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Our Friendly Immune System
Blog #5: The innate immune system (The start of an amazing journey)
It’s simple! Immunity is our body’s battle of “self-versus-non-self.” The ability of your body, which we’ll call “self,” to resist things like bugs or infection and irritating substances in the air like dust, mold, or even toxic substances like smoke and pollutants. We’ll call these external irritants “non-self” or foreign matter, or the scientific term for them, “antigens.” Your body is constantly fighting off these foreign, “non-self” substances by using specialized molecules in your body and in your blood called “immune cells,” certain kinds of white blood cells called “lymphocytes” and molecules called “antibodies.” These blood cells and molecules are part of your immune system and their actions to protect us and eliminate the bad guys are called our immune response or immunity.
As part of the complexity of our immune system, there are an abundance of mysteries and contradictions that the book, The Paradox of the Immune System, identifies and “tries” to explain. The “self-versus-non-self,” battle described above represents perhaps its most prominent paradox of the immune system. It also sets the stage that explains how the system works to protect us 24/7. The system functions as a natural process in our body and we call this natural, normal immune process “innate immunity.” But sometimes our innate immunity is insufficient to overcome those antigens we’ve described and it has to “adapt” itself to function in a tougher and more specialized way. This more aggressive level is called “adaptive immunity.” Blog #9 will address the specialized ways, called the molecular biology, of how adaptive immunity works to protect us. But first, we want to understand how innate immunity works to protect us under normal circumstances and what happens when it can’t complete the job.
Certain organs in our body (Figure 1.1) produce those white blood cells (WBCs) or lymphocytes we mentioned above. There are numerous organs that produce these immune cells (Figure 1.2), but most of them come from the thymus gland in the upper center of our chest and from the inner core of our bones called the marrow. The WBCs including the now famous T and B lymphocytes and some other cells that assist in the protective immune functions. And start thinking big here because we’re talking about trillions (with a T) of these immune cells. The innate system also uses some of the body’s gross anatomical structures, especially the skin and mucous membranes as protection against attacking antigens. So, as you are reading or
listening to this blog, you are being constantly attacked by countless foreign antigens including dust, pollen, spores, virtually anything airborne or touching you. Your T “helper” cells are going to work to recognize those antigens and activating your innate immune response. To do this, certain programmed genes developed over eons of evolution recognize the antigen and determine the level of threat and if the Th cells should “attack or stand down.” If the foreign substance presents a danger to the body, the Th cells are directed by chemical signals to attach themselves to surface proteins on other immune cells and together, bind and disable the antigen molecules (Figure 1.3). This amazing system of “antigen recognition” protects us from overworking our immune system and more so, protects us, “most of the time” from attacks on our own body. This starts the intimate relationship between our immune system and our genes, a relationship that will direct and control the immune system going forward.
The chemical signals and proteins generated in this exquisite natural process of innate immunity also stimulate other specialized T cells called T regulatory cells (Treg ) and another category of lymphocyte cells called B cells. These critically important B cells will begin to produce antibodies, the molecules that will also recognize the attacking antigen through their own specialized genes and will assist the Th cells in binding remaining antigens or antigens that might be resisting or escaping the Th cell attack. This overall immune process is called the “regulated” innate immune response. And the functions already described, the T and B cells will begin to generate memory cells to protect our bodies against any future attacks and reinfection by similar antigens.
In some instances, albeit rare relative to the trillions of antigens our body is constantly defending against, the antigen load may prove to be too great, too strong, not being removed quickly enough, or the immune system itself is suppressed for some reason (called “immunosuppression”). In these cases, the innate immune system keeps fighting harder but is also creating an abnormmal, increasing accumulation of cells and chemicals in our tissues that can begin to be interpreted as “foreign” and producing “stress” and disruption of the normal physiological balance (remember homeostasis?) our body is used to. All this can lead to a “dysregulated” immune system where confusion (or paradox) develops as to “who are the good guys and who are the bad guys?”
This dysregulated system now begins to interpret “too much self” as a “foreign stimulus.” It starts to generate an increasing cell and chemical response or an “overreaction response” as part of its protective function. This is when the innate immune system begins to “adapt” into a the more aggressive “adaptive immune system.” This is the system that the body will now use to deal with accumulated debri, its increasing stress on the body, and the new risk of reacting to itself, or “autoantigenicity.” The first event this adaptive immune system will initiate in mounting its defense is a classic clinical process called “acute inflammation.” We will be describing that in detail in Blog #9, “The adaptive (aka “acquired”) immune system: from friend to foe.”
