Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by...

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Pathogenesis of Type 1 DM Dr. Abdulmoein Al-Agha, Consultant, Pediatric Endocrinologist, King AbdulAziz University Hospital, Jeddah

Transcript of Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by...

Page 1: Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β cells in the pancreas by CD4+ and CD8+

Pathogenesis of Type 1 DM

Dr. Abdulmoein Al-Agha, Consultant, Pediatric Endocrinologist, King AbdulAziz University Hospital,

Jeddah

Page 2: Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β cells in the pancreas by CD4+ and CD8+

Pathophysiology

“Polygenic disorder”

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Pathogenesis of Type 1 DM

• Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β cells in the pancreas by CD4+ and CD8+ T cells and macrophages infiltrating the islets

• The disease accounts for about 10% of all cases of diabetes

• There is a marked geographic variation in incidence, with a child in Finland being about 400 times more likely than a child in Venezuela to acquire the disease

• The current global increase in incidence of 3% per year

• This rapid rise strongly suggests that the action of the environment on susceptibility genes contributes to the evolving epidemiology of type 1 diabetes

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Geographic variation in annual incidence of type 1 diabetes

Gillespie K M CMAJ 2006;175:165-170

©2006 by Canadian Medical Association

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Not all type 1 DM is autoimmune!

• In 5-10 % of cases

Idiopathic Type 1 Diabetes

• No known etiology.

• Permanent insulinopaenia.

• Not HLA associated.

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Genetic and environmental interactions

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Model of the pathogenesis and natural history of type 1 diabetes.

Atkinson M A Cold Spring Harb Perspect Med

2012;2:a007641

©2012 by Cold Spring Harbor Laboratory Press

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• Type 1 diabetes results from the autoimmune destruction of insulin-producing β cells in the pancreas

• Genetic and, as yet undefined, environmental factors act together to precipitate the disease

• Monozygotic twins have historically been considered to have a disease concordance rate of 30%–50%, with Dizygotic twins having a concordance of 6%–10%.

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• 85% of new T1D cases reside in individuals with no known family history for the disease

• Another interesting observation is that differences in risk are also dependent on which parent has diabetes

– children of T1D mothers have only a 2% risk of developing T1D, whereas children of T1D fathers have a 7% risk

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GENETIC SUSCEPTIBILITY

• The major susceptibility genes for type 1 diabetes are in the HLA region on chromosome 6p

• This region contains genes that code for MHC class II molecules expressed on the cell surface of antigen-presenting cells such as macrophages

• These MHC molecules consist of alpha and beta chains that form a peptide-binding groove in which antigens involved in the pathogenesis of type 1 diabetes are bound

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• HLA class II molecules DR3 & DR4 are associated strongly with IDDM

• More than 90% of whites with IDDM express 1 or both of these molecules, compared to 50-60% in the general population

• Patients expressing DR3 also risk developing other autoimmune endocrinopathies & celiac disease

• These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function

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• There are three classes of HLA genes, with class II genes having the strongest association with T1D

• The great majority of T1D patients carry the HLA-DR3 or -DR4 class II antigens, with ∼30% being DR3/DR4 heterozygous.

• In Caucasians, the DR3/DR4 genotype confers the highest T1D risk, followed by DR4 and DR3 homozygosity, respectively.

• Conversely, the class II allele, DQB1*0602, in linkage disequilibrium with DR2, is associated with protection from the development of T1D and is found in <1% of patients with T1D

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HLA – CLASS II antigens

• DR – antigens DR 3 & DR 4

• DQ – antigens stronger > DR – antigens

- DQ 2 & DQ 8

- DQB 1 Alleles * 02 / 0302

• DP - antigens

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Putative functions of non-HLA-associated loci in type 1 diabetes.

