bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thyroglobulin-induced murine thyroiditis assessed by intrathyroidal T cell receptor sequencing.
Authors: Matsuoka N , Unger P , Ben-Nun A , Graves P , Davies T F 
Published: December 2022

Abstract
Thyroid glands from CBA/J (H-2k) mice, with human thyroglobulin (Tg)-induced thyroiditis, were removed and total cellular RNA was prepared and reverse transcribed as target cDNA for PCRs to detect 17 murine T cell receptor (mTCR) V beta families. Southern analysis of the resulting PCR fragments showed a marked bias in the intrathyroidal expression of mTCR V beta gene families with only 10 detectable V beta gene families of the 17 tested. Four Tg-specific CBA/J T cell lines also showed a biased use of mTCR V beta gene families with only 7 V beta gene families detected of the 17 tested. Sequence analysis showed evidence of oligoclonal expansion of the intrathyroidal T cell populations, and some of the CDR3 sequences found in the thyroid infiltrates were identical, or similar, to examples of the patterns of CDR3 sequences seen in the Tg-specific lines. Overall, however, there was marked N-D-N sequence variation in both the lines and thyroid infiltrates. These data indicated that 1) mTcR V gene analysis of intact thyroid tissue reflected the thyroid Ag-specific T cells infiltrating the thyroid gland; 2) confirmed the phenomenon of oligoclonal expansion in early thyroiditis; 3) showed that certain V beta gene families may be overemployed in the T cell recognition of Tg in the context of H-2k; and 4) revealed, by the varied patterns of the CDR3 sequences, that the V gene itself may be more important in thyroid Ag recognition than N-D-N region motifs.
Predominant TCR-alpha beta variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies.
Authors: O'Hanlon T P , Dalakas M C , Plotz P H , Miller F W 
Published: December 2022

Abstract
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases in which autoreactive T cells are thought to play a pathogenetic role. We have determined the pattern of TCR-alpha beta gene expression by muscle-infiltrating lymphocytes within clinically and serologically defined groups of IIM patients. We utilized the PCR to study TCR V gene expression in muscle biopsies from nine polymyositis (PM) and eight dermatomyositis (DM) patients, all of whom had autoantibodies directed against histidyl-transfer RNA synthetase (anti-Jo-1 autoantibodies). While the TCR repertoire in DM patients was generally polyclonal, an oligoclonal profile characterized PM patients. Certain V gene families were predominantly expressed; V alpha 1 and V beta 6 gene families were detected in 82 and 91% of PM biopsies, respectively. TCR expression was characterized further by analyzing J gene usage from four PM patients expressing the V beta 6 gene. Sequence analysis of 40 independent recombinants (10 per patient) identified only seven V beta 6 clonotypes and restricted usage of the related J beta 2.1, -2.3, and -2.7 genes. These data, describing predominant TCR V and J gene usage by muscle-infiltrating lymphocytes in myositis patients, suggest that Ag-driven T cell responses may play a primary role in mediating some forms of the IIM.
Nucleotide sequence analysis of natural and combinatorial anti-PDC-E2 antibodies in patients with primary biliary cirrhosis. Recapitulating immune selection with molecular biology.
Authors: Pascual V , Cha S , Gershwin M E , Capra J D , Leung P S 
Published: December 2022

Abstract
We have analyzed at the nucleotide level the variable region gene sequences of five human mAbs and five recombinant Fab fragments derived from the mesenteric lymph nodes of patients with primary biliary cirrhosis. Both mAbs and Fabs were monospecific for dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex, which has been shown to be the major autoantigen of primary biliary cirrhosis. We found that although the mAbs, mainly of the IgM isotype, were encoded by a diverse array of VH and VL gene segments either as direct copies of germline genes or somatically mutated, the recombinant IgG Fabs expressed clonally related heavy chains displaying a high number of somatic mutations that very likely occurred in the context of Ag selection. Combinatorial pairing of clonally related heavy chains with highly homologous light chains suggests that the IgG anti-pyruvate dehydrogenase complex repertoire of primary biliary cirrhosis patients is the result of the clonal expansion of a restricted set of B cells.
Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells.
Authors: Sakaguchi N , Miyai K , Sakaguchi S 
Published: December 2022

Abstract
Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4+ T cells mediated the autoimmune prevention but CD8+ T cells did not. CD4+ T cells also appeared to mediate the TLI-induced autoimmune disease because CD4+ T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells.
T cell receptor V beta 15 dominates the antiacetylcholine receptor response in Lewis rat T cell lines.
Authors: Smith L R , Kono D H , Asthana D , Balderas R S , Fujii Y , Lindstrom J , Theofilopoulos A N 
Published: December 2022

Abstract
Ten Lewis rat T cell lines responsive to Torpedo californica acetylcholine receptor (AChR) were assayed for TCR V beta usage. All lines were CD4+, OX-22-, and exhibited reactivity to one or more AChR chains. Several different V beta s were expressed by these lines, but V beta 15 was dominant in 5 of 10 lines. Unique CDR3 sequences were observed among the 10 lines, although three of the V beta 15 rearrangements used J beta 1.4. These data suggest that V beta 15+ T cells are selected in the in vitro response to the antigenically complex AChR in the Lewis rat.
High resolution epitope mapping of an anti-DNA autoantibody using model DNA ligands.
Authors: Swanson P C , Cooper B C , Glick G D 
Published: December 2022

