Degenerative diseases occur through several overarching mechanisms. Errors happen all the time, either spontaneously or through promotion due to an outside factor such as UV radiation or chemicals. Usually, the body is able to catch these errors as they occur and prevent them from piling up, using some of the mechanisms already outlined above. There are several instances where the body’s surveillance mechanisms do not work as expected, which can cause errors.
These errors in surveillance can be classified into four major groups. The first example of a surveillance error is when that surveillance system is reduced. Surveillance can also become overwhelmed and, thus, ineffective. Surveillance mechanisms can make mistakes in what it is they are targeting, such as those observed in auto-immune diseases. Finally, surveillance can become overexcited. In the course of my class, students will explore many different NCDs. As such, I have decided to showcase only a few diseases in this introductory unit as examples that highlight and model how these specific errors can cause disease.
It is also important to note that these errors do not always fit neatly into a category. Many times, there are multiple levels of surveillance error at work that lends itself to the formation of a particular disease. As such, some diseases may be mentioned multiple times. Each particular disease must be studied
in situ
to determine the specific mechanisms that may cause it to arise.
Surveillance is Turned off or Broken
Errors are constantly being made in the body, however the various surveillance protocols in place are able to catch and repair a majority of these mistakes before they become an issue. As a person ages, the surveillance mechanisms lose efficiency or are turned off. This process of cell mortality is called senescence. Encoded in the cells that are responsible for maintaining surveillance of our bodies are specialized sections called telomeres. Every time a cell divides, the telomere shortens. Over time, surveillance begins to break down, as do the rest of a person’s cells, resulting in aging.
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This process allows more and more errors to accumulate until eventually the body is no longer removing offending proteins. For example, through-out a person’s lifetime the body is constantly making the amyloid proteins that are responsible for the plaques associated with Alzheimer’s disease.19 These proteins, however, are targeted for degradation by surveillance mechanisms and are removed before they can aggregate and cause real damage.
In human papilloma virus (HPV), surveillance is turned off through another method. HPV infects squamous epithelial cells of the cervix where it can cause cervical cancers. HPV-16, the strain that is most representative in cervical cancers—integrates into the host DNA.
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Along with the other genes in the viral genome, it also has two oncogenes which, when translated, destroy the human tumor suppressor gene p53.20
Tumor suppressor genes like p53 are important quality control proteins used to halt cellular division when there are errors in the DNA. In the cell cycle, it is important for DNA to be error free when it is being copied. If there are mistakes in the copying of DNA or if part of the genome is missing or damaged, there can be deleterious effects on the daughter cells.20 P53 causes cell cycle arrest. If the damage is unable to be fixed, p53 will then mark the cell for apoptosis, preventing the error from being passed into the daughter cells.20 When p53 is down-regulated, mutations can accumulate, leading to the formation of cancerous cells.
HPV, and other cancers, can turn off this quality control mechanism either by expressing proteins that cause p53 to be destroyed or by preventing p53 from forming correctly. In HPV, one of the viral genes E6 binds to an ubiquitin ligase which in turn bind to p53.20 This complex is then destroyed by a proteasome complex in the host cell.
Surveillance is Overwhelmed
One example of the surveillance system becoming overwhelmed is with the introduction of advanced glycation end products (AGEs) or glycotoxins. AGEs, can be found in most modern diets if they contain processed food items. These compounds are found in animal-derived products that are higher in fat and protein content. As the foods are cooked, more of these compounds are developed and, eventually consumed. These glycotoxins can also form within the human body through a multi-step process
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AGEs develop when a sugar reacts with a protein. This forms when the glucose binds to a lysine or arginine found in a compound like a lipid, protein, or even DNA. This develops a Schiff base-- a complex that has a carbon-nitrogen double bond. The Schiff bond then forms a secondary compound called an Amadori product which has the ability to form crosslinks with other proteins.
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This is a slow process that can take months and it is irreversible. These compounds are especially dangerous because they accumulate within the cell and inhibit normal cellular function. Within the tissues of the body, they can cause inflammation.
These compounds are known to cause several different NCDs including diabetic nephropathy
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, cardiovascular disease
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, and the formation of amyloid beta proteins found in Alzheimer’s disease
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. In diabetic nephropathy, AGEs bind to the receptors on the cell surface, limiting the ability of nerve bundles inhibiting their normal function.
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This may lead to many of the neurological complications of diabetes including loss of vision and painful tingling in the extremities. The link between cardiovascular disease and AGEs involve the ability of AGEs to form stiff cross-linked structures with collagen. In the arteries, AGEs bind to the walls, decreasing their elasticity which can lead to heart failure.
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In Alzheimer’s disease, AGE modifies the amyloid beta seeds, which increases the aggregation of these plaques in the brain.
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A key way to prevent the formation and possibly break the bonds between AGEs and their linked compounds is through the use of AGE-inhibitors. Currently, ALT-711 has been found to increase elasticity in cardiac tissue, improve the hydration of the epidermis, and potentially prevent secondary diabetes related conditions like renal failure.27 While it is unlikely ALT-711 will completely undo the damage caused by AGEs on the body’s tissues, it may restore some of the functionality of affected areas.27
A second series of diseases that deal with the overwhelming of surveillance mechanisms are those dealing with protein misfolding and recruitment. Proteostasis, the combination of the words protein and homeostasis, is responsible for the suppression of protein aggregations or plaques
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. This series of pathways is responsible for removing proteins that are misfolded. As previously mentioned, one of the pathway is the ER unfolding response that is responsible for tagging misfolded or unfolded proteins for removal and degradation. When these proteins are not removed and enter into the body tissues, they can overwhelm the correct phenotypes, causing disease.