Atkinson M A Cold Spring Harb Perspect Med

2012;2:a007641

©2012 by Cold Spring Harbor Laboratory Press

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• Example of non-HLA gene associated with T1D is CTLA-4 (cytotoxic T lymphocyte associated-4)

• Gene that plays an important role in the regulation of T-cell functionality and overall immune responsiveness

• Other specific genes finding some degree of support for their influence on T1D include PTPN22 as well as CD25, each thought to provide influence to immune responsiveness .

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Autoimmunity

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• Currently, autoimmunity is considered the major factor in pathogenesis of type 1 DM

• Approximately 85% of patients have circulating islet cell antibodies (ICA) & insulin autoantibodies (IAA)

• Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) & other auto-antigens within β- cells (IA2)

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• T1D-associated autoantibodies are typically present in 70%–80% of patients newly diagnosed disease

• In contrast, 0.5% of the general population and 3%–4% of relatives of patients with T1D are autoantibody-positive

• wide variety of factors contribute to these percentages, including:

– geographic population where studied,

– age and gender of the individual tested,

– race and ethnicity,

– quality and format for the autoantibody assay

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• The 3 principal auto antigens identified were glutamic acid decarboxylase (GAD 65), a protein tyrosine phosphatase-like molecule (IA-2) and insulin

• It is now clear that about 90% of people with newly diagnosed type 1 diabetes have autoantibodies to at least 1 of these 3 antigens

• There is variability in the pattern of humoral immunity, however: insulin autoantibodies are more prevalent in young children

• IA-2 antibodies often decrease after diagnosis, and antibodies to GAD tend to persist

• It is in the pre-diabetes phase that islet autoantibodies have been most useful

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Type 1 diabetes risk stratification by islet autoantibody properties.

Atkinson M A Cold Spring Harb Perspect Med

2012;2:a007641

©2012 by Cold Spring Harbor Laboratory Press

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Environmental Factors

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Environmental factors:

• Environmental factors are important because even identical twins have only 60% concordance for IDDM

• No single factor has been identified, but infections & diet are considered the 2 most likely environmental candidates

– Viral infections e.g., mumps, rubella, Coxsackie B4

– Nutritional factors e.g. cow's milk in infancy

– Recent evidence suggests role for vitamin D deficiency in pathogenesis & prevention of DM

– ? Toxic chemicals e.g. food preservatives

– Cesarean section delivery Vs SVD ?

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Role of viruses

• Viruses can cause diabetes in animal models either by directly infecting and destroying beta cells or by triggering an autoimmune attack against these cells

• Although isolated case reports have suggested direct viral destruction of beta cells, this is probably extremely rare.

• A careful autopsy study found no evidence for acute or persisting infection from Coxsackie, Epstein-Barr virus, mumps, or cytomegalovirus in the pancreatic tissue of 75 patients who died within a few weeks of developing type 1 diabetes

• However, some unusual forms of diabetes have been associated with the presence of Coxsackie virus in a large number of beta cells

• Coxsackie B virus-specific IgM responses have been found in 39 percent of children with newly diagnosed type 1 diabetes, compared with only 6 percent of normal children

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• The possibility of viral-induced autoimmunity or molecular mimicry is supported by long-term follow-up of infants with the congenital rubella syndrome.

• Autoimmune diabetes and other autoimmune diseases may occur 5 to 20 years after infection, especially in those subjects who have HLA-DR3

• long latent period between peak immunologic activity and clinical disease means that measuring viral titers at the onset of hyperglycemia is unlikely to be helpful.

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• The most popular viruses, are enteroviruses, rotavirus and rubella

• The strongest data to date have supported a role for rubella

• Infants infected with congenital rubella syndrome are said to be at increased risk of type 1 diabetes

Other implicated viruses

• mumps, intrauterine rubella, coxsackie B virus, echo virus, cytomegalo virus and herpes virus

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• These observations suggest that exposure to enteroviruses, both in utero and in childhood, can induce beta cell damage and lead to clinical diabetes

• Significant homology has been found between human GAD and the F2C protein of Coxsackievirus B4, suggesting a possible role for molecular mimicry