Blog #6: The immune system millions of years ago (Part 1)
Strictly speaking, the evolutionary development of the immune system should be the first topic of discussion, but I postponed it to after Blog #5 so as to provide a review of the biology that is a significant part of the immune system’s evolution. I actually scattered evolution discussions throughout the book rather than a dedicated chapter and in retrospect, after doing some post-publication research on immune evolution and realizing its importance, I could have kicked myself. I assure you it will warrant a full chapter in the next edition of the book, but in the meantime, the next two blogs will cover some of the most valuable information on evolution and the immune system.
Around 600 million years ago, small living organisms began to evolve and then, over the following few million years, they began to develop sophisticated biological systems including an immune system. They call this period the “immunologic big bang.” Using Darwin’s natural selection, it included the evolution of the blood cells that control the immune response (remember lymphocytes?) and the surface proteins those cells use for identifying antigens, and the cells' genetic processes that created DNA and RNA. It was during this “big bang” period that the innate immune system formed to provide our self-defense against foreign microbes, called pathogens and it produced a protective mechanism against them called inflammation. Higher forms of developing animals also began to develop a more aggressive “adaptive immune system” as further protection against those deadly pathogens.
Besides Darwin’s natural selection, another type of evolution was developing called the Lamarckian “Theory of Inheritance of Acquired Characteristics.” This theory explains the ability of a developing organism, rather than using natural selection, to pass on physical characteristics to its offspring that had been originally developed through use or disuse over time. This theory continues to be confirmed, even today with development of a new generation of gene editing tools, e.g., CRISPR that we'll cover in great detail in future blogs.
Most healthy humans have the ability to activate and utilize the multitude of immune responses that they are born with. But individuals differ in that degree at birth, during aging, sex differentiations, and when encountering new environmental factors. The ability to utilize the range of immune responses is rooted in our evolutionary pasts where genes develop to control the vast array of immune traits that collectively make up the human genome. These evolutionary roots apply to genetic differences between males and females and are directly related to the risks for immune-related diseases including autoimmunity and infection.
Viruses, bacteria, fungi and other microbes existed in the cosmic environment prior to human evolution more than 3 billion years ago. So, the human genome, the host for all these colonizing microbes, eventually evolved the human microbiome, also called "the second genome" (Blog #13). Through natural selection, the microbiome, along with the coexisting environmental microbes create a harmonious balance beneficial to the host, i.e., the human, and other species living in or around it. More on this phenomenon in the embryology and pregnancy blog #8. But first, let’s continue with Part 2 of evolutionary development in Blog #7.
Blog #7: The immune system millions of years ago (Part 2)
We spoke in the last blog about how, over hundreds of millions of years, the immune system became capable of identifying virtually any foreign, antigen that might attack us. That sounds incredible when you think of the trillions of antigens we have mentioned in previous blogs. But, I guess over hundreds of millions of years, good old Darwinian natural selection put us in a pretty good place relative to our environment. (Einstein had a saying, “The environment is everything that isn’t me.” And evolution created this amazing feature of immunity through the development of something called the “antibody-encoding gene.” Its discovery won a Nobel Prize in 1987).
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Since the immune system is pivotal in human survival, its evolution had to create protection for all the body’s systems and did so through a process referred to as the “allocation rule of the life-history theory.” The body’s systems require energy to function and this evolutionary process used natural selection (there it is again) to create a strategy wherein the immune system proportions or “allocates” its energy to individual body functions and stores the excess energy for other body functions if and when needed. Kind of a “rainy day” system of protection. All pretty amazing stuff and it tells us that the immune system is still evolving and hopefully, will provide future protection against diseases and, even aging.
It seems that women have evolutionary bias towards producing more immune B cells that produce antibodies which is good news…and bad (more immune paradoxes). It certainly adds protection against those nasty pathogens, but too many antibodies or “too much self” can also begin convert to autoantibodies and produce autoimmune reactions and disease. But evolution also used this increased B cell generation in females to allow better maternal protection for her offspring. So it seems that evolution promotes protect against infection regardless of the cost as in the offspring example in women. On the other hand, men have evolved with more T cells which protects them, a little at least, from those autoimmune disease of which that women suffer more.
