Type 1 Diabetes Autoimmune Disease

Autoimmune Diseases Associated With Type 1 Diabetes

Type 1 diabetes research at Garvan

Type 1 diabetes is an autoimmune disease in which the immune system destroys the pancreatic cells that make insulin. Autoimmune diseases are linked together by a certain genetic predisposition to produce antibodies that attack certain organs in particular. Therefore, it is not unusual for Type 1 diabetes to be accompanied by other conditions.

Inconsistencies In The Role Of T Cells

A different stand on a role of T cells in the pathogenesis of T1DM can easily be defended . Islet autoreactive T cells are common in the healthy population, and nine out of ten individuals with islet autoantibodies will never develop T1DM,,. Most patients with T1DM have immune regulation that is indistinguishable from that of healthy individuals, and over 99% of patients with cancer who are treated with immune checkpoint inhibitors do not develop T1DM,,. Furthermore, some patients with T1DM present with negligible T cell autoimmunity. Moreover, induction of autoimmune diabetes mellitus in mice by vaccination with islet autoantigens is very difficult, if not impossible. Even when transduction of human islet autoreactive TCRs in humanized mice leads to high frequencies of T cell autoimmunity to islets, no diabetes mellitus was induced. In addition, thus far, progression of T1DM has not been found to accelerate after patients with T1DM are injected with islet autoantigens,,,. Of note, HLA upregulation as an early sign of islet distress frequently occurs without inflammation, even if -cells are still present,, while insulitis is a rare feature in individuals who have islet autoantibodies but not T1DM. Furthermore, immunotherapies in T1DM have not yet shown a durable effect on disease progression. These inconsistencies in our understanding of the critical role of islet autoimmunity, and T cells in particular, require reconciliation.

Pathogenesis Of Type 1 Diabetes Disease In Humans

Although there is extensive information on the pathogenesis of autoimmune diabetes in the NOD mouse and the BB rat, there is relatively little direct information on the pathogenesis of type 1 diabetes in humans. In fact, many of our ideas about the pathogenesis of human type 1 diabetes are the result of extrapolation from rodents. The NOD mouse has proved to be an excellent model for studies on autoimmunity, but there are considerable differences between the mouse model and the human disease, and direct information on etiology and pathogenesis at the human level is still needed.

Of great importance, but still unresolved, is whether the infiltrating inflammatory cells themselves express cytokines that lead to cellular cytotoxicity or autoantibody formation. A cocktail of IL-1, INF-, and TNF- is known to be toxic to human islet cells in vitro . ELISPOT or soluble HLA class II tetramer assays might be used to characterize the responses of individual peripheral or infiltrate-associated T cells and should help resolve the role of these cytokines. An alternative approach, although perhaps less convincing, is the measurement of immunoglobulin isotypes, which are thought to be surrogate markers for identifying Th1 and Th2 responses. These studies have shown that the autoantibodies to IA-2 and GAD65 are primarily of the IgG1 isotype, which argues in favor of a cytotoxic, Th1-type immune response in autoimmune type 1 diabetes .

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What Happens To The Pancreas

In type 1 diabetes, the pancreas, a large gland behind the stomach, stops making insulin because the cells that make the insulin have been destroyed by the bodys immune system. Without insulin, the bodys cells cannot turn glucose , into energy.

People with type 1 diabetes depend on insulin every day of their lives to replace the insulin the body cannot produce. They must test their blood glucose levels several times throughout the day.

The onset of type 1 diabetes occurs most frequently in people under 30 years, however new research suggests almost half of all people who develop the condition are diagnosed over the age of 30. About 10-15 per cent of all cases of diabetes are type 1.

T1dm As An Autoimmune Disease

A connection between the immune system and T1DM was first suggested in 1973, when HLA antigens were found to be associated with insulin-dependent diabetes mellitus but not with insulin-independent diabetes mellitus. Since then, genome-wide association studies have confirmed that HLA genes account for up to 50% of the genetic risk of T1DM , which suggests that the selective presentation of specific autoantigen peptides is involved in the pathogenesis of T1DM,,. Meta-analyses have also linked non-HLA high-risk polymorphisms within INS-VNTR , PTPN22, CTLA4 and IL2RA with a reduction in central and peripheral immune tolerance to self and increased T cell activation and proliferation,,,, which emphasizes the participation of the immune system in the development of T1DM.

