Anti-CD38 autoantibodies: characterisation in new-onset type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies (original) (raw)
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Diabetes, 2001
Insulin secretion is one of the functions mediated by CD38, a nonlineage pleiotropic cell surface receptor. The molecule is the target of an autoimmune response, because serum autoantibodies (aAbs) to CD38 have been detected in diabetic patients. In the healthy Caucasian population, the CD38 gene is bi-allelic (86% CD38*B and 14% CD38*A), whereas an Arg140Trp mutation has been identified in Japanese diabetic patients. We investigated the relationship between CD38 and diabetes in Caucasian patients by characterizing anti-CD38 aAbs in terms of prevalence and function (agonistic/nonagonistic activity) and by exploring the potential influence of the CD38 genetic background. A novel enzymatic immunoassay, using recombinant soluble CD38 as the target antigen, was developed for the analysis of anti-CD38 aAb titers. Sera from 19.15% of type 1 and 16.67% of type 2 diabetic patients were positive. The majority of anti-CD38 aAbs (57.14%) displayed agonistic properties, i.e., they demonstrated ...
Diabetologia, 2002
Aims/hypothesis. Autoantibodies against CD38 have been found in some patients with Type II (non-insulindependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i) overlaps with anti-GAD autoimmunity, (ii) identifies an insulin-deficient phenotype, (iii) is under the influence of genetic factors. Methods. We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects). Results. CD38-autoantibodies were found in 8.4% of Type II diabetic patients (p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD38ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti-CD38 positive had DQB1*02 compared with 38% of anti-CD38 negative (p=0.04).
Autoantibody Response to CD38 in Caucasian Patients With Type 1 and Type 2 Diabetes
Diabetes, 2001
Insulin secretion is one of the functions mediated by CD38, a nonlineage pleiotropic cell surface receptor. The molecule is the target of an autoimmune response, because serum autoantibodies (aAbs) to CD38 have been detected in diabetic patients. In the healthy Caucasian population, the CD38 gene is bi-allelic (86% CD38*B and 14% CD38*A), whereas an Arg140Trp mutation has been identified in Japanese diabetic patients. We investigated the relationship between CD38 and diabetes in Caucasian patients by characterizing anti-CD38 aAbs in terms of prevalence and function (agonistic/nonagonistic activity) and by exploring the potential influence of the CD38 genetic background. A novel enzymatic immunoassay, using recombinant soluble CD38 as the target antigen, was developed for the analysis of anti-CD38 aAb titers. Sera from 19.15% of type 1 and 16.67% of type 2 diabetic patients were positive. The majority of anti-CD38 aAbs (57.14%) displayed agonistic properties, i.e., they demonstrated ...
Diabetes, 1999
The type II transmembrane glycoprotein CD38 (ADPribosyl cyclase/cyclic ADP-ribose hydrolase) has been proposed as a mediator of insulin secretion from pancreatic -cells and as a candidate for autoimmune reactions in type 2 diabetes. We evaluated the presence of anti-CD38 autoantibodies in Caucasian patients with diabetes and investigated the effect of these antibodies on insulin secretion from isolated human pancreatic islets. The presence of anti-CD38 autoantibodies was evaluated by using Western blot analysis in 236 patients with type 2 diabetes (mean age 63 years), in 160 patients with type 1 diabetes (mean age 38 years), and in 159 nondiabetic subjects. Anti-CD38 autoantibody titers at least 3 SD above the mean value of the control group were found in 9.7% of type 2 diabetic patients and in 13.1% of type 1 diabetic patients ( 2 = 15.9, P = 0.0003 vs. 1.3% of control subjects). No significant differences were observed in sex distribution, current age, age at diabetes onset, BMI, fasting serum glucose, or glycemic control between anti-CD38 + and anti-CD38diabetic patients in either the type 2 or type 1 diabetic groups. The effect of 23 anti-CD38and 13 anti-CD38 + sera on insulin secretion at low (3.3 mmol/l) or high (16.7 mmol/l) medium glucose concentrations was evaluated in isolated human pancreatic islets. Data are medians (interquartile range). The anti-CD38 + s e r a potentiated insulin release both at low [95 (64) vs. 23 (12) µU/ml of control incubations, respectively, P < 0.0001] and high [271 (336) vs. a control of 55 (37) µU/ml, respectively, P = 0.001] medium glucose concentrations, whereas the anti-CD38sera did not. Furthermore, in the pooled data from all 36 tested sera, insulin levels in the islet incubation medium were directly related to the anti-CD38 antibody titer. We conclude that autoantibodies to CD38 are associated with both type 1 and type 2 diabetes in Caucasian subjects. These autoantibodies exert a stimulatory effect on insulin secretion by cultured human islets. The role of this autoimmune reaction in the pathogenesis of diabetes remains to be elucidated.