There are many different types of diseases that are related to protein folding mistakes including cystic fibrosis, Huntington's, and the previous disease we covered Alzheimer’s.
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Unlike Alzheimer’s, which occurs when the surveillance mechanisms are turned off over time, the proteostasis diseases that follow occur when the network is overwhelmed and is unable to keep up with the removal of misfolded proteins. As these proteins build up in the tissues, they overwhelm the correctly folded protein and cause disease.
Two very similar examples of proteostasis diseases that overwhelm the body’s surveillance mechanisms are Kuru or new variant Creutzfeldt-Jacob’s Disease (nvCJD). In both of these diseases, the patient come into contact with a misfolded protein called a prion. A prion is more stable the native protein and yet it is in a shape that rarely occurs by itself. Most native proteins are only weakly stable, probably to allow for functional degradation by the cell.
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However, prions are highly resistant to degradation because of the repeating side chains that form beta sheets. This makes it difficult to remove prion proteins from the body. Furthermore, when the normal protein comes into contact with the disease shape, this ends up converting the native protein into more of the disease shape.31
In these diseases, a person comes into contact with tissue that has prion proteins—human brain tissue in Kuru or tainted beef in nvCJD-- that contains these prion proteins. These prion proteins migrate to the brain in a currently unknown mechanism where they act as a “seed”, recruiting healthy brain proteins to refold into prion protein amyloid plaques.31 This process does not happen automatically—it may take years for the formation of these amyloid plaques. However, when it does occur, it is a rapid process which overwhelms the body’s ability degrade proteins and is often difficult if not impossible to treat.
Surveillance is Hypersensitive
Allergies are an example of the body’s surveillance system becoming overexcited. The immune system, as previously explained, is constantly surveying the internal environment for any harmful particles that do not belong. If a person is exposed to a particular particle, or antigen, over time they may develop a hypersensitivity to it even if that particle is not harmful. Particles that cause hypersensitivity might be exogenous like pollen or dander, or endogenous like the tissues in your cells or a piece of peanut that was eaten.
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Normally, these particles would interact with the body and not trigger any problems with the immune system. In people with allergies, or Type 1 hypersensitivity, contact with a particle that they have become sensitized to triggers a number of reactions.32
When an allergen enters the body, it is identified by B cells. These B cells begin producing IgE, a type of immunoglobulin that is released to protect against parasites and other foreign agents. IgE will then interact with mast cells. When this happens, mast cells react by releasing histamine. Histamines cause an inflammatory response in tissues, causing the area to swell.32 This response usually happens a few minutes after exposure to the antigen. A few hours after the exposure, cytokines also enter the tissue, which may cause additional swelling.32 Depending on the severity of the hypersensitivity, a person may experience a wide variety of symptoms from itchy, runny eyes to anaphylaxis.
Surveillance Makes a Mistake
As previously discussed, part of our body’s natural defense system is the ability to recognize self vs non-self. This step is crucial in the recognition of foreign antigens and removing them before they can cause harm to tissues. The immune system does a decent job at targeting molecules that have foreign antigens and developing strategies for dealing with the same infection should it reappear. However, the immune system can become overzealous in its duty and may actually attack normal, healthy somatic cells due to a case of mistaken identity. This type of reaction is very similar to the reactions shown above in hyperactive surveillance. Just like with allergies, the body mistakes a protein as harmful when it isn’t, triggering an immune response. This type of sensitization is classified as Type 2 hypersensitivity or autoimmune cytotoxic events. In autoimmune diseases, the body turns on itself and attempts to damage healthy tissue after mistaking it as foreign.
Autoimmune diseases form for a variety of reasons. If the immune system is exposed to a bacteria or a virus that presents an antigen, it develops antibodies that are targeted to that specific epitope. After the foreign agent is removed from the body, the memory of that antigen remains, preparing the body to respond should infection by the same agent recur.
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The trouble lies with antigens that have epitopes that are very similar to the protein markers embedded in body tissue. In the case of autoimmune diseases, the body is now over-sensitive to these markers and, instead of recognizing them as ‘self’ tissue and leaving them alone, attack those tissues. This can lead to a number of autoimmune conditions, depending on the particular disease.
One example of this occurs as through a combination of a primary infection with the sexually transmitted infectious agent chlamydia in persons with the presence of genetic factor HLA-B27.
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Chlamydia trachomatis
bacteria are passed between an infected individual and their partner during sex. This bacterium can cause burning, itching sensations in the genitals and is often treated using antibiotics.34 The immune system also responds to the infection by producing T cells that interact with infected cells and lymphocytes that respond to the epitopes that are found on the bacteria’s surface.34 This infection leads to long term immune memory against the particular antibodies found on chlamydia by the adaptive immune system. CD4+ T cells, a special subset of the immune T cells, circulate through the body looking for chlamydia after the infection has been cleared up as a way to defend the body against further attack.34 Unfortunately, in a disorder known as Reiter’s syndrome, these T cells cause a reactive response by these same cells against synovial joints in the body, causing arthritis.34
There is a similar relationship between diabetes and an enterovirus like Coxsackievirus. The exact relationship between viruses and type 1 diabetes is not fully understood and there are still conflicting theories about the exact involvement, however it is believed that the specific CVB4 enterovirus plays a role in activating the immune system. In fact, one experiment was able to use isolated CVB4 from a type 1 diabetic and induce diabetes in mice.
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It is believed that CVB4 infects the islet cells of the pancreas using receptors that are on the cell’s surface. After the infection is cleared it, it is believed that the T cells are still primed and now attack the cells of the pancreas, inhibiting their ability to produce insulin.
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Much is still unknown about this exact process.
