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P Santamaria

Publications and source records attributed to P Santamaria.

At least 19 recordsLinked to original sources
PubMed1999

Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice.

The development of autoimmune diabetes in NOD mice results from selective destruction of beta-cells by a T-cell-dependent autoimmune process. However, the mechanisms that control the generation of beta-cell cytotoxic T-cells in vivo are poorly understood. We recently established 8.3-T-cell receptor (TCR)-beta transgenic NOD mice that show a selective acceleration of the recruitment of CD8+ T-cells into the islets of prediabetic animals, resulting in rapid beta-cell destruction and early onset of diabetes. This study was initiated to determine the role of macrophages in the development and activation of diabetogenic CD8+ T-cells in 8.3-TCR-beta transgenic NOD mice. Inactivation of macrophages in these transgenic mice resulted in the complete prevention of diabetes. When splenic T-cells from macrophage-depleted 8.3-TCR-beta transgenic NOD mice were transfused into severe combined immunodeficiency disease (NOD.scid) mice, none of the recipients developed diabetes up to 10 weeks after transfer, while most of the recipients of T-cells from age-matched control 8.3-TCR-beta transgenic NOD mice became diabetic. When intact NOD islets were transplanted under the renal capsule of macrophage-depleted 8.3-TCR-beta transgenic NOD mice, the majority of the grafted islets remained intact, while most of the islets grafted into age-matched, control 8.3-TCR-beta transgenic NOD mice were destroyed within 3 weeks after transplantation. The depletion of macrophages in these mice resulted in a decrease in the Th1 immune response along with an increase in the Th2 immune response because of significant decreases in the expression of macrophage-derived cytokines, particularly interleukin-12, and a decrease in beta-cell-specific T-cell activation, as shown by significant decreases in the expression of Fas ligand (FasL), CD40 ligand (CD40L), and perforin, as compared with control mice. We conclude that macrophages are absolutely required for the development and activation of beta-cell cytotoxic CD8+ T-cells in 8.3-TCR-beta transgenic NOD mice.

Animals↗
PubMed1998

New bronchodilators selected by molecular topology.

Molecular topology has been applied to find new lead compounds with bronchodilator activity. Among the selected compounds stands out 3-(1H-tetrazol-5yl)-9H-thioxanthene-9 -one-10,10-dioxide, anthrarobin, 9-oxo-9H-thioxantene-3-carboxylic-10,10-dioxide acid, acenocoumarol and griseofulvin, with a percentage of relaxation, at 0.1 mM, of 91, 92, 85, 69, and 74%, respectively. Theophylline shows a correspondent value of 77% (Emax = 100% at 1 mM).

Animals↗
PubMed1998

Biostat 1000 and Daugirdas blood-based hemodialysis quantification: agreement and reproducibility.

Agreement and reproducibility of Daugirdas blood-based and Biostat 1000 dialysate-based Kt/V estimation were explored. Fifty-two dialysis treatments in 19 patients were studied. All patients were dialyzed by arteriovenous (AV) access. Good agreement was found in the comparison between laboratory predialysis blood urea nitrogen (BUN) and Biostat 1000 BUN. Each treatment was assessed for Kt/V simultaneously by Biostat 1000 and by Daugirdas methods based on predialysis and postdialysis BUN. Four Daugirdas blood-based Kt/V estimations per session were obtained; two were single pool Kt/V, the first using an "arterial" postdialysis BUN and the second a "mixed venous" postdialysis BUN, whereas the other two were double pool (or equilibrated) eKt/V obtained by factoring the respective single pool "arterial" and "mixed venous" Kt/V for the relative rate of solute removal. The four blood-based and Biostat 1000 Kt/V were examined for pooled-within-patient variability in 15 of the patients in whom three dialysis sessions on the same dialysis prescription were available, and these were not significantly different between the blood-based and Biostat 1000 Kt/V. The four blood-based Kt/V were then compared with the Biostat 1000 Kt/V using the concordance correlation coefficient (CC, 1 indicating pairs of observations fall on a line of identity, 0 indicating no relationship), and bias and range of agreement as defined by the Bland and Altman technique of analysis. The "mixed venous" eKt/V had the closest agreement with the Biostat 1000 Kt/V (CC = 0.77), but the range of agreement as defined by Bland and Altman was 0.62, implying that for a single session, there was a 95% chance that the "mixed venous" eKt/V would lie within +/- 0.31 of the Biostat 1000 Kt/V. It is concluded that Biostat 1000 Kt/V results are comparable in large groups to certain Daugirdas blood-based Kt/V, although for a given dialysis session, clinically important differences in resulting Kt/V parameters may be seen between these two methods of estimating Kt/V.