Immune memory is another important trait that improves human protection against reinfection. This memory function exists in both the passive innate immune system as well as the more aggressive adaptive immune system which we’ll be describing in Blog #9. The innate immune memory is more non-specific and can’t really adapt to variants in antigens. It uses mostly T cell memory and is called “primed or trained immunity.” The adaptive immune system, on the other hand, evolved later than the innate form and has the capability to recognize different antigens and pathogens by using combinations of antibodies and those B cell antibody-encoding genes mentioned above, to build a more diversified memory capability. Remembering that females have more B cells, the increased level of B-cells and resultant B-memory cells may also contribute to increased adaptive immune memory in females. Yet another female bias.
Finally, that adaptive immunity that we’re building up to in Blog #9, evolved the ability to diversify its antigen receptor genes, those receptors on the lymphocyte cells that recognize antigens. This enables these specialized cells to produce antibodies with greater binding power to antigens. At birth, females activate these stronger cell-binding powers while it takes males as long as 36 months to acquire similar cellular capabilities. Thus, once again, females demonstrate stronger immune systems as compared to the immature male system even as early as birth. And introducing natural selection one more time, these differences between a stronger immune system in females persist over time leading to the female having greater protection against infectious disease than the male.
Blog #8: "It's an immune system!" Embryology and pregnancy
Mother’s womb is an absolute germless or sterile environment. As such, the fetus does not need an immune system. In fact, if it did have an immune system, it would react to the mother’s cells as being “foreign.” So nature has provided a safety valve by suppressing mother’s immune system in the womb during the early stages of fetal development. But these genetically distinct fetal cells start crossing the placenta into Mom and can be detected by the 4th or 5th week of the pregnancy and those fetal cells will remain in Mom’s immune system for years thereafter. A little benefit of this phenomenon is enhancement of mother’s milk for the newborn baby. But the real benefit of this process called “microchimerism” is believed to be the reason that Mom’s immune system adapts to the fetal cells and doesn’t interpret the growing fetus as foreign.
During fetal development, the immune systems of the developing fetus and the Mom are precisely timed during the pregnancy to achieve the best outcomes for both. During the first 12 weeks of the pregnancy, Mom’s innate immune system becomes more aggressive than normal to establish a successful implantation of the embryo where mother’s immune cells are active and produce a unique (to pregnancy) immune response called “passive immunity.” This immunity provides an abundance of chemical and proteins like immunoglobiins IgG and IgM that help the fetus get fully established during implantation. After that, for about 15 weeks, Mom’s immune system pretty much shuts down to the womb and allows the fetal cells to grow. Meanwhile, the fetus is developing its own immune system. Kind of interesting to have two immune systems functioning in one body. But it works! And finally, after the 12 weeks, Mom starts generating an aggressive immune system as she nears delivery. This is when certain chemicals produced by Mom help with the labor response.
The majority of genes shared in the mother and child relationship originate, would you believe, from Mom’s gut, or her gastrointestinal track. It makes sense when you realize that she is transferring them to the newborn during breast feeding and physical contact with the baby. The gut is part of a rather complex system of microorganisms called the microbiome. It’s a fascinating and extensive feature of human biology which we’ll take up in depth in Blog #13 and revisit it frequently throughout most of the other blogs. This microbial transfer from mother to baby is likely the reason mothers are the primary providers of the majority of genetic information to their offspring. Another fascinating aspect of this transfer of fetal cells from mother to fetus and newborn is the fact that the DNA of the cells from a male or female baby are detectable in the mother, especially in her brain, for the rest of her life. They call this “pregnancy brain” and is believed to have lifelong effects, positively in protection to the woman, and negative like lifelong potential autoimmune effects in the mother.
The distinctions and superiority of the female immune system that we have mentioned numerous times by now begins even earlier than its evolutionary origins. That passive immunity we mentioned above, produces a transfer of maternally-derived antibodies like IgG that transferred and shared in fetal circulation prior to birth through the placenta and through mother’s milk following birth. This does increase the risk of disease exposure, it also allows the infant's immune system to begin to “learn” about the local disease environment and causes the fetus to begin to acquire specific immune defenses that will endure beyond the pregnancy when passive immunity is no longer operative. In a sense, passive immunity can be viewed as a transient process (as in the Lamarckian theory of inheritance we mentioned in Blog #6) of acquired characteristics passed on from mother sharing her knowledge of disease to provide a kind of a buffer period while the infant builds its own repertoire of defenses through a Darwinian evolutionary process. Thus, to minimize the potential for off-spring infection in this passive immunity process, natural selection has evolved an increased antibody production in females.
