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Source: Antibodies  Oct 15, 2020  3 years, 1 month, 2 weeks, 5 days, 23 hours, 50 minutes ago

A Guide To Understanding Antibodies And ADE (Antibody-Dependent Enhancement)

A Guide To Understanding Antibodies And ADE (Antibody-Dependent Enhancement)
Source: Antibodies  Oct 15, 2020  3 years, 1 month, 2 weeks, 5 days, 23 hours, 50 minutes ago
Antibodies, Antibody test and ADE are a few words that has been in many news articles in the last few months as a result of the ongoing COVID-19 pandemic but many people still do not really have a proper perspective about what they are properly, hence we created this guide with the hope that it might help some of our readers. The summarized guide is not in detailed but just enough for individuals to get a proper perspective.

Our human body has a very specialized immune system that is consist of two parts the innate, (general) immune system and the adaptive (specialized) immune system.
Antibodies are part of the adaptive immune system ie the arm of the immune system that learns to recognize and eliminate specific pathogens and they are like part of the our bodies’ specialized search-and-destroy army.
When a pathogen like a virus enters the body through whichever means, antibodies are key players in that fight against the pathogen.
Antibodies are released from the cells and they go out and hunt when a pathogen is in the body. Antibodies are specialized, Y-shaped proteins that bind like a lock-and-key to the body's foreign invaders whether they are viruses, bacteria, fungi or parasites. They are the ‘special forces reconnaissance and tag’ troops of the immune system's search-and-destroy system, tasked with finding an enemy and marking it for destruction.
Upon finding their targets, antibodies bind to it, which then triggers a cascade of actions including macrophages destroying it through phagocytic actions, hence vanquishing the invader.
The two arms at the top of the antibody's Y shape bind to what's known as the antigen. The antigen can be a molecule, or a molecular fragment often some part of a virus or bacteria. (For instance, the new coronavirus SARS-CoV-2 has unique "spikes" on its outer coat, and some antibodies bind to and recognize these spike proteins others recognize the N proteins of the coronavirus while other yet recognizes only the RDB proteins.)
The bottom of the Y, or the stalk, binds to several other immune-system compounds that can help kill the antigen or mobilize the immune system in other ways. One set of these, for instance, triggers the complement cascade.
"Complements are actually the executioner," that punches holes in the target cell, such as the membrane of a virus.
Antibodies, which are also called immunoglobulins (Ig), all have the same basic Y-shape, but there are five variations on this theme called IgG, IgM, IgA, IgD and IgE.
Each variation looks slightly different and plays slightly different roles in the immune system. For instance, immunoglobulin G, or IgG, is just one Y, whereas IgM looks a bit like the 10-armed Hindu goddess Durga, with five Ys stacked together, and each prong can bind one antigen.
IgG and IgM are the antibodies that circulate in the bloodstream and go into solid organs.
IgA is "squirted out of the body," in mucus or secretions. IgE is the antibody that typically triggers allergic responses, such as to pollen or peanuts.   IgD has historically been enigmatic, but one of its roles is to help activate the cells that make antibodies.
In order to understand antibodies, you first need to know about B-cells, which are a type of white blood cell that forms in the bone marrow.
There are about a trillion B-cells in the body, and each one has a unique IgM antibody that sits on the B-cell surface and each binds, to one antigen.
This staggering level of variation allows the body to recognize almost any substance that could enter. Here’s how it achieves that diversity: In each B-cell, the genes that code for the antibody's binding site are shuffled like playing cards in a deck.
"The amount of rearrangement that can occur is enormous.”
These B-cells then patrol the body, often lingering longer in areas like the lymph nodes or the tonsils. Most of the time, these B-cells don't bind anything. But if, by a one- in-a-million chance, a B-cell does bind some foreign substance, "that triggers the B-cell to say 'Hey we need to get activated.”
The B-cell grows in size and starts to divide in what's called "clonal expansion.”
It's an identical copy of the parent, just like the mother. After a week or so, there may be hundreds of thousands to a million of these copies.
Eventually, these clonally expanded B-cells differentiate into plasma cells, which are ‘antibody factories.’
"They secrete 10,000 antibodies per cell per second. They can do that for weeks or years if one is lucky"
However not all B-cells divide the same amount.
"If you consider the B-cell to be a lock, and you consider all of these different things to be floating around to be different keys, then some of the keys will fit better, some will fit worse, and some won't fit at all. And depending on how well the key fits into the lock on the surface of a particular B-cell, that cell will be triggered to divide more. Then, the more prolific B-cells produce more plasma cells and churn out more of a specific type of antibody.