Diabetes, 2002
Autoantibodies against CD38 (adenosine-5-diphosphate[ADP]-ribosyl cyclase/cyclic ADP-ribose hydrolase) have been described in 10 -12% of patients with type 2 diabetes. In human islets, anti-CD38 autoantibodies (CD38Abs) acutely stimulate insulin release (IR) and increase the cytosolic calcium concentration ([Ca 2؉ ] i ). Whether CD38Abs affect human islet cell function and survival upon prolonged in vitro exposure is not known. We cultured human islets for up to 7 days in the presence of sera from 10 patients with type 2 diabetes that had neither CD38Ab-nor [Ca 2؉ ] i -mobilizing activity (؊/؊), sera from 6 patients with type 2 diabetes that was CD38Ab-positive and had [Ca 2؉ ] imobilizing activity (؉/؉), or no sera (control). At baseline, ؉/؉ sera caused a significant (P < 0.002) acute stimulation of IR (IR at 3.3 mmol/l glucose was 45 ؎ 19, 84 ؎ 24, and 34 ؎ 12 U/ml in control, ؉/؉, and ؊/؊ sera, respectively; the corresponding IR at 16.7 mmol/l glucose was 72 ؎ 25, 204 ؎ 56, and 80 ؎ 32 U/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 ؎ 18, 27 ؎ 11, and 43 ؎ 24 U/ml (P ؍ 0.0003) for control, ؉/؉, and ؊/؊ sera, respectively, whereas at 16.7 mmol/l glucose, it was 95 ؎ 76, 45 ؎ 35, and 76 ؎ 42 U/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/l glucose was 40 ؎ 11, 28 ؎ 12, and 35 ؎ 15 U/ml, respectively, whereas at 16.7 mmol/l glucose it was 79 ؎ 39, 39 ؎ 17, and 62 ؎ 39 U/ml. At both 3 and 7 days, IR still increased when switching from 3.3 to 16.7 mmol/l glucose (P < 0.0003), and incubation with ؉/؉ sera induced a significant decrease in the insulin response (P < 0.002). At 7 days, the number of dead cells (as evaluated by an enzyme-linked immunosorbent assay technique) differed significantly between control (1.2 ؎ 0.3 OD units) cells, islets exposed to ؊/؊ sera (1.4 ؎ 0.1), and islets coincubated with ؉/؉ sera (1.9 ؎ 0.4, P < 0.01). We conclude that prolonged exposure of human islets to sera positive for the presence of CD38Abs with [Ca 2؉ ] i -mobilizing activity impairs -cell function and viability in cultured human pancreatic islets. Diabetes 51 (Suppl. 3):S474 -S477, 2002 From the [Ca 2ϩ ] i , cytosolic calcium concentration; CD38Ab, anti-CD38 autoantibody; fluo-3-AM, fluo-3-acetoxymethyl ester; HBSS, Hanks' balanced salt solution; IR, insulin release; KRB, Krebs-Ringer bicarbonate; KRH, Krebs-Ringer-HEPES; mAb, monoclonal antibody; MFI, mean fluorescence intensity. The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris. S474 DIABETES, VOL. 51, SUPPLEMENT 3, DECEMBER 2002 *P Ͻ 0.0001 vs. control and P ϭ 0.02 vs. negative sera by Bonferroni-Dunn test.
