Type 1 diabetes associated autoimmunity George J. Kahaly, Martin P. Hansen PII: DOI: Reference:
S1568-9972(16)30044-1 doi: 10.1016/j.autrev.2016.02.017 AUTREV 1835
To appear in:
Autoimmunity Reviews
Received date: Accepted date:
13 February 2016 15 February 2016
Please cite this article as: Kahaly George J., Hansen Martin P., Type 1 diabetes associated autoimmunity, Autoimmunity Reviews (2016), doi: 10.1016/j.autrev.2016.02.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TYPE 1 DIABETES ASSOCIATED AUTOIMMUNITY
PT
GEORGE J KAHALY & MARTIN P HANSEN
RI
Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
NU
SC
SHORT TITLE: Diabetes and autoimmunity
MA
WORD COUNT, Abstract: 197; Text: 3182; 26 references, one table
AC CE P
CORRESPONDENCE
TE
D
DISCLOSURE: The authors have nothing to disclose
George J. Kahaly, MD, PhD
Professor of Medicine and Endocrinology / Metabolism Department of Medicine I
Johannes Gutenberg University (JGU) Medical Center Mainz 55101, Germany.
Phone: +49 - 6131 – 17-2290 Fax: +49 - 6131 – 17-3460 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune
PT
disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and
RI
multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune
SC
disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid
NU
disease, Addison’s disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease.
MA
Approximately 0.5% of diabetic patients have concomitant Addison’s disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5 to 10% and 2.6 to 4% respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to
TE
AC CE P
symptoms of underlying disease.
D
prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and
KEY WORDS: Type 1 diabetes, endocrine autoimmunity, autoimmune thyroid disease,
TAKE-HOME MESSAGES
The economic costs and burden of type 1 diabetes are considerable given the cardiovascular complications and co-morbidities that it may entail.
Susceptibility to type 1 diabetes includes a strong genetic component, with the strongest risk attributable to genes that encode the classical human leukocyte antigens.
Type 1 diabetes shows ∼40% concordance rate in monozygotic twins suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease
Patients with type 1 diabetes exhibit an increased risk of other autoimmune disorders
The association between type 1 diabetes and organ-specific autoimmune disease can be explained by sharing a common genetic background, but also by a defective immunoregulation
Early detection of antibodies and latent organ-specific dysfunction is advocated
2
ACCEPTED MANUSCRIPT 1.
INTRODUCTION AND CLINICAL PHENOTYPE
Diabetes mellitus is increasing in prevalence worldwide. The economic costs and burden of the disease are considerable given the cardiovascular complications and co-morbidities that it may entail. Two major groups of
PT
diabetes mellitus have been defined, type 1, or immune-based, and type 2. In recent years, other subgroups have been
RI
described in-between these major groups. Correct classification of the disease is crucial in order to ascribe the most efficient preventive, diagnostic and treatment strategies for each patient [1].
SC
Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells.