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Hygiene “sanitation” Theory

• Concept of the hygiene hypothesis, which proposes that environmental exposure to microbes, other pathogens and their products early in life promotes innate immune responses that suppress atopy and perhaps autoimmunity

• In Western cultures, the developing immune system of the infant is no longer exposed to widespread infection, which may contribute to the current increases in incidence observed in atopic and autoimmune disease

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Perinatal factors

• Several pregnancy-related and perinatal factors were associated with a small increase in risk of type 1 diabetes

• They were maternal age >25 years, preeclampsia, neonatal respiratory disease, and jaundice, especially that due to ABO blood group incompatibility; protective factors were low birth weight and short birth length

• Not proven associations

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Childhood immunization

• There has been concern that childhood vaccination may be associated with later development of chronic diseases, including type 1 diabetes.

• immunization of genetically pre-disposed infants (siblings with type 1 diabetes) with viral (and bacterial) antigens (BCG) does not appear to be associated with an increased risk of developing type 1 diabetes

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Cow’s milk

• Several dietary factors may influence the development of type 1 diabetes, with most attention having been paid to cow's milk

– It has been proposed that some component of albumin in cow's milk (bovine serum albumin), the basis for most infant milk formulas, may trigger an autoimmune response

– epidemiologic data from Finland suggest that there is an increased risk of type 1 diabetes associated with introduction to dairy products at an early age and with high milk consumption during childhood

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Cereals

• In infants , the timing of initial exposure to cereals may affect the risk of developing islet cell autoantibodies (IA)

• In two large prospective cohort studies of newborns at high risk for type 1 diabetes either:

– high risk HLA genotype, first exposure to cereal before age three months was associated with an increased risk of developing IA compared with infants whose first exposure was between ages four to six months

• Early introduction of gluten (<3 months of age) increases the risk of celiac disease

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Omega -3 fatty acids/ vitamin D

• Preliminary studies in animals support a protective role of omega-3 fatty acids in the inflammatory response associated with autoimmune islet cell destruction

• In a case-control study from Norway, children with type 1 diabetes were less likely to be given cod liver oil (containing omega-3 fatty acids and vitamin D) during infancy than children without diabetes

• In addition, a longitudinal observational study of children at increased risk for type 1 diabetes reported an inverse association between omega-3 fatty acid intake and development of islet autoimmunity

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Vitamin D supplements

• Although cow's milk may be associated with an increase of risk for type 1 diabetes, one component, vitamin D, may be protective

• Postnatal dietary factors, such as vitamin D and omega-3 fatty acid ingestion may also be important

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Nitrates

• The incidence of type 1 diabetes correlates with the concentration of nitrates in the drinking water

• The incidence is about 30 percent higher in areas with nitrate concentrations above 14.8 mg/L compared with areas with concentrations below 3.2 mg/L

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SUMMARY

• Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans

• This process occurs in genetically susceptible subjects, is probably triggered by one or more environmental agents, and usually progresses over many months or years during which the subject is asymptomatic and euglycemic.

• This long latent period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs

• Genes in both the major histocompatibility complex (MHC) and elsewhere in the genome influence risk, but only HLA alleles have a large effect

Page 39: Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β cells in the pancreas by CD4+ and CD8+

SUMMARY

• There are a number of autoantigens within the pancreatic beta cells that may play important roles in the initiation or progression of autoimmune islet injury including glutamic acid decarboxylase (GAD), insulin, insulinoma-associated protein 2 (IA-2)

• It is not certain, however, which of these autoantigensis involved in the initiation of the injury and which are secondary, being released only after the injury

• Environmental factors that may affect risk include pregnancy-related and perinatal influences, viruses, and ingestion of cow’s milk and cereals, nitrates and vitamin D deficiency

Page 40: Pathogenesis of Type 1 DM - kau Pathogenesis of Type 1 DM • Type 1 diabetes is characterized by autoimmune destruction of insulin-producing β cells in the pancreas by CD4+ and CD8+

THANKS