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The type of immunopathology that is associated with virus induced Type 1 Diabetes.
Diseases are most often associated with specific immune responses and immunopathology is the branch of medicine that focuses on and tries to explain these associations. It deals with dysfunctions or “failures” that occur with the various immune responses of immunity. These dysfunctions can be categorised as immunodeficiency, hypersensitivity and autoimmunity. (Dr Russell Watkins, 2009) For the purposes of this research, autoimmunity will be discussed as this is the type of immunopathology that deals with virus induced type 1 diabetes.

Autoimmunity is a condition that involves the loss of the immune system’s natural ability to be immunologically tolerant to autoreactive immune cells and hence the organism produces an abnormal response to its own tissues where the individual’s own immune system initiates an attack against itself instead of the antigen. It is the inability of the cells that are involved in the immune response to recognize or differentiate between self and non-self-antigens. (Kawasaki, 2014) Or in other words, it is the loss of tolerance to self. It involves self-reactive T-cells and autoantibodies (autoreactive T and B cells) that are suppressed during normal functionality of the immune system after the positive (in the cortical region of the thymus) and negative (in the medulla region of the thymus) selection processes has been completed. (Smith and Germolec, 1999)

Positive selection, selects for the survival of T cells that contain receptors that allow them to recognise and bind to self-MHC class I or class II molecules. This occurs when the T cells (CD4+ and CD8+) are exposed to epithelial cells that express the self-MHC class I and class II molecules. (Kawasaki, 2014) Programed cell death eliminates those of T cells that do not bind to the MHC molecules and those that bind goes on to become differentiated into CD4 (those associated with MHC class II) and CD8 (those associated with MHC class I). (Kawasaki, 2014) CD4 and CD8 then move to the medulla of the thymus where they are exposed to the self-MHCs and autoantigens to undergo the negative selection process. The CD4 and CD8 (T cells) that bind with high affinity to the autoantigens are eliminated via programed cell death that is TCR-mediated and those that bind with low affinity is suppressed in the peripheral lymphoid tissues. (Smith and Germolec, 1999)

However, there are a few cases where these autoreactive T cells escape the processes of positive and negative selection and become activated. These activated autoreactive T cells are the ones that are responsive to self-antigens and causes or results in malfunction / defects in either the innate or the adaptive immune response that can then encourage disorders (diseases or illness). Autoimmune diseases can be divided into two categories, organ specific and systemic. Note that autoreactive B lymphocytes may also be involved in the development of autoimmune diseases via association with the activated autoreactive T cells. (Smith and Germolec, 1999)
As said before, autoimmune diseases can be classified into two groups, organ specific autoimmune disease, which are those where the autoreactive antibodies and T-cells react to target self-antigen that are localized in one specific tissue / specific organ resulting in either thE damaging of the organ or inhibition or over stimulation of its function. For systemic autoimmune diseases however, the target self-antigen or antigens are widely distributed in several tissues throughout the body and the damage is therefore distributed over the several tissues (Smith and Germolec, 1999). See Appendix A for examples of autoimmune diseases.

Global prevalence of autoimmunity
The prevalence and incidences of autoimmune diseases are increasing around the world. According to evidence provided by epidemiological data, Westernized societies has been a faced with a steady significant increase in the prevalence of autoimmune diseases over the last few decades (30 years). (Forouhi and Wareham, 2014) Various studies and observations in selected migrant population has also shown that there is a relationship between the socioeconomic status and the rapid increase in the occurrence of autoimmune diseases. This also indicated that there may be some form of impact from various environmental factors such infection, ecology and nutrition and not just the long-term genetic influence which are driving these processes. Western dietary habits, environmental surroundings and pollution exposure, infectious habitats and stress load all have led to a parallel rise in autoimmune diseases. (Forouhi and Wareham, 2014)

Another specific research project obtained results, such that the net increased incidences / prevalence of autoimmune diseases in Northern and Western countries compared the Southern and Eastern one follows the global geo-epidemiological trends of autoimmune diseases.
Latest estimates show a global prevalence of 382 million people with diabetes in the year 2013 and it was expected to rise to 592 million by the year 2035, where type 1 diabetes accounted for ~15% of the total diabetes prevalence. (Guifeng Xu, 2018) Type 1 diabetes is one of the most chronic diseases in childhood and the incidence is increasing especially in children of ~14 years of age (Forouhi and Wareham, 2014) and is diagnosed at an increasing rate in adults. See Appendix B the general increase in the prevalence of autoimmune diseases.