NU
The pathogenesis of T1D is multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets [2]. Adaptive immunoregulatory
MA
T cells contribute to the modulation of the development and evolution of T1D [3]. T1D results from autoimmune destruction of insulin-producing β cells and is characterized by the presence of insulitis and β-cell autoantibodies (Ab). The model of T1D begins with environmental triggers in genetically susceptible persons, progressing to
D
autoimmunity with appearance of β-cell Ab, further evolving towards metabolic dysregulation with loss of first-
TE
phase insulin response, increasing glycosylating hemoglobin within the normal range, impaired fasting glycaemia or
AC CE P
impaired glucose tolerance, and finally resulting in overt T1D and loss of C-peptide [4-5]. The first-phase insulin response measured by intravenous glucose tolerance testing is the sum of insulin levels the first and third minute after administration of an intravenous glucose load. Many subjects with T1D had a low first-phase before the diagnosis of T1D, and this may persist for years before clinical disease onset. These data suggest that subjects go through a phase of decreasing β-cell mass. The exact β-cell mass at diagnosis is poorly defined. For patients with long-term T1D, it is usually decreased to less than 1% of normal. Residual β-cell function can also be analyzed according to the measurement of C-peptide release as induced by a hyperglycemic clamp procedure. Low first phase C-peptide response specifically predicts impending T1D while a low second phase response probably reflects an earlier disease stage. A typical de novo T1D patient presents with hyperglycemia and polyuria, polydipsia and weight loss. Ketoacidosis is common and Ab-status at the moment of T1D diagnosis should be verified [6]. T1D and autoimmune thyroid diseases (AITD) frequently occur in the same individual suggesting a strong shared genetic susceptibility. The co-occurrence of T1D+AITD in the same individual is classified as autoimmune polyglandular syndrome (APS) type 3 [7-9]. Fifteen to 30% of T1D subjects have AITD, Hashimoto’s (HT) or Graves’ disease (GD), 0.5% has Addison’s disease (AD), 5 to 10% are diagnosed with autoimmune gastritis and/or pernicious anemia, 4 to 9% present with celiac disease (CD), and 2 to 10% show vitiligo. Up to one third of T1D
3
ACCEPTED MANUSCRIPT patients develop an APS. Children and adolescents with T1D may also develop organ-specific multiple autoimmunity in the context of APS. The most frequently encountered associated autoimmune disorders in children with T1D are AITD, followed by CD, autoimmune gastric disease and other rare autoimmune conditions [8]. These
PT
diseases are characterized by the presence of Ab to certain antigens of the gland, mostly intracellular enzymes, which
RI
appear in the blood. These include thyroid peroxidase (for HT), thyroid stimulating hormone (TSH) receptor (for GD), 21-hydroxylase (for AD), parietal cell or intrinsic factor (for autoimmune gastritis/ pernicious anemia), and
SC
tissue transglutaminase (for CD). The role of such Ab remains unclear, but they are important as diagnostic
NU
messengers and appear commonly before clinical hormone deficiency. Early detection of Ab and latent organspecific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease.
MA
Thus screening for these Ab allows early detection and the potential to prevent significant morbidity related to unrecognized disease. However, the frequency of screening for and follow-up of patients with positive Ab remain controversial. Hashimoto’s hypothyroidism may cause weight gain, hyperlipidemia, goiter, and may affect diabetes
D
control, menses, and pregnancy outcome. In contrast, Graves’ hyperthyroidism may induce weight loss, atrial
TE
fibrillation, heat intolerance, and ophthalmopathy. Adrenal insufficiency may cause vomiting, anorexia,
AC CE P
hypoglycemia, malaise, fatigue, muscular weakness, hyperkalemia, hypotension, and generalized hyperpigmentation. Autoimmune gastritis may manifest via iron deficiency or vitamin B12 deficiency anemia with fatigue and painful neuropathy. Clinical features of CD include abdominal discomfort, growth abnormalities, infertility, low bone mineralization, and iron deficiency anemia.
2.
PANCREATIC AUTOIMMUNITY
T1D is characterised by the appearance of insulitis and the presence of β-cell Ab. Several lines of evidence support the autoimmune nature of the β-cell destructive process: a) Infiltration of the pancreatic islets by lymphocytes and macrophages (insulitis), b) presence of Ab to islet cell antigens (ICA), tyrosine phosphatase (IA2), glutamic acid decarboxylase-65 (GAD), insulin (IAA), and zinc transporter ZnT8 (Slc30A8), c) a preferential occurrence of T1D in persons carrying specific allelic combinations at immune response loci within the HLA gene complex, d) Increased prevalence of organ-specific autoimmune disorders in T1D, e) the disease can be transferred by spleen or bone marrow cells, and finally f) animal models of T1D that show a defect in immunoregulation contributing to the onset of disease [10].
