Big Picture

The immune system is a complex defense system designed to protect the body from invading toxins and organisms. When we wash our hands with soap or cover our mouths to prevent the spread of germs, we perform behaviors that can prevent illness from being introduced into our bodies, but no matter what we do, every day our bodies are exposed to a truly incredible number of microorganisms that can make it beyond external barriers such as our skin, and into our bodies through so many paths, that it is ultimately impossible for us to keep 100% of exposures prevented. On a daily basis, it is our immune system that prevents invading organisms from overrunning our bodies, which act as both food sources and incubators to both diseases and to friendly organisms, an example of the latter of which is the biota that live in our guts, and that help us to digest.

Invader Recognition: Antigens and Epitopes

Since our body is composed of cells, and since the invaders are made of cells as well, our defense system is armed with a method of detection that allows us to distinguish friend from foe. It is the unique job of the immune system to identify, learn about, and destroy invaders that we come into contact with, as well as our own cells that have become infected (viruses do this). The immune system does so by learning the surface molecules expressed by invaders that are different from our own. Any molecular structure that the immune system can learn to identify is referred to as an antigen, and the structural regions of the antigens that make them recognizable are called epitopes.

To illustrate roughly what this means, look at the following line, and see if you recognize anything

Sdflkerk2o324ksdklfjjklsjdkjlthis-is-an-epitope234298098.dioj

There is very little there that lends itself well to our recognition as readers, but the portion that says “this-is-an-epitope” jumps out at us as we scan our eyes across the line. The line as a functional unit represents an antigen, while the recognizable sub-portion represents an epitope.

Even when our cells are not infected, they bring pieces of themselves to the surface, presenting “self” antigens that are recognized by the immune system. While presentation of self should not provoke a reaction from the immune system there are times when our cells do present foreign material to provoke an immune response, for instance when a cell is infected with virus, or when an invading bacterium has been eaten by one of our cells. When this happens, pieces of the invader are randomly taken to the surface, which are then recognized as “not-self.” When the immune system mobilizes against the infection as a whole, signals are released for local cellular destruction and to mount an inflammatory reaction in the area. These signals are proteins called “cytokines,” and they result in a wide range of effects including blood profusion of tissue or the invasion of the local area by immune cells looking for targets.

Cytokine Basic Definition

The word cytokine translates to “cell mover,” and cytokines are used by nearly all cells to coordinate behaviors, but in the immune system, the end result is the destruction of infected cells and foreign molecules. In healthy patients, only the presentation of foreign antigens from invaders, rather than “self” antigens should cause a reaction, but in autoimmunity, both “self” and “not-self” provoke aggressive immune responses. The loss of protection for “self” is referred to as a failure in “tolerance,” which refers to the immune system’s tolerance of “self.” Attack on self causes inappropriate inflammation, cellular death, and the release of toxic defenses meant for invaders that aren’t present. Because this can happen all over the body, and because the mechanisms for recognition and defense are so complex, autoimmune diseases have a very broad range of symptoms and causative mechanisms that make them difficult to address.

Antibodies and Innate VS Adaptive Immunity

The immune system is also divided into two main categories of protection since it must protect against invaders it has never encountered but can adapt to invaders it has seen before. The immune system has a specific class of molecules it uses to target the learned epitopes of invaders that it has previously captured and killed. Once cells are mobilized, the recognition of invaders is facilitated by molecules that have been specially created to recognize foreign epitopes and that attract immune destroyer cells. These molecules are called antibodies, and they are part of the adaptive immune system.

The adaptive immune system is what allows vaccinations to work. The adaptive immune system is a lagging defense that takes two weeks to learn an invader and mount a stronger, more efficient defense. Because this is too long for first encounter, the first line of defense is the innate immune system, the set of cells that attempts to run down infections and stop them, even when the body hasn’t encountered them before, but the innate immune system is not very specific and is less adept at finding and recognizing the infections, which is why on first encounter we tend to get sicker than we do when exposed again.

When the body has time to adapt to a new antigen it hasn’t encountered before, the adaptive system creates incredibly specific antibodies that circulate in the blood, stick to their targets, and much more specifically attract immune cells, or that may even physically interfere with the mode of action of foreign toxins, thus inactivating them. Antibodies can be used medicinally by exposing an animal to an antigen, culturing the cells responsible for producing the resulting antibodies, and growing the cell cultures out to mass produce antibody.