During the development of T1DM, seroconversion of islet autoantibodies to insulin, glutamate decarboxylase, insulinoma antigen 2 or zinc transporter 8 represents the first notable sign of autoimmunity and their combined presence in serum remains the best predictor for both loss of immune tolerance and clinical manifestation of T1DM, albeit that their role in -cell destruction remains unclear,. During disease progression, immune cells that infiltrate the pancreas and target insulin-producing cells create an inflammatory environment characteristic of insulitis that triggers and accelerates T1DM development by increasing exposure of islet antigens presented by HLA class I molecules to the immune system,,, .

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What Happens In The Body Of A Person With T1d

People are typically diagnosed with T1D after showing symptoms . As the body becomes incapable of creating insulin, which allows the body to use the sugar found in food, called glucose, as energy, people with T1D must work closely with their endocrinologists to determine the insulin doses and lifestyle changes needed to manage their blood-sugar levels.

If not treated properly, people with T1D are vulnerable to health issues ranging from minor to severe. Most people with T1D spend the majority of their time with blood-glucose levels outside the recommended healthy range, which can lead to potentially deadly episodes of hyperglycemia and hypoglycemia . Chronic high blood sugar often causes devastating health complications later in life, including blindness, kidney failure, heart disease and nerve damage that can lead to amputations.

Triggers Of Type 1 Diabetes

Both genetic and environmental factors have been implicated as triggers in the pathogenesis of type 1 diabetes. Of particular importance are the HLA genes that are involved in antigen presentation. While certain HLA haplotypes, such as DQA1*0301B1*0302 and A1*0501B1*0201, are positively associated with type 1 diabetes, others, such as DQA1*0102B1*0602, are negatively associated with type 1 diabetes . The positive association is far from absolute and, in fact, decreases in strength with increasing age of onset . Similarly, the negative association does not eliminate the possibility of developing type 1 diabetes but appears to slow the process and makes the development of the disease unlikely before age 30. Although the binding of antigens to different HLA molecules has been extensively studied, why some HLA haplotypes are positively associated and others negatively associated with type 1 diabetes is not clear.

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What Causes Type 1 Diabetes

Type 1 diabetes is thought to be caused by an autoimmune reaction . This reaction destroys the cells in the pancreas that make insulin, called beta cells. This process can go on for months or years before any symptoms appear.

Some people have certain genes that make them more likely to develop type 1 diabetes. However, many of them wont go on to have type 1 diabetes even if they have the genes. A trigger in the environment, such as a virus, may also play a part in developing type 1 diabetes. Diet and lifestyle habits dont cause type 1 diabetes.

Box 3 Evidence Supporting A Role For

Type 1 diabetes (autoimmune diabetes) | cause and consequences

Smaller size of pancreas and islet mass in patients with type 1 diabetes mellitus and individuals at risk

Studies of human insulitis have revealed that danger signals from stressed -cells might precede insulitis. Among these signals, hyper-expression of HLA class I was noted across pancreata from patients with newly diagnosed T1DM. In addition, islets secrete the chemokine CXCL10, attracting leukocytes expressing its receptor CXCR3 to the lesion. This chemokine production by stressed -cells might present a master switch of islet inflammation and has attracted interest from the pharmaceutical industry as an opportunity for intervention therapy. Other strategies include efforts to reduce -cell stress with verapamil, where early studies have shown promise for delaying T1DM disease progression. Intriguingly, high levels of insulin-specific autoreactive human T cells only precipitated insulitis and selective -cell destruction in humanized mice in vivo after the mice had been vaccinated with insulin peptide to prime an autoimmune response and subjected to low-dose streptozotocin to stress the -cells. This finding underscores the need for -cell perturbation and loss of autoimmune tolerance to -cells to create a perfect storm that causes their destruction.

