Unravelling the Causes of Type 1 Diabetes

Although not common, there are a couple type 1a diabetics living among us in school. It is an autoimmune disease resulting in a person’s CD4+ and CD8+ T-lymphocytes attacking and destroying the β-cells in the pancreas (β-cells are responsible for producing insulin). This results in the patient having hyperglycaemic and hypoglycaemic issues. Why this happens in humans is not precisely known. However, there are models, such as the non-obese diabetic mouse (NOD mouse), that explain the progression and pathogenesis of the disease. The β-cell antigens are presented on antigen presenting cells (APC); this activates the autoreactive CD4+ cells and the CD8+ cells, causing them to attack the β-cells. CD8+ cells are considered the primary effector in the destruction of β-cells as they
release enzymes such as perforin and granzymes. Perforin forms pores in the cell surface membrane, allowing granzymes to get in and induce apoptosis. The destroyed β-cells release cytokines and autoantigens, giving positive feedback and, therefore, attracting more CD8+ cells to the area, causing inflammation. Even when the pancreas tries to reconstruct the β-cells, they trigger more of the apoptosis of the β-cells since the β-cells are more susceptible to apoptosis during that time. The chronic inflammation and destruction of β-cells caused by the autoimmune attacks causes insulin production to decrease exponentially. This means that the insulin receptors don’t bind to enough insulin, and certain downstream signalling pathways are not activated, resulting in cells not being able
to utilise and uptake glucose. Type 1b is caused by an unknown destruction or failure of β-cells, which is much rarer than type 1a as approximately only 5% of patients suffering from T1D have it. In this essay, I will be covering the genetic and viral causes of T1D.

The exact causes of T1D are unknown. However, genetics do play a huge role in the development of T1D in children (around 50%). There are specific haplotypes (a set of DNA variants from a single parent) located at chromosome 6p21.3 that have a high probability of causing T1D. The variants include HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes, all belonging to a family of genes known as the human leukocyte antigen (HLA) complex (HLA is the same as MHC, just specific to humans). The combination of all these increases the chances of a person getting T1D. These genes are found within the human major histocompatibility complex (MHC). The amino acid in the 57th position of HLA-DQB1, when substituted, causes a major increase (15%) in the risk of acquiring the disease. Amino acid substitutions in the other genes contribute to the remaining 27-34% of risks. Outside of MHC genes, there are a lot of other loci (locations on the chromosome) that contribute to
increased risk. The genome-wide association studies have identified more than 80 of these non-MHC genes, including mutations in the INS and CTLA4 genes.

Mutations in the HLA gene of the pancreatic beta cells cause the immune system to attack the cells. As antigen-presenting cells bind to these unrecognised/mutated antigens, they enable T-lymphocytes to recognise and attack them. In normal β-cells, like any normal cell, HLA class I is found; this is a protein expressed on the cell surface membrane to allow CD8+ cytotoxic t-killer cells to recognise whether a cell has to be killed or not. However, in patients with T1D, HLA class II is also found on β cells, allowing CD4+ T helper cells to coordinate further attacks on the local site.

Viruses could also trigger an attack on the β-cells. Scientists have identified several viruses that might contribute to T1D. The ones with the most sufficient evidence are the Human Enteroviruses (HEV), such as Echoviruses (E11) and CVBs. HEVs are viruses that infect the gastrointestinal tract; they could be transmitted via contaminated water, coughs or sneezes of an infected person, physical contact or skin blisters. While the pathogenesis does not directly explain the persistence of the infection, the microenvironment might play a part in it. β-cells possess a distinctive surface receptor called CAR. The isoform (a variant of the CAR caused by splicing) of this protein that is specific to the virus and is highly expressed on insulin-secreting granules when fusing with the surface membrane, is referred to as CAR-SIV. The HEVs take advantage of this receptor and enter the β-cells
through a Trojan horse mechanism. During exocytosis of insulin granules produced by the β-cells, the exposed CAR-SIV is taken advantage of by the virus; then, the virus enters the cell through endocytosis, where it can be transferred into the cell, allowing it to replicate further.

After the initial infection of the β-cells, the proliferation of the virus could be caused by defects in the immune system. If the immune system is healthy and manages to rid the cells of the virus, then the infection stops. However, if the immune system is impaired, the virus can utilise the host cell for productive lytic infection cycles. This is a mechanism of the HEVs where they infect a cell, then
replicate into virions (fully assembled infectious viruses), and cause the cell to burst, resulting in the release of the virions and the infection of other cells. In people with genes susceptible to T1D, this could initiate the autoimmune response. There is one more condition where the host’s cells could actually promote the persistence of the virus. In patients where their immune system could only
partially inhibit the viral replication, a persistent infection might develop as the virus starts making double-stranded RNA (dsRNA) responsible for the overexpression of interferons (the primary cytokine) and the presentation of HLA class I molecules on the cell surface membrane, leading to the autodestruction of β-cells.