Vaccines

Vaccines work by taking the antigens of potential invaders and exposing the body to them, typically before a real infection has ever occurred. The body then takes the usual two weeks to create its antibodies, but now if it is exposed to the invader after two weeks, there is no lag before the strength of the adaptive immune system can be used against the invader. In rare cases such as rabies, in which the infection incubates for longer than two weeks, and would not otherwise be spotted by the immune system before symptoms start occurring, vaccines can be used after infection to outrace the disease. In fact, the first rabies vaccination was used this way to save a young boy who had been bitten by a rabid dog. In contrast, fast moving illnesses like flu will only be effective if the vaccine is administered with a two week lead on infection because the time from exposure to massive infection (and possibly death) from illnesses like the flu are much shorter than two weeks. In cases like this, the vaccination would only serve to distract, and weaken, the immune system, and could make the patient feel worse by confusing the body into thinking it is more invaded than is true.

Because of the times we live in, it is difficult when speaking about vaccination to not address the meritless debate around vaccines. While there is a large debate right now around vaccination and autism, the truth is that the arguments have no scientific merit and have been repeatedly disproven by the scientific community, and even falsified by the original researcher who put the idea of the linkage forward.

While the arguments largely hinge around a fear of what goes into vaccines and what is not known about the long term effects of chemical exposure, these debates often spring from a poor understanding of orders of magnitude. The human body on a daily basis is generally exposed to a large amount of chemicals and external influences that should play a far greater role (if any) than trace chemicals administered once in a vaccine, the latter of which has never been shown to correlate with developmentally deleterious effects. As is mostly always true in science, it is impossible to prove a negative, which is how these debates are sustained. No matter how much evidence is presented, sceptics always feel entitled to say that no amount will ever be enough. While we cannot prove that exposure to a given chemical in combination to some other chemical in the future will not have a certain effect, we can prove that in the past it has not had a certain effect.

The anti-vaccination movement tends to want conclusive evidence that something cannot happen, when in fact, that is not how science works. If nearly 100% of children are vaccinated in the US, then nearly 100% of autistic children will have been exposed to a given chemical, but that does not prove causation for the autism. In fact, 100% of those children will have been exposed to water as well, and aside from fear, there is no more proof that one exerts an effect than the other. Moreover, the better to be safe than sorry argument holds a false appeal as well because children exposed to vaccines have no known, or proven, probability of deleterious effects (in fact there is decades of evidence to the contrary) whereas children not administered vaccines are known to have a high probability of developing illness and endangering others by cutting down on “herd immunity,” which refers to how vaccines, while conferring partial immunity, do not stop the initial invasion of microorganisms so much as make the invasion short lived. If your child’s classmate is not vaccinated and becomes a factory for virus, it makes your child more likely to become infected, even if the symptoms are less damaging overall by merit of your child having been vaccinated. This same effect also means that anyone else who hasn’t been vaccinated becomes more likely to become exposed and sick because there are more “vectors” (modes of transportation, in this case the children) for the illness in play.

Essentially, choosing not to vaccinate is a gamble that resists being informed by the odds, a lighthearted example of which is the moment in the movie Austin Powers when any card Austin could get in blackjack will get him closer to 21, but despite the odds, he decides to tell the dealer that he will “stay.” While this scene is cartoonish due to the seeming obviousness of the situation, the reason it is funny is because it strikes at a basic human propensity for willfully ignoring basic probabilities when the information in play does not feel emotionally right, despite the being a logically obvious choice available. Sadly, the public’s reactions in weighing science against emotional fear often follows a similar formula because misinformation is often given equal weight with hard science. Unfortunately, the anti vaccination movement is no laughing matter since children’s lives and wellbeing are at stake.

Please see the following links for more information:

• Origins of Anti-Vaccination Movement
• Newsweek On Anti-Vaccination-Funded Study

Receptor Anatomy & The Importance of the Gamma Chain Family

The Cytokine classification is comprised of a broad range of molecular families with a broad range of functions, but a vital class involved in the immune system, and now addressable with Bioniz’s technology, is a subset of the “interleukin” family (abbreviated “IL”) known as the gamma-chain interleukins, or the IL-2 family. Each of the cytokines of the gamma chain family are derivations of the same molecular ancestor, and while each of the family’s members has a distinct receptor, each receptor has a common component for which the cytokine family is named, in this case, the gamma chain. To explain further, receptors are not really one molecule but a complex of proteins that collectively comprises what we refer to as a receptor, which can be thought of as a functional unit that, when bound by a ligand (signaling molecule), passes that signal across the membrane of the cell that it belongs too, to molecular mechanisms that sit on the inside of the membrane, and that then propagate the message internally. In the case of the gamma chain family of receptors, every complex has a gamma chain, which is called a “conserved region” because its vital nature does not allow for mutation (offspring with a mutated gamma chain gene do not tend to survive to reproduce, and so the gene does not change quickly with successive generations).

