IMMUNOLOGY 101: THE IMMUNE SYSTEM (REPOST/UPDATE)
05 May 2021/Wednesday/930pm CST
"I find it astonishing that the immune system embodies a degree of complexity which suggests some more or less superficial though striking analogies with human language, and that this cognitive system has evolved and functions without assistance of the brain."
-Niels K. Jerne, 1984, Danish immunologist and 1984 Nobel Laureate in Medicine for his theories on development and control of the immune system and the principles for the production of monoclonal antibodies
High resolution version of today's graphic:
https://drive.google.com/file/d/1DlfcouQkiNMegezxfx6Z8zygg4_us3dx/view?usp=drivesdk
BACKGROUND
I had posted the above graphic on 21 December but in light of the vaccination campaign and some narratives I am seeing out there on using antibody testing to "document" immunity, I thought it worth reposting this again along with some updated text.
The human immune system is probably one of the most remarkable organ systems it the body for it acts near-autonomously , independent of any sort of external controls by any other human organ system. In today's discussion, a basic review of how our immune system works is an essential pre-requisite to understanding how the vaccines work and some of the treatments that are in use in this pandemic.
I put together this graphic to illustrate the key concepts of how the human immune system works. There are quite obviously further elements missing which aren't needed in today's discussion- what I've done here is take everything down to it's basic operating principles.
While my graphic shows two primary arms of immunity, humoral immunity and cell-mediated immunity, there is also a third arm beyond today's discussion called innate immunity. What I have shown here today is what we call "adaptive immunity". Humoral immunity and cell-mediated immunity are the two arms of adaptive immunity. For today's post, we'll just be focusing on the two main arms of this adaptive immunity.
ANTIGEN PRESENTING CELLS (MACROPHAGES)
Antigens are any bits of anything that stimulates an immune response. Usually these are protein structures or bits of protein structures of any infectious invader like a bacteria or a virus.
Antigen presenting cells are broad set of specialized cell types that act as sentinels in the human body, on the look out for possible invaders which they engulf and take bits of antigen to activate the two arms of adaptive immunity.
Macrophages are one type of antigen presenting cell or APC.
HELPER T-CELLS
APCs "present" the antigens to the next set of immune system cells called Helper T-cells. As their name indicates, helper T-cells activate the two main arms of adaptive immunity via the release of specialized mediators called cytokines. Cytokines are like signals from helper T-cells that activate both B-cells and T-cells.
The role of helper T-cells is seen in HIV (human immunodeficiency virus) which causes the clinical syndrome we call AIDS (acquired immunodeficiency syndrome). The HIV virus directly attacks the helper T-cells, resulting in a loss of proper adaptive immunity in those infected with HIV.
T-CELLS VERSUS B-CELLS
T-cells are so called because they mature in the thymus gland in the upper front part of our chest cavity- "T = Thymus". They directly attack infected cells, hence they are a part of what we call "cell-mediated immunity".
B-cells are so called because of where they were first discovered- in a specialized bird organ called the Bursa of Fabricus- "B = Bursa". Scientists in the 1950s discovered that removing this organ in young chickens resulted in their failure to produce antibodies.
B-cells are what produce antibodies- small protein molecules that neutralize and/or tag foreign invaders or infected cells for destruction. Because antibodies are found liquid part of blood, the serum, B-cells are part of what we call "humoral immunity". It is the immune function found in the body fluids or humors.
CELL-MEDIATED IMMUNITY
The primary cells responsible for cell-mediated immunity are the T-cells.
Once activated by the APCs, the helper T-cells activate what are called cytotoxic T-cells which are also called killer T-cells or T-killer cells. Cytotoxic T-cells attack and destroy cancer cells, cells that are infected with viruses, or damaged cells that need to be eliminated.
Activated T-cells are directed against a specific antigen. So they're like precision guided weapons.
The basic population of Cytotoxic T-cells is made up of active cytotoxic T-cells which are out doing their job, and memory T-cells which "remember" specific antigens and await future activation by the immune system.