What is Type 1 Diabetes
Type-1 diabetes can be defined as an autoimmune disease in which the immune system CD4+ and CD8+ T-cells (autoreactive cells) are activated and they can identify pancreatic insulin producing ?-cells and destroy them. (Gustaf Christoffersson, 2016). Insulin producing ?-cells that is located in the islets of Langerhans within the pancreas have the ability to package, synthesize as well as secretes the hormone insulin. Insulin in the body aids in helping the glucose in the bloods to be delivered to the cells and cells utilize the glucose molecules as energy. Absence of insulin in the body leads to an alarming hyperglycemia levels in patient results in clinical diagnosis of type-1 diabetes. So therefore type-1 diabetics will rely on exogenous insulin. (Elizabeth Blair, 2016).

The first evidence serologically of an autoimmune response towards beta cells of the pancreas is the development autoantibodies due to abnormal trigger of the immune system. After some time, the presence of autoantibodies in the body functions against the proteins present in Beta cells (Kimber M Simmons and Aaron W Michels, 2015). Autoantibodies can be measurable in serum prior the diagnosis of type-1 diabetes; hence type-1 diabetes can be considered as a predictable disease. There are four known biochemical islet autoantibodies, which are: islet antigen-2, glutamic decarboxylase (common in adults), Insulin autoantibodies (mIAA-first to appear in young children) and zinc transporter-8 (Kimber M Simmons and Aaron W Michels, 2015). Evidence have reported that ninety percent (90%) of individual that develop two or more autoantibodies are clinically diagnose with type-1 diabetes, however other 10% of the individual that have develop autoantibodies may fight against antigens that have not yet been discovered. Usually the first autoantibody to evolve in children is the insulin-IAA autoantibody, a continuous high levels of this autoantibody in children progresses unto the development of type-1 diabetes. However, in adult individuals that is diagnose with type-1 diabetes have high levels of the autoantibody glutamic decarboxylase (Kimber M Simmons and Aaron W Michels, 2015). See appendix C for the clinical symptoms associated with type 1 diabetes.

Therapies available for Type 1 Diabetes
The therapy is lifelong administration of exogenous insulin is introduced into the body of type-1 diabetics via injection of the insulin and by insulin pumps. (JDRF International, 2016)
For the injection of insulin, the injection can be carried out by the used of insulin pen, fine needle and syringe. Injections of insulin is required multiple times of the day and night, however the frequency and the type of insulin dosage when injecting usually varies based of the case of the patient. The types of insulin are: short- acting insulin, rapid-acting insulin, long-acting insulin and intermediate-acting insulin (JDRF International, 2016).
? Short-acting insulin- this kind of insulin is administered about 30 minutes prior meal intake to control blood glucose elevation after meal, this type of insulin is administered along with long-acting insulin (controls blood glucose throughout the day). The effect of short-acting insulin work as long as 12 hours. (Elizabeth Blair, 2016)
? Rapid-acting insulin- this king of insulin is administered right before meals to counteract the carbohydrate intake, this insulin is paired with long-acting insulin (controls blood glucose throughout the day). The effect of rapid-acting insulin work as long as 3 to 5 hours (Elizabeth Blair, 2016).
? Long-acting insulin- this king of insulin is administered once or twice daily and this insulin is merge with rapid-acting or short-acting insulin. This insulin controls blood
glucose throughout the day when the effect of rapid-acting insulin ceases. The effect of long-acting insulin work as long as 24 hours (Elizabeth Blair, 2016).
? Intermediate-acting insulin- this king of insulin is administered twice daily and it controls blood glucose elevation when the effect of rapid-acting insulin ceases. This insulin is usually combined with rapid insulin (counteract the carbohydrate intake after meals) or short acting insulin (control blood glucose elevation after meal). The effect of intermediate-acting insulin work as long as 24 hours (Elizabeth Blair, 2016).

For insulin pumps, this device is approximately the size of a cell-phone, the insulin pumps have up to 300 units of insulin present in its reservoir and to the reservoir there is a tube that connected to a tiny catheter (Kandaswamy Jayarag, 2001). The catheter is the part of the pump that is inserted subcutaneous layer of the arms, thigh, abdomen and buttocks. The insulin imitates a normal healthy pancreas, half the amount of insulin that is secreted is for basal secretion that have control over the output of hepatic glucose and the other half amount of insulin is secreted as boluses that are meal-related which have control over the postprandial hyperglycemia (Kandaswamy Jayarag, 2001). The main purpose is to keep the glucose levels in the blood within a healthy range. The insulin pumps are electrically control which are designed to automatically and continuously liberate a particular or small amount of insulin doses. The doses of basal insulin are pre-set by the patient and the doses usually vary throughout the day. For the boluses, prior to the intake of meals the boluses insulin can be calculated by the patient (Kandaswamy Jayarag, 2001).