4
ACCEPTED MANUSCRIPT One or more β-cell Ab is present in approximately 90% of new-onset patients with T1D. They appear to develop sequentially. Insulin-Ab is often the first expressed, especially in younger children. GAD-Ab positivity is suggested to represent a propensity for general autoimmunity, while IA2-Ab positivity may be a more specific marker of β-cell
PT
destruction. Beta-cell Ab also represents important preclinical markers of the disease as they may be present for
RI
years before T1D diagnosis. The risk of T1D for a first-degree relative depends on the number and type of Ab that are present. Family members who express insulin, GAD and IA2-Ab have a 75% risk of developing T1D within the
SC
next five years, as compared with a 10 to 25% five-year risk in those expressing only one of the Ab. The general
NU
five-year risk for T1D is 34% in subjects positive for ≥ three Ab. Progression to T1D amounted to 12% within five years among siblings positive for IAA, 20% for ICA, 19% for GAD but 59% for IA-2-Ab. IA-2-Ab were detected in
MA
1.7% of all siblings and in 56% of the prediabetic subjects on first sampling [4-6]. T1D was one of the earliest disorders to be associated with the phenomenon of autoimmunity and is one of the most studied organ-specific autoimmune diseases at the epidemiologic, immunologic and genetic level [11]. Despite this,
D
and the emergence of a plethora of strategies for trying to intervene in, or prevent the disease, it remains at some
TE
distance from being reliably and safely tractable by immunotherapy, a source of great frustration in this research
AC CE P
field. The key concepts that might impact upon this lack of success in the clinic going forward include new insights into autoreactive CD4 and CD8 T cell biology and a discussion of the concept of disease heterogeneity as it applies to T1D. The onset of disease is characterised by a delicate equilibrium of proinflammatory and regulatory T cells, which are termed "balanced autoreactive set-point", and which may be amenable to antigen-specific immunotherapies that alter the rate of disease progression. Advances in the characterization of T cells, especially at the single cell level, could be rewarding, notably from the vantage point of biomarker and surrogate discovery. A better understanding of T cell targeting, autoantigen processing and the β-cell-immune interface is also needed, although access to diseased tissues is a major limitation in this effort. Finally, recent findings demonstrate that MicroRNAs (miRNAs) which regulate T cell development and function and, whose disruption in natural regulatory CD4+ FOXP3+ T cells (nTreg) leads to autoimmune disease in mice, are markers of risk and T cell dysfunction in T1D when differentially expressed in CD4+ T cell subsets [12].
3.
IMMUNOGENETICS
Among genes associated with T1D, the HLA gene complex on chromosome 6p21 is the genetic factor with the strongest association [13]. Another gene located on chromosome 11p15 in the upstream region of the insulin gene
5
ACCEPTED MANUSCRIPT also confers susceptibility to T1D. Multiple additional genes also contribute to T1D susceptibility. One of these is IDDM12 on chromosome 2q33, which contains two autoimmune disease candidate genes: cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and CD28, encoding for T-cell receptors involved in controlling T-cell proliferation.
PT
Other important genes include the MHC I-related gene A (MIC-A) and the protein tyrosine phosphatase non-receptor
RI
type 22 (PTPN22). Ninety percent of Caucasian T1D patients express the HLA DR3 and/or DR4 alleles [14]. These HLA alleles are expressed in 30-40% of the general white population. Expression of HLA DR2 is decreased in
SC
persons with T1D. Certain combinations of HLA alleles are found with a frequency greater than expected and are
NU
thus not randomly distributed within the general population. This phenomenon is called linkage disequilibrium. Particularly, HLA DQA1*0301-DQB1*0302 (in linkage disequilibrium with DR4) and DQA1*0501-B1*0201 (in
MA
linkage disequilibrium with DR3) haplotypes confer a high diabetic risk. The absolute risk of a child with this DR3/DR4 genotype developing T1D from the general population is similar to a first-degree relative of a T1D patient (one in 20). DQB1*0602 and DQA1*0102 alleles are associated with dominant protection [15].