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What Is Juvenile Diabetes

Juvenile diabetes can occur at any age. It is most often diagnosed in children, adolescents, or young adults. Insulin is a hormone produced in the pancreas by special cells called beta cells. The pancreas is below and behind the stomach. Insulin is needed to move blood sugar into cells. Inside the cells, glucose is stored and later used for energy. With type 1 diabetes, beta cells produce little or no insulin. Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. This buildup of glucose in the blood is called hyperglycemia. The body is unable to use the glucose for energy. This leads to the symptoms of type 1 diabetes. The exact cause of type 1 diabetes is unknown. Most likely it is an autoimmune disorder. This is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. With type 1 diabetes, an infection or another trigger causes the body to mistakenly attack the cells in the pancreas that make insulin. The tendency to develop autoimmune diseases, including type 1 diabetes, can be passed down through families.

Type 1 Diabetes: Is The Immune System Weakened

Immune system dysfunction is often referred to as immune deficiency, also known as immunodeficiency or immunosuppression. This happens when the immune system fails, in whole or in part, to fight off foreign agents, which increases vulnerability to infections. Immunodeficiency can be present at birth or occur later in life .

People with autoimmune diseases such as type 1 diabetes are not usually considered immunocompromised unless they are taking certain drugs that slow down their immune system .

Even though the immune system of people living with T1D is dysfunctional, the bodys ability to defend itself when necessary remains unaffected. However, elevated blood sugar levels can reduce the effectiveness of immune defences and feed certain aggressors such as bacteria.

In short, T1D is an autoimmune disease that does not directly involve immunodeficiency.

References :

Kahaly, George J, and Martin P Hansen. Type 1 diabetes associated autoimmunity. Autoimmunity reviews vol. 15,7 : 644-8. doi:10.1016/j.autrev.2016.02.017
Critchley, Julia A et al. Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study. Diabetes care vol. 41,10 : 2127-2135. doi:10.2337/dc18-0287
Carey, Iain M et al. Risk of Infection in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study. Diabetes care vol. 41,3 : 513-521. doi:10.2337/dc17-2131

Type 1 Diabetes And Autoimmune Thyroid Disease

It is well known that T1D is frequently associated with other organ-specific autoimmunediseases, including autoimmune thyroid disease , pernicious anemia, and idiopathicAddisons disease . Table 1 summarizes the prevalence of organ-specific autoimmune disease complicatingT1D in Japanese and Caucasoid patients . InJapanese patients with T1D, the most common coexisting organ-specific autoimmune disease isAITD . The prevalence of anti-thyroid autoantibodies in children with T1D atdisease onset is about 20%, and anti-thyroid autoantibodies are particularly common ingirls. Furthermore, it is reported that the prevalence of anti-thyroid antibodies increaseswith increasing age and that the presence of anti-thyroid antibodies at diagnosis of T1Dpredicts the development of future thyroid disease . Patients with anti-thyroid antibodies are 18 times more likely to developthyroid disease than patients without anti-thyroid antibodies . Therefore, for early detection of AITD in children with T1D, Glastras etal. suggested measurement of anti-thyroid antibodies and TSH at T1D onset and inyearly intervals after the age of 12 yr. Furthermore, the International Society forPediatric and Adolescent Diabetes Consensus Clinical Guidelines recommend thescreening of thyroid function by analyzing circulating TSH at the diagnosis of diabetes and,thereafter, every 2nd yr in asymptomatic individuals without goiter and more frequent ifgoiter is present.

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Type 1 Diabetes With Other Autoimmune Diseases

Editors Note: This content has been verified by Marina Basina, MD, a Clinical Associate Professor at Stanford University. Shes a clinical endocrinologist and researcher with a focus on diabetes management and diabetes technology. Dr. Basina is an active member of multiple medical advisory boards and community diabetes organizations, and she is on the Beyond Type 1 Science Advisory Council.

People with Type 1 diabetes, an autoimmune disease, are more likely to have a co-occurring autoimmune disorder. An autoimmune disease means that your immune system sees your bodys own tissue as foreign invaders and attacks itself. For example, if you have Type 1, your body mistakenly attacks the insulin-producing cells in your body. The reason that co-occurring autoimmune disorders are so common isnt exactly known, although we do know that genetics play a significant role.

Because we know that having Type 1 puts you at a higher risk of developing other autoimmune diseases, its important to be aware of what the signs and symptoms are. The following are warning signs that are common for all autoimmune diseases, including Type 1:

Is There A Cure For Type 1 Diabetes

There is currently no cure for Type 1 diabetes, but scientists are working on ways to prevent or slow down the progression of the condition through studies such as TrialNet.

