Biomedical subjects

A Kershnar

Publications and source records attributed to A Kershnar.

12 recordsLinked to original sources

PubMed1990

Heterogeneity in the specificity of the islet cell cytoplasmic antibody response in insulin-dependent diabetes mellitus.

We assessed the heterogeneity in the islet cell cytoplasmic antibody (ICA) response of insulin-dependent diabetes mellitus (IDDM) patients via indirect immunofluorescence on frozen sections of human, bovine, and porcine pancreas. The three substrates detected comparable frequencies of ICA positives among the IDDM sera tested, whereas control sera were ICA negative on all three substrates. However, individual IDDM serum samples showed heterogeneity in ICA binding on the three pancreata. Of 28 sera tested on all three substrates, 22 were ICA positive on human pancreas, three were ICA positive on bovine pancreas, and two were ICA positive on porcine pancreas. Sensitivity of ICA epitopes to neuraminidase treatment and periodate oxidation suggests that glycoconjugates are recognized by serum ICA. Cholera toxin blocked ICA binding. However, the functional cholera toxin receptor ganglioside Gm1 is resistant to neuraminidase treatment and periodate oxidation. Therefore, it is unlikely that Gm1 is the ICA determinant. These data suggest that not all ICA antigens are equivalently expressed on islets from different pancreata and/or that each individual responds to a hierarchy of islet antigens such that restricted patterns of specific ICA binding are found.

Animals↗

PubMed1988

Interferon responsiveness of natural killer cells in type I human diabetes.

Abnormally low circulating numbers and function of NK cells are associated with new onset type I diabetes. Since alpha interferon is a stimulator of NK function, enriched T and non-T lymphocytes were incubated with 0, 100 and 1,000 units/ml of recombinant alpha interferon (rIFN alpha) and natural killing against K562 and pancreatic islet cell targets was measured. The killing of K562 (1:20 target:effector ratio) cells by non-T cells incubated with 0, 100 and 1,000 units/ml of rIFN alpha in patients was decreased to 27% (p less than 0.014 vs control), 34% (p less than 0.001) and 39% (p less than 0.003) when compared to killing by normal control non-T cells (48%, 74% and 58% respectively). T cell mediated killing of K562 cells in patients was decreased to 3.9% (p less than 0.03), 5.3% and 6.6% (p less than 0.003) when compared to that of controls (8.7%, 10-8% and 22.6% respectively). Non-T cell mediated killing of islet cells (1:20 target:effector ratio) following treatment of effector cells with 0, 100 and 1,000 units/ml of rIFN alpha in patients was 19%, 27%, and 26% which was comparable to control subjects killing of 31%, 18% and 37% respectively. Similar data were obtained using T-cells as effectors. These data indicate that in new onset type I diabetes; (a) NK cell functional activity is diminished in both T and non-T lymphocyte subpopulations and (b) NK activity is suboptimally enhanced with rIFN alpha.

Adolescent↗

PubMed1987

Natural killer cell and islet killer cell activities in human type 1 diabetes.

Peripheral blood mononuclear cells from 14 type 1 diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean cytotoxicity of K562 cells by unseparated mononuclear cells derived from new onset type 1 patients (12 +/- 1.6%) was lower (P less than .01) than that observed in non diabetic controls, (25 +/- 4.2%). Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (41 +/- 5.8%) was also lower (P less than 0.03) than in the control group (56 +/- 3.7%). Specificity of these findings was evaluated by also examining other diabetic patient subgroups. Mean non T cell mediated natural killer cell activity in type 2 diabetic patients and type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.001 vs new onset type 1 patients). Longitudinal studies of new onset type 1 patients during the remission (honeymoon) phase revealed no improvement of impaired natural killer cell activity. In 30 new onset and 11 remission diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled pancreatic islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in nondiabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity returned to normal values in over half of the patients. There was no correlation between K562 and islet cell cytotoxicity in either of the latter two patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1986

Natural killer cell and islet killer cell activities in type 1 (insulin-dependent) diabetes.

Peripheral blood mononuclear cells from 20 Type 1 (insulin-dependent) diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (37 +/- 4.0%) was lower (p less than 0.03) than in controls (56 +/- 3.7%). Specificity was evaluated by examining other patient subgroups. Mean non-T cell mediated natural killer cell activity in Type 2 (non-insulin-dependent) diabetic patients and Type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.003 vs new onset Type 1 patients). Longitudinal studies of new onset Type 1 patients during the remission (honeymoon) phase revealed persistently impaired natural killer cell activity in 3 of 4 patients. In 30 new onset and 11 remission Type 1 diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in non-diabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity remained at similar or elevated levels in most patients. In patients evaluated simultaneously for K562 and islet cell cytotoxicity, natural killer cell activity was decreased, whereas islet killing was increased. These results suggest a dichotomy in natural killer cell and islet killer cell activities in new onset Type 1 diabetes that could have an important role in the pathogenesis of Type diabetes.

