Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease

Seißler, Jochen; Sonnaville, J.J.J. de; Morgenthaler, Nils G.; Steinbrenner, Holger; Glawe, D.; Khoo-Morgenthaler, U. Y.; Lan, Michael S.; Notkins, Abner Louis; Heine, Robert J.; Scherbaum, Werner A.

doi:10.1007/s001250051004

Cited by 132 publications

(109 citation statements)

References 34 publications

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“…This point is relevant as there are patients who are positive only for ICA but for neither anti-GAD nor anti-IA-2 [12,21]: this additional ICA subspecificity is not as yet defined, and it does not correspond to anti-CD38 as well. The finding that anti-CD38 aAbs are not an ICA subfraction is not surprising if a key difference in the epitopes recognised is considered.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-IA-2 aAbs are responsible for another major subfraction of the ICA reactivity [8,11] and, together with anti-GAD aAbs, they account for about 90% of ICA immunofluorescence [8]. Anti-IA-2 aAbs are an early marker of islet autoimmunity, being mainly found at disease onset [8,11]; they are also found with higher frequency in younger patients [12] independently of disease duration [13], probably reflecting a severe beta-cell destruction leading to the clinical onset of the disease early in life [14,15,16,17]. Although these markers are mainly found in Type I diabetic patients, a subgroup of patients routinely classified as Type II was also found to show high prevalences of ICA and anti-GAD, but not of anti-IA-2 aAbs.…”

mentioning

confidence: 99%

“…Although these markers are mainly found in Type I diabetic patients, a subgroup of patients routinely classified as Type II was also found to show high prevalences of ICA and anti-GAD, but not of anti-IA-2 aAbs. These patients have later been classified as having a slow progressive form of Type I diabetes, defined as Latent Autoimmune Diabetes of the Adult (LADA) [12,13,18,19,20,21,22].…”

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confidence: 99%

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Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

Mallone¹,

Ortolan²,

Pinach³

et al. 2002

Diabetologia

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Aims/hypothesis. Serum anti-CD38 autoantibodies (aAbs) have been reported in 17 to 19% of patients with long-standing Type I (insulin-dependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes mellitus. Whether these aAbs are also found in new-onset Type I diabetes and in Latent Autoimmune Diabetes in Adults (LADA) is not known, as is their relationship with conventional islet aAbs. Methods. These issues were addressed by studying new-onset Type I and LADA diabetic cohorts with a recently developed anti-CD38 enzymatic immunoassay. Results. Anti-CD38 aAb prevalence among newonset Type I patients (3.8%) was lower than previously found in long-standing Type I diabetes (11.7%, as defined with the 97.5 percentile cutoff; p=0.01), suggesting a late appearance of these aAbs. Among LADA patients, 14.9% were anti-CD38 + . Anti-CD38 were only associated with anti-GAD aAbs in newonset Type I diabetes. Although the CD38 target molecule was expressed in human pancreatic islets, anti-CD38 aAbs did not contribute to the islet cell antibody (ICA) immunofluorescence reactivity. All the positive sera analysed for Ca 2+ release were found to mobilise it. In agreement with these agonistic features, anti-CD38 + new-onset Type I patients showed higher fasting C-peptide values as compared to negative counterparts; the association was stronger when the analysis was limited to the agonistic anti-CD38 + sera. A similar trend was found among LADA patients. Conclusion/interpretation. Anti-CD38 aAbs are distinct markers of islet autoimmunity which are more prevalent in long-standing disease, as opposed to the other known islet aAbs. Their in vitro agonistic properties could be operating in vivo as well, as they identify sub-groups of patients with higher residual betacell function. [Diabetologia (2002[Diabetologia ( ) 45:1667[Diabetologia ( -1677

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

Mallone¹,

Ortolan²,

Pinach³

et al. 2002

Diabetologia

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“…Autoantibodies to tyrosine phosphatase IA-2 (IA2-Ab) are present in 50-70% of children and adolescents and in 30-50% of adults at the manifestation of type 1 diabetes (6,8,10,11). The most sensitive detection can be achieved by RIAs using human recombinant antigen.…”

