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R A Jackson

Publications and source records attributed to R A Jackson.

At least 19 recordsLinked to original sources
PubMed1998

Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes.

Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) is a disease controlled by the major histocompatibility complex (MHC) which results from T-cell-mediated destruction of pancreatic beta-cells. The incomplete concordance in identical twins and the presence of autoreactive T cells and autoantibodies in individuals who do not develop diabetes suggest that other abnormalities must occur in the immune system for disease to result. We therefore investigated a series of at-risk non-progressors and type 1 diabetic patients (including five identical twin/triplet sets discordant for disease). The diabetic siblings had lower frequencies of CD4-CD8- Valpha24JalphaQ+ T cells compared with their non-diabetic sibling. All 56 Valpha24JalphaQ+ clones isolated from the diabetic twins/triplets secreted only interferon (IFN)-gamma upon stimulation; in contrast, 76 of 79 clones from the at-risk non-progressors and normals secreted both interleukin (IL)-4 and IFN-gamma. Half of the at-risk non-progressors had high serum levels of IL-4 and IFN-gamma. These results support a model for IDDM in which Thl-cell-mediated tissue damage is initially regulated by Valpha24JalphaQ+ T cells producing both cytokines; the loss of their capacity to secrete IL-4 is correlated with IDDM.

Antigens, CD1↗
PubMed1997

Misleading results from immunoassays of serum free thyroxine in the presence of rheumatoid factor.

A novel interference with measurements of serum free thyroxine (FT4) caused by rheumatoid factor (RhF) is described. We found misleading, sometimes gross, increases of FT4 results in 5 clinically euthyroid elderly female patients with high RhF concentrations. All 5 patients had high FT4 on Abbott AxSYM or IMx analyzers. "NETRIA" immunoassays gave misleading results in 4 of the 5 patients; Amerlex-MAB in 2 of 4 patients; AutoDELFIA in 2 of the 5; and Corning ACS-180 and Bayer Diagnostics Immuno 1 in 1 of the 5. BM-ES700 system results for FT4 in these women remained within the reference range. Results for serum T4, thyroid-stimulating hormone, free triiodothyronine, thyroid-hormone-binding globulin, and FT4 measured by equilibrium dialysis were normal in all 5 patients. Drugs, albumin-binding variants, and anti-thyroid-hormone antibodies were excluded as interferences. Addition to normal serum of the RhF isolated from each of the 5 patients increased the apparent FT4 (Abbott AxSYM). Screening of 83 unselected patients demonstrated a highly significant positive correlation between FT4 (Abbott AxSYM) and RhF concentrations. Discrepant, apparently increased FT4 with a normal result for thyroid-stimulating hormone should lead to measurement of the patient's RhF concentration.

Aged↗
PubMed1996

Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies.

Islet cell antibodies (ICAs) are predictive of type I diabetes in first-degree relatives, but this immunohistochemical assay has proven difficult to standardize. As an alternative, we assessed the use of radioassays for antibodies against three molecularly characterized islet autoantigens, including ICA512bdc (amino acid residues 256-979 of the IA-2 molecule, incorporating the intracellular domain). We measured insulin autoantibodies (IAAs), GAD autoantibodies (GAAs), and ICA512bdc autoantibodies (ICA512bdcAAs) by radioassay, in addition to ICAs, in 882 first-degree relatives of patients with type I diabetes, 50 of whom later developed diabetes with a median follow-up of 2.0 years (maximum 11.3 years). The cutoff for each radioassay was determined by testing >200 control subjects. When autoantibody frequencies among the relatives were analyzed according to relationship to the proband, the offspring of diabetic fathers had a higher frequency of ICA5I2bdcAAs (P = 0.008), IAAs (P = 0.0001) and GAAs (P = 0.0001) than the offspring of diabetic mothers. ICA512bdcAAs and IAAs both showed a significant association with HLA-DR4-DQ8 (P = 0.0005). Among relatives developing diabetes, 98% had one or more of IAAs, GAAs, or ICA512bdcAAs, and 80% had two or more of these autoantibodies, compared with none of the control subjects. Using survival analysis to allow for different lengths of follow-up, there was a significant increase in the risk of diabetes with the number of these autoantibodies present, comparing zero, one, two, and three autoantibodies (P < 0.0001, log-rank test), and by Cox regression analysis, this was independent of ICAs and age. For relatives with two or more of these autoantibodies, the risk of diabetes within 3 years was 39% (95% CI, 27-52) and the risk within 5 years was 68% (95% CI, 52-84). Relatives with all three autoantibodies had a risk within 5 years estimated to be 100%. The presence of low first-phase insulin release further increased the risk for relatives with one or two autoantibodies. We conclude that the presence of two or more autoantibodies (out of IAAs, GAAs, and ICA512bdcAAs) is highly predictive of the development of type I diabetes among relatives.