D
In addition to the HLA region numerous other gene loci have shown association with T1D. The effect of 39 single
TE
nucleotide polymorphisms (SNP) on the development of Ab positivity was assessed on progression from Ab
AC CE P
positivity to clinical disease and on the specificity of the Ab initiating the autoimmune process in 521 Ab-positive and 989 control children from a follow-up study starting from birth [16]. Interestingly, PTPN2 rs45450798 gene polymorphism was observed to strongly affect the progression rate of beta-cell destruction after the appearance of humoral beta-cell autoimmunity. Moreover, primary autoantigen dependent associations were also observed as effect of the IKZF4-ERBB3 region on the progression rate of β-cell destruction was restricted to children with GAD Ab as their first Ab whereas the effect of the INS rs 689 polymorphism was observed among subjects with insulin as the primary autoantigen. In the whole study cohort, INS rs689, PTPN22 rs2476601 and IFIH1 rs1990760 polymorphisms were associated with the appearance of beta-cell Ab. These findings provide new insights into the role of genetic factors implicated in the pathogenesis of T1D. The effect of some of the gene variants is restricted to control the initiation of β-cell autoimmunity whereas others modify the destruction rate of the β-cells. T1D shows ∼40% concordance rate in monozygotic twins suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. Recent findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D [17].
6
ACCEPTED MANUSCRIPT 4.
ORGAN-SPECIFIC AUTOIMMUNITY
Organ-specific autoimmunity is frequent in T1D subjects. This might be due to the fact that these patients show multiple immunological abnormalities [18-19]. These include an imbalance in B and T lymphocytes, or an increased
PT
tendency to react strongly against certain antigens or a (genetically determined) poor ability to develop tolerance to
RI
autoantigens. Individuals with one autoimmune disease are known to be at increased risk for other autoimmune processes. Most of the autoimmune endocrine disorders appear initially as infiltration of the gland by lymphocytes
SC
and macrophages. This may lead to destruction and atrophy of the gland with deficiency of its hormone. The
NU
destructive process is presumed to be T-cell mediated. There are several direct links between genetics and autoimmune disease: the developmental maturation of T cells in a genetically susceptible individual occurs through
MA
molecular interactions between the T-cell receptor and the HLA-antigen complex. Selection of T cells with receptors, likely to contribute to autoreactivity, may preferentially occur in the context of specific HLA-DQ alleles that are prone to T1D, AITD, AD, CD, and other auto-immune diseases. Indeed, disease-prone HLA molecules may be
D
ineffective at binding and presenting peptides derived from tissue-specific antigens, and such a poor presentation in
TE
the thymus could impair mechanisms of negative selection allowing autoreactive T cells to survive the passage
AC CE P
through the thymus. Subsequent activation of these T cells in the context of recognizing islet-associated antigens can trigger a poorly regulated immune response that results in progressive tissue destruction. Other important genetic factors include CTLA-4, MIC-A and PTPN22 [20-21]. CTLA-4, being expressed on activated CD4+ and CD8+ T-cell membranes, inhibits T-cell activation by binding costimulatory molecules. Polymorphisms within the CTLA-4 gene have been associated with T1D and AITD, particularly the CT60 A/A polymorphism, and with AD (table 1). The MIC-A protein is expressed in the thymus and is thought to interact with a receptor, NKG2D, which may be important for thymic maturation of T cells. NKG2D regulates the priming of human naive CD8+ T cells, providing a possible explanation for the association with autoimmune diseases. MIC-A polymorphisms have also been linked to T1D, (the 5 allele and 5.1 allele), CD (allele 4 and 5.1), and AD (allele 5.1). The PTPN22 gene is expressed in T cells, encoding for lymphoid tyrosine phosphatase (LYP). A specific polymorphism at position 620 (Arg rgTrp) may decrease that ability of LYP to interact with its target molecules and down-regulate T-cell receptor signaling. This has been observed in GD and weakly in AD.
7
ACCEPTED MANUSCRIPT 5.