Scientists are also working on research into pancreatic islet transplantation an experimental treatment for people who have brittle diabetes.

Pancreatic islets are clusters of cells in the pancreas that make insulin. Your immune system attacks these cells in Type 1 diabetes. A pancreatic islet transplant replaces destroyed islets with new ones that make and release insulin. This procedure takes islets from the pancreas of an organ donor and transfers them to a person with Type 1 diabetes. Because researchers are still studying pancreatic islet transplantation, the procedure is only available to people enrolled in a study.

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Autoantibodies As Predictors Of Type 1 Diabetes

Hundreds of studies have now been carried out in laboratories around the world to determine the relationship between autoantibodies to GAD/IA-2/insulin and type 1 diabetes . Approximately 7080% of newly diagnosed type 1 diabetes patients have autoantibodies to GAD65. Nearly the same number or slightly less have autoantibodies to IA-2. Overall, fewer patients appear to have insulin autoantibodies, but this is due to a pronounced age effect: children with newly diagnosed type 1 diabetes have a markedly higher frequency of autoantibodies to insulin than teenagers or young adults . Some patients carry autoantibodies to only one of the major autoantigens, but others may react to all three. In newly diagnosed subjects, up to 90% have autoantibodies to one or more of these antigens. The percent positivity depends on a variety of factors, including not only the age of the subjects, but also the duration of the disease and, in some cases, their ethnic origins. Some intrinsic variability is also seen in the assay, particularly at the limit of its range of detection. In general, GAD65 autoantibody positivity tends to be stable, whereas IA-2 autoantibodies tend to decrease with duration of disease, and insulin autoantibodies cannot be usefully measured after initiation of insulin therapy. Extensive analyses of these autoantibodies in normal controls suggest that about 1.0% have autoantibodies to IA-2, GAD65, or insulin.

Insulin And Insulin Signaling

Diabetes LADA – Latent Autoimmune Diabetes

T1DM is characterized by insulin and C-peptide deficiencies due to destruction of pancreatic -cells. T2DM, on the other hand, shows initial hyperinsulinemia secondary to insulin resistance. The insulin receptor is widely but unevenly distributed in the PNS. In peripheral nerve trunks IR is concentrated to the node, paranode and the Schmidt-Lanterman incisures and to the interendothelial junctions of endoneurial vessels. In DRG the IR is predominantly localized to small nociceptive neurons and in the spinal cord to nociceptive interneurons, whereas the concentration of IR in motor neurons is low . In insulinopenic T1DM the IR expression is suppressed in DRGs, although initially it may be increased , whereas in T2DM it is unaltered or slightly upregulated in sensory ganglia . In the sciatic nerve, on the other hand, the IR is upregulated in T1DM but severely downregulated in T2DM . Therefore perturbations of the IR expression and the presence or absence of insulin will have implications as to insulin signaling activities.

Other contributing factors to the Na+/K+-ATPase defect is the activated polyol pathway with depletion of myo-inositol and impaired activation of PKC leading to impaired neural Na+/K+-ATPase activity .

Johan Verhaeghe, Roger Bouillon, in, 2008

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Box 2 Observations Inconsistent With T Cells As A Driving Force In T1dm

Islet-specific autoreactive T cells in the healthy population,,,
No development of insulitis or selective loss of -cells in humanized mice transduced with islet antigens specific T cell receptor and immunized with islet antigen
No development of autoimmune diabetes mellitus in HLA class II transgenic mice immunized with islet autoantigens,
No development of type 1 diabetes mellitus in pancreatitis, even with high risk HLA
No lasting effect of immunotherapy on preservation of -cell function,,,
Most patients with cancer who are treated with co-stimulation blockade never develop T1DM,
Most patients with T1DM do not display abnormalities in immune regulation
HLA class I upregulation without islet inflammation,
Paucity of insulitis in individuals with islet autoantibodies
Limited rate of insulitis at diagnosis of T1DM, even with more widespread -cell stress,
Immunization with islet autoantigens does not cause T1DM,,,