Adolescent↗
PubMed1995

Late progression to diabetes and evidence for chronic beta-cell autoimmunity in identical twins of patients with type I diabetes.

Previous studies suggest that after 6 years of discordance, identical twin pairs rarely become concordant for type I diabetes. With up to 39 years of follow-up from the onset of diabetes in the index twin, we determined how many discordant twins have evidence of beta-cell autoimmunity and how many develop overt diabetes. We longitudinally followed 23 pairs of identical twins (or triplets) that were selected from a total group of 30 pairs because they were discordant for type I diabetes when first ascertained. Seven developed diabetes after 3, 3, 7, 8, 9, 31 and 36 years of discordance. By survival analysis, the concordance after 10 years from the onset of diabetes in the index twin was estimated as 23% (95% confidence interval, 5-40%), increasing to 38% (95% confidence interval, 8-69%) after 31 years. Among 16 twins remaining nondiabetic at last follow-up (8-39 years of discordance), 12 were assessed with serial intravenous glucose tolerance tests and a total of 407 measurements by radioassay of antibodies against three defined autoantigens (glutamic acid decarboxylase, insulin, and the recently cloned molecule ICA512). Two-thirds (8 of 12) had evidence of beta-cell autoimmunity (persistently positive autoantibody levels) and/or first-phase insulin release less than the 1st percentile of control subjects. In summary, identical twins may develop diabetes after a prolonged period of discordance and approximately two-thirds of long-term discordant twins have evidence of persistent beta-cell autoimmunity and/or beta-cell damage. The concordance for beta-cell autoimmunity, therefore, is much higher than for overt diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.

HLA-DQB1 alleles confer susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). We investigated whether the susceptibility alleles DQB1*0302 and DQB1*0201 affect progression to diabetes among islet cell antibody-positive (ICA+) first-degree relatives of IDDM patients and whether the protective allele DQB1*0602 can be found and is still protective among such relatives. We human leukocyte antigen-typed and periodically tested beta-cell function (first-phase insulin release [FPIR] during the intravenous glucose tolerance test) in 72 ICA+ relatives, of whom 30 became diabetic on follow-up (longest follow-up 12 years); 54 (75%) relatives carried DQB1*0302 and/or DQB1*0201. The frequency of DQB1*0302 and DQB1*0201 and of the high-risk genotype DQB1*0302/DQB1*0201 did not differ significantly between diabetic relatives and those remaining nondiabetic. On follow-up, progression to IDDM was not statistically different for relatives with or without the DQB1*0302/DQB1*0201 genotype. However, those relatives with the DQB1*0302/DQB1*0201 genotype had a tendency to develop diabetes at an earlier age (log-rank P = 0.02). We found DQB1*0602 in 8 of 72 (11.1%) ICA+ relatives. Relatives with DQB1*0602 did not develop diabetes or show any decline of FPIR versus 28 of 64 DQB1*0602- relatives who developed IDDM (log-rank P = 0.006; Wilcoxon's P = 0.02). The protective allele DQB1*0602 is found in ICA+ relatives who have minimal risk of progression to IDDM. Therefore, DQB1*0602 is associated with protection from IDDM both in population studies and among relatives with evidence of autoimmunity who should not enter prevention trials.

Adolescent↗
PubMed1994

The paternally inherited insulin gene B allele (1,428 FokI site) confers protection from insulin-dependent diabetes in families.

