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Featured researches published by Catherine E. Grubin.


Diabetologia | 1994

A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood iDDM

Catherine E. Grubin; T. Daniels; B. Toivola; Mona Landin-Olsson; William Hagopian; L. Li; Allan E. Karlsen; Esper Boel; B. Michelsen; Åke Lernmark

SummaryInsulin-dependent diabetes mellitus (IDDM) is associated with autoreactivity against GAD but the diagnostic sensitivity (positivity in disease) and specificity (negativity in health) of isoform-specific GAD antibodies have yet to be defined in assay systems suitable for screening large number of samples. One set of IDDM patient (n=10) and control (n=50) standard sera were used to develop quantitative antibody assays with in vitro synthesized recombinant 35S-methionine-labelled GAD65 and GAD67, respectively, and protein A-Sepharose to separate free from antibody-bound ligand. Binding levels were not normally distributed (p<0.0001) and therefore, the diagnostic accuracy of GAD antibodies was analysed by the ROC plots in population-based, consecutively-diagnosed, recent onset, 0–14 year-old patients (n=105), and matched, healthy control subjects (n=157). The ROC plots showed that the diagnostic sensitivity of GAD65 antibodies was 77% and the specificity 92% compared with 8% and 98%, respectively for GAD67 antibodies. In the IDDM sera, GAD65 and GAD67 antibodies were concordant in 7% (6 of 81) and GAD65 antibodies and ICA in 89% (72 of 81) without a correlation between the autoantibody levels. Autoantibodies to recombinant human islet GAD65 are specific and sensitive markers for childhood IDDM in this immunoassay with in vitro synthesized 35S-methioninelabelled recombinant GAD.


Immunity | 1997

Deficient Positive Selection of CD4 T Cells in Mice Displaying Altered Repertoires of MHC Class II–Bound Self-Peptides

Catherine E. Grubin; Susan Kovats; Paul deRoos; Alexander Y. Rudensky

The role of self-peptides in positive selection of CD4+ T cells has been controversial. We show that some self-peptides are presented by the MHC class II molecule I-A(b) in mice lacking Ii or H-2M but not in mice expressing a transgene-encoded peptide fused to I-A(b). In experiments using specific antibodies to block selection, these low-abundance self-peptides were implicated in the positive selection of some CD4+ T cells in H-2M-/- mice. However, all three mutant backgrounds failed to positively select two class II-restricted transgenic T cell receptors. Our findings suggest that minor components of the self-peptide repertoire can contribute to positive selection of a significant number of CD4+ T cells. In addition, the data suggest that T cell receptor repertoires selected in wild-type mice and in mice displaying limited spectra of self-peptides are distinct.


Journal of Clinical Investigation | 1993

Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type.

William Hagopian; Allan E. Karlsen; Anders Gottsäter; Mona Landin-Olsson; Catherine E. Grubin; Göran Sundkvist; Jacob S. Petersen; Esper Boel; Thomas Dyrberg; Åke Lernmark

At and before onset, most insulin-dependent diabetics (IDDM) have islet GAD65 autoantibodies (GAD65Ab). Since IDDM also occurs in older patients where non-insulin-dependent diabetes is common, we studied GAD65Ab at onset to classify diabetes type. Our quantitative immunoprecipitation assay uses recombinant human islet GAD65 stably expressed in hamster fibroblasts. Electrophoretic mobility was identical to native islet GAD65. Like native antigen, recombinant GAD65 migrated as two bands during electrophoresis, but converted to one under stronger reduction. Immunoprecipitation was linear with respect to antibody or antigen concentration. In 120 population-based diabetic patients of all ages grouped by treatment at onset and after 18 mo, GAD65Ab were present in 70% on insulin (n = 37), 10% on oral agent (n = 62, P < 0.0001), 69% changing from oral agent to insulin (n = 16, P < 0.001), and 1 of 33 controls. 65% with GAD65Ab, versus 8% without, changed from oral agent to insulin (P < 0.01). The GAD65Ab quantitative index was remarkably stable, and only 2 of 32 patients changed antibody status during follow-up. Concordance between GAD65Ab and islet cell antibodies was 93%. Quantitative correlation was approximate but significant. This highly sensitive, quantitative, high capacity assay for GAD65Ab reveals treatment requirements better than clinical criteria, perhaps guiding immunomodulatory therapy.


Diabetes | 1993

Autoantibodies in IDDM Primarily Recognize the 65,000-Mr Rather Than 67,000-Mr Isoform of Glutamic Acid Decarboxylase

William Hagopian; Birgitte Michelsen; Allan E. Karlsen; Fleming Larsen; Alistar Moody; Catherine E. Grubin; Rachel Rowe; Jacob Sten Petersen; Robert McEvoy; Åke Lernmark