Adult↗
PubMed1998

Needs and targets for the multi sex combs gene product in Drosophila melanogaster.

We have analyzed the requirements for the multi sex combs (mxc) gene during development to gain further insight into the mechanisms and developmental processes that depend on the important trans-regulators forming the Polycomb group (PcG) in Drosophila melanogaster. mxc is allelic with the tumor suppressor locus lethal (1) malignant blood neoplasm (l(1)mbn). We show that the mxc product is dramatically needed in most tissues because its loss leads to cell death after a few divisions. mxc has also a strong maternal effect. We find that hypomorphic mxc mutations enhance other PcG gene mutant phenotypes and cause ectopic expression of homeotic genes, confirming that PcG products are cooperatively involved in repression of selector genes outside their normal expression domains. We also demonstrate that the mxc product is needed for imaginal head specification, through regulation of the ANT-C gene Deformed. Our analysis reveals that mxc is involved in the maternal control of early zygotic gap gene expression previously reported for some PcG genes and suggests that the mechanism of this early PcG function could be different from the PcG-mediated regulation of homeotic selector genes later in development. We discuss these data in view of the numerous functions of PcG genes during development.

Alleles↗
PubMed1998

Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells.

Insulin-dependent diabetes mellitus (IDDM) is caused by the progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the study of IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogenic mechanisms involved in this disease. In these animals, macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-complete prevention of insulitis and diabetes in both NOD mice and BB rats. The presentation of beta cell-specific autoantigens by macrophages and/or dendritic cells to CD4+ T helper cells, in association with MHC class II molecules, is considered the initial step in the development of autoimmune IDDM. The activated macrophages secrete IL-12, which stimulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and IL-2. IFN-gamma activates other resting macrophages, which, in turn, release cytokines, such as IL-1beta, TNF-alpha, and free radicals, which are toxic to beta cells. During this process, IL-2 and other cytokines induce the migration of CD8+ peripheral T cells to the inflamed islets, perhaps by inducing the expression of a specific homing receptor. The precytotoxic CD8+ T cells that bear beta cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect beta cell damage by releasing perforin and granzyme, and by Fas-mediated apoptosis. In this way, macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM.

Animals↗
PubMed1997

Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice.

It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell-dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell-reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell-specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd- or I-Ag7-restricted beta cell-specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2-deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2(-/-) 4.1-NOD mice, which only bear beta cell-specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2(-/-) 8.3-NOD mice, which only bear beta cell-specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2(+) 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2(-/-) 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell-cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell-derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell- specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell-reactive CD8+ T cells to islets requires the assistance of beta cell-reactive CD4+ T cells.

Animals↗
PubMed1997

A mechanism for the major histocompatibility complex-linked resistance to autoimmunity.

Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta cell-reactive, I-Ag7-restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic mice (H-2(g7)) undergoes thymocyte negative selection in diabetes-resistant H-2(g7/b), H-2(g7/k), H-2(g7/q), and H-2(g7/nb1) NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow-derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but are invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype.

Animals↗
PubMed1997

Reproductive isolation and morphogenetic evolution in Drosophila analyzed by breakage of ethological barriers.

This article reports the breaking of ethological barriers through the constitution of soma-germ line chimeras between species of the melanogaster subgroup of Drosophila, which are ethologically isolated. Female Drosophila yakuba and D. teissieri germ cells in a D. melanogaster ovary produced functional oocytes that, when fertilized by D. melanogaster sperm, gave rise to sterile yakuba-melanogaster and teissieri-melanogaster male and female hybrids. However, the erecta-melanogaster and orena-melanogaster hybrids were lethal, since female D. erecta and D. orena germ cells in a D. melanogaster ovary failed to form oocytes with the capacity to develop normally. This failure appears to be caused by an altered interaction between the melanogaster soma and the erecta and orena germ lines. Germ cells of D. teissieri and D. orena in a D. melanogaster testis produced motile sperm that was not stored in D. melanogaster females. This might be due to incompatibility between the teissieri and orena sperm and the melanogaster seminal fluid. A morphological analysis of the terminalia of yakuba-melanogaster and teissieri-melanogaster hybrids was performed. The effect on the terminalia of teissieri-melanogaster hybrids of a mutation in doublesex, a regulatory gene that controls the development of the terminalia, was also investigated.

Animals↗
PubMed1996

Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains.

The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.

