Genetic aetiology to initiate islet autoimmunity
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page207-210
2025-11-11
58
Longitudinal studies of newborn children at increased genetic risk either as a first- degree relative (father, mother, or sibling has type 1 diabetes) or by cord blood HLA typing have identified infants who developed a first islet autoantibody during the first year of life. The first autoantibody was either IAA or GADA, rarely IA- 2A or ZnT8A, but two or more autoantibodies occurred as blood sampling was not more frequent than three months apart. There was a strong association between HLA- DR4- DQ8 and IAA as the first β- cell autoantibody. GADA as a first islet autoantibody was associated with HLA- DR3- DQ2; indeed GADA- first was exclusive to homozygous HLA- DR3- DQ2 children. These observations suggest a paradigm shift in the understanding of the association between HLA and type 1 diabetes. The primary effect would be an association between HLA and the first- appearing autoantibody and not type 1 diabetes per se. The mechanism by which HLA contributes to the aetiological triggering of islet autoimmunity should be sought, as it may have nothing to do with loss of β cells, dysglycaemia, and diabetes.
The genetics of type 1 diabetes have been studied extensively during the past 50 years, especially since the mode of inheritance has remained uncertain. HLA represents ~50% of the familial risk of type 1 diabetes. It should be noted that alleles in the HLA region, such as the HLA class II DR and DQ alleles, are in linkage disequilibrium, which means that among hundreds of alleles certain allele combinations are inherited as extended haplotypes. The reduced rate of recombination events in the HLA region is not understood and it complicates the dissection of which allele and protein product is mechanistically responsible for the association between HLA and the first- appearing islet autoantibody. A suitable example is the recently discovered tri- SNP (single- nucleotide polymorphism) in the first intron of HLA- DRA. The HLA- DRA protein, representing the A- chain of the DR heterodimer, does not vary between people. However, the recent finding suggests the presence of an intron poly morphism that may regulate the expression not only of HLA- DR, but also the DQ heterodimer.
The class II HLA- DR- DQ haplogenotype DR3- DQ2 (DRB1* 03- DQA1*0501- B1*0201)/DR4- DQ8 (DRB1*04- DQA1*03 : 01- B1*03 : 02) confers the highest risk for type 1 diabetes. The risk of the heterozygous DQ2/8 genotype for type 1 diabetes is complicated by the possibility that DQA1*05 : 01- B1*03 : 02 and DQA1*03 : 01- B1*02 : 01 haplotypes form heterodimer molecules in trans that con tribute to risk by unique antigen- presenting capabilities. The HLA DQ2/8 genotype may therefore represent not only two but four potential antigen- presenting heterodimers. The DR3- DQ2/DR4- DQ8 genotype was found in more than 95% of individuals with type 1 diabetes younger than 30 years of age compared to 25–30% of the general population. The HLA DR3- DQ2 and DR4- DQ8 haplotypes, alone or in combination, may therefore be regarded as necessary but not sufficient for aetiology currently measured as the risk of developing a first- appearing islet autoantibody (Figure 1). In children developing a second islet autoantibody, the risk that the pathogenesis will end up in clinical onset has been estimated as 70% within 10 years.
Fig1. Staging of the natural history of autoimmune type 1 diabetes. The aetiological stage is thought to be associated with enterovirus infection in people at increased genetic risk for type 1 diabetes. A series of unknown events, such as prolonged shedding of virus, may trigger islet autoimmunity by yet unknown mechanisms. A first islet autoantibody against islet antigen or glutamic acid decarboxylase, dependent on genetic risk, appears and represents the biomarker for islet autoimmunity. Following the appearance of a second autoantibody, the person is classified in stage 1, which is defined by the presence of two or more islet autoantibodies, normoglycaemia, and no symptoms. In stage 2 the person has multiple autoantibodies and has developed dysglycaemia or impaired glucose tolerance without symptoms. Stage 3 is also characterized by multiple autoantibodies. Individuals may lose autoantibodies prior to stage 3. Diabetes is diagnosed according to the American Diabetes Association and World Health Organization criteria and the person may have symptoms and will also require insulin. Sources: Adapted from Insel et al. 2015 and Lloyd et al. 2022.