Abstract
Although Ab-DNA complexes are involved in the pathogenesis of SLE, the mechanism by which anti-DNA recognize their DNA targets remains elusive. We have designed and synthesized small test DNA ligands that model ssDNA and dsDNA determinants commonly recognized by anti-DNA autoantibodies. These ligands were used in DNA footprinting assays to conduct a high resolution epitope-mapping study of anti-ssDNA BV04-01, which is typical of anti-ssDNA expressed in (NZB x NZW)F1 mice. We find that BV04-01 recognizes the ssDNA, but not dsDNA, epitopes presented on the test ligands, and makes specific base and backbone contacts with the DNA. Moreover, BV04-01 binding induces conformational changes in both the single-stranded and duplex region of the ligands. The epitope-mapping data is used in conjunction with computational molecular modeling to construct a three-dimensional model of a BV04-01-ligand complex. The salient aspects of this model are consistent with many features observed in the crystal structure of BV04-01 liganded to d(pT)3. This work extends previous anti-DNA binding studies and attempts to provide a unified approach that draws upon the merits of many precedented experimental methods to assemble three-dimensional structures of anti-DNA-DNA complexes. Analysis of these structures may ultimately help guide the development of molecules designed to inhibit anti-DNA binding in SLE.
Expression of functional trk tyrosine kinase receptors after T cell activation.
Authors: Ehrhard P B , Erb P , Graumann U , Schmutz B , Otten U 
Published: December 2022

Abstract
Increasing evidence indicates that nerve growth factor (NGF), in addition to its neurotrophic actions, exerts specific effects on cells of the immune system. This report show that the CD4-positive T cell line 9/6 expresses trk protooncogene, the signal transducing receptor unit for NGF, after TCR-mediated activation by Ag and APC. This receptor is of functional importance because interaction of NGF with Ag-stimulated 9/6 T cells induced the transcriptional activation of the c-fos gene, a hallmark of the biochemical response to NGF. Our findings that neither mitogen nor Ag stimulation induced the expression of the low affinity NGF receptor in 9/6 T cells indicate that trk alone is sufficient to mediate biologic activity of NGF in T lymphocytes.
c-kit expression by B cell precursors in mouse bone marrow. Stimulation of B cell genesis by in vivo treatment with anti-c-kit antibody.
Authors: Rico-Vargas S A , Weiskopf B , Nishikawa S , Osmond D G 
Published: December 2022

Abstract
To examine the in vivo role of c-kit receptor in B lymphopoiesis we have evaluated precursor B cell populations expressing c-kit in mouse bone marrow and the effects on B cell genesis of administering a neutralizing anti-c-kit mAb, ACK2. Double immunofluorescence labeling and mitotic arrest were used to examine bone marrow cells from BALB/c mice. Almost one-half of TdT+ cells and one-quarter of B220+ cells coexpressed c-kit, mainly at low intensities, and were actively proliferating in vivo. c-kit+ cells that lacked B lineage markers expressed c-kit in high intensities and entered mitosis at an exceptionally rapid rate. In ACK2-treated mice, erythroid and granulocytic cells were almost completely absent from the bone marrow, whereas, in contrast, B lymphopoiesis was stimulated. Pre-B cells expressing cytoplasmic mu-chains; as well as TdT+B220+ cells before mu expression, were increased two- to fourfold in number and production rate. IgM-bearing B lymphocytes were increased in bone marrow and spleen. The results demonstrate that many early precursor B cells in mouse bone marrow constitutively express c-kit receptor. The failure of ACK2 treatment to block B lymphopoiesis, however, suggests that c-kit receptor function is not essential for precursor B cell development in vivo, but can be replaced by alternative signaling systems. The stimulation of B cell genesis by ACK2 treatment may reflect a conferred advantage in the competition for microenvironmental factors which underlies the balance between B lymphopoiesis and other hemopoietic lineages in vivo.
Cyclosporin A inhibits positive selection and delays negative selection in alpha beta TCR transgenic mice.
Authors: Urdahl K B , Pardoll D M , Jenkins M K 
Published: December 2022

Abstract
Cyclosporin A (CsA) is an immunosuppressive drug that inhibits TCR-mediated signal transduction. This drug has two major effects on developing alpha beta thymocytes in normal mice: it blocks the development of most mature CD4+8- and CD4-8+ thymocytes and inhibits the deletion of some but not all self-specific thymocytes. The latter effect may explain how CsA treatment can paradoxically induce autoimmunity in certain situations. Here we investigated the effects of CsA on thymocyte development in transgenic mice that express on most of their T cells an alpha beta TCR specific for male H-Y Ag bound to H-2 Db class I molecules, a model system in which positive and negative selection have been clearly defined. Positive selection occurs in female mice, resulting in the development of mature CD4-CD8+ T cells, whereas negative selection occurs in male mice, resulting in the deletion of self-reactive CD4+8+ thymocytes. CsA blocked positive selection, as evidