Disclaimer: This substack entry contains informal musing about variety of scientific issues. It is a messy notebook by design. Hence by its very nature it is bound to include errors, inaccuracies, omissions and other blemishes. Please keep it in mind while reading.
Innate vs Adaptive Immunity.
How it is possible that the human body can miraculously distinguish the one set of the peculiar protein structures as a threat to be eliminated - from the gazillions of neutral and even useful proteins? And do it - at least in general and in most of the cases correctly. But not always, since the phenomenon of autoimmunity - when the body attack itself is well known in pathology.
Viral Spike protein of COVID VIRUS is naturally one small part of the virus which is an enemy of the human body. One of gazillions of such enemies. While we will discuss later why specifically this part of the COVID virus was chosen to be produced by the mRNA platform in vaccines - let’s talk first in general how the body is able in GENERAL to identify and destroy its perceived enemies (for better or worse…).
To answer this question we shall remind ourselves about the basic concepts of immunology. Specifically review the concepts of the INNATE IMMUNITY vs ADAPTIVE immunity.
The immune system of humans possesses both innate and adaptive components:
What is a difference between those two:
Innate immunity - as defined by the pioneering immune researchers Medzhitov and Janeway: is as a system of rapid immune responses that are present from birth and not adapted or permanently/temporally heightened as a result of exposure to micro-organisms (which is typical for adaptive immunity described below)
Adaptive immune system (or acquired immunity) develops and adapts as a result of exposure to the foreign elements such as spike protein. Like the innate system, the adaptive immune system includes both humoral immunity components and cell-mediated immunity components aimed at destroys of invading pathogens. Unlike the innate immune system, which is pre-programmed from birth to react to common broad categories of pathogen - the adaptive immune system is very specific to each particular pathogen the body has encountered. Hence, the adaptive immunity creates immunological memory after an initial response to a specific pathogen. That memory leads to an enhanced response to future encounters with that pathogen. Adaptive immunity both humoral (antibodies) and cellular (T and B lymphocytes) can provide long-lasting protection, sometimes for the person's entire lifetime. But not always. For example, someone who recovers from measles will be protected against measles for their lifetime - unless his immune system will be damaged. But in other cases it does not provide lifetime protection (eg with chickenpox or flu).
Concept of vaccination is based upon the process of the adaptive immunity.
But let’s review all of those defensive mechanisms to understand how the body deals with foreign elements such as spike protein.
INNATE IMMUNITY (humoral and cellular):
Humans live in an environment teeming with micro-organisms and could not exist as a species without highly effective mechanisms of host defense.
The innate immune system constitutes the first-line barrier, the rapid-response mechanism, to prevent microbial invasion. Its components are inherited from parent to child and directed against molecules expressed only by micro-organisms. These host defense components are evolutionarily ancient, found in all multicellular organisms, and expressed in humans as conserved elements (homologs) shared with other vertebrates and, in some form, even with insects and plants.
As discussed above, the innate immune system is basically the inherited, defense mechanisms that are directed against molecular components found only in micro-organisms.
This system have been refined by evolution over generations and can still be "trained" through epigenetic changes to express enhanced response to the original pathogen and also to other threats which appeared through the centuries.
In addition to providing a first line of defense against microbes, the innate immune system ALSO:
activates and instructs adaptive immune responses,
regulates inflammation, and
mediates immune homeostasis (the balance between opposing proinflammatory and anti-inflammatory processes).
The cells of the innate immune system use pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) on micro-organisms, and communicate through cytokines.
PRRs also recognize and direct removal of components of damaged tissue (damage-associated molecular patterns, DAMPs)
Activation of the innate immune system begins with resident cells in the tissues at the site of the insult (macrophages, epithelial cells, mast cells, innate lymphoid cells aka ILCs). If the threat of infection accelerates, these cells recruit other cells (neutrophils, natural killer [NK] cells, dendritic cells, monocytes, platelets) from the circulation into the inflamed tissues.
Many of the same cells and mechanisms used to recognize and attack microbes and initiate inflammatory reactions are also used to clear away damaged and dying cells and their cell components, then downregulate inflammation to maintain homeostasis within the host.
The innate immune system extends its capacity to react quickly to invading micro-organisms by communicating directly, cell-to-cell, with adaptive immune cells and releasing mediators that activate and instruct the adaptive immune system.
In these ways, innate immune mechanisms enhance and instruct antigen-specific T and B lymphocyte responses and the development of immunologic memory.
So there is a CROSS-TALK between innate and adaptive immunity.