Several polymorphisms of the insulin gene and its flanking regions (INS region) are in linkage disequilibrium and confer susceptibility to insulin-dependent diabetes (IDDM). We have analysed INS AA and AB-BB genotypes at the 1,428 FokI site (3' of the insulin gene) in 217 patients with IDDM, 402 non-diabetic first degree relatives negative for insulin (IAA) and islet cell autoantibodies (ICA), and 116 autoantibody positive (for ICA or IAA, or both) relatives of whom 39 became diabetic on follow-up. Most IDDM patients (83.4%, 181/217) had the AA genotype vs. 50% (25/50) of the controls (P < 10(-6)). Only 16.6% (36/217) of IDDM patients carried the AB genotype and none was BB homozygous, suggesting a protective effect of the B allele. By segregation analysis of the B allele in the IDDM offspring of informative families (only one AB parent) from the United States, the maternal B allele was inherited by 19/35 (54.2%) of the IDDM offspring. In contrast, only 4/26 (15.3%) of the IDDM offspring inherited the paternal B allele (P = 0.001), suggesting maternal imprinting of the INS region. Therefore, the INS B allele may be protective only when paternally inherited. Among the 39 of 116 autoantibody positive relatives who developed IDDM on follow-up, only five of them had the B allele. The frequency of the B allele in this group was much lower (12.8%, 5/39) than that observed in non-diabetic autoantibody positive relatives (32.5%, 25/77, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes.

Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles deriving from the evolutionary lineage 4 (*0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (*0101, *0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles were IAA-positive, with lower levels than relatives with lineage 1-3 alleles (mean = 55 +/- 15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0.004). The amino acid sequences of lineage 1-3 alleles uniquely share glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (often DQA1 *0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer recessive low responsiveness to insulin.

Alleles↗
PubMed1994

Pre-endoscopic antibiotics for the prevention of bacterial endocarditis: do we use them appropriately?

OBJECTIVE: Because native valve bacterial endocarditis following endoscopic procedures is extremely rare, recent guidelines have discouraged indiscriminate use of pre-endoscopic antibiotics. The purpose of this study was to determine whether these guidelines have had an impact in prescribing antibiotic prophylaxis prior to endoscopic procedures. METHODS: All ambulatory endoscopic procedures carried out from January 1, 1992, through December 31, 1992, in a 412-bed community hospital in Northern Virginia were reviewed to identify cases receiving antibiotic prophylaxis. Inpatients, percutaneous gastrostomies, and ERCPs were not included, since many had received antibiotics for reasons other than endocarditis prophylaxis. We also surveyed a random sample of board certified gastroenterologists practicing at teaching hospitals in Northern Virginia and Washington, DC, to determine their practice patterns. We used the recent recommendations of the American Heart Association with minor modification as the "appropriate" guideline. RESULTS: Only 10% of physicians use antibiotic prophylaxis appropriately. Most physicians over-utilize antibiotics in a variety of settings that do not require such measures. Conversely, many physicians do not prescribe antibiotics for disorders which do require prophylaxis. CONCLUSION: Although "appropriate" guidelines for prophylactic antibiotics are available, and we have estimated the risk of acquiring native valve bacterial endocarditis following endoscopic procedures to be only 1 in 5-10 million procedures, the majority of physicians do not use prophylactic antibiotics appropriately.

Ambulatory Care↗
PubMed1993

Insulin prophylaxis in individuals at high risk of type I diabetes.

Prevention of type I diabetes is now a practical goal thanks to the ability to define confidently a high-risk group and the success of preventive strategies in animal models. We describe here a pilot trial of low-dose insulin to prevent diabetes in relatives of patients with type I diabetes.

Adolescent↗
PubMed1993

Distinction between transient hyperglycemia and early insulin-dependent diabetes mellitus in childhood: a prospective study of incidence and prognostic factors.