Causative Agents
The diet and viral infections have been implicated as the causes of type 1 diabetes. Vitamin D was once thought to be a factor that triggers ?-cell autoimmunity because in Northern Europe where the amount of sunlight varies, type 1 diabetes have been the highest. Studies showed that in infants who did not substitute that lack of natural vitamin D from the sunlight by taking them orally, their likelihood of acquiring type 1 diabetes had increased. However, this relation of the disease to vitamin D deficiency have been ruled out by two arguments; vitamin D intake in Northern Europe was recommended to be given at infancy and more than 95% of parents did follow suit and incidence of type 1 diabetes was still low in some other regions in Northern Europe such as Russian Karelia (Knip et al 2005).

Where the diet is concerned, there is thought to be a link between cow’s milk and the disease. This is because in developed countries, cow’s milk is one of the first sources of dietary protein. In a study that was done, it was found that infants who were given cow’s milk before the age of 3 months had higher levels of IgG antibodies that were produced in comparison to infants that were breastfed at that same age. However, following this, the levels of antibodies started to decrease as they started to develop a tolerance. Those infants who did breast feed in their first three months were given cow’s milk subsequent to that and the levels of IgG antibodies started to increase until they reached 12 months, after which it leveled off. This observation indicated that the tolerance to bovine insulin (which is present in the milk) had not yet been developed leading to early signs of ?-cell autoimmunity. Studies were also done to test the relation between the disease and cow’s milk as a causative factor in older children. Results from such studies have been conflicting, as there was some evidence in Finland, of diabetes associated autoantibodies and the disease present in children who were initially unaffected but had consumed high amounts of cow’s milk. These children had siblings who do have the disease. In a Swedish population on the other hand, children who presented with the disease had consumed lower amounts of cow’s milk than those who were unaffected. There is need for further research to confirm the relatedness of cow’s milk in the implication of type 1 diabetes (Knip et al 2005).

There are several viruses that have been reportedly associated with type 1 diabetes development in humans such as the coxsackie B virus, cytomegalovirus, rubella virus, mumps virus, Epstein-Barr virus and Varicella Zostar virus. The enterovirus family particularly echoviruses 4,6,9,14 and 30 among others have been identified as causes of type 1 diabetes and are shown to impair or kill human beta cells (Ghazarian, Diana, Simoni, Beaudoin and Lehuen 2012, 246).

The major difficulty in proving the direct role that enteroviruses play is the interval between when the infection occurs and onset of type 1 diabetes. A link between enteroviruses and Type 1 diabetes have been determined by more than 24 retrospective and prospective studies. A Finnish study in 1995 showed that antibodies produced against enteroviral antigens were more frequent in siblings who developed T1D than those who did not have diabetes. Another Finnish study showed that 57% of the cases had developed autoantibodies 6 months after infection. In a Finnish trial enteroviral RNA was detected more frequently in children who developed autoantibodies than in children who did not. In the US a study referred to as DAISY was conducted on 2,365 at risk children, of which 140 developed autoantibodies. Of these 140 children, 61% that had the enteroviral RNA developed T1D and 28% did not possess the RNA (Ghazarian, Diana, Simoni, Beaudoin and Lehuen 2012, 245). In the United Kingdom a study was conducted which outlined the importance of also using peripheral blood mononuclear cells rather than just serum. This was because in using peripheral blood mononuclear cells 4 out of 10 patients with T1D were found to have enteroviral RNA compared to the 2 out of 10 in serum (Ghazarian, Diana, Simoni, Beaudoin and Lehuen 2012, 246).

It was previously thought that the Coxsackie B virus was able to induce type 1 diabetes in humans by molecular mimicry because the sequence of its P2-C protein is similar to the GAD65 that is expressed by beta cells, however this was later ruled out by further studies (Ghazarian, Diana, Simoni, Beaudoin and Lehuen 2012, 246). A significant body of evidence for the association between viral infections and autoimmune diabetes comes from investigations using animal models (Filippi and Herrath 2008).

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