The cells and circulating factors of the innate immune system represent a potent first line of defense, but they cannot function optimally without the specific antibodies and sensitized T cells that effect adaptive immunity.
So again: the adaptive immune system enhances innate immunity and vice-versa.
ADAPTIVE IMMUNITY HUMORAL:
The humoral immune response denotes immunologic responses that are mediated by the antibodies.
An antibody - is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses.
The antibody recognizes a unique molecule of the pathogen, called an antigen.
Each tip of the "Y" of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (analogous to a key) on an antigen: this allows these two structures to bind together with precision.
Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly. It can be done by blocking a part of a virus that is essential for its invasion - just as it is done in BLOCKING COVID VIRUS SPIKE PROTEIN which the virus uses to enter the cell.
Neonates rely heavily on maternal immunoglobulin G (IgG) passed through the placenta and on IgA transferred through colostrum and breast milk. After infancy, the child's immunoglobulins gradually increase as levels of maternal antibodies wane
Antibodies are produced when B cells encounter antigen and respond by undergoing activation, proliferation, and differentiation. B cell antigens may be categorized as thymic-independent (TI) and thymic-dependent (TD) antigens. TD B cell antigens require T cell help to generate antibodies.
B cells require multiple signals to become activated and begin differentiating into memory or plasma cells. If these activating signals are not received, the B cell may respond with anergy to that antigen.
Germinal centers (GCs) are the areas within secondary lymphoid tissues in which the humoral immune response to TD antigens is refined. Within GCs, B cells change their B cell receptors to maximize antigen affinity and class-switch to produce antibodies with a diverse array of effector functions.
Plasma cells and memory B cells formed within GCs provide long-lasting immunity and enable rapid recall immunologic responses upon subsequent antigen exposures.
Receptors binding the Fc region of specific immunoglobulin isotypes provide various effector, regulatory, and transport functions to innate and adaptive immune cells.
Natural antibodies are constitutively formed and play a protective role at early time points in infections, particularly infections with encapsulated organisms. But they also constitute the subsequent response to the reinfection with the same organism in the future.
ADAPTIVE IMMUNITY CELLULAR:
T cells are the effectors of antigen-specific cell-mediated immunity (CMI).
CMI is important in the elimination of cells infected with pathogens that replicate intracellularly (eg, viruses, mycobacteria, and some bacteria) and cells exhibiting aberrant differentiation (eg, neoplasms). CMI also destroys allogeneic cells (graft rejection).
In addition, it is involved in cellular autoimmune responses, as well as type IV allergic reactions to drugs and contact dermatitis.
T cell responses are initiated by antigen-presenting cells (APCs), primarily dendritic cells (DCs).
T cell activation is thought to occur via a two-signal model:
Signal 1 derives from contact of the T cell receptor (TCR)-CD3 complex with a major histocompatibility complex (MHC)-peptide complex.
Signal 2 derives from costimulatory pathways.
Helper T cells may be subdivided into: effector populations with distinct cytokine secretion profiles.
T cells are critical in the regulation of both humoral (antibody) and cellular effector mechanisms.
Antibody responses to the vast majority of protein and glycoprotein antigens require T cell help.
Regulatory T cells (Tregs) also control specific cellular cytotoxicity. T cell regulation is mediated by cellular contacts and soluble factors.
Most cytotoxic T lymphocytes (CTLs) express the alpha-beta TCR heterodimer with the CD8 molecule and recognize peptide antigens in association with MHC class I. These cells kill target cells by two principal mechanisms:
exocytosis of cytolytic granules containing perforin, granzymes, and other cytotoxic molecules and
the interaction of Fas ligand (FasL) on CTLs with Fas expressed on target cells.
T cell regulation is mediated by cellular contacts and soluble factors. The cellular immune response can be amplified through positive feedback loops or dampened through negative regulation.
Most gamma-delta T cells do not express either CD4 or CD8. However, they can be divided into functional subsets similar to helper, cytotoxic, and regulatory T cells that express the alpha-beta receptor. The ligands for gamma-delta TCRs in most cases are not peptide MHC complexes but rather pathogen-associated molecules that interact by different mechanisms with MHC-like molecules.
IN SUMMARY:
So that is how the body can be so “smart” to distinguish and destroy the peculiar compound such as COVID virus spike protein, while do not bother other compounds which it deems safe: by the intricateinterplay of the innate and adaptive immunity mechanisms.
Next, we will discuss why the Spike Protein was chosen as the key component of mRNA vaccines.
To be continued.