We prospectively studied 63 children with transient hyperglycemia to determine their risk of acquiring insulin-dependent diabetes mellitus (IDDM) and to evaluate the predictive value of immunologic markers of prediabetes and of the intravenous glucose tolerance test. Children with transient hyperglycemia were identified by a prospective systematic review of the laboratory reports of a large children's hospital and an office-based pediatric practice and by referral from pediatricians. Transient hyperglycemia occurred in 0.46% of children seen in the children's hospital and in 0.013% of children attending a pediatric office practice. Insulin-dependent diabetes mellitus developed within 18 months of identification in 32% of children in whom transient hyperglycemia was discovered in the absence of a serious illness, compared with 2.3% of children identified during a serious illness (relative risk, 13.9; 95% confidence interval, 1.56 to 123.5). Islet cell antibodies and competitive insulin autoantibodies each had a 100% positive predictive value for IDDM; the negative predictive value of islet cell antibodies and competitive insulin autoantibodies was 96% and 98%, respectively. The stimulated insulin release during an intravenous glucose tolerance test, adjusted for age, had the highest overall accuracy of prediction. All children less than 6 years of age with stimulated insulin release levels < 85 pmol/L (12 microU/ml) subsequently had IDDM, as did an 11-year-old child whose stimulated insulin release level was below the 1st percentile of 170 pmol/L (24 microU/ml). To date, no child whose stimulated insulin release level was above the 5th percentile has had IDDM. We conclude that when transient hyperglycemia occurs during a serious intercurrent illness, the risk of progression to IDDM is low. In contrast, one third of children in whom transient hyperglycemia is identified without a serious illness can be expected to have IDDM within 1 year. A combination of islet cell antibodies, competitive insulin autoantibodies, and stimulated insulin release levels during an intravenous glucose tolerance test can accurately distinguish children with prediabetes from those with presumed benign transient increases in plasma glucose concentrations.

Adolescent↗
PubMed1993

Decreased risk of type I diabetes in offspring of mothers who acquire diabetes during adrenarchy.

Fathers with type I diabetes transmit diabetes to their offspring 2-3 times more frequently than mothers with type I diabetes. This phenomenon has provoked both genetic and nongenetic hypotheses, but the mechanism remains obscure. We find that mothers who develop diabetes before age 8 transmit diabetes at the same rate as diabetic fathers, and that the sex difference in diabetes transmission is explained by a decreased transmission rate in mothers who acquired diabetes after age 8. We constructed a data base containing 2156 nondiabetic and diabetic offspring of parents with type I diabetes. Families were selected from our main data base, which contains demographic information and diabetes autoantibody test results on > 8000 first-degree relatives of patients with type I diabetes and diabetic probands. Identification of offspring was made through diabetic parents who had participated in our autoantibody screening program at the Joslin Diabetes Center between 1983 and 1990. Questionnaires were sent to all other family members to determine the number of diabetic and nondiabetic offspring in each family. The 20-yr life-table risk of diabetes in offspring of diabetic fathers and mothers is 8.9 +/- 1.0 and 3.4 +/- 0.6%, respectively. For mothers acquiring diabetes before or after age 8, the risk of diabetes in offspring is 13.9 +/- 4.4 and 2.4 +/- 0.6% at 20 yr of age, respectively. Furthermore, we find that duration of diabetes in mothers before pregnancy has no effect on the risk of diabetes in their offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study.

OBJECTIVE: To help standardize methodology for intravenous glucose tolerance testing in preclinical IDDM by comparing a 30-s bolus and a 3-min infusion of glucose. RESEARCH DESIGN AND METHODS: We tested 20 healthy nondiabetic adults at four centers (in Seattle, Boston, Melbourne, and London). Each subject had four intravenous glucose tolerance tests (two bolus and two infusion). The acute insulin response to glucose was calculated as the mean of the 1' + 3', the mean of 1' to 10', or as the integrated area from 0 to 10'. Glucose and insulin profiles and intrasubject coefficient of variation were compared. RESULTS: With the infusion protocol, the 1' insulin was significantly higher, resulting in a higher acute insulin response to glucose when calculated as 1' + 3' (525 +/- 66 vs. 376 +/- 35 pM, P < 0.004). When calculated over 10 min, however, the acute insulin response to glucose was not different between protocols. In addition, the intrasubject coefficient of variation was significantly better when calculated over 10 min in both protocols, but no significant differences were noted between the bolus and infusion (infusion: AIRg [area from 0 to 10'] 10.4 +/- 2.1% vs. AIRg [1' + 3'] 14.9 +/- 2.8%, P < 0.007; bolus: AIRg [area from 0 to 10'] 14.6 +/- 2.8% vs. AIRg [1' + 3'] 19.8 +/- 3.5%, P < 0.007). Comparison of the insulin assays between the four centers showed close correlation and gave indistinguishable results in terms of within-subject coefficient of variation. Glucose profiles were similar in both protocols. Although the glucose values were lower with the bolus protocol from 4' to 40', the rate of fall from 10 to 30' (and thus the rate of glucose disposal) was indistinguishable between the two. CONCLUSIONS: These data suggest that neither protocol gives significant advantage over the other. However, to allow comparison of the acute insulin response to glucose between different protocols used in centers around the world, the ICARUS 3-min infusion protocol is recommended, with acute insulin response to glucose calculated over 10 min after the end of glucose administration; this reduces the within-subject coefficient of variation and provides similar acute insulin response to glucose with both protocols.