While it is possible to measure and assess cell-mediated immunity in humans, it's not practical in clinical medicine as it's time consuming and requires highly specialized laboratory work.
HUMORAL IMMUNITY
The primary cells responsible for humoral immunity are the B-cells.
Once activated by the APCs, the helper T-cells activate the B-cell population against a specific antigen, just like the cytotoxic T-cells of cell-mediated immunity. There are two basic sets of B-cells- plasma B-cells are what produce antibodies specific to a particular antigen and memory B-cells "remember" specific antigens and await future activation by the immune system.
Antibodies bind to what are called epitopes. Epitopes are parts of antigen that an antibody is directed against. Antibodies binding to epitopes can block action of a foreign invader- we are very interested in antibodies that bind to the COVID-19 spike protein and keep it from docking with the human host receptor, ACE2, that it needs to hijack our cells and start the process of infection.
Antibodies bound to an invader also tag it for destruction by the immune system's cytotoxic T-cells. So in a way, antibodies are both precision guided weapons but also designate targets for the other weapons of the immune system.
LONG TERM IMMUNITY
There are three basic sets of long term immunity cells in the body- memory B-cells for humoral immunity, memory T-cells for cell-mediated immunity, and memory helper T-cells to trigger the process again in the future when needed.
The memory cells basically lay at readiness, awaiting orders from the immune system to activate. That's the next exposure to a specific antigen like from a virus or bacteria or other invader. The memory cells "prime" the immune system to react more quickly on the second time a specific antigen is detected.
CLINICAL RELEVANCE
Vaccines introduce specific antigens to the body which are processed by the APCs. Whether its influenza, tetanus, or COVID, instead of the challenge coming from an actual infection and illness, a specific antigen is introduced to activate the immune system without causing the actual illness.
That soreness or blah-feeling some get after vaccination IS NOT THE ACTUAL ILLNESS. That, if it occurs, is due to the signals and mediators of the immune system doing their job as designed to prime your immune system for the day that it does encounter what you're being vaccinated against- influenza, tetanus, chicken pox, meningitis, or COVID or whatever.
A second exposure to that antigen or a booster shot then activates the memory cells which "reinforces" the long term memory of the immune system.
In this pandemic, there are now monoclonal antibody treatments as well as donor convalescent plasma (from those who had COVID and survived) that are like "adding" more antibodies into the system.
Think of monoclonal antibody treatment as optimized for full effect against the virus while convalescent plasma is the infectious disease world's version of an antibody "shotgun". Monoclonal antibody treatment is like a sniper, targeting a specific epitope, whereas convalescent plasma is like a shotgun, sending out antibodies against multiple epitopes. Some may neutralize the virus, some may not.
We already know from research into the other vicious coronaviruses SARS (emerged in 2003) and MERS (emerged in 2012), that even years after antibodies specific for those viruses cannot be detected, cell-mediated immunity with the T-cells is still very robust. There is no reason that COVID would not act the same way given their high degree of similarities at the molecular level. What this means is that using antibody testing to document your immunity against COVID is pointless. The long term memory of the immune system is such that even the absence of antibodies against COVID, the memory cells lay in wait, ready to activate the immune system again.
But understand that the development of antibodies is a multistep process that varies based on amount of virus, individual factors like age or other medical conditions, and a whole host of genetic factors that make each of us unique.
The mutation E484K is of particular concern for us as it significantly impacts an important epitope on the spike protein that is an important neutralizing antibody target. The E484K mutation is present in several variants now circulating in the United States- B.1.526, B.1.351, and P.1. There are early indications the new dominant variant in the United States that is more contagious, B.1.1.7, is acquiring the E484K mutation as well.
What this all means is that antibody tests still cannot be relied on at this time because of the dynamics of response are variable and in some ways, still poorly understood when it comes to the antibody response to COVID. There is no clear uniform standard on what constitutes a positive or negative antibody test. They are useless for the diagnosis of COVID and equally sketchy for the documentation of past infection or exposure.