Amino Acid Sequence↗
PubMed1996

Morphometric investigation of condylar cartilage and disc thickness in the human temporomandibular joint: significance for the definition of ostearthrotic changes.

106 human TMJ specimens from 53 individuals (age: 65-85 years) were examined macro- and microscopically and measured for discal and condylar cartilage thickness at five points defined on a mediolateral axis along the middle dense part of the disc. 27% of the discs showed lateral and laterocentral perforations. In 8% the lateral portion was thinned down to a translucent layer. 62% showed no gross destruction or deviation in shape and thickness. The remaining 3% displayed extensive destruction and their condyles were osteoarthritic. All discs showed a significant decrease in thickness from their medial towards their lateral portions. The condyles displayed either a smooth articular surface (16%) or an irregular and progressively remodelled surface (81%) with histologically normal fibrocartilage. The condylar cartilage did not show a significant gradient of thickness in amediolateral direction. The results support our previously developed working hypothesis, that the joint is seemingly loaded along its entire articular surface and that a lateral disc perforation in older individuals can be due to a physiological process of wearing rather than to a pathological sequel of functional disorders.

Aged↗
PubMed1996

Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8+ T-cell clones in vivo.

NOD mouse-derived beta-cell-specific cytotoxic T-cell (beta-CTL) clones are diabetogenic in adult NOD mice, but only if co-injected with splenic CD4+ T-cells from diabetic animals. This investigation was initiated to determine whether infiltration of pancreatic islets by beta-CTL is a major histocompatibility complex (MHC) class I-restricted response, and whether beta-CTL has a direct cytopathic effect on beta-cells in vivo. Pancreatic islets from BALB/c (H-2d) or B6 (H-2b) mice were transplanted under the renal capsule of streptozotocin (STZ)-induced diabetic (NOD x BALB/c) F1 (H-2Kd, H-2Dd,b) or NOD x B6) F1 (H-2Kd,b, H-2Db) mice, respectively. H-2Kd-restricted beta-CTL clones from NOD mice were transfused into euglycemic mice within 3 days after transplantation. In all of the H-2d islet-grafted (NOD x BALB/c) F1 mice that received the beta-CTL clones, the beta-CTLs homed into the grafts, recruited host Mac-1+ cells and CD4+ and CD8+ T-cells, and caused diabetes within 7 days. In contrast, none of the H-2b islet-grafted (NOD x B6) F1 mice who received the beta-CTL clones and none of the H-2d islet-grafted (NOD x BALB/c) F1 mice who received a non-beta-cell cytotoxic CTL clone (N beta-CTL) developed graft inflammation or diabetes. Depletion of CD4+ T-cells in H-2d islet-grafted (NOD x BALB/c) F1 mice did not prevent beta-CTL clone-induced diabetes but reduced its severity. In contrast, when the beta-CTL clones were injected > 8 days after transplantation, none of the H-2d islet-grafted (NOD x BALB/c) F1 mice became diabetic or developed graft inflammation. We conclude that (1) islet-derived beta-CTLs can destroy beta-cells in vivo; (2) infiltration of grafted islets by beta-CTLs is an MHC class I-restricted response; (3) beta-CTLs can recruit naive CD4+ T-cells to the site, leading to further beta-cell damage; and (4) revascularized islet grafts are, like pancreatic islets of irradiated adult NOD mice, "sequestered" from circulating beta-CTLs.

Animals↗
PubMed1995

Beta-cell-cytotoxic CD8+ T cells from nonobese diabetic mice use highly homologous T cell receptor alpha-chain CDR3 sequences.

Insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a cell-mediated autoimmune process against pancreatic beta-cells. We have shown that beta-cell-cytotoxic CD8+ T cell clones can transfer IDDM to irradiated NOD mice if co-injected with nondiabetogenic CD4+ spleen T cells. To determine whether CTLs recruited to pancreatic islets recognize a restricted set of local Ags, we sequenced TCR-alpha and TCR-beta cDNA generated by anchor PCR from CD8+ CTL lines and clones derived from islets of 10 different NOD mice. These CTL lines were oligoclonal, but did not show skewed V alpha, V beta, J alpha, or J beta gene usage when compared with CD8+ spleen T cells. However, of the 26 different CTL-derived TCR-alpha sequences from all of these CTL lines and clones, 17 (65%) used one of three highly related, N region-encoded, CDR3 motifs. Motifs 1 and 2 (7 clonotypes each) contained a hydrophobic amino acid followed by Arg and a negatively charged or a polar residue (Asn or Gly), respectively. Motif 3 (3 clonotypes) was x-Arg-Gly. In 12 of these 17 rearrangements, the core sequence was followed by Tyr or Ser. By contrast, none of 31 different TCR-alpha rearrangements used by CD8+ spleen T cells encoded motifs 1 or 2, and only one encoded motif 3. Different TCR-beta rearrangements within individual lines also used homologous CDR3 sequences, but these sequences varied between lines. Skewed TCR-alpha-CDR3 usage by islet-derived CTLs was substantiated further by isolation of CTL clones transcribing highly homologous TCR-alpha, but different TCR-beta, rearrangements. These data suggest that CTLs recruited to pancreatic islets during spontaneous IDDM recognize a restricted set of beta-cell autoantigenic determinants.