Glutamic acid decarboxylase autoantibodies may aid in rapid screening strategies predicting IDDM before clinical onset. Rat islets contain GAD65 and GAD67 autoantibody targets, but human islets express only GAD65, now confirmed by direct immunoprecipitation from radiolabeled rat and human islets. Because human IDDM involves β-cell-specific autoimmunity, we tested 190 new IDDM patients and 51 healthy control subjects for antibodies to recombinant human islet GAD65, rat islet GAD67, or human insulinoma/cerebellum GAD67, each expressed separately in hamster fibroblasts. By using immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and densitometric fluorogram scanning, 132 of 190 (70%) of new IDDM patients had GAD65 autoantibodies, whereas only 17 of 190 (9%) had antibodies to rat GAD67 (P < 0.001). Of healthy control subjects, 2 of 51 (3.9%) and 1 of 51 (1.9%) had antibodies to GAD65 and GAD67, respectively. All 17 GAD67 antibody-positive patients also had GAD65 antibodies; 14 of 17 with greater GAD65 than GAD67 index. Control studies showed comparable reactivity between recombinant rat and human GAD67 and between different subcellular preparations of recombinant GAD67 of either species. In conclusion, only GAD65 is expressed in human islets, the autoantibody response is primarily to this isoform, and GAD67 antibodies add little to IDDM detection.


Brain Research Bulletin | 1993

Differential effect of fasting on hypothalamic expression of genes encoding neuropeptide Y, galanin, and glutamic acid decarboxylase

Michael W. Schwartz; Alfred J. Sipols; Catherine E. Grubin; Denis G. Baskin

The effect of caloric deprivation to stimulate hypothalamic neuropeptide Y (NPY) gene expression is hypothesized to represent a physiologically important adaptation in body weight homeostasis. To evaluate the specificity of this response, we used in situ hybridization histochemistry to measure hypothalamic expression of mRNA encoding NPY, galanin, and the two isoforms of glutamic acid decarboxylase (GAD67 and GAD65) in male Wistar rats either fed ad lib or deprived of food for 24 or 48 h. As expected, food deprivation for 24 and 48 h increased preproNPY mRNA levels in the arcuate nucleus by 43 +/- 13% (p = NS) and 127 +/- 29% (p < 0.05 vs. both fed and 24-h fasted groups) when compared to ad lib-fed controls, and hypothalamic preproNPY mRNA levels were significantly correlated to the percent change in body weight over the three groups of rats (r = -0.72; p < 0.05). In contrast, no significant effects of either 24 or 48 h of fasting were observed on hypothalamic levels of preprogalanin, GAD67, or GAD65 mRNA, and no relationship between percent change in body weight and expression of any of these mRNA species could be demonstrated. In conclusion, fasting increases preproNPY mRNA levels in the arcuate nucleus but does not alter expression of other hypothalamic mRNA species pertinent to feeding behavior. This supports the hypothesis that stimulation of NPY gene expression represents an important component of the hypothalamic response to caloric deprivation.


Diabetes | 1992

Recombinant Glutamic Acid Decarboxylase (Representing the Single Isoform Expressed in Human Islets) Detects IDDM-Associated 64,000-Mr Autoantibodies

Allan E. Karlsen; William Hagopian; Jacob Sten Petersen; Esper Boel; Thomas Dyrberg; Catherine E. Grubin; Birgitte Michelsen; Ole D Madsen; Åke Lernmark

GAD is an autoantigen in IDDM. Molecular cloning and specific antibodies allowed us to demonstrate that only the lower Mr GAD64 isoform is expressed in human islets, in contrast to human brain, rat islets, and rat brain, all of which express both GAD64 and GAD67. Expression of the human islet GAD64 isoform in COS-7 and BHK cells resulted in an enzymatically active rGAD64, which is immunoreactive with diabetic sera comparable with that of the islet 64,000-Mr autoantigen. Immunoprecipitation analyses showed that 21/28 (75%) IDDM sera had rGAD64 antibodies compared with only 1/59 (1.7%) of the healthy control sera. In immunoblot analyses, an SMS serum—but only 1/10 randomly selected IDDM sera—recognized the blotted rGAD64 without relation to immunoprecipitation titers. In conclusion, only the GAD64 isoform is expressed in human islets, in contrast to rat islets, which also express the GAD67 isoform. The immunological properties of human rGAD64 are comparable with the native 64,000-Mr islet autoantigen, allowing further studies of the immunopathogenesis of IDDM.


Proceedings of the National Academy of Sciences of the United States of America | 1991

Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10

Allan E. Karlsen; William Hagopian; Catherine E. Grubin; S Dube; Christine M. Disteche; David A. Adler; H Bärmeier; S Mathewes; Francis J. Grant; Donald C. Foster


Journal of Experimental Medicine | 1998

INVARIANT CHAIN-INDEPENDENT FUNCTION OF H-2M IN THE FORMATION OF ENDOGENOUS PEPTIDE-MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II COMPLEXES IN VIVO

Susan Kovats; Catherine E. Grubin; Susan Eastman; Paul deRoos; Ashok Dongre; Luc Van Kaer; Alexander Y. Rudensky


Archive | 1992

Cloning and expression of human islet glutamic acid decarboxylase autoantigen

Åke Lernmark; Allen E. Karlsen; Catherine E. Grubin; William Hagopian; Patrick J. A. O'Hara; Donald C. Foster


Genomics | 1993

Mapping of Glutamic Acid Decarboxylase (GAD) Genes

Susanne Edelhoff; Catherine E. Grubin; Allan E. Karlsen; David A. Adler; Don Foster; Christine M. Disteche; Åke Lernmark

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Alexander Y. Rudensky

Memorial Sloan Kettering Cancer Center

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