Molecular biology of autoimmune diseases.
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Animals↗
Biomedical subjects
C Boitard
Publications and source records attributed to C Boitard.
High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.
Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.
Chromosome Mapping↗
Studies on the thymus in nonobese diabetic mouse. I. Changes in the microenvironmental compartments.
The nonobese diabetic (NOD) mouse develops an autoimmune type I diabetes, which is predominantly seen in females, is triggered by T cells, and whose frequency is enhanced following thymectomy at weaning. Attempting to characterize a thymic pathology in these animals, we analyzed the microenvironmental compartment of the organ with respect to structural and functional molecules expressed by thymic epithelial cells (TEC), as well as extracellular matrix components. We observed, in both males and females, a precocious decrease in the cell numbers of discrete medullary TEC subsets, namely, those respectively defined by the expression of cytokeratins 3/10 and cytokeratin 19. In addition, some cells bearing the TR.5 phenotype (normally restricted to the medulla) could be detected in the NOD mouse thymic cortex. There was also a significant early decrease in thymulin production in females, as compared to males. As regards the extracellular matrix compartment, the most striking alteration was the presence of abnormally enlarged perivascular spaces, increasing in size with age. In these structures large amounts of T cells and, to a lesser extent, B cells were consistently encountered. In addition to B cells, the NOD mouse thymus showed on both TEC and extracellular matrix the presence of deposits of immunoglobulins, revealed with fluorescence-labeled goat anti-mouse Ig sera. Finally, the NOD mouse sera labeled both TEC and extracellular matrix proteins on normal mouse thymus frozen sections. Together, these data clearly demonstrate that the NOD mouse thymus undergoes a variety of microenvironmental changes, whose particular role in the pathophysiology of the disease is yet to be demonstrated.
Animals↗
[Decrease of early insulin secretion, risk factor of insulin-dependent diabetes. Prospective study in families with diabetic children].
In order to study the capacity of the first phase insulin response (FPIR) for predicting insulin-dependent diabetes (IDDM), we have performed one or more intravenous glucose tolerance tests (IVGTT) and determined islet-cell antibodies (ICA) and HLA-types in 220 first degree relatives of IDDM patients (194 siblings, 26 offsprings) aged 2 to 29 years. They were prospectively followed for periods ranging from 18 months to 8 years. The immunological and metabolic changes in 9 subjects who have developed IDDM or impaired glucose tolerance during the study and in 3 ICA-positive non-diabetic subjects were compared to those in ICA-negative subjects. Although the mean FPIR (1 + 3 min. plasma insulin) was significantly lower in ICA-positive compared with ICA-negative subjects, a unique low FPIR had no predictive value at the individual level. At repeated tests, the two groups followed distinctive evolutive patterns: ICA-negative subjects usually had higher FPIRs at a 2nd test, while FPIRs remained low or still decreased in ICA-positive subjects. Follow-up of subjects at high risk showed good concordance between the different predictive factors: among the 9 subjects who have developed IDDM, 7 had persisting ICA, 8 were HLA-DR3, DR4; the FPIR was consistently low in 3 and low at least once in 4. Progressive loss of the FPIR allowing to predict the time of onset of IDDM, was not observed.
Adolescent↗
[Type 1 diabetes mellitus, autoimmune disease: physiopathologic aspects and practical applications].
Type 1 (insulin-dependent) diabetes mellitus results from an autoimmune disease which is directed to insulin-secreting islet cells. In man, it is closely associated to definite major histocompatibility complex alleles. The islets are infiltrated by inflammatory cells (insulitis). Anti-islet cell autoantibodies are present in most patients and represent a valuable marker for the autoimmune reaction. The major role of autoreactive T lymphocytes has been demonstrated in animal models of spontaneous insulin-dependent diabetes (the BB rat and the NOD mouse). Such pathophysiological concepts already have clinical applications. The presence of anti-islet cell antibodies identifies patients with type 1 diabetes of slow onset who initially present with non-insulin dependent diabetes. In the same respect it is now feasible to predict the possible occurrence of diabetes in 'at risk' subjects (such as siblings of a diabetic patient) on the basis of HLA typing and the presence of markers of anti-beta cell immunity. Lastly, both in animal models and in human diabetes, it has been demonstrated that immune intervention can alter the course of anti-islet autoimmunity. From these results one may hope in the future to get preventive treatment of type 1 diabetes before the onset of metabolic disturbances.
Autoantibodies↗
Heterogeneity of HLA genetic factors in IDDM susceptibility.
