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Risk factors for T1DM Development of T1DM Children who express >2
Early islet inflammation probably involves activation of innate immunity and autoantibodies reacting with
Genetic risk of T1DM is conferred by polymorphisms in numerous genes that
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crosstalk between immune cells and pancreatic cells. Cytokines and chemokines insulin, GAD65, IA-2 and/or ZnT8
regulate innate and adaptive immunity, -cell function and apoptosis rate. These
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released by both cell types, as well as danger signals provided by dying cells, will in 8090% of cases progress
polymorphisms modulate immune responses at various stages of disease
Relative risk
5 to T1DM, although in some
progression and influence the ability of cells to endure or escape the 4
activate and attract immune cells to pancreatic islets (a process termed insulitis),
which eventually escalates to a full-blown autoimmune assault. individuals this process can take
autoimmune process. An individuals HLA haplotype accounts for >50% of their 3
Once islet autoimmunity is triggered, which is potentially marked by the initial more than a decade.
genetic risk of T1DM, but over 50 non-HLA loci also contribute to disease 2
susceptibility. For example, disease-associated polymorphisms in INS, the 1 appearance of islet cell autoantibodies, multiple -cell autoantigens are
Major islet Insulin
preproinsulin gene, are thought to reduce thymic expression of proinsulin, which 0 progressively targeted. autoantibodies autoantibodies
shifts the balance of peripheral T cells recognizing this key autoantigen from a Killing of cells probably results from multiple mechanisms, most notably
A
PT S
IL 2
A
HL
2R
IN
2
PN
predominantly TREG to a predominantly effector T-cell population. Other genes recruitment of cytotoxic CD8+ T cells and indirect, cytokine-mediated upregulation of
influence innate responsiveness to inflammation (e.g. IFIH1) and regulation of Genes with -cell apoptosis.
immune responses (IL2RA, IL2, PTPN22). polymorphisms Loss of cells within the pancreas is lobular and asynchronous, such that healthy
Rare syndromes associated with T1DM include APS1, caused by loss-of- islets coexist with islets infiltrated by T cells and islets in which all cells have Targets
function mutations in AIRE that abrogate expression of insulin in the thymus, and IPEX, caused by been destroyed. Furthermore, in children monitored from birth until the
mutations in FOXP3 that lead to loss of TREG cells. development of T1DM, levels of autoantibodies fluctuate independently. These
Several putative nongenetic factors also influence the risk of T1DM: breastfeeding may be protective, observations imply heterogeneity in the timing and intensity of autoimmunity
whereas viral infection, vitamin D deficiency, Caesarean section and low birth weight may increase during the prodrome of T1DM. However, high titres of insulin autoantibodies and
risk. Notably, early life events seem to be important determinants of geneenvironment interactions the presence of multiple autoantibody specificities correlate with an increased ZnT8 IA-2 GAD65 Insulin
leading to T1DM. rate of disease progression.
Thymus Pancreas
cell IL-17
Presentation of
(modified) antigens Cell death IL-1 IL-1
TNF TNF
T cell
Chemokines
Cytokines
B cell
Dendritic Antigen
T cell cell uptake by Macrophage
dendritic cells
Production of islet
autoantibodies
Lymph node
Migration of
dendritic cells
Lymph
node MHC
class I TCR
TREG
CD8+
MHC
Autoantigen class II TCR CD4+
engulfed
and processed
into peptides
Defective generation of TREG cells TCR CD40L
CD4+
Epidemiology of T1DM The stages of -cell loss and timing of prevention strategies
The incidence of T1DM Disease trigger
varies from <5 cases per 60
Finland Primary prevention Secondary prevention Tertiary prevention
Incidence in children aged 914 years