Adolescent↗

PubMed1986

Multiparameter immunologic studies in patients with newly diagnosed type 1 insulin-dependent diabetes mellitus.

Peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus were examined for the proportion of monoclonal antibody-defined T-cell subsets, natural killer (NK) cells, and macrophages and the proliferative response to phytohemagglutinin (PHA), Concanavalin A (Con A), pokeweed mitogen (PWM) and in the autologous mixed lymphocyte reaction (AMLR) and allogeneic mixed lymphocyte reaction (MLR). The in vitro response of purified IL-2 on PHA- and PWM-induced proliferative response was also examined. Total T cells (Leu 1+), helper/inducer phenotype (Leu 3+) T cells, suppressor/cytotoxic phenotype (Leu 2+) T cells, surface Ig+ B lymphocytes and monoclonal antibody-defined monocytes (Mac +) in patient group were comparable to the control group. The Leu 7+ NK cells were, however significantly (p less than 0.05) decreased in the diabetic group. The NK function was also deficient in the diabetic group when compared to healthy non-diabetic controls. The proliferative responses to all 3 concentrations of PHA, PWM, and Con A, and in the MLR were similar in 2 groups. However, the proliferative response in the AMLR was significantly reduced (p less than 0.05) in the diabetic group. Exogenous purified IL-2 failed to induce any enhancement in the PHA- and PWM-induced proliferative response; this was in contrast to control group in which IL-2 enhanced proliferative response to both mitogens. This study demonstrates deficiency of the AMLR, Leu 7+ and of natural killer cell function and unresponsiveness of mitogen-activated T cells to purified IL-2. The significance of these findings is discussed.

Adolescent↗

PubMed1985

Complement activation in type 1 human diabetes.

Complement activation was quantitated in serum and plasma of diabetic and normal subjects by sensitive competitive equilibrium radioimmunoassays (RIA) for C3a, C4a, C5a, Factor B, and a newly described C5 neoantigen (termed C5 activation antigen, and abbreviated C5-AA) in a stable 54-kDa fragment of C5. Plasma C3a levels were significantly elevated in 8 of 16 patients with newly diagnosed Type 1 diabetes (P less than 0.0005) with the mean C3a concentration for these patients being more than 10-times greater than the mean value of normal controls. C4a levels were also elevated in 2 of these patients (P less than 0.02), but C5a levels, although higher than normal, were not significantly increased. In contrast, the levels of C5-AA in the serum of all patients (11/11) with chronic Type 1 diabetes were significantly higher than in control Type 2 patients (noninsulin-dependent diabetes) (P less than 0.0005) and 4 of 7 patients with new onset insulin-dependent diabetes mellitus also had significantly higher levels of C5-AA than the Type 2 patients (P less than 0.01). The levels of Factor B in the serum of 5 of 9 patients with new onset diabetes were significantly higher than normal (P less than 0.0025). Five recent onset Type 1 diabetes patients were evaluated longitudinally for C3a, C4a, and C5a: in 3 the levels of C3a were elevated during new onset disease decreasing into the normal range during remission; in 2 of these patients C4a was also significantly elevated and the levels decreased during remission; and in 3 patients the levels of C5a were not significantly elevated but they decreased during remission. Purified human complement proteins and complement hemolytic assays were used to measure complement activation in serum during incubation with rat pancreatic islet cells. With diluted normal human serum, less than 20% of C3 or Factor B were consumed during 30 min at 37 degrees C, while with new onset Type 1 diabetic patient sera up to 90% of C3 and Factor B were consumed in 5/6 sera and 4/6 sera, respectively. These findings suggest (a) that complement activation fragments C3a, C4a, and C5a are generated in vivo in new onset Type 1 diabetes; (b) that both the classical and the alternative complement pathways may be activated; and (c) that this may result in a measurable activation of C5 generating biologically and immunologically active C5a and other C5 activation fragments.(ABSTRACT TRUNCATED AT 400 WORDS)

Complement Activation↗

PubMed1984

Autologous mixed lymphocyte reaction in man: XV. Cellular and molecular basis of deficient autologous mixed lymphocyte response in insulin-dependent diabetes mellitus.

The autologous mixed lymphocyte response (AMLR) and the allogeneic mixed lymphocyte response were deficient in a subset of patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM). Using a single set of HLA-identical twins, the cellular and molecular basis of deficient AMLR was investigated and appears to be due to a defect in both responder T cells and stimulator non-T cells. Interleukin-2 production was diminished in the patient but not in the healthy twin. The in vitro addition of purified interleukin-2 enhanced the depressed AMLR in the diseased twin. This suggests that the deficient AMLR in IDDM may be in part due to a deficiency in the production of interleukin-2.

Adolescent↗

PubMed1984

Deficiency of monoclonal antibody (Leu 7) defined NK cells in newly diagnosed insulin-dependent diabetes mellitus.