The association of certain HLA-D alleles with insulin-dependent diabetes mellitus (IDDM) is well known. One hundred and sixty-one non-related diabetic individuals and 142 non-related healthy controls were typed for the HLA DR-DQw-Dw association, using a restriction fragment length polymorphism (RFLP) typing method that combines three probe/enzyme systems: DRB/Taq I, DQB/Taq I, and DQB/Bam HI. Comparison of frequencies in both diabetics and controls confirms previous results in terms of HLA class II and IDDM association. Moreover, we have found that DR3/3 heterozygous individuals are more susceptible to IDDM when they are also Dw25 (associated with B18) than when they are Dw24 (associated with B8). Using oligonucleotide dot-blot hybridizations we analyzed the HLA-DQB1 sequence of DR3,Dw24 and DR3,Dw25 homozygous individuals, and we found no difference at position 57 between these two DR3-carrying haplotypes. This observation points to the heterogeneity of HLA genetic factors in IDDM susceptibility.
Alleles↗
Assessment of precision, concordance, specificity, and sensitivity of islet cell antibody measurement in 41 assays.
Forty-one assays were analysed at the 3rd International Workshop on the standardisation of islet cell antibodies. Analysis of precision demonstrated assays consistently detecting blind duplicates within one doubling dilution and capable of discriminating one doubling dilution differences in islet cell antibody concentration. Some assays, however, reported duplicates discrepantly by more than seven doubling dilutions, and consequently could not distinguish even large quantities of islet cell antibodies. Precision was best in assays from laboratories which had participated in all three Standardisation Workshops and was not dependent upon methodology. The use of the Juvenile, Diabetes Foundation reference islet cell antibody standard and standard curves reduced the scatter of results, and was best amongst assays with better precision. Twenty-seven assays reported all ten blood donor sera as negative. However, 14 assays did not, and specificity (negativity in health) was less than 50% in three assays. Low specificity was strongly associated with poor precision. The detection limit of assays ranged from less than 5 to 50 JDF units and was partially dependent upon methodology. Assays incorporating extended incubation had the lowest detection limits without a decrease in the specificity of the ten blood donor sera. Precise quantification is fundamental for the standardisation and comparability of islet cell antibodies. Precise quantitative assays have been identified and reference standards and common units established.
Autoantibodies↗
Immunology of insulin-dependent mellitus.
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Animals↗
Cyclosporine therapy for severe systemic sclerosis associated with the anti-Scl-70 autoantibody.
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Autoantibodies↗
Control of diabetes in NOD mice by suppressor cells.
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Animals↗
Renal hemodynamics and segmental tubular reabsorption in early type 1 diabetes.
To investigate mechanisms underlying GFR control in diabetes mellitus, renal hemodynamics and segmental tubular handling of sodium, using lithium clearance, were assessed in 41 insulin-dependent diabetics (IDD) treated by insulin for 11 +/- 8 days, and in 19 normal controls. Average GFR and effective renal plasma flow (ERPF) were slightly but not significantly higher (136 +/- 22 vs. 123 +/- 16 ml/min.1.73 m2) in IDD than in normal subjects. GFR and ERPF were positively and strongly correlated in controls (r = 0.61, P less than 0.001) and in diabetics (r = 0.72, P less than 0.0001) indicating the marked flow dependency of GFR in both populations. After adjustment for ERPF, GFR was significantly higher in diabetics, suggesting a role of increased glomerular capillary pressure and ultrafiltration coefficient in the subset of "hyperfiltering" patients. Both fractional (FPRNa) and absolute (APRNa) proximal sodium reabsorption were significantly higher in IDD and significantly correlated with GFR. The ensuing decrease in sodium distal delivery could deactivate the tubuloglomerular feedback response and thus favor sustained vasodilation and high GFR in some diabetics. The renal effects of acute administration of drugs acting predominantly at either the pre- or the postglomerular resistance using nicardipine (N = 16) or captopril (N = 25) were further evaluated in IDD. The renal response to captopril or nicardipine was different in IDD. Whereas both drugs induced a marked decrease in renal vascular resistance, GFR was slightly decreased by captopril and was unchanged after nicardipine; these results are similar to those observed in normotensive non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renal haemodynamic effects of short term cyclosporin A administration in patients with insulin-dependent diabetes mellitus.
To investigate the time relationships involved in cyclosporin-induced nephrotoxicity we studied changes in blood pressure, renal haemodynamics and sodium excretion in 22 adult patients with insulin-dependent diabetes mellitus treated with cyclosporin (CsA) for 4 +/- 2 days, compared to 22 insulin-dependent diabetic patients receiving conventional insulin therapy, who were matched for age and duration of diabetes. To further clarify the pathogenic role of the renin-angiotensin system, insulin-dependent diabetic patients receiving CsA were studied before and after sublingual administration of 75 mg captopril. An average of 4 days CsA treatment markedly increased blood pressure and renal vascular resistance, but did not alter glomerular filtration rate, renal plasma flow, sodium urinary excretion, or body-weight. The marked renal vasoconstriction without early changes in GFR suggests that the late decrease in GFR may involve other factors in addition to renal hypoperfusion. Acute inhibition of angiotension II formation was still able to decrease blood pressure and renal vascular resistance, although not to normal control values. These results indicate that a physiological concentration of angiotensin II may potentialise but may not be the sole factor involved in the vasopressor effect of CsA.