On the outside of the cell, external receptor components “complex” (come together to form a functional unit) to bind their cytokine. The way that the “private chain” that is specific to each cytokine complexes with the gamma chain to bind the cytokine’s “active region” is what makes a given complex specific to its cytokine. The external components connect through the membrane to an internal component like a wire run through a wall, and internally, a component called JAK3 is activated when the receptor binds its cytokine. When activated, JAK3 initiates the mechanisms inside the cell that pass on a continuation of the molecular signal from outside the cell, in this case a molecular pathway known as STAT5.

What is known about the gamma chain family of cytokines is that mutations can cause Severe Combined Immunodeficiency (SCID), a complete collapse of the immune system resulting in rapid infection and death, and what this tells us is that this family is critical to the functioning of the immune system as a whole.

Knowledge of Cytokine Functions Varies

Individually, the functionalities of each of the cytokines are in various stages of being characterized. IL-2, for instance, is well known to be involved with T-cell differentiation and the promotion of self-tolerance in the Thymus, and more broadly, it is involved in both the suppression of, as well as the promotion of, immune responses depending on context. It is also known that IL-2 has significant functional overlap with IL-15. In contrast, significantly less is known about the overall function of IL-21, for instance when, where, and why it is employed.

Difficulties In Choosing Cytokine Targets for Therapeutics Development

Different autoimmune disorders tend to have different profiles of cytokine activation because they are driven by different causative mechanisms, for instance HAM/TSP patients have overactivation of IL-2 and IL-15, but other diseases such as Celiac Disease have different patterns (e.g. IL-15 and IL-21 in Celiac), and so the cytokine profile for patients with different diseases may differ significantly. Conversely, different mechanisms may also happen to produce similar profiles of cytokine overactivation, just driven by different causes, in which case the use of therapeutics may overlap between diseases. Ultimately, what determines choosing targets for the development of a battery of therapeutics for use in the treatment of a given disease state is how much is known about the specific patterns of cytokine functioning in that disease, which is ultimately a function of how much funding a disease state is receiving, and how active it is as an area of research.

Ultimately, while cytokines are the most attractive target for attempts at immune system correction, knowing which to target, and in what ratio, is a body of knowledge that is under very active investigation, and that is unevenly characterized between disorders.

Antibody Therapies & The Difficulty of Hitting Gamma-Chain

Despite great interest from the immunology community, relatively few effective molecules have been developed to directly target cytokine pathways. Generally, the three main classes of drug used to suppress an autoimmune attack fall into three main categories, steroids, JAK inhibitors, and monoclonal antibodies (see therapies section). Steroids are general and affect the immune system as a whole; JAK3 inhibitors can be somewhat specific at low doses but tend to shut down the broad uses of JAK in the body when used at more therapeutic dosages (preventing vital cellular processes beyond the immune system); and monoclonal antibodies (mABs), while very specific to those molecules against which they can be successfully developed, have proven impractical for use against diseases that are sustained through redundant cytokine pathway involvement.

The community has focused on the monoclonal antibody class of molecules as the best hope for targeted therapeutics because of the incredible specificity with which those molecules bind the targets against which they have been developed, but while several effective antibody drugs have been created, such as Humira for TNF-alpha, which is projected to become the most successful drug of all time in 2018, in general, efforts to create mABs for other desperately needed targets have so far been unsuccessful. In particular, the lack of success by researchers at the NIH to create MABs against the gamma-chain family of cytokines directly lead Bioniz’s founders, Dr. Nazli Azimi and Dr. Yutaka Tagaya, who had been two of those researchers, to try small peptides, a new approach that lead to the creation of Bioniz’s core technology.

The Problem of Cytokine Redundancy

Cytokine redundancy refers to the immune system’s use of cytokines with overlapping functionalities to prevent any single cytokine pathway disruption from causing a functional failure of the immune response.

From a therapeutic perspective, cytokine redundancy is the next layer of complexity beyond the difficulty that is already inherent in developing therapeutics that can antagonize single cytokine targets. Redundancy, while protecting the immune system from loss of functionality from a single pathway failure, compounds the difficulty of treating autoimmunity because, even when it is possible to block one of the pathways driving an autoimmune reaction, the immune signal still mostly persists since it only requires the messengers that have not been blocked to reach their targets.

While an argument could be made that blocking even one pathway should provide some relief, since the strength of the signal causing the immune response should be diminished, in practice, this is not what has been observed. What patients need is more comprehensive modulation of all malfunctioning pathways, and while this may theoretically be possible through a “cocktail” of mABs, ultimately, such a therapeutic regimen would be impractical for a number of logistical reasons including cost, mode of administration, and regulatory complexity.