OWN FINDINGS IN TYPE 1 DIABETES ASSOCIATED ENDOCRINE AUTOIMMUNITY
A deficiency in the DNase enzyme, and thereby, a failure to remove DNA from nuclear antigens promotes disease susceptibility to autoimmune disorders. A controlled study examined in patients with T1D and AITD whether a
PT
reduced DNase activity is associated with sequence variations in the DNASE1 gene [22]. In patients with endocrine
RI
autoimmunity, a novel mutation (1218G >A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. The allele frequency of the mutation was increased in patients vs controls (P
S1568-9972(16)30044-1 doi: 10.1016/j.autrev.2016.02.017 AUTREV 1835
To appear in:
Autoimmunity Reviews
Received date: Accepted date:
13 February 2016 15 February 2016
Please cite this article as: Kahaly George J., Hansen Martin P., Type 1 diabetes associated autoimmunity, Autoimmunity Reviews (2016), doi: 10.1016/j.autrev.2016.02.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TYPE 1 DIABETES ASSOCIATED AUTOIMMUNITY
PT
GEORGE J KAHALY & MARTIN P HANSEN
RI
Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
NU
SC
SHORT TITLE: Diabetes and autoimmunity
MA
WORD COUNT, Abstract: 197; Text: 3182; 26 references, one table
AC CE P
CORRESPONDENCE
TE
D
DISCLOSURE: The authors have nothing to disclose
George J. Kahaly, MD, PhD
Professor of Medicine and Endocrinology / Metabolism Department of Medicine I
Johannes Gutenberg University (JGU) Medical Center Mainz 55101, Germany.
Phone: +49 - 6131 – 17-2290 Fax: +49 - 6131 – 17-3460 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune
PT
disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and
RI
multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune
SC
disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid
NU
disease, Addison’s disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease.
MA
Approximately 0.5% of diabetic patients have concomitant Addison’s disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5 to 10% and 2.6 to 4% respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to
TE
AC CE P
symptoms of underlying disease.
D
prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and
KEY WORDS: Type 1 diabetes, endocrine autoimmunity, autoimmune thyroid disease,
TAKE-HOME MESSAGES
The economic costs and burden of type 1 diabetes are considerable given the cardiovascular complications and co-morbidities that it may entail.
Susceptibility to type 1 diabetes includes a strong genetic component, with the strongest risk attributable to genes that encode the classical human leukocyte antigens.
Type 1 diabetes shows ∼40% concordance rate in monozygotic twins suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease
Patients with type 1 diabetes exhibit an increased risk of other autoimmune disorders
The association between type 1 diabetes and organ-specific autoimmune disease can be explained by sharing a common genetic background, but also by a defective immunoregulation
Early detection of antibodies and latent organ-specific dysfunction is advocated
2
ACCEPTED MANUSCRIPT 1.
INTRODUCTION AND CLINICAL PHENOTYPE
Diabetes mellitus is increasing in prevalence worldwide. The economic costs and burden of the disease are considerable given the cardiovascular complications and co-morbidities that it may entail. Two major groups of
PT
diabetes mellitus have been defined, type 1, or immune-based, and type 2. In recent years, other subgroups have been
RI
described in-between these major groups. Correct classification of the disease is crucial in order to ascribe the most efficient preventive, diagnostic and treatment strategies for each patient [1].
SC
Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells.