The human body does not just produce one type of antibody either; it produces a messy, chaotic mass of them. Each locks onto different parts of an invader. 
Furthermore not all antibodies do the same thing once they've bound to a target. Some will nip infection in the bud by directly neutralizing a threat, preventing a pathogen from entering a cell. Others tag invaders, so that the immune system's killer cells (which aren’t antibodies) can remove it.
Still others may wrap viruses or bacteria in a gooey coating. And other antibodies might tell Pac-Man-like immune cells called macrophages to come gobble up the invader.
This strategy can sometimes backfire with viruses, which may co-opt this response to invade new cells.(will elaborate on this in a continuing article)
The first type of antibody to form after you are exposed to a virus is typically the IgM, which emerges within 7 to 10 days after exposure.
IgM can bind to an invader, but each "Y" in this 10-armed protein does so fairly weakly. But, just as five weak people working together can tackle a large, strong adversary, IgM's five Y's (10 arms) working together can bind tightly to an antigen.
At about 10 to 14 days, the body begins making IgG, which is the immune system's "major workhorse.” IgG can cross the placenta in a pregnant woman, giving a newborn passive protection against disease until their own immune system can ramp up.
In most circumstance, the immune system is stunningly good at recognizing the enemy and ignoring, or tolerating, our own cells.
However sometimes, this process goes awry. That’s when T-cells (another type of white blood cells) come in. The body uses these T-cells to cross-check targets only if both a B-cell and a T-cell recognize something as a foreign invader will an immune response be triggered.
The body is supposed to remove B-cells that make so-called auto-antibodies, which react to the body's own cells. But when that doesn't happen, the body may mark its own cells for destruction and then relentlessly eliminate them. Autoimmune diseases such as lupus, rheumatoid arthritis, or type 1 diabetes can result.
There are more than 100 autoimmune disorders, according to the American Autoimmune Related Diseases Association.
Monoclonal Antibodies
Antibodies have become the basis for some of the most useful medicines, as well as some of the most powerful lab techniques in biology. One of these clinical and therapeutic superstars is what's known as a monoclonal antibody. 
In order to create a monoclonal antibody, researchers vaccinate an animal or possibly a human to stimulate the production of antibodies against a particular substance. The body will gradually make antibodies that are more and more effective against that antigen.
These antibody-producing cells are then filtered out of white blood cells and put into a dish to see which cells bind the antigen best. The cell that binds the best is then isolated and is then used as an antibody-producing factory, specifically honed to churn out one super-selective antibody.
That cell is fused to a blood cancer cell, producing something called a hybridoma. This hybridoma, or monoclone, is an inexhaustible generator of exactly the same antibody, over and over and over.
(Scientist binds the monoclonal cell to a cancer cell because cancer just continues to reproduce.)
It just produces and produces and produces, and it will never stop, and it's a cancer, so it's essentially immortal. This is what produces is a monoclonal antibody.
Such cell lines have an incredibly diverse range of uses. There are millions of commercial monoclonal antibodies, which are used in labs to tag the tiniest, most specific cellular targets for study.
"They're amazingly precise tools."
Monoclonal antibodies also form the basis for many blockbuster drugs. For instance, the drug adalimumab (brand name Humira), is a monoclonal antibody that treats rheumatoid arthritis by inhibiting an inflammatory protein known as a cytokine. Another, called bevacizumab (Avastin), targets a molecule that fuels blood vessel growth; by blocking this molecule, bevacizumab can slow the growth of lung, colon, kidney and some brain cancers.
In the current SARS-CoV-2 pandemic, researchers and doctors around the world are racing to create monoclonal antibodies that will hopefully neutralize the new coronavirus. These antibodies are filtered from the plasma of people who have recovered from COVID-19 (also called convalescent serum).
The hope is that by isolating the most effective antibodies, and then producing them en-masse, researchers and doctors can create a treatment that provides a temporary, "passive" immunity until the body can catch up and mount an effective, more long-lasting response on its own.
Polyclonal antibodies
By contrast, polyclonal antibodies are derived from multiple B-cells. Polyclonal antibodies are a library of antibodies that all bind to slightly different parts of the antigen, or target. Polyclonal antibodies are typically produced by injecting an animal with the antigen, stimulating an immune response, and then extracting the animals' plasma to produce antibodies en masse.
