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M C Honeyman

Publications and source records attributed to M C Honeyman.

At least 19 recordsLinked to original sources
PubMed1995

HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus.

IDDM results from the immune-mediated destruction of pancreatic islet beta cells. Clinicopathologic heterogeneity in IDDM is reflected in part by the wide age range over which the onset of clinical symptoms can occur, after months to years of subclinical "insulitis." Because MHC genes play a critical role in immune function we studied their possible contribution to IDDM heterogeneity by analyzing HLA profiles of 194 IDDM patients in relation to their age at diagnosis. Restriction of HLA-DR heterogeneity was observed in patients diagnosed before age 21 years. Frequencies of DR3 and DR3/4 were highest in the < or = 6-year-old age group and thereafter declined with increasing age at diagnosis. In contrast, the frequency of DR4 remained increased up to age 30 years at diagnosis. DR7, normally considered to be a neutral allele, was like DR2 and DR5, significantly decreased in patients diagnosed before age 21 years. The A30-B18-DR3 haplotype was significantly increased in the < or = 6-year-old age group, A1-B8-DR3 was increased in the > or = 31-year-old group. B62-DR4 was increased only in the > 12-year-old age group. In DR4 patients the frequency of DQ8 was increased across all age groups. A sex difference was observed in those diagnosed at < or = 12 years of age, with an excess of females in the DR3+/DR4- group and males in the DR3-/DR4+ group. An association of DPB1 with IDDM was revealed by an increased frequency overall of DPB1*0301 and/or DPB1*0401, being more pronounced in patients diagnosed at > 20 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease.

BACKGROUND: Individuals at risk for insulin-dependent diabetes mellitus (IDDM), with an affected first-degree relative, can be identified by the presence of islet cell antibodies (ICA). ICA-positive relatives progress at variable rates to IDDM and identification of those at highest risk is a prerequisite for possible preventative treatment. Those who develop IDDM may exhibit less genetic heterogeneity than their ICA-positive or ICA-negative relatives. Specific human leucocyte antigen (HLA) genes predispose to IDDM but could also influence the rate of progression of preclinical disease. Therefore, by comparing HLA antigen frequencies between first-degree relatives, we sought to identify HLA genes that influence progression to IDDM. MATERIALS AND METHODS: HLA antigen frequencies were compared in 68 IDDM, 53 ICA-positive, and 96 ICA-negative first-degree relatives from 40 Caucasoid families. Predictions were tested in a panel of 270 unrelated IDDM subjects. HLA typing was performed serologically (HLA class I and II) and by sequence-specific oligotyping (11th International Histocompatibility Workshop protocol) (HLA class II). ICA tests were measured by an internationally standardized indirect immunofluorescence assay. RESULTS: In general, known susceptibility class II HLA antigens increased in frequency and known protective class II HLA antigens decreased in frequency, from ICA-negative to ICA-positive to IDDM relatives. Thus, DR4 and DQ8 increased whereas DR2 and DQ6 decreased; DR3 and DQ2 increased from ICA-negative to ICA-positive relatives, but not further in IDDM relatives. The high-risk DR3, 4 phenotype increased across the three groups; DR4,X was unchanged, and DR3,X and DRX,X both decreased. The HLA class I antigen, A24, occurred more frequently in ICA-positive relatives who developed IDDM and, in 270 unrelated IDDM subjects, was associated with an earlier age at diagnosis of IDDM in those with the lower risk class II phenotypes DR4,4 and DR3,X. CONCLUSIONS: HLA-DR3 and DQ2 predispose to islet autoimmunity, but not development of clinical IDDM in the absence and DR4 and DQ8. DR4 and DQ8 predispose to the development of clinical IDDM in ICA-positive relatives, in combination with DR3-DQ2 and other haplotypes but not when homozygous. HLA-A24 is significantly associated with rapid progression to IDDM in ICA-positive relatives and with an earlier age at clinical diagnosis. Analysis of IDDM families reveals that HLA genes not only predispose to islet autoimmunity but influence progression to clinical disease. The findings have implications for identifying high-risk relatives as candidates for possible preventative therapy.

Adult↗
PubMed1995

Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes.

BACKGROUND: Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM. MATERIALS AND METHODS: Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay. RESULTS: Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects. CONCLUSIONS: This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

Adolescent↗
PubMed1993

Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes.

Glutamic acid decarboxylase (GAD) in pancreatic beta cells is an autoantigen in insulin-dependent diabetes (IDD). We measured immunity to GAD in 31 first-degree relatives of IDD patients judged to be at risk of developing IDD themselves because of the presence of islet-cell antibodies. We found that in most of the subjects GAD autoimmunity was either predominantly humoral or predominantly cellular. High concentrations of circulating autoantibodies that precipitate native GAD activity were associated with low proliferation of peripheral-blood T cells to recombinant GAD; conversely, low concentrations of autoantibody to GAD were associated with high T-cell proliferation to GAD. Although T-cell proliferation was measured in the presence of autologous serum, GAD autoantibodies did not have a blocking effect in vitro. This dichotomy of the immune response to GAD defined heterogeneity within at-risk relatives and could have prognostic importance. We postulate that, if GAD is a pathogenetic autoantigen, sensitisation to beta-cell GAD is more likely to lead to IDD when the immune response deviates towards the expansion of autoreactive T cells rather than towards generation of autoantibodies. This idea is consistent with evidence that beta-cell destruction is mediated by T cells and that high concentrations of GAD antibodies are associated with slower progression to clinical disease.

Adolescent↗
PubMed1993

Glutamic acid decarboxylase 67-reactive T cells: a marker of insulin-dependent diabetes.

Glutamic acid decarboxylase (GAD) has been shown to be a target of autoantibodies in insulin-dependent diabetes (IDD). Two forms of GAD, with molecular weights of 67,000 and 65,000, have been cloned from separate genes. As pancreatic islet beta cell destruction DD is an autoimmune process mediated by T cells, we sought to determine if recombinant GAD67 was recognized by T cells in IDD subjects and particularly their first-degree relatives with islet cell antibodies known to be at risk for IDD. The central regions of human islet and brain GAD67 (amino acids 208-404) were cloned as fusion proteins with glutathione-S-transferase (GST). Proliferation of peripheral blood T cells in the presence of recombinant GAD67 was significantly higher in both at-risk relatives and recent-onset IDD subjects than in other autoimmune disease subjects and human histocompatibility leukocyte antigen (HLA)-matched healthy controls. Thus, 12 of 29 (41%) at-risk relatives and 11 of 29 (38%) recent-onset IDD subjects responded to GAD67, compared with 1 of 7 (14%) other autoimmune disease subjects and 1 of 23 (4%) HLA-matched controls. T cell responses to GST alone or to tetanus toxoid were not different between the groups. These findings demonstrate that GAD67 is a target autoantigen of T cells in IDD and suggest the possibility that GAD-reactive T cells may delineate asymptomatic subjects at increased risk for IDD.

Adolescent↗
PubMed1993

Transcription factor jun-B is target of autoreactive T-cells in IDDM.

Target antigens defined by autoantibodies in IDDM include insulin, a putative glycolipid that reacts with islet cell antibodies, and a 64,000-M(r) protein recently identified as glutamic acid decarboxylase. In addition, some IDDM sera that contain antibodies to glutamic acid decarboxylase also coprecipitate a 38,000-M(r) protein from islets. This study used a high titer anti-38,000-M(r) serum to screen bacteriophage lambda cDNA expression libraries and identified human islet and placental clones encoding jun-B, the nuclear transcription protein, of predicted 38,000 M(r). Peripheral blood T-cells exhibited significant proliferation in response to a recombinant fragment of jun-B (amino acids 1-180) in 12 of 17 (71%) recent-onset IDDM subjects, 8 of 16 (50%) ICA-positive first-degree relatives of IDDM subjects who were at risk, 3 of 12 (25%) other autoimmune disease subjects, and 0 of 10 healthy control subjects. Proliferation to tetanus toxoid did not differ significantly between the groups. Responses to jun-B were not related to age, sex, or human leukocyte antigen status. Thus, autoreactive T-cells identify a novel antigen, p38 jun-B, in IDDM and appear to indicate subjects at risk for the development of clinical disease.

Adolescent↗
PubMed1992

A 64 kDa antigen/glutamic acid decarboxylase (GAD) in fetal pig pro-islets: co-precipitation with a 38 kDa protein and recognition by T cells in humans at risk for insulin-dependent diabetes.