NU
The pathogenesis of T1D is multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets [2]. Adaptive immunoregulatory
MA
T cells contribute to the modulation of the development and evolution of T1D [3]. T1D results from autoimmune destruction of insulin-producing β cells and is characterized by the presence of insulitis and β-cell autoantibodies (Ab). The model of T1D begins with environmental triggers in genetically susceptible persons, progressing to
D
autoimmunity with appearance of β-cell Ab, further evolving towards metabolic dysregulation with loss of first-
TE
phase insulin response, increasing glycosylating hemoglobin within the normal range, impaired fasting glycaemia or
AC CE P
impaired glucose tolerance, and finally resulting in overt T1D and loss of C-peptide [4-5]. The first-phase insulin response measured by intravenous glucose tolerance testing is the sum of insulin levels the first and third minute after administration of an intravenous glucose load. Many subjects with T1D had a low first-phase before the diagnosis of T1D, and this may persist for years before clinical disease onset. These data suggest that subjects go through a phase of decreasing β-cell mass. The exact β-cell mass at diagnosis is poorly defined. For patients with long-term T1D, it is usually decreased to less than 1% of normal. Residual β-cell function can also be analyzed according to the measurement of C-peptide release as induced by a hyperglycemic clamp procedure. Low first phase C-peptide response specifically predicts impending T1D while a low second phase response probably reflects an earlier disease stage. A typical de novo T1D patient presents with hyperglycemia and polyuria, polydipsia and weight loss. Ketoacidosis is common and Ab-status at the moment of T1D diagnosis should be verified [6]. T1D and autoimmune thyroid diseases (AITD) frequently occur in the same individual suggesting a strong shared genetic susceptibility. The co-occurrence of T1D+AITD in the same individual is classified as autoimmune polyglandular syndrome (APS) type 3 [7-9]. Fifteen to 30% of T1D subjects have AITD, Hashimoto’s (HT) or Graves’ disease (GD), 0.5% has Addison’s disease (AD), 5 to 10% are diagnosed with autoimmune gastritis and/or pernicious anemia, 4 to 9% present with celiac disease (CD), and 2 to 10% show vitiligo. Up to one third of T1D
3
ACCEPTED MANUSCRIPT patients develop an APS. Children and adolescents with T1D may also develop organ-specific multiple autoimmunity in the context of APS. The most frequently encountered associated autoimmune disorders in children with T1D are AITD, followed by CD, autoimmune gastric disease and other rare autoimmune conditions [8]. These
PT
diseases are characterized by the presence of Ab to certain antigens of the gland, mostly intracellular enzymes, which
RI
appear in the blood. These include thyroid peroxidase (for HT), thyroid stimulating hormone (TSH) receptor (for GD), 21-hydroxylase (for AD), parietal cell or intrinsic factor (for autoimmune gastritis/ pernicious anemia), and
SC
tissue transglutaminase (for CD). The role of such Ab remains unclear, but they are important as diagnostic
NU
messengers and appear commonly before clinical hormone deficiency. Early detection of Ab and latent organspecific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease.
MA
Thus screening for these Ab allows early detection and the potential to prevent significant morbidity related to unrecognized disease. However, the frequency of screening for and follow-up of patients with positive Ab remain controversial. Hashimoto’s hypothyroidism may cause weight gain, hyperlipidemia, goiter, and may affect diabetes
D
control, menses, and pregnancy outcome. In contrast, Graves’ hyperthyroidism may induce weight loss, atrial
TE
fibrillation, heat intolerance, and ophthalmopathy. Adrenal insufficiency may cause vomiting, anorexia,
AC CE P
hypoglycemia, malaise, fatigue, muscular weakness, hyperkalemia, hypotension, and generalized hyperpigmentation. Autoimmune gastritis may manifest via iron deficiency or vitamin B12 deficiency anemia with fatigue and painful neuropathy. Clinical features of CD include abdominal discomfort, growth abnormalities, infertility, low bone mineralization, and iron deficiency anemia.
2.
PANCREATIC AUTOIMMUNITY
T1D is characterised by the appearance of insulitis and the presence of β-cell Ab. Several lines of evidence support the autoimmune nature of the β-cell destructive process: a) Infiltration of the pancreatic islets by lymphocytes and macrophages (insulitis), b) presence of Ab to islet cell antigens (ICA), tyrosine phosphatase (IA2), glutamic acid decarboxylase-65 (GAD), insulin (IAA), and zinc transporter ZnT8 (Slc30A8), c) a preferential occurrence of T1D in persons carrying specific allelic combinations at immune response loci within the HLA gene complex, d) Increased prevalence of organ-specific autoimmune disorders in T1D, e) the disease can be transferred by spleen or bone marrow cells, and finally f) animal models of T1D that show a defect in immunoregulation contributing to the onset of disease [10].