Amino Acid Sequence↗
PubMed1994

Retroviruses in invertebrates: the gypsy retrotransposon is apparently an infectious retrovirus of Drosophila melanogaster.

Retroviruses are commonly considered to be restricted to vertebrates. However, the genome of many eukaryotes contains mobile sequences known as retrotransposons with long terminal repeats (LTR retrotransposons) or viral retrotransposons, showing similarities with integrated proviruses of retroviruses, such as Ty elements in Saccharomyces cerevisiae, copia-like elements in Drosophila, and endogenous proviruses in vertebrates. The gypsy element of Drosophila melanogaster has LTRs and contains three open reading frames, one of which encodes potential products similar to gag-specific protease, reverse transcriptase, and endonuclease. It is more similar to typical retroviruses than to LTR retrotransposons. We report here experiments showing that gypsy can be transmitted by microinjecting egg plasma from embryos of a strain containing actively transposing gypsy elements into embryos of a strain originally devoid of transposing elements. Horizontal transfer is also observed when individuals of the "empty" stock are raised on medium containing ground pupae of the stock possessing transposing elements. These results suggest that gypsy is an infectious retrovirus and provide evidence that retroviruses also occur in invertebrates.

Animals↗
PubMed1994

Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice.

CD8+ islet cell-specific CTL lines and clones were established from lymphocytes infiltrating the pancreatic islets of acutely diabetic nonobese diabetic (NOD) mice from two subcolonies (NOD/Yn and NOD/Lt). CTL from NOD/Yn mice were predominantly cytotoxic against H-2b+ islet cells and to a lesser extent against H-2d+ islet cells. On the other hand, CTL from NOD/Lt mice were cytotoxic against H-2d+ but not against H-2b+ islet cells. Three of four CTL clones derived from NOD/Yn mice were H-2Db restricted, whereas two of two CTL clones derived from NOD/Lt mice were H-2Kd restricted. However, all of the H-2Kd restricted T cell clones expressed the same TCR, regardless of the NOD subcolony from which they were derived, compatible with a restricted repertoire. When two representative CTL clones were transferred into irradiated young NOD mice, neither induced insulitis or diabetes. However, transfer of these clones, together with CD4(+)-rich NOD splenocytes depleted of CD8+ T cells, caused severe insulitis and diabetes. When recipient NOD mice were treated with anti-CD4 mAbs, none of the mice developed insulitis or diabetes. Most of the irradiated NOD mice that received CD8-depleted splenocytes alone did not become diabetic. Through these studies we show that CTL clones can destroy pancreatic beta-cells as final effectors but that these clones require signals from CD4+ T cells to effect beta-cell damage.

Amino Acid Sequence↗
PubMed1994

Frequent HLA class I and DP sequence mismatches in serologically (HLA-A, HLA-B, HLA-DR) and molecularly (HLA-DRB1, HLA-DQA1, HLA-DQB1) HLA-identical unrelated bone marrow transplant pairs.

The rates of graft-versus-host disease (GVHD) and rejection are significantly higher among recipients of unrelated donor marrow (BM) than in recipients of marrow from HLA-identical siblings, even when donors and recipients are mixed lymphocyte culture (MLC) compatible and serologically and Dw identical. It has been hypothesized that phenotypically silent HLA class I and DP sequence mismatches might be associated with these differences, but little is known about their incidence. We have sequenced the HLA-A, HLA-B, HLA-C, HLA-DPA1, and HLA-DPB1 genes expressed by 12 unrelated marrow transplant pairs, 11 of whom were molecularly matched at DRB, DQA1, and DQB1 loci. Nine of these pairs were also HLA-A and HLA-B matched by serology. Six of these nine "HLA-identical" pairs were HLA-A (2 of 6), HLA-B (1 of 6), and HLA-C (6 of 6) mismatched at the sequence level. The mismatched class I alleles of all these pairs had strikingly different sequence motifs in the six specificity pockets of their antigen recognition site, and in five pairs they also had sequence differences at positions implicated in T-cell receptor (TCR) binding. Two of the three pairs who were serologically mismatched for one HLA-A or HLA-B antigen were also sequence mismatched at HLA-C. Finally, 10 of 11 pairs tested expressed different DP sequences. These data indicate that HLA class I, especially HLA-C, and DP sequence mismatches are frequent among unrelated subjects defined as HLA identical by current typing methods. We speculate that these sequence differences may explain, at least in part, the higher incidence of acute GVHD and rejection in unrelated BM transplantation as opposed to transplantation between HLA-identical siblings. Because of their high frequency, the role of HLA-A, HLA-B, HLA-C, and HLA-DP mismatches in transplantation outcome is now amenable to direct study.

