Not belonging to the gene pool of the life form.

Immune System Surveillance Methods

in work and incomplete

Entry Controls

Against many pathogens a physical barrier is the first and most effective line of defence. Where possible this defense mechanism is in place. However where a an exchange of chemical and biological substance is needed no complete physical barrier is possible but other obstacles are in place:

• alveoli in the lung: exchange of oxygen => the respiratory tract evolved such that most particles don’t reach the alveoli, described in Particle Dynamics in the Respiratory Tract.
• Intestine in the alimentary => To take up nutrients the intestine needs to be permeable to chemical and biological substance and the substance also need to reach it. To reduce the amount of pathogens reaching the intestine, the acidic stomach is in front of the alkaline intestine.

Inspect the Transport Systems

Both the blood and the lymph are inspected.

• The blood has an army of circulating immune cells and humoral substances (e.g. antibodies).
• In the lymph nodes the body wast is inspected. If there are signs of damage the causal agents are identified and termed as dangerous.

Supervise the Production

The immune system tightly supervises the production of substances especially enzymes. Enzymes are mostly either proteins, a combinations of proteins and RNA and sometimes RNA only. Since nearly all enzymes are produced within cells, the intracellular controls are crucial.

Immune System in Action: From Surveillance to Alarms to Learning to an Effector Response

in work 5.8.

Surveillance State

Any of the surveillance methods can ring the bells or directly initiate an effector immune response.

Alarm State

Learning State

Effector Response State

Immune Responses

The surveillance part can ring the bells once if strange or dangerous things happen.

Variability of the Immune System

The entire immune system varies both during lifetime and from generation to generation:

1. the way and strength of protection provided at each location in the body.
2. the mechanisms targets are handled
3. the targets recognized and handled.

(1.) and (2.) don’t involve a change of the targets throughout the lifetime. The part of the immune system which vary only through 1. and 2. are called innate immunity, since the target capabilities are present upon birth. The parts of the immunity which can acquire new target capabilities upon encounter with new things are called acquired immunity i.e. the target capabilities are acquired throughout lifetime and not present upon birth.

Factors Influencing Variability

The immune adaption depends both on the personal history of exposure to pathogens and the one, ones the ancestors have been exposed to (genetic adaption)

• Lifetime adaption: personal history of exposure to antigens experienced to be harmful. One hand hand more immune cells may relocate or replicate increased in locations where pathogens haven been observed. On the other hand the specific parts of immune systems have mechanism of memorizing seen pathogens (Variable Immune System). How the immune system develops during lifetime is discussed in the chapter Immunity throughout Lifetime.
• Generational adaption: personal and ancestral exposures are memorized and cause both the innate and acquired immune system to adapt

Target Variability

Innate Immune System

Innate Immunity

The innate immunity are mechanisms that target the same recognition patterns throughout lifetime.

Since targets stay constant throughout lifetime, the information is usually stored in lifetime storage) and is inherited.

Acquired Immune System

The life spans of life forms and the evolutionary rate of life forms vary. Life forms evolving slow at the molecular level need to handle interactions with life forms evolving much faster at the molecular level e.g. viruses infecting vertebrates evolve magnitudes of orders faster than their vertebrate hosts. To keep up with fast evolving pathogens, the ‘slow evolving’ hosts life forms have mechanisms to learn new molecular patterns during lifetime.

Acquired Immunity

Mechanisms of the immune system which are able to acquire new skills upon encounters with pathogenic life forms or substances. This acquiring of of new skills is done during the lifetime.

Acquiring of Specific Target Capabilities

• B cells (called plasma cells = activated B cells) can produce antibodies. Antibodies bind to specific substances (called antigens) and thereby inactivate or mark them.
• T cells (T cell Training) can inspect substances including proteins .
  • CD8 T cells inspect the proteins cells produces: Fragments of the proteins translated inside a cell are presented via the surface receptor MHC 1 which is inspected by CD8 T cells.

Allergy

Sometimes proteins parts not associated to pathogens are classified as being harmful. This yields allergies.

