Stepwise or Linear Decrease in Penetrance of Type 1 Diabetes With Lower-Risk HLA Genotypes Over the Past 40 Years

Steck, Andrea K.; Armstrong, Taylor; Babu, Sunanda; Eisenbarth, George S.

doi:10.2337/db10-1419

Cited by 55 publications

(52 citation statements)

References 23 publications

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“…Put another way, less genetic predisposition to T1D (i.e., class II alleles of the major histocompatibility complex, or MHC) appears to be required in order to develop the disease now, versus decades ago. This notion finds support with at least two studies, one in Europe, the other in the United States (Gillespie et al 2004;Steck et al 2011).…”

Section: Epidemiology: Incidence and Prevalencesupporting

confidence: 56%

The Pathogenesis and Natural History of Type 1 Diabetes

Atkinson

2012

Cold Spring Harbor Perspectives in Medicine

250

176

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Section: Epidemiology: Incidence and Prevalencesupporting

confidence: 56%

The Pathogenesis and Natural History of Type 1 Diabetes

Atkinson

2012

Cold Spring Harbor Perspectives in Medicine

250

176

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“…This difference was not explained by the inclusion of 19 children with DS and diabetes from the State of Kuwait, a population where HLA-mediated susceptibility to diabetes may be different, as the pattern was the same when these individuals were removed from the analysis. This increased penetrance of lowrisk HLA class II haplotypes in DSD children mirrors the trend observed in the general population as type 1 diabetes incidence is increasing (20)(21)(22)(23). Understanding how autoimmunity occurs in the absence of HLA risk genotypes in children with DS could therefore provide important insights into disease mechanisms in the general population.…”

Section: Islet Autoantibodiesmentioning

confidence: 75%

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

et al. 2013

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OBJECTIVEdDown syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes.RESEARCH DESIGN AND METHODSdClinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age-and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay.RESULTSdAge at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P , 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early-and later-onset DSD compared with age-matched children with type 1 diabetes (P , 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at #2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort.CONCLUSIONSdEarly-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.

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“…Our results also raise the possibility that individuals with a β57D + -containing DQ allele may have the ability to produce a regulatory response to the insulin epitope. With the genetics of T1D shifting toward more new-onset patients with at least one of these alleles (33), insulin-specific immune therapies are an appealing approach for diabetes prevention, because there is now a robust means to assess proinflammatory and regulatory T-cell responses from the peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA g7 , in an unfavorable position or register. Because of the similarities between IA g7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulinspecific therapies to prevent diabetes onset.T ype 1 diabetes (T1D), the autoimmune form of diabetes, results from T cell-mediated destruction of insulin-producing β-cells within pancreatic islets (1). The disease is dramatically increasing in incidence, doubling in the last two decades (2, 3), and now predictable with the measurement of antibodies directed against insulin and other proteins found in β-cells (4). Major efforts at disease prevention have been undertaken using preparations of insulin (s.c., oral, and intranasal) to induce tolerance and delay the onset of clinical symptoms (5-7). Measuring insulin-specific T-cell responses from the peripheral blood has been challenging but would allow for assessment of therapeutic response, which has been a major obstacle in these trials. In our study, we sought to detect peripheral T-cell responses to insulin in T1D patients and nondiabetic controls using a modified insulin B-chain peptide.Insulin is a major self-antigen for both T and B cells in murine and human T1D, with insulin B-chain amino acids 9-23 (B:9-23) being a key epitope presented by major histocompatibility complex class II (MHCII) molecules to CD4 T cells targeting pancreatic β-cells (8-10). There is strong evidence from the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes that the NOD MHCII molecule, IA g7 , is required for development of T1D and that pathogenic CD4 T cells recognize insulin B:9-23 presented in an unfavorable position or register (Reg3) in the IA g7 peptide binding groove (9, 11,...

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Stepwise or Linear Decrease in Penetrance of Type 1 Diabetes With Lower-Risk HLA Genotypes Over the Past 40 Years

Cited by 55 publications

References 23 publications

The Pathogenesis and Natural History of Type 1 Diabetes

The Pathogenesis and Natural History of Type 1 Diabetes

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

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