Peripheral blood from 11 newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) was studied for the proportion of monoclonal antibody (HNK 1, Leu 7) defined natural killer (NK) cells using a fluorescence-activated cell sorter analyzer. The proportion of Leu 7+ cells in patients with IDDM (7.0 +/- 4.0) was significantly (P less than 0.001) lower than in simultaneously studied healthy controls (16.8 +/- 7.0). A 2-yr-old boy with recent onset IDDM had a deficiency of Leu 7+ NK cells (6.1%), while his healthy identical twin had normal proportions of Leu 7+ cells (22.2%), when compared to a simultaneously studied healthy control. Two patients reexamined in remission and one other studied in remission alone, showed deficiency of Leu 7+ NK cells. This study demonstrates a quantitative deficiency of monoclonal antibody (Leu 7+) defined NK cells in newly diagnosed patients with IDDM that persists during remission of the disease and therefore appears to be independent of metabolic abnormality. The deficiency of NK cells may predispose genetically susceptible individuals to viral-induced islet cell injury, contributing to the pathogenesis of IDDM.

Adolescent↗

PubMed1984

Immunological events in new onset diabetes.

Data from our laboratory are reviewed showing that both cell-mediated cytotoxicity, complement-dependent antibody-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and complement-augmented antibody-dependent cellular cytotoxicity may provide mechanisms which kill pancreatic islets during pathogenesis of insulin-dependent (type I) diabetes. Xenogenic test systems employing dispersed rat islet target cells were employed. Most of the findings were reversible during clinical remission of diabetes.

Animals↗

PubMed1983

Immune islet killing mechanisms associated with insulin-dependent diabetes: in vitro expression of cellular and antibody-mediated islet cell cytotoxicity in humans.

Because immune mechanisms are associated with insulin-dependent diabetes, multiple organ specific and xenogeneic cytotoxicity assays were developed. Human cellular and antibody effector systems were incubated with 51Cr-labeled dispersed normal rat islet target cells. In eight of 11 diabetic patients, nonenriched mononuclear cells incubated with islet target cells were more cytotoxic than cells from age- and sex-matched controls (p less than 0.01). When non-T cell-enriched mononuclear cells were used at diabetes onset, seven of 11 patients' cells showed excessive islet cytotoxicity (p less than 0.05). In four patients showing elevated cytotoxicity at diabetes onset, cytotoxicity decreased to control levels during diabetes remission. Islet specificity was suggested in that mononuclear cells derived from diabetic subjects did not mediate cytotoxicity against rat spleen or macrophage target cells. Three cytotoxic antibody mechanisms were also evaluated. C-dependent antibody-mediated cytotoxicity with the use of patient serum-coated islet target cells was elevated above control levels in four of 14 patients. Antibody-dependent cellular cytotoxicity exceeded control values in only two of 16 patients, although four assay systems were evaluated. C-augmented antibody-dependent cellular cytotoxicity was elevated in three of 14 patients. No differences were observed for antibody-mediated mechanisms in four patients evaluated at both diabetes onset and remission. Cytotoxic antibody was present in only about one-half of the patients showing increased cellular cytotoxicity, whereas most patients expressing increased cytotoxic antibody had cellular cytotoxicity. Islet cell cytotoxicity assays with the use of effector systems from patients with recent onset insulin-dependent diabetes suggest that direct cellular cytotoxicity is more active than antibody-mediated cytotoxic mechanisms, and that cellular cytotoxicity can correlate with disease activity.

Adolescent↗

PubMed1980

Immunological suppressor cell activity in insulin dependent diabetes.

We have measured suppressor activity of the peripheral blood lymphocytes and monocytes from 13 insulin dependent diabetics with established disease for two or more years. A statistically significant increase in suppressor T-lymphocyte activity was demonstrated in patients who had a positive response in this assay. There was no alteration in the activity of prostaglandin synthetase dependent mononuclear cell activity. There was no correlation of lymphocyte suppressor activity with HLA type of these patients. These results may contribute to the understanding of the propensity for infection in patients with insulin dependent diabetes.

Adult↗

PubMed1980

Decreased incidence of HLA-A11 and increased incidence of HLA-B8 in a North American population of insulin dependent diabetics.

Seventy-four North American Caucasian insulin dependent diabetics are presented and compared to 100 healthy controls relative to HLA-A and B locus antigens. A highly significant increase in the frequency of HLA-B8 was found (p < 0.01, relative risk 3.67). The presence of HLA-A11 conferred statistically significant protection against disease development in these patients (p < 0.01, relative risk 0.19). There was no significant difference in the frequency of HLA-B7, B8, or B15 between the study and control groups. The patient group does show a significant increase in heterozygosity for HLA-B8 and HLA-B15 when compared to healthy controls (p < 0.05, relative risk 7.17). Increased incidence of HLA-B18 has previously been noted in French and English populations only. Since most of our HLA-B18 patients are of English extraction, it is concluded tht the altered incidence of the HLA-B18 allele in insulin dependent diabetes does persist in this migratory European population.

Diabetes Mellitus↗