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Type 1 diabetes mellitus

Mark Peakman, Decio L. Eizirik, George S. Eisenbarth and Flemming Pociot


T1DM is a chronic, progressive, autoimmune disorder with incomplete The incidence of T1DM in developed countries is 1060cases per
penetrance (estimated as 4070% from monozygotic twin studies). 100,000 people, and is increasing by ~4% per year. Improved
In individuals with a genetic susceptibility to T1DM, an abnormal, understanding of disease-relevant immunological pathways has led
unregulated, autoimmune response targeting cells can develop, to new intervention strategies, several of which are in clinical
which leads to progressive islet damage and insulin insufficiency. The development. These offer some hope that -cell destruction can be
environmental triggers that interact with susceptibility and resistance halted and immunological tolerance restored in patients with T1DM,
genes to initiate and perpetuate the disease remain to be defined. although many challenges undoubtedly lie ahead.
Supplement to Nature Publishing Group journals

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
7
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
6
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

PAE TLR3 and 4, RIG-I,


cell MDA-5, other receptors IFN-
Cytokine receptor signalling
Caspase
Granzymes activation
IFN-
PAE STAT-1, NFB, IRF-3, others (?) TNF
cell Islets of Perforin
Jun-B MHC
Langerhans TCR class I cell

Fas FasL
CD8+
MHC Endoplasmic Apoptotic
class I reticulum stress signalling CD4+

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+

MHC class II CD40


Breaking of tolerance to cells
TREG
cells
CD80 CD28 B cell
Autoreactive Activation and clonal expansion
effector T cells
Effector
T cells

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

100,000 people in Sweden 100


developing countries to 50 Colorado Overt immunologic Progressive decline Overt Minimal
Genetic predisposition
(per 100,000 individuals)

90 abnormalities in insulin release diabetes C-peptide


>60 cases per 100,000 Germany
40 80
people in Finland. Normal insulin Blood glucose levels C-peptide Autoimmunity
-cell mass (%)

70 release mostly normal present wanes


Incidence is increasing
30 60
in most countries where
50
data are being collected,
20 40
especially in children
30
under 5 years of age.
10 20
This trend probably
reflects changing 10
0 0
environmental influences
1950 1960 1970 1980 1990 2000 2010 Birth Disease course
rather than changes in
Year
the gene pool. Note that the colours used in this graph correspond to the box colours throughout the poster.

Abbreviations References Affiliations


Remaining questions for future studies APS1 autoimmune polyendocrinopathy candidiasis ectodermal dystrophy 1. Eizirik, D. L. Colli, M. L. & Ortis, F. The role of inflammation in Department of Immunobiology, Kings College London, 2nd Floor
IA-2 islet-associated tyrosine phosphatase insulitis and -cell loss in type 1 diabetes. Nat. Rev. Endocrinol. 5, Borough Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT,
Which environmental factors trigger insulitis and T1DM? IPEX immunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome 219226 (2009). UK (M.Peakman).
How do these environmental factors interact with T1DM Fas apoptosis-mediating surface antigen FAS 2. Eizirik, D. L., et al. The human pancreatic islet transcriptome: Laboratory of Experimental Medicine, Universit Libre de Bruxelles,
resistance and susceptibility genes? FasL Fas antigen ligand expression of candidate genes for type 1 diabetes and the impact
GAD65 glutamic acid decarboxylase-65 808 Route de Lennik, B-1070 Brussels, Belgium (D. L. Eizirik).
Which polymorphisms in susceptibility loci cause T1DM? of pro-inflammatory cytokines. PLoS Genet. 8, e1002552 (2012).
IFN interferon School of Medicine, Barbara Davis Center for Diabetes, University
What are the functional roles of candidate resistance and 3. Stadinski, B. Kappler, J. & Eisenbarth, G. S. Molecular targeting of
IRF-3 interferon regulatory factor 3 of Colorado, Anschutz Medical Campus, 13001 East 17th Place,
susceptibility genes for T1DM? islet autoantigens. Immunity 32, 446456 (2010).
Jun-B transcription factor Jun-B Aurora 80045, Colorado, USA (G. S. Eisenbarth).
Which are the major effector mechanisms of -cell death in MDA-5 melanoma differentiation-associated protein 5 4. Parikka, V. et al. Early seroconversion and rapidly increasing
autoantibody concentrations predict prepubertal manifestation of Glostrup Research Institute, Glostrup Hospital, DK-2600 Glostrup,
T1DM? NFB nuclear factor B Denmark (F.Pociot).
PAE peripheral antigen expressing type 1 diabetes in children at genetic risk. Diabetologia 55,
Are these mechanisms modulated by the genetic background of
RIG-I retinoic acid-inducible gene-I 19261936 (2012).
affected individuals? 5. Pociot, F. et al. Genetics of type 1 diabetes: what's next? Diabetes Edited by Katherine Smith and Linda Koch. Designed by Laura
STAT-1 signal transducer, activator of transcription-/
Can insulitis be resolved? If yes, what are the steps and TCR T-cell receptor 50, 15611571 (2010). Marshall, Nicole Sidoti and Emma Carter.
regulatory mechanisms involved in termination of the T1DM type 1 diabetes mellitus 6. Bergholdt, R. et al. Identification of novel type1 diabetes
The poster content is peer reviewed, editorially independent and the
inflammatory response and restoration of islet homeostasis? TH1 T-helper-1 cell candidate genes by integrating genome-wide association data,
sole responsibility of Nature Publishing Group.
Will combinations of immunotherapies that target different TLR Toll-like receptor protein-protein interactions and human pancreatic islet gene
TNF tumour necrosis factor expression. Diabetes 61, 954962 (2012). 2012 Nature Publishing Group.
disease pathways have synergistic effects on T1DM?
TREG T-regulatory cell 7. Ziegler, A. G. & Nepom, G. T. Prediction and pathogenesis in type
ZnT8 zinc transporter 8 1 diabetes. Immunity 32, 468-478 (2010). http://www.nature.com/nrendo/posters/type1diabetesmellitus/

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