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Biomedical subjects

W J Riley

Publications and source records attributed to W J Riley.

At least 55 records · Page 3Linked to original sources
PubMed1989

Insulin dependent diabetes mellitus, an autoimmune disorder?

During the last 25 years the concept of a chronic autoimmune process leading to the development of insulin dependent diabetes (IDD) has emerged. The presence of two animal models for IDD, the BB rat and the NOD mouse, has improved our ability to understand the process leading to beta cell destruction. The hallmark of an autoimmune disease is the characteristic pathologic lesion of mononuclear infiltration of the pancreatic islets. Further histologic studies of the diabetic pancreas have identified the type of cells infiltrating the islets and led to the concept of pancreatic beta cells capable of presenting antigen. The initial description of linkage disequilibrium of HLA DR3 and DR4 alleles with IDD has now progressed to the molecular level with the identification of residue 57 of the HLA DQ beta chain as crucial to the genetic predisposition to IDD. Autoantibodies to cytoplasmic antigens (ICA), surface antigens, or a membrane protein of 64 kDa identified by immunoprecipitation, autoantibodies to secreted products such as insulin and proinsulin, and autoantibodies that are cytotoxic to cultured beta cells are islet specific autoantibodies that have been described. Some are probably only markers of immunologic activity; others might participate in the destruction itself. The use of ICA as a screening tool has been successful in identifying individuals prior to the onset of IDD. Widespread cellular immunological defects have been identified both in animal models and in man. In the BB rat, a seeming paradox of severe immunodeficiency occurs in an animal with autoaggressive destruction of beta cells. More subtle defects in immunoregulation have been described in the NOD mouse and in human IDD. The response of IDD in both animal models and in man to immunomodulation and to immunosuppression offers further evidence of an immunologically mediated disease. However, some therapies in the animal models, not typically considered immunologic, such as protein restriction and insulin therapy, have prevented IDD. The possibility of intervening prior to the onset of clinical disease at the level either of the initial process of recognition of the pancreatic beta cell as a target organ or of the effector mechanism is approaching a reality in human IDD.

Animals↗
PubMed1989

Natural history of incidental hyperglycemia and glycosuria of childhood.

We prospectively followed 29 children and adolescents over a 1- to 8-year period who were referred for evaluation of hyperglycemia (in the absence of diabetes) or glycosuria found on routine screening or during acute illness. On initial examination, four subjects had islet cell autoantibodies, 4 of 22 had an abnormal intravenous glucose tolerance test result, 6 of 22 had low first-phase insulin release on intravenous glucose tolerance testing, and 10 of 20 had impaired glucose tolerance on oral glucose tolerance testing. On follow-up, insulin-dependent diabetes had developed in two of the four subjects with islet cell autoantibodies. The other two subjects with islet cell antibodies have had persistently abnormal glucose tolerance on both oral and intravenous glucose tolerance testing and have low first-phase insulin responses. Diabetes has developed in none of 25 subjects without islet cell antibodies, although two have persistently abnormal glucose tolerance or insulinopenia. All five subjects with islet cell antibodies or human leukocyte antigen DR3/DR4 with initial impaired glucose tolerance have either acquired diabetes or have abnormal glucose tolerance. In contrast, only one of five subjects with initial impaired glucose tolerance but lacking these markers has persistent glucose intolerance. We conclude that in the absence of islet cell antibodies or human leukocyte antigen DR3/DR4 heterozygosity, incidental hyperglycemia or glycosuria is unlikely to be associated with progression or diabetes.

Adolescent↗
PubMed1989

Long-term immunoregulatory effects of therapy with corticosteroids and anti-thymocyte globulin.

Corticosteroids and anti-thymocyte globulin (ATG) have been extensively used in the treatment of autoimmune diseases, aplastic anemia and organ graft rejection; nonetheless, the precise mechanisms of action of these agents are unknown. Studies of their long term immunoregulatory effects, particularly in humans, have been limited. We examined the long term effects of therapy with ATG given for 2-4 weeks and prednisone for 2 months in 4 patients with newly diagnosed insulin dependent diabetes (IDD). Three matched newly-diagnosed untreated IDD patients and 17 healthy volunteers served as controls. No differences in total lymphocyte count, percentage of B cells, percentage of total T cells (CD3), helper-inducer T cells (CD4) or cytotoxic-suppressor cells (CD8), lymphocyte blastogenesis assays, or pokeweed mitogen-induced IgG secretion in T & B cell co-cultures were detected before therapy. A transient lymphopenia following ATG administration was the only immunological defect found in the first month of therapy. At 2 months, however, patients treated with ATG and prednisone had diminished immunoregulatory T cell function demonstrated by production of only 28 +/- 3% IgG expected in T & B co-culture, compared to 205 +/- 35% for untreated IDD patients and 107 +/- 13% for normals (p less than 0.01). This diminished IgG production resulted from excessive suppressor function, since co-cultures of T cells from treated patients with T and B cells from normal volunteers suppressed the latter's IgG production by 76 +/- 9%. This enhanced suppressor activity persisted for 3-6 months following therapy. Other immunological functions were not statistically different from those present at the inception of the study. Thus, treatment with corticosteroids and ATG produces long-term enhanced suppressor activity, a finding which suggests that treatment with combination ATG and Prednisone is a rational form of immunomodulation in conditions associated with decreased suppressor function.