The development of insulin-dependent diabetes mellitus (IDDM) is associated with circulating antibodies to a pancreatic islet protein of MW 64,000 (64 kDa), reported to be glutamic acid decarboxylase (GAD). To investigate the antigenic properties of the 64 kDa antigen/GAD in IDDM we employed fetal pig pro-islets, a convenient source of islet antigens and an alternative to adult human islets for transplantation. Pro-islets contained a 64 kDa protein precipitated by antibodies in the sera of 9/14 (64%) at-risk IDDM, 12/33 (36%) recent-onset IDDM and 4/12 (33%) established IDDM patients and in 1/18 (5%) healthy control subjects. In addition, a 38 kDa protein was co-precipitated with the 64 kDa protein by 6/14 (43%) at-risk IDDM, 5/33 (12%) recent-onset IDDM, 1/12 (8%) established IDDM patient sera and 1/18 (5%) control subject serum. Both 64 kDa and 38 kDa antigens were specific to pro-islets; neither was detected in fetal pig thyrocytes, hepatocytes or splenocytes. The majority of the 64 kDa protein was co-precipitated with GAD enzymatic activity from pro-islets by either IDDM sera or a sheep anti-GAD serum. Previously, we showed that peripheral blood mononuclear cells (PBMC) from over half the subjects defined as being at risk for IDDM proliferate in response to fetal pig pro-islets. Proliferative responses of PBMC from pre-diabetic subjects to a crude extract of pro-islets were therefore measured before and after depletion of GAD by adsorption of the extract against GAD-1 monoclonal antibody. In 5/10 at-risk subjects, T cell stimulation indices were greater than the control mean + 2 SD and decreased in four by > 50% after depletion of GAD. In summary, a 64 kDa protein with the properties of GAD is present in fetal pig pro-islets and is recognized by both antibodies and T cells in a significant proportion of subjects at risk for early IDDM. Some subjects with anti-64 kDa antibodies also have antibodies that co-precipitate a 38 kDa pro-islet protein. Prospective studies of T cell reactivity in at-risk IDDM subjects are required to delineate the role of GAD and other candidate autoantigens in the initiation and progression of beta cell destruction.

Adolescent↗
PubMed1992

Islet-reactive T cells are a marker of preclinical insulin-dependent diabetes.

The destruction of pancreatic islet beta cells in insulin-dependent diabetes mellitus (IDDM) is thought to be T cell mediated. To directly identify islet-reactive T cells in asymptomatic, "preclinical" IDDM individuals with islet cell antibodies (ICA), proliferation of peripheral blood mononuclear cells (PBMC) was measured in the presence of sonicated fetal pig proislets. Stimulation indices (mean +/- SD) for [3H]thymidine uptake by PBMC cultured with sonicated proislets were: preclinical IDDM subjects (n = 22) 6.10 +/- 6.50, recent-onset IDDM subjects (n = 29) 3.66 +/- 3.35, Graves' disease subjects (n = 6) 2.17 +/- 0.93, scleroderma subjects (n = 4) 1.65 +/- 0.19 and normal control subjects (n = 14) 1.63 +/- 0.62. 68% (15/22) of preclinical IDDM, 41% (12/29) of recent-onset IDDM and 17% (1/6) of Graves' disease subjects had T cell reactivity greater than the mean + 2 SD of controls. T cell reactivity to proislets was tissue specific, and greater in magnitude and frequency than to human insulin. The majority of preclinical subjects with ICA greater than 20 Juvenile Diabetes Foundation (JDF) units (12/15, 80%) or antibodies to a 64-kD islet autoantigen (11/15, 73%) had significant T cell reactivity to proislets. ICA greater than 40 JDF units, a strong prognostic marker for progression to clinical IDDM, was an absolute index of T cell reactivity. Overall, the frequency of T cell reactivity in preclinical subjects, 68% (15/22), was comparable to that of ICA greater than 20 JDF units or 64-kD antibodies. Greater T cell reactivity to proislets in preclinical subjects accords with the natural history of autoimmune beta cell destruction. The direct assay of islet-reactive T cells in peripheral blood may have prognostic significance for the development of clinical IDDM and should facilitate identification of the primary target autoantigen(s).

Adolescent↗
PubMed1975

HL-A antigens in congenital rubella and the role of antigens 1 and 8 in the epidemiology of natural rubella.

Study of 87 patients (53 adults, 23 males; 34 children, 18 males) with congenital rubella revealed an increased incidence of several HL-A antigens, including HL-A5, HL-A1, HL-A3 and HL-A8, the frequency of HL-A1 being raised because of the statistically significant increase of this antigen in the adult female subjects compared with normal controls. Correlation of the level of seropositivity to rubella virus in 29 normal adult populations, according to racial origin and geographic location, with the frequency of various HL-A antigens revealed the most significant association with HL-A1 (r equals 0.71). It is suggested that the presence on the cell surface of HL-A1 or the combination of HL-A1 and 8 may fovour rubella virus infection.

Adult↗