Adult↗
Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin.
Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean +/- SE duration of 316 +/- 21 days (range 31-850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of beta-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18-24 mo of treatment were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin.
Remission from insulin dependency in insulin-treated recent-onset type I (insulin-dependent) diabetic patients can result from a partial recovery of insulin secretion, an improvement in tissue sensitivity to insulin, or both. The same hypothesis must be analyzed when remission occurs in cyclosporin A (CsA)-treated patients. In this study, plasma C-peptide levels were serially measured in the basal state and after stimulation in 219 recent-onset type I diabetic patients; 129 received CsA, and all patients were similarly monitored and insulin treated. The results were analyzed in view of the occurrence of remission. Remission was defined as good metabolic control in the absence of hypoglycemic treatment for greater than or equal to 1 mo. Remission occurred in 44% of the CsA-treated group and lasted for mean +/- SE 10.0 +/- 0.9 mo vs. 21.6% in the non-CsA-treated group with a duration of 4.4 +/- 0.8 mo. Plasma C-peptide levels were initially dramatically lower than normal in both groups in the basal and stimulated states. C-peptide levels increased significantly later, at 3 and 6 mo, in both groups. C-peptide values were proportional to the rates of remission in both groups. In the non-CsA-treated group, C-peptide levels later decreased, and these patients inexorably relapsed to insulin dependency. In contrast, in the CsA-treated group, the initial recovery in insulin secretory capacity was maintained over the 18-24 mo of the study. Furthermore, higher remission rates and longer-lasting remission were obtained in patients who reached higher C-peptide levels at the 3rd mo of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Current concepts in autoimmunity.
Autoimmune diseases are subsequent to tissue damage mediated by an immune reaction directed toward autoantigens. Activation of CD4+ T cells reactive to carrier determinants on foreign antigenic complexes or autoreactive CD4+ T cells are central to the triggering of immune effector mechanisms. Transfer experiments in animals, demonstration of suppressor T cells, study of antigen-presenting cells--CD4+ T cells interaction, isolation of T cell clones and study of transgenic mice have recently brought new insight into the understanding of autoimmunity.
Animals↗
Pathophysiology of autoimmune diseases.
Immune reactions towards self antigens can lead to cell destruction and autoimmune disease. In this review it is summarized, how autoimmune diseases are classified from a clinical standpoint into organ-specific and systemic involvement and how our understanding has evolved during recent history. The experimental basis is discussed with transfer models, T-cell suppressor control, T-cell recognition of antigen presenting cells, T-cell clones and more recent transgenic mouse models. It is finally concluded that autoimmunity develops due to the direct activation of autoreactive CD4 positive T-cells. Monoclonal antibodies interfering with this interaction may prove a useful immune-intervention. However, antigens and relevant epitopes for autoimmune induction still need to be identified and characterized.
Animals↗
[Result of 3 years of screening for preclinical phase of juvenile insulin-dependent diabetes mellitus].
We screened 1,000 individuals for pre-type I diabetes mellitus: 927 were first degree relatives of patients treated at our institution, 31 other had related autoimmune diseases, 42 had fortuitously discovered slight hyperglycemia. Islet cell antibodies were present in 31 subjects, 13 adults and 18 children. Among these 18 children, 7 also had complement-fixing islet cell antibodies, and 5 anti-insulin antibodies. All but one initially had a normal insulin response to intravenous glucose. The child with the abolished response, as well as another whose insulin secretion fell down during the study period, became diabetic. Based on these preliminary data, we are developing large scale family screening of pre-type I diabetes.
Adolescent↗
[Antioxidant enzymes in insulin-dependent diabetes in the child and adolescent].
Superoxide dismutase, glutathione peroxidase and glutathione reductase activities were measured in erythrocytes of 214 young patients with insulin-dependent diabetes and 37 healthy subjects with similar age and sex distribution. The diabetic patients were divided into groups and subgroups according to sex, age, duration of disease, existence of diabetes complications and family history of atherogenic risks. Data analysis was performed by comparing enzyme activities in subgroups according to the degree of diabetes control and the plasmatic level of various lipid fractions. Results showed that superoxide dismutase, glutathione peroxidase and glutathione reductase activities in young diabetic patients were similar to those in controls, except for patients with retinopathy, whose glutathione peroxidase activity was decreased. This last finding might suggest that there is a relationship between the development of diabetic microvascular complications and the accumulation of free radicals and peroxide lipids.
Adolescent↗