HLA DR- DQ genes are transcribed and translated into the α and β transmembrane chains that pair to form a heterodimer (Figure 2). The heterodimer creates a peptide- binding region between the α- and β- chains. The peptide- binding region has pockets to bind amino acid residues, but it is the physicochemical nature of the peptide- binding region that dictates the binding of peptides from exogenous and endogenous protein antigens (Figure2). The peptide- binding region with bound peptide is the ligand, the trimolecular complex, for the T- cell receptor (TCR). The genetic aetiology of islet autoimmunity is reflected by the amino acid residues coded for by different DRB1* and DQA1*- DQB1* for either risk or protection. Amino acid residues associated with islet autoimmunity were αa1, α44, α157, α196 on the DQ A- chain, and β9, β30, β57, β70, β135 on the DQ B- chain. These motifs capture all known susceptibility and resistant type 1 diabetes associations. Three motifs, DCAA- YSARD (representing DQ2.5), DQAA- YYARD (representing DQ8), and DQDA- YYARD (representing DQ8.1), accounted for the structures needed to develop islet autoimmunity and risk for type 1 diabetes. Ten motifs were significantly associated with resistance to type 1 diabetes. The nine amino acid residues were within or near anchoring pockets of the peptide- binding region (α44, β9, β30, β57, and β70); one was the N- terminal of the alpha chain (αa1), one in the CD4- binding region (β135), one in the putative cognate TCR- induced αβ homodimerization process (α157), and one in the intra- membrane domain of the alpha chain (α196) (Figure 2). These motifs are critical to the understanding of the mechanisms by which immunological tolerance is broken and islet autoimmunity is allowed to develop. The structure and physicochemical property of the highest- risk HLA class II molecules have been specified and the question that remains to be answered is what peptides will form a trimolecular complex that interact with CD4+ T cells able to trigger islet autoimmunity.
Fig2. Molecular illustrations of insulin peptides bound to (a) human leucocyte antigen (HLA)- DQ heterodimers at risk (DQ8 with insulin B11–24); (b) neutral risk (DQ6.4 with insulin B5–15); and (c) protection (DQ6.2 with insulin B5–15). (a) is based on a crystallized complex while (b) and (c) are based on molecular simulations. The HLA- DQ- insulin peptide complexes are shown in their secondary structure formation (α- helix in red; β- sheet in turquoise; β- turn, random coil, or any other form in grey). The β134–148 CD4- binding stretch is shown in purple. The HLA- DQ amino residues in both the A- and B- chains are shown in stick form (atom colour convention: carbon, grey; oxygen, red; nitrogen, blue; sulfur, yellow; hydrogen, white). The insulin peptide is shown in stick form in (a) (thinner sticks, with the same colour convention), and in space- filling form in (b) and (c) with the p1Leu, p4Ala, p6Leu, and p9Ala anchor residues opaque. The remaining residues are non- transparent surfaces coloured by atom charge (red, negative; blue, positive; partial charges coloured with shades in between), in order to appreciate the positioning and orientation of the different amino acid residues. The trimolecular complexes depicted in (a–c) from risk to protection are clearly different in appearance to indicate that T- cell receptors on CD4+ T cells will differ markedly in binding characteristics to go from risk to protection.
The concomitant inheritance of both HLA and non- HLA high- risk alleles and haplotypes appears to increase the risk of type 1 diabetes significantly through synergistic association of their single risks. In individuals with type 1 diabetes, DQ8 (DQA1*0301- B1*0302) is mostly inherited with variants of DRB1*04, especially DRB1*04 : 01, DRB1*04 : 04, DRB1*04 : 05 or DRB1*04 : 02, but not DRB1*04 : 03 or DRB1*04 : 07. DRB1*04 : 01 confers a higher risk than DRB1*04 : 04, while DRB1*04 : 03 or DRB1*04 : 07 is negatively associated with type 1 diabetes. The limited genetic differences between these alleles are reflected in the structure of the heterodimeric proteins formed by the DRA- coded A- chain and the DRB1- coded B- chain. The peptide- binding groove attains physicochemical characteristics that differ between the heterodimers despite a limited number of amino acid substitutions. These amino acid substitutions may account for most of the DRB1*04 contribution to type 1 diabetes risk. Further studies are needed to establish the way genetic polymorphisms within the HLA region are related to the binding of peptides and subsequent antigen presentation that can be linked to the risk of developing a first autoantibody as a biomarker of the initiation of islet autoimmunity.
The most common protective haplotypes are DQ6 (DQA1*01 : 02 B1*06 : 02 and DQA1*01 : 02- B1*06 : 03) and also DQA1*01 : 01- B1*05 : 03 and DQA1*02 : 02- B1*03 : 03. Furthermore, other HLA class II (such as DPB1) and class I alleles have also been associated with type 1 diabetes and the search for new associations is continuing.
The genetic aetiology is further complicated by a large number of genetic variants found to be associated with type 1 diabetes in whole- genome association studies. From studies of more than 60 000 people, 78 genome- wide significant regions were reported. A subset of these type 1 diabetes–associated genetic variants was enriched particularly in CD4+ effector T cells. It will be important to analyse the non- HLA genetic variants for the aetiology and triggers of islet autoimmunity. Type 1 diabetes–associated common genetic variants have therefore been combined in a genetic risk score approach to make use of all the genetic information in order not only to dissect the heterogeneity of diabetes, but also the aetiology and pathogenesis of the disease. A genetic risk score was developed to distinguish monogenic diabetes from type 1 diabetes or type 1 diabetes from type 2 diabetes. Using 41, 61, or 67 genetic risk variants, risk scores were developed not only to classify type 1 diabetes, but also to identify neonates with a significant risk of developing a first islet autoantibody and then progressing to clinical onset. The polymerase chain reaction (PCR) testing used is cost- effective and the type 1 diabetes genetic risk score should prove useful both in neonatal screening for children at high risk of type 1 diabetes as well as for disease classification.
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