After birth, the immune system continues to develop robustly until about age seven to eight when it reaches its strongest levels. At that point, general health, proper diet, and exercise will maintain a strong immune system for many years thereafter. But as we age, to be expected as with so many things, the system will begin to slow down a bit in response time and of course, it can be dangerously impaired with any form of immunocompromising disorders. But, by and large, the immune system continues to be our principal defense mechanism throughout life, notwithstanding increased risks of certain diseases (e.g., cancers) due to its slower response times with aging.
Blog #9: The adaptive immune system: (When a friend turns on us)
Back in Blog #5, we closed with a segue from innate immunity to adaptive immunity, or the more natural immunity to the acquired, more aggressive adaptive form of immunity. We talked about a “regulated” system in innate immunity and now we will “progress,” not the perfect descriptor, into a “dysregulated” immune system. This adverse change in the immune systems is caused by adverse factors we mentioned towards the end of Blog #5 which you may want to review. But let’s also consider 4 possible mechanisms that can reverse this negative response. First, if the removal of the bad guys, the antigen, occurs for any reason, a process called “feedback inhibition” reduces negative immune influences and effectively reduces and reverses dysregulation. Second, complex systems in the brain that control the immune response can regulate and reduce the problem. We’ll be talking a lot more about these neurological in Blog #17. The third mechanism is when one of the T cell types, T regulatory (Treg), reduces T helper cells which, as you may recall stimulate the B cells. So this reduction in Th cells reduces B-cell activity which could be causing the dysregulation. And finally, the fourth mechanism is a very complex genetic mechanism that we are going to postpone discussion until Blog #33 regarding cancer treatment in which complex (B cell idiotype circuit) mechanism plays a role. I think you’ll find the mechanism and its association to cancer very interesting. But let’s deal with this adaptive immunity progression now.
Failure to remove an offending antigen in a timely manner or a malfunction of any one of the four mechanisms described above, can lead to a negative response resulting in a clinical effect you have heard about and undoubtedly have experienced yourself somewhere along the line. It’s called “acute inflammation.” What’s developing now as adaptive immunity begins to develop from an antigen overcoming the innate system, a race to eliminate the bad guys (antigens) ensues, a race in most cases, given an otherwise healthy person, the innate immune systems will win. If, however, the underlying health of the patient is not adequate enough to sustain the aggressive activity of the adaptive immune response, things could begin to deteriorate further. All those T’s and B’s and immune chemicals now begin to initiate four types of overreactions we mentioned in the later part of the innate immune system discussion (Blog #5). These four overreactions develop as a product of different types of antigen categories, 4 types which produce 4 specific immune cellular responses. We won’t describe each reaction yet (later in Blog #14), but simply indicate that one or more of these reactions will produce the acute inflammation I mentioned above, and something called the “inflammatory cascade” (Figure 2.1) which is a flow of chemicals, cells and proteins that will ultimately produce clinical effects we all have encountered somewhere in our lives. They include redness or vasodilation which is caused by dilated blood vessels; swelling or edema and infiltration, both caused by accumulation or diffuse discharge; and finally, ulceration or the breakdown of tissue (Figure 2.2).
Interestingly, notwithstanding its negative signs and symptoms, acute inflammation can be considered a healing or protective adaptive immune process which is trying to fight off a foreign antigenic invasion. Nonetheless, because of its negative effects, the fundamental treatment for acute inflammation is the removal of the offending antigen in a timely manner and treating the clinical signs and symptoms. We use cold to reduce the redness and swelling by reducing the vasodilation and, when necessary, steroids to interrupt the chemistry of the inflammatory cascade (Figure 2.3 and 2.4). Failure to do these treatment steps can lead to the more destructive, often irreversible ulceration with associated tissue loss and even the potential for DNA disturbance. Once again, the stress creating this “dysregulated” state in tissues or organ systems from the inflammatory cascade creates the potential for a self-sustaining cycle (Figure 5.1). But the most
serious consequence of acute inflammation, if not treated promptly and effectively within days or weeks, is the risk of the adaptive immune response lapsing into a chronic condition called “chronic inflammation.”
While acute inflammation is only one route to chronic inflammation, there are other causes, some understood and some unknown. And as we discussed in Blog #2 (and again later in Blog #14), albeit similar in name, chronic inflammation, beyond its “chronic” duration, introduces an entirely distinct and far more dangerous path towards unremitting clinical disease.