Autoimmunity Reviews, 2009
Type 1 diabetes mellitus (T1DM) has been shown to be a disease characterized by immunemediated destruction of the insulin-producing islet beta-cells (β-cells) in the pancreas. Intensive studies, in both patients and animal models are trying to elucidate the specific antigenic targets that are responsible for islet cell autoimmunity. So far, the most important molecules that have been recognized are the native insulin, the 65-kDa form of glutamic acid decarboxylase (GAD 65) and the insulinoma-antigen 2 (IA-2). Identification of those specific autoantibodies that are involved in the primary immunological events of the autoimmune disease process will allow the development of novel diagnostic procedures for early detection and initiation of potential therapy prior to irreversible loss of β-cells. Within the framework of polyglandular disorders, T1DM may coexist with other organ specific autoimmune diseases such as autoimmune thyroid disease (ATD), autoimmune gastritis (AG), celiac disease (CD) and Addison's disease (AD), which are associated with the production of organ-specific autoantibodies. So, as a subset of patients with those autoantibodies will develop clinical disease, screening T1DM patients could prognosticate morbidity relative to unrecognised clinical entities. The close follow-up of patients with organ-specific autoantibodies could lead to seasonable identification of those requiring therapy.
Diabetologia, 1987
To evaluate the behaviour and predictive value of islet cell and insulin autoantibodies in patients with organspecific autoimmune diseases, we followed 21 non-diabetic subjects for a mean period of 84 4-27 months. Ten patients were persistently seropositive for complement-fixing islet cell antibodies and high titres of immunoglobulin G islet cell antibodies (>--1 : 8). The prevalence of persistent insulin autoantibodies in this group was 67%. Seven patients (70%) developed Type I (insulin-dependent) diabetes mellitus after a latency period of 2-60 months. The predictive value of complement-fixing islet cell antibodies was 65%, and in the presence of both complement-fixing islet cell and insulin autoantibodies the predictive value rose to 76%. Eleven patients were seronegative for complement-fixing islet cell antibodies and had low immunoglobulin G islet cell antibodies titres (< 1 : 8) that were either persistent or transient, or that fluctuated during follow-up. The prevalence of persistent insulin autoantibodies in this group was 45%; only one subject developed Type 1 diabetes. The predictive value of persistent islet cell antibodies (complement-fixing positive/negative) was 54%, and it rose to 70% when both islet cell and insulin autoantibodies were present. Individuals with only insulin autoantibodies or immunoglobulin G islet cell antibodies did not develop diabetes mellitus. A high frequency of HLA-DR3 and/or DR4 was found in patients who developed diabetes mellitus. Thus, the presence of both islet cell and insulin autoantibodies in patients with organ-specific autoimmune disease appears to confer the highest risk of progression toward Type 1 diabetes.
Diabetes, 2005
Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens—GAD65, IA-2, or insulin—signals an autoimmune pathogenesis of β-cell killing. A β-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to β-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the ...
International Journal of Basic Science in Medicine
Introduction: This study was aimed to assess the prevalence of islet cell autoantibodies (ICAs) in type 2 diabetes mellitus (T2DM) patients and to compare some clinical and metabolic markers between ICA-negative and ICA- positive groups in South Khorasan province, East of Iran.Methods: In this cross-sectional study, 384 T2DM patients, all over 30 years old, were selected. None of the patients needed insulin therapy for at least 6 months following diagnosis. Demographic data including gender, age, age at diagnosis, disease duration, health status, family history of diabetes, body mass index (BMI) and treatment type were collected from all subjects. ICA assays were conducted using commercial enzyme-linked immunosorbent assay (ELISA) kits. In addition, blood pressure, as well as cholesterol, serum C-peptide and HbA1c levels were compared between ICA-negative and ICA-positive groups. Data were analyzed using SPSS software and P < 0.05 was considered as statistically significant.Resul...