Adolescent↗
PubMed1988

Comparison of the performance and clinical utility of a carboxy-terminal assay and an intact assay for parathyroid hormone.

A comparison of the performance of a two-site immunochemiluminometric assay for intact parathyroid hormone with that of an in-house radioimmunoassay for carboxy terminal parathyroid hormone has been performed on samples from unselected patients being investigated for hypercalcaemia. The intact parathyroid hormone assay was found to be a simple and robust technique with a broad working assay range (CV less than 10% between 1.8-212 pmol/l) and a detection limit of 0.2 pmol/l. Clinically it is superior to the carboxy terminal assay in its ability to distinguish between patients with hyperparathyroidism from those with other causes of hypercalcaemia especially in the presence of impaired renal function.

Adult↗
PubMed1988

Association between HLA phenotype and HLA concentration in plasma or platelets.

To understand the relationship between HLA phenotype and plasma or platelet HLA better, concentrations of plasma and platelet HLA were measured in 215 individuals of known HLA phenotypes. Precise quantitation of HLA antigens was achieved by means of an enzyme-linked immunoassay using the W6/32 monoclonal antibody and purified HLA molecules. The mean plasma and platelet HLA concentrations were 2.04 +/- 1.67 micrograms/ml (+/- SD, n = 215) and 11.28 +/- 4.65 fg/cell (+/- SD, n = 213), respectively. Statistical analysis of associations between HLA phenotypes and plasma HLA revealed that the mean plasma HLA concentration of individuals with HLA-A23 or HLA-A24 was 1.4 (p less than 0.002) or 1.9 (p less than 0.001) times higher than those without these two HLA antigens. Furthermore, the mean plasma HLA concentration of individuals who have HLA-A26 was 25% less than those without HLA-A26 (p less than 0.05). In contrast, the only association between HLA phenotypes and HLA concentrations of platelets was observed in HLA-B7-positive individuals. The mean platelet HLA concentration of HLA-B7 individuals was 27% higher than those without HLA-B7 (p less than 0.005). This finding is in accordance with previous observations made on red blood cells. The results indicate that the HLA concentrations in plasma are regulated, at least in part, by genetic factors that are different from those regulating platelet HLA.

Adolescent↗
PubMed1988

Polyclonal nature of islet cell antibodies in insulin-dependent diabetes.

Islet cell antibodies (ICA) are associated with insulin-dependent diabetes mellitus (IDD) and have been proposed as predictive markers for the disease. To determine whether ICA result from the activation of single autoreactive B-lymphocyte clones or are the result of polyclonal B-cell activation, we assayed ICA using polyvalent antisera specific to kappa or lambda light chains as well as monoclonal antibodies to IgG1, IgG2, IgG3 and IgG4 heavy chains by indirect immunofluorescence. Sera from 38 newly diagnosed IDD patients with IgG-ICA titers greater than 1:8 by end-point dilution were studied. ICA of both kappa and lambda light chains were present in all sera. The ICA were predominantly of the IgG1 subclass (38/38), although ICA were also found to be IgG2 in 53% (20/38), IgG3 in 29% (11/38) and IgG4 in 16% (6/38). The distribution of IgG heavy chains in ICA was compared to the ICA titer, age of onset of IDD and HLA-DR phenotype of the patient. No statistical correlation could be detected at a P value less than 0.05. Our findings more likely exclude the occurrence of a single aberrant lymphocyte clone secreting ICA that may have arisen by somatic mutation in individual patients. Rather, these results are consistent with the hypothesis that ICA arise by polyclonal B-lymphocyte activation as a result of a defect of immune regulation. Since human antibodies to protein antigens are found predominantly in the IgG1 subclass, our findings support the belief that the autoantigen involved in the stimulation of ICA formation is comprised, at least in part, of protein.

Adolescent↗
PubMed1987

Maturity-onset diabetes of youth in black Americans.

Twelve of 129 black patients with youth-onset diabetes were identified as having an unusual clinical course, with apparent insulin dependence at the time of presentation followed by absence of dependence months to years later. This atypical form of diabetes was found in at least two generations in 9 of the 12 families of the propositi. Fourteen of the diabetic relatives, as well as the 12 propositi, were studied. Islet-cell autoantibodies were not found in any of the patients, and thyroid microsomal auto-antibodies were found in only one. The frequencies of the insulin-dependent-diabetes-associated antigens HLA-DR3 and DR4 were not increased among the propositi, and diabetes did not cosegregate with HLA haplotypes in the informative families. Insulin secretion, as measured by C-peptide responses to a liquid mixed meal (Sustacal), was intermediate between secretion in nondiabetic controls and that in patients with classic insulin-dependent diabetes. Peripheral-blood monocytes expressed increased numbers of insulin receptors as well as decreased empty-site affinities. The atypical form of diabetes in black Americans can be distinguished from classically defined insulin-dependent diabetes and may be best classified as a form of maturity-onset diabetes of youth.

Adult↗