Adolescent↗
PubMed1994

HLA-DQB1-associated susceptibility that distinguishes Hashimoto's thyroiditis from Graves' disease in type I diabetic patients.

Insulin-dependent diabetes (IDDM) is frequently associated with autoimmune thyroid disease (ATD) within families. In these families, HLA polymorphism may modulate the susceptibility to each disease. Families with IDDM were further categorized as to the presence of ATD. IDDM-affected subjects from families without ATD were compared with subjects with ATD or with IDDM and ATD from IDDM/ATD families and with a control group. IDDM susceptibility in IDDM/ATD families was negatively associated with the presence of DQB1*0602 [relative risk (RR) = 0.038; P = 0.0001; corrected P (Pc) = 0.0005] and *0301 (RR = 0.3; P = 0.002; Pc = 0.01) and positively associated with the presence of DQB1*0201 (RR = 3.4; P = 0.0007; Pc = 0.0035) and *0302 (RR = 5; P = 0.0001; Pc = 0.0005), regardless of ATD. Compared with the IDDM-only group, the ATD-only group had an increased frequency of subjects with DQB1*0602 (RR = 0.14; P = 0.031), suggesting that the known IDDM-protective effect of this allele may be independent of susceptibility to ATD; however, this difference was not significant when the P value was correlated for the number of alleles tested. In these families, susceptibility to ATD was only associated with DQB1*0201 (RR = 5.71; P = 0.0043; Pc = 0.021). Among subjects with DQB1*0201, there was a weak negative association between the presence of DQB1*0302 on the second haplotype and Hashimoto's thyroiditis (RR = 0.237; P = 0.026; Pc > 0.05). We conclude that in IDDM/ATD families, IDDM-affected subjects are at risk for ATD, especially those carrying DQB1*0201. This risk may be influenced by the alleles carried on the second haplotype, with DQB1*0302 (or a closely linked gene) protecting from Hashimoto's thyroiditis and favoring Graves' disease.

Adult↗
PubMed1994

Skewed T-cell receptor usage and junctional heterogeneity among isletitis alpha beta and gamma delta T-cells in human IDDM [corrected].

Because of anatomical limitations, molecular characterization of islet-inflammatory T-cells in human insulin-dependent diabetes mellitus (IDDM) has remained elusive. We have isolated isletitis T-cells from pancreas graft biopsies of two patients (syngeneic and allogeneic, respectively) shortly after onset of recurrent IDDM and have characterized their repertoire by sequencing T-cell receptor (TcR)-specific cDNAs. Histopathological analysis of the grafts revealed selective beta-cell loss and isletitis characteristic of recurrent disease with no evidence of chronic inflammation or rejection. Most of the in vivo-activated isletitis T-cells were CD8+TcR alpha beta+ and CD4-CD8-TcR gamma delta+ in both patients. Comparison of the different TcR alpha,beta,gamma, and delta sequences revealed V(D)J junctional heterogeneity but skewed TcR usage within patients. Eighth of 13 different isletitis TcR beta sequences (19 of 26 cDNAs) from the syngeneic graft of patient 1 were V beta 3+, as opposed to only 1 of 31 peripheral TcR beta sequences (1 of 31 cDNAs) (61.5 vs. 3.2%, P < 0.0001). Of the 19 different isletitis TcR alpha clonotypes of this patient (24 of 42 cDNAs), 5 were V alpha 14+. The isletitis TcR beta clonotypes of the human leukocyte antigen-identical allogeneic graft of patient 2 showed selective J beta, but not V beta, gene usage. Two of three predominant isletitis clonotypes of patient 2 were V alpha 22+ (19 of 28 cDNAs) and the other (5 of 28 cDNAs) was also V alpha 14+.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