Adult↗
PubMed1993

T-cell antigen receptor gamma chain polymorphisms in type 1 diabetes.

The T-cell antigen receptor gamma chain, in conjunction with the delta chain, forms a functional receptor on a small percentage of circulating T-cells. Using restriction enzymes Msp 1 and Stu 1, and a human gamma chain cDNA probe, pT gamma 1, frequent restriction fragment length polymorphisms (RFLPs; 8 kb Msp 1 band; 7.6, 5.0, and 4.3/4.0 kb Stu 1 bands) were detected using DNA from healthy controls. These RFLPs allowed determination of parental alleles at the gamma chain locus, and follow up of their inheritance within families. Since Type 1 diabetes is an organ-specific autoimmune disease thought to be mediated by T-cells, the association of gamma chain polymorphisms with Type 1 diabetes was studied in a population study. No significant association was found with any of the polymorphic bands. The segregation of the gamma chain alleles among diabetic sibs in 6 multiplex families with Type 1 diabetes was also studied but linkage with diabetes could not be demonstrated.

Adult↗
PubMed1992

Insulin autoimmunity: the rate limiting factor in pre-type I diabetes.

Type I diabetes is preceded by a series of autoantibodies including recently recognized subtypes of cytoplasmic islet cell antibodies (ICA) which we have termed 'restricted' and 'non-restricted'. Amongst the autoantibodies detected in prediabetics the antibodies to insulin are unique in that their levels correlate with the rate of progression to type I diabetes. The levels of insulin autoantibodies appear to be stably regulated prior to the appearance of ICA and the highest levels are associated with expression of DR4. The above studies have led to the hypothesis that an immune response to insulin is an early and central feature of anti-islet autoimmunity and that such as immune response when associated with loss of tolerance to other islet antigens (e.g. ICA) is pathogenic.

Age Factors↗
PubMed1992

Prognostically significant heterogeneity of cytoplasmic islet cell antibodies in relatives of patients with type I diabetes.

A significant proportion of relatives of patients with insulin-dependent (type I) diabetes with high titers of cytoplasmic islet cell autoantibodies (ICAs) do not progress to overt diabetes with up to 8 yr of follow-up. This may reflect that follow-up of such relatives has not been long enough to observe diabetes, that despite expression of identical ICAs, some relatives will not progress to diabetes; or that there is heterogeneity in what is identified as ICA. We identified a subset of ICA that was restricted in its species (not reacting with mouse islets) and cell-type reactivity within islets (beta-cell specific). Only one of eight relatives whose sera had the restricted pattern of reactivity progressed to overt diabetes, and on sequential evaluation, all but the one relative who progressed to diabetes have maintained normal first-phase insulin secretion to intravenous glucose. In contrast, by life-table analysis, 70% of relatives expressing nonrestricted ICA became diabetic within 5 yr of follow-up (1 of 8 vs. 16 of 25 diabetic at last follow-up, P less than 0.02). Moreover, preliminary data suggest a significant association of the human leukocyte antigen DQB1*0602 allele of DR2 haplotypes with the restricted ICA pattern (4 of 5 DQB1*0602 restricted vs. 0 nonrestricted ICA, P = 0.006). We propose that expression of a genetically determined restricted ICA pattern confers a markedly lower risk for progression to diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