Section: Autoantibodies Against Tyrosine Phophatase Ia-2mentioning

confidence: 99%

“…For problems in differential diagnosis we.g., maturity onset diabetes of the young, other congenital or secondary diabetes types (Table 1), early diagnosis without insulin dependencyx, immune diagnostics can be very helpful. Combined screening for IAA and GADA (age -10 years) or IA2-Ab and GADA (age )10 years) is the recommended first-line analysis ( Figure 2) (7,8,10,11,19). The detection of one autoantibody provides evidence of an ongoing autoimmune process.…”

Section: Strategies For Differential Diagnosis Autoimmune Diagnosticsmentioning

confidence: 99%

Autoimmune diagnostics in diabetes mellitus

Seißler

Scherbaum

2006

Clinical Chemistry and Laboratory Medicine (CCLM)

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Type 1 diabetes results from a specific destruction of the insulin-producing b-cells of the pancreas. The disease is characterized by the appearance of specific autoantibodies against islet cell antigens. Autoantibodies to insulin, glutamic acid decarboxylase, tyrosine phosphatase IA-2 and cytoplasmic islet cell antibodies are useful markers for the differential diagnosis of type 1 diabetes when clinical and metabolic criteria alone do not allow definite classification. Autoimmune diagnostics is of particular importance in adults to discriminate between type 1 and type 2 diabetes and to assess the diagnosis of latent autoimmune diabetes in adults.

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Humoral beta‐cell autoimmunity in relation to HLA‐defined disease susceptibility in preclinical and clinical type 1 diabetes

Knip

Kukko²,

Kulmala

et al. 2002

Am. J. Med. Genet.

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We have studied the relationship between diabetes-associated autoantibodies and various HLA genotypes and alleles in patients with newly diagnosed type 1 diabetes, in non-diabetic siblings and in children representing the general population to test the hypothesis that specific HLA genes regulate the humoral immune response to various autoantigens. Among the newly diagnosed patients we observed that those carrying the DR4-DQB1*0302 haplotype had increased levels of insulin autoantibodies (IAA) and IA-2 antibodies (IA-2A), but low levels of GAD antibodies (GADA). In contrast, those with the DR3-DQB1*02 haplotype had increased GADA titers but low IAA and IA-2 levels. DQB1*02-homozygous patients had a conspicuously low frequency and low levels of IA-2A. Among the siblings there was an apparent association between genetic risk and the prevalence of islet cell antibodies (ICA), IAA, GADA, IA-2A and multiple autoantibodies, the latter being detectable at a frequency of 24.1% in high risk siblings and at a frequency of only 0.9% in those with genotypes conferring disease protection. Among 7-16-year-old Finnish schoolchildren there was an association between GADA and the DQB1*02/*0302 genotype and the DQB1*0302 allele. Among young children identified from the general population based on high (DQB1*02/0302 heterozygosity) or moderate (DQB1*0302/x; x not equal *02, *0301, *0602, *0603) genetic risk for type 1 diabetes the high risk children seroconverted more often to positivity for ICA, GADA and IA-2A over their first 2 years of life. Among older sibs of these children we observed an obvious relationship between the degree of genetic risk and the frequency of ICA, IAA, GADA, IA-2A, and multiple antibodies. Taken together these observations suggest that HLA genes have a strong impact on the appearance of diabetes-associated autoantibodies both in first-degree relatives of affected children and in the general population. In patients with newly diagnosed disease IA-2A may be a more specific marker of beta-cell damage, whereas GADA might reflect a propensity to autoimmunity in general.

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Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease

Cited by 132 publications

References 34 publications

Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

Autoimmune diagnostics in diabetes mellitus

Humoral beta‐cell autoimmunity in relation to HLA‐defined disease susceptibility in preclinical and clinical type 1 diabetes

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