4
ACCEPTED MANUSCRIPT One or more β-cell Ab is present in approximately 90% of new-onset patients with T1D. They appear to develop sequentially. Insulin-Ab is often the first expressed, especially in younger children. GAD-Ab positivity is suggested to represent a propensity for general autoimmunity, while IA2-Ab positivity may be a more specific marker of β-cell
PT
destruction. Beta-cell Ab also represents important preclinical markers of the disease as they may be present for
RI
years before T1D diagnosis. The risk of T1D for a first-degree relative depends on the number and type of Ab that are present. Family members who express insulin, GAD and IA2-Ab have a 75% risk of developing T1D within the
SC
next five years, as compared with a 10 to 25% five-year risk in those expressing only one of the Ab. The general
NU
five-year risk for T1D is 34% in subjects positive for ≥ three Ab. Progression to T1D amounted to 12% within five years among siblings positive for IAA, 20% for ICA, 19% for GAD but 59% for IA-2-Ab. IA-2-Ab were detected in
MA
1.7% of all siblings and in 56% of the prediabetic subjects on first sampling [4-6]. T1D was one of the earliest disorders to be associated with the phenomenon of autoimmunity and is one of the most studied organ-specific autoimmune diseases at the epidemiologic, immunologic and genetic level [11]. Despite this,
D
and the emergence of a plethora of strategies for trying to intervene in, or prevent the disease, it remains at some
TE
distance from being reliably and safely tractable by immunotherapy, a source of great frustration in this research
AC CE P
field. The key concepts that might impact upon this lack of success in the clinic going forward include new insights into autoreactive CD4 and CD8 T cell biology and a discussion of the concept of disease heterogeneity as it applies to T1D. The onset of disease is characterised by a delicate equilibrium of proinflammatory and regulatory T cells, which are termed "balanced autoreactive set-point", and which may be amenable to antigen-specific immunotherapies that alter the rate of disease progression. Advances in the characterization of T cells, especially at the single cell level, could be rewarding, notably from the vantage point of biomarker and surrogate discovery. A better understanding of T cell targeting, autoantigen processing and the β-cell-immune interface is also needed, although access to diseased tissues is a major limitation in this effort. Finally, recent findings demonstrate that MicroRNAs (miRNAs) which regulate T cell development and function and, whose disruption in natural regulatory CD4+ FOXP3+ T cells (nTreg) leads to autoimmune disease in mice, are markers of risk and T cell dysfunction in T1D when differentially expressed in CD4+ T cell subsets [12].
3.
IMMUNOGENETICS
Among genes associated with T1D, the HLA gene complex on chromosome 6p21 is the genetic factor with the strongest association [13]. Another gene located on chromosome 11p15 in the upstream region of the insulin gene
5
ACCEPTED MANUSCRIPT also confers susceptibility to T1D. Multiple additional genes also contribute to T1D susceptibility. One of these is IDDM12 on chromosome 2q33, which contains two autoimmune disease candidate genes: cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and CD28, encoding for T-cell receptors involved in controlling T-cell proliferation.
PT
Other important genes include the MHC I-related gene A (MIC-A) and the protein tyrosine phosphatase non-receptor
RI
type 22 (PTPN22). Ninety percent of Caucasian T1D patients express the HLA DR3 and/or DR4 alleles [14]. These HLA alleles are expressed in 30-40% of the general white population. Expression of HLA DR2 is decreased in
SC
persons with T1D. Certain combinations of HLA alleles are found with a frequency greater than expected and are
NU
thus not randomly distributed within the general population. This phenomenon is called linkage disequilibrium. Particularly, HLA DQA1*0301-DQB1*0302 (in linkage disequilibrium with DR4) and DQA1*0501-B1*0201 (in
MA
linkage disequilibrium with DR3) haplotypes confer a high diabetic risk. The absolute risk of a child with this DR3/DR4 genotype developing T1D from the general population is similar to a first-degree relative of a T1D patient (one in 20). DQB1*0602 and DQA1*0102 alleles are associated with dominant protection [15].