However unlike monoclonal antibodies, which can take up to 6 months to produce, polyclonal antibodies can be made in 4 to 8 weeks, and require less technical expertise.
Interestingly, for certain types of tests where one is trying to detect the antigen, polyclonal antibodies might have a better chance of binding to the target antigen, making them potentially more sensitive. The downside of polyclonal antibodies is that, because each individual animal might produce a different array of antibodies, making polyclonal antibodies that are consistent from batch to batch can be more challenging, and it isn't as easy to have a large.
Antibody Cocktails
Antibody cocktails are two or more cocktails either produced separately and then combined or produced by polyclonal techniques and then filtered to other unwanted antibodies.
Antibody tests
So called rapid antibody tests detect whether the body has produced detectable quantities of antibodies to a certain molecule, and can therefore reveal whether someone has been infected by a specific virus or bacteria in the past. Usually, these tests are detecting IgM or IgG.
For instance, SARS-CoV-2 antibody tests typically detect either part or all of the coronavirus' spike protein and can reveal whether someone has had COVID-19 in the past. Because the body takes time to ramp up its production of antibodies, people usually only test positive about two weeks after they were first exposed to the pathogen.
Read this previous article about how certain current rapid antibody tests are not accurate:
There are two common types of antibody tests lateral flow assays and enzyme-linked immunosorbent assay (ELISA) tests. Both involve fixing an antigen to a surface and then detecting whether an antibody binds to that antigen. Usually, a chemical reaction, such as fluorescence or a color-change, is triggered when the antibody binds to the antigen. Lateral flow assays are similar to pee-on-a-stick pregnancy tests; rather than pee, for antibody tests, blood or serum is washed over the flat surface, which is usually paper. ELISA tests work on a similar principle, only the tests are conducted in microplates and require a lab technician, and the results may not read out instantly.
A good antibody test is one that produces few false positives and few false negatives. To ensure that happens, scientists need to "calibrate" their test, for instance, by making sure that samples known to not have the antigen do not falsely produce a positive test. For instance, with SARs-CoV-2, that would mean testing blood samples from before the pandemic started and making sure no samples come up positive. They also need to take samples that definitely have the antibody in them, and make sure the antibody test does a good job of detecting those positives. 
ADE or Antibody-Dependent Enhancement 
Antibody-dependent enhancement (ADE) is a situation in which the antibodies instead of immediately destroying the invading virus helps it to get into immune cells and allow it to continue to replicate while destroying the immune cells and also triggering a cytokine cascade. Understanding the dynamics and kinetics of the process is important.
Now not all antibodies have a neutralizing effect on a virus ie that bind and lead to the fast destruction of the virus and prevent it from replication.
In a normal situation of neutralization of a virus by the right antibody, the antibody binds to the virus and then a macrophage comes along and destroys the binded complex immediately.
In ADE attention has to be paid to the dynamic process that involves the kinetics of both viral replication and antibody production.
Though the body can produce millions of antibodies, the virus is able to replicate at much faster speeds that you need to ensure that when the virus first enters the host the correct neutralizing antibodies attacks the corresponding virus immediately and prevents it from replicating.
In the case of ADE, what happens are that there are antibodies that can bind but do not neutralize the virus immediately. The resultant binded complex is attracted to certain immune cells that have a protein receptor on them called Fc receptor. Such immune cells includes B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelet and mast cells.
The Fc receptor then helps the binded complex (ie the virus and the non-neutralizing antibody) to get into these immune cells where the virus continues to replicate while killing the immune cells.
Now in this dynamic scenario what is happening is that the presence of these non-neutralizing antibodies are disrupting the actual neutralizing antibodies from their doing their job while the viral load is fast increasing. The virus ‘dedicates’ a proportion of its population be killed by the neutralizing antibodies and another to the non-binding antibodies that are still helping it to continue replicating and then there is the group that that is not affected by the antibodies but are entering cells and replicating.
As a result there comes a time when the viral loads are hundreds of thousands fold more than the amount of actual circulating neutralizing antibodies and this is where the host has lost the game and typically severe conditions sets in as the high viral load coupled with so many immune cells being destroyed sets a cytokine cascade.
This just a simple explanation of ADE. In actually reality there are far more complicated different subsets of scenarios depending of viruses and the strains and also the other effects of the virus on other aspects of the immune system.
For more on Antibodies, keep on logging to Thailand Medical News.


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