GLUTAMIC-ACID DECARBOXYLASE-67-REACTIVE T-CELLS - A MARKER OF INSULIN-DEPENDENT DIABETES

被引:113
作者
HONEYMAN, MC
CRAM, DS
HARRISON, LC
机构
[1] Burner Clinical Research Unit, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, VIC
关键词
D O I
10.1084/jem.177.2.535
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 in IDD 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.
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页码:535 / 540
页数:6
相关论文
共 14 条
[1]   RESPONSE OF PERIPHERAL-BLOOD MONONUCLEAR-CELLS TO GLUTAMATE-DECARBOXYLASE IN INSULIN-DEPENDENT DIABETES [J].
ATKINSON, MA ;
KAUFMAN, DL ;
CAMPBELL, L ;
GIBBS, KA ;
SHAH, SC ;
BU, DF ;
ERLANDER, MG ;
TOBIN, AJ ;
MACLAREN, NK .
LANCET, 1992, 339 (8791) :458-459
[2]   IDENTIFICATION OF THE 64K AUTOANTIGEN IN INSULIN-DEPENDENT DIABETES AS THE GABA-SYNTHESIZING ENZYME GLUTAMIC-ACID DECARBOXYLASE [J].
BAEKKESKOV, S ;
AANSTOOT, HJ ;
CHRISTGAU, S ;
REETZ, A ;
SOLIMENA, M ;
CASCALHO, M ;
FOLLI, F ;
RICHTEROLESEN, H ;
CAMILLI, PD .
NATURE, 1990, 347 (6289) :151-156
[3]   QUANTIFICATION OF ISLET-CELL ANTIBODIES AND PREDICTION OF INSULIN-DEPENDENT DIABETES [J].
BONIFACIO, E ;
BINGLEY, PJ ;
SHATTOCK, M ;
DEAN, BM ;
DUNGER, D ;
GALE, EAM ;
BOTTAZZO, GF .
LANCET, 1990, 335 (8682) :147-149
[4]   2 HUMAN GLUTAMATE DECARBOXYLASES, 65-KDA GAD AND 67-KDA GAD, ARE EACH ENCODED BY A SINGLE GENE [J].
BU, DF ;
ERLANDER, MG ;
HITZ, BC ;
TILLAKARATNE, NJK ;
KAUFMAN, DL ;
WAGNERMCPHERSON, CB ;
EVANS, GA ;
TOBIN, AJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (06) :2115-2119
[5]   CLONING AND PARTIAL NUCLEOTIDE-SEQUENCE OF HUMAN GLUTAMIC-ACID DECARBOXYLASE CDNA FROM BRAIN AND PANCREATIC-ISLETS [J].
CRAM, DS ;
BARNETT, LD ;
JOSEPH, JL ;
HARRISON, LC .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 176 (03) :1239-1244
[6]   GLUTAMIC-ACID DECARBOXYLASE AUTOANTIBODIES IN PRECLINICAL INSULIN-DEPENDENT DIABETES [J].
DEAIZPURUA, HJ ;
WILSON, YM ;
HARRISON, LC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (20) :9841-9845
[7]   AN ELISA FOR ANTIBODIES TO RECOMBINANT GLUTAMIC-ACID DECARBOXYLASE IN IDDM [J].
DEAIZPURUA, HJ ;
HARRISON, LC ;
CRAM, DS .
DIABETES, 1992, 41 (09) :1182-1187
[8]   ISLET-REACTIVE T-CELLS ARE A MARKER OF PRECLINICAL INSULIN-DEPENDENT DIABETES [J].
HARRISON, LC ;
CHU, SX ;
DEAIZPURUA, HJ ;
GRAHAM, M ;
HONEYMAN, MC ;
COLMAN, PG .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 89 (04) :1161-1165
[9]   ISLET CELL ANTIGENS IN INSULIN-DEPENDENT DIABETES - PANDORA BOX REVISITED [J].
HARRISON, LC .
IMMUNOLOGY TODAY, 1992, 13 (09) :348-352
[10]  
HARRISON LC, 1990, ADV ENDOCRINOL METAB, V1, P35