For more details, I suggest reading the serology section of the Infectious Diseases Society of America's guidelines on COVID: https://www.idsociety.org/practice-guideline/covid-19-guideline-serology/
In my links below is my own summary of an excellent Mayo Clinc Grand Rounds on COVID-19 testing pitfalls and why serology is about as useful as taking an accordion deer hunting in most clinical scenarios.
(Spoiler alert: Except in very specific unusual situations, don't do antibody tests.)
We call that "correlates of protection"- what measurable level of antibody or other measurable parameter equates to immunity against COVID? As we vaccinate more and more people, that data is being generated and we are getting closer to an answer but we don't have that exact answer just yet. But the real-world data from millions and millions of people not just in the United States but worldwide getting vaccinate is signposting the way the forward out of this pandemic.
KEY IMMUNOLOGY CONCEPTS
1/ APCs act as sentinels against ANY invader and start the activation process for the adaptive part of the immune system.
2/Helper T-cells activate BOTH arms of the adaptive immune system, cell-mediated immunity and humoral immunity.
3/Cytotoxic T-cels target cells infected by a SPECIFIC invader.
4/Plasma B-cells produce antibodies SPECIFIC to a particular antigen belonging to a particular invader.
5/Antibodies neutralize a SPECIFIC antigen. Locking on to an epitope (specific target on an antigen), this can either render the invader useless or designated for attack by T-cells.
6/Memory cells are SPECIFIC for a particular antigen and are the core of the immune system's long term memory. This memory exists, ready for activation of the whole process, EVEN IN THE ABSENCE OF DETECTABLE ANTIBODIES.
7/A second exposure will directly activate the memory cells, resulting in a faster and more intense immune response than the first challenge.
8/Vaccination is a way to "prime" the immune system and "teach" it to recognize a particular potential invader ahead of time. Because that second activation is faster and more intense, vaccination makes the immune system respond more effectively to potential invaders.
9/Our innate immunity has a whole different mechanism that acts in concert with the humoral immunity and cell-mediated immunity, the two main arms of adaptive immunity. That part of immunity is not depicted on my graphic.
10/Antibody testing is useless for diagnosis or documenting past exposure. A negative antibody test doesn't mean a damn thing and a positive antibody test doesn't equal immunity or protection.
PARTING THOUGHTS
Public mask use, social distancing, capacity restrictions and other pandemic mitigation measures are still important to give us the time to get as many people vaccinated as possible. We are in a race- we are trying to vaccinate as many as we can before the other variants create problems. The surge seen in Michigan was driven by a variant, B.1.1.7. Many other states experienced variant-case increases as well.
This isn't over yet. The dynamics of this pandemic in 2021 are different than 2020 for two main reasons- first of all, we have a very large fraction of those 55 and older vaccinated which means cases and hospitalizations are going to be driven by younger people and secondly, we have multiple COVID variants around the world, many of them already spreading here in the United States.
PRIOR PANDEMIC POSTS (FACEBOOK LINKS)
QUICK UPDATE: AMERICAN INDIANS/ALASKA NATIVES LEAD THE WAY ON VACCINATIONS (29 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218763919866049
QUICK UPDATE: BY THE NUMBERS (27 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218750780817581
COVID VARIANTS OVERVIEW AND UPDATE (22 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218722676514991
NEW COVID VARIANT OF INTEREST: B.1.617 (18 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218699298170547
CASE SURGES CAN RESULT IN COVID VARIANTS (12 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218657527966318
THE OVERVIEW & STATUS OF COVID VARIANTS (9 April 2021): https://www.facebook.com/jp.j.santiago/posts/10218637120816152
MAYO CLINIC GRAND ROUNDS: COVID TESTING (12 March 2021): https://www.facebook.com/jp.j.santiago/posts/10218453381862793
QUICK UPDATE: THE COVID FAMILY TREE (01 February 2021): https://www.facebook.com/jp.j.santiago/posts/10218211054244754
COVID MUTANTS: VARIANTS OF CONCERN (31 January 2021): https://www.facebook.com/jp.j.santiago/posts/10218204381877949
COVID MOLECULAR BIOLOGY: THE SPIKE (6 January 2021): https://www.facebook.com/jp.j.santiago/posts/10218019683340601