Mechanisms to Acquire Different Target Capabilities

One mechanisms to acquire specific targeting is to produce different cells able to bind to different substances. This is done by rearrangements of the DNA which encodes the binding parts. Now the immune system needs to check that:

1. Be Nice: these randomized binding sites don’t bind to something useful e.g. healthy cells belonging from the same organism (self).
2. Be Useful: these randomized binding sites are useful i.e. they bind to something harmful.

Checking these conditions is called training (described for T cells in T Cell Training).

Immune System Members

Intra Cellular Immunity

The intracellular immunity is cell type dependent and varies much, even within an organism. Most cells a surveillance system of different receptors supervise in a default allow scheme and the cell intern RNA is strictly monitored often by a default deny scheme i.e. only RNA which looks good is translated to proteins.

Self Checks of Cells

[in work] Self checks of the cells:

• RNA sequence inspection and possibly silencing
• Detect foreign RNA e.g. double stranded
• Detect stress e.g. Ribosome permanently producing.

Upon detection of anomalies, the cells can go into an alert state, ring the bells or even induce apoptosis.

Extern Checks of Cells

Cells present what they produce on the outside (via MHC 1 proteins): Immune cells (e.g. T cells) inspect these substances and can induce cell death and/or ring the bells.

Immune Cells

Immune cells are cells which have a direct immune function.

In work and incomplete and inaccurate.

B Cells

B cells can produce antibodies.

T Cells

• T cells are in the blood and locally in tissues.
• T cells can check if cells do what they are supposed to do. Virus infected cells have a changed metabolism since they produce proteins encoded by the viruses. T cells can detect the virus proteins exposed.
• To control coronaviruses infections CD8 T cells are key [citation coming].
• T cells can prime B cells.

Locality of T Cells

T cells are in the blood, in lymph nodes and resident T cells in tissues. Lymph nodes and the mucosal sites are the places where pathogens arrival is most likely e.g. the mouth is a common entry point for viruses, so close to the mouth there are many T cells [in work].

Tissue Resident T Cell

Local T cell

Tissue resident T cells in literature, often shortened to local T cells on this page, are T cells which survey the tissues integrity. They reside and sometimes move within tissues but do not circulate with the blood.

T Cell Training

[in work, to be completed and to be checked]

1. Bone Marrow: In the bone marrow new immune cells are produced. Some of the immune cells differentiate into T cells and move to the thymus. [to check and clarify].
2. Thymus: The genes encoding the T cell receptor (TCR) undergo somatic recombination => the TCRs differ from T cell to T cell. In the thymus it is checked if the cells have the right binding capabilities: The TCR should bind the MHC 1 receptors neither to weak nor to strong. Don’t attack self substances.
   • Fail (wrong MHC binding strength or self substances attacked) => trigger cell death (if goes wrong, an autoimmune disease can result)
   • Succeed (right MHC binding strength If the cell does not bind self) => send the cell to the lymph nodes.
3. Lymph Nodes: In the lymph nodes T cells are presented antigens by antigen presenting cells (APCs). If a T cells recognizes an antigen which is classified as dangerous, the T cell transforms from the naive to a mature state [to check and cite].

References

[in work]

Interspecies Transmission, Adaption & Evolution

vanderhoek2012

Dijkman, R., Jebbink, M. F., Gaunt, E., Rossen, J. W., Templeton, K. E., Kuijpers, T. W., & van der Hoek, L. (2012). The dominance of human coronavirus OC43 and NL63 infections in infants. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology, 53(2), 135–139. https://doi.org/10.1016/j.jcv.2011.11.011

Adaption of the Innate Immune System

Netea

Netea MG, Joosten LAB. Trained Immunity and Local Innate Immune Memory in the Lung. Cell. 2018;175(6):1463–1465. https://doi.org/10.1016/j.cell.2018.11.007

References Books

[in work]

Lydyard

Immunology, Third Edition Peter Lydyard, Alex Whelan, Michael Fanger