D
In addition to the HLA region numerous other gene loci have shown association with T1D. The effect of 39 single
TE
nucleotide polymorphisms (SNP) on the development of Ab positivity was assessed on progression from Ab
AC CE P
positivity to clinical disease and on the specificity of the Ab initiating the autoimmune process in 521 Ab-positive and 989 control children from a follow-up study starting from birth [16]. Interestingly, PTPN2 rs45450798 gene polymorphism was observed to strongly affect the progression rate of beta-cell destruction after the appearance of humoral beta-cell autoimmunity. Moreover, primary autoantigen dependent associations were also observed as effect of the IKZF4-ERBB3 region on the progression rate of β-cell destruction was restricted to children with GAD Ab as their first Ab whereas the effect of the INS rs 689 polymorphism was observed among subjects with insulin as the primary autoantigen. In the whole study cohort, INS rs689, PTPN22 rs2476601 and IFIH1 rs1990760 polymorphisms were associated with the appearance of beta-cell Ab. These findings provide new insights into the role of genetic factors implicated in the pathogenesis of T1D. The effect of some of the gene variants is restricted to control the initiation of β-cell autoimmunity whereas others modify the destruction rate of the β-cells. T1D shows ∼40% concordance rate in monozygotic twins suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. Recent findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D [17].
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ORGAN-SPECIFIC AUTOIMMUNITY
Organ-specific autoimmunity is frequent in T1D subjects. This might be due to the fact that these patients show multiple immunological abnormalities [18-19]. These include an imbalance in B and T lymphocytes, or an increased
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tendency to react strongly against certain antigens or a (genetically determined) poor ability to develop tolerance to
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autoantigens. Individuals with one autoimmune disease are known to be at increased risk for other autoimmune processes. Most of the autoimmune endocrine disorders appear initially as infiltration of the gland by lymphocytes
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and macrophages. This may lead to destruction and atrophy of the gland with deficiency of its hormone. The
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destructive process is presumed to be T-cell mediated. There are several direct links between genetics and autoimmune disease: the developmental maturation of T cells in a genetically susceptible individual occurs through
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molecular interactions between the T-cell receptor and the HLA-antigen complex. Selection of T cells with receptors, likely to contribute to autoreactivity, may preferentially occur in the context of specific HLA-DQ alleles that are prone to T1D, AITD, AD, CD, and other auto-immune diseases. Indeed, disease-prone HLA molecules may be
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ineffective at binding and presenting peptides derived from tissue-specific antigens, and such a poor presentation in
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the thymus could impair mechanisms of negative selection allowing autoreactive T cells to survive the passage
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through the thymus. Subsequent activation of these T cells in the context of recognizing islet-associated antigens can trigger a poorly regulated immune response that results in progressive tissue destruction. Other important genetic factors include CTLA-4, MIC-A and PTPN22 [20-21]. CTLA-4, being expressed on activated CD4+ and CD8+ T-cell membranes, inhibits T-cell activation by binding costimulatory molecules. Polymorphisms within the CTLA-4 gene have been associated with T1D and AITD, particularly the CT60 A/A polymorphism, and with AD (table 1). The MIC-A protein is expressed in the thymus and is thought to interact with a receptor, NKG2D, which may be important for thymic maturation of T cells. NKG2D regulates the priming of human naive CD8+ T cells, providing a possible explanation for the association with autoimmune diseases. MIC-A polymorphisms have also been linked to T1D, (the 5 allele and 5.1 allele), CD (allele 4 and 5.1), and AD (allele 5.1). The PTPN22 gene is expressed in T cells, encoding for lymphoid tyrosine phosphatase (LYP). A specific polymorphism at position 620 (Arg rgTrp) may decrease that ability of LYP to interact with its target molecules and down-regulate T-cell receptor signaling. This has been observed in GD and weakly in AD.
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OWN FINDINGS IN TYPE 1 DIABETES ASSOCIATED ENDOCRINE AUTOIMMUNITY
A deficiency in the DNase enzyme, and thereby, a failure to remove DNA from nuclear antigens promotes disease susceptibility to autoimmune disorders. A controlled study examined in patients with T1D and AITD whether a
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reduced DNase activity is associated with sequence variations in the DNASE1 gene [22]. In patients with endocrine
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autoimmunity, a novel mutation (1218G >A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. The allele frequency of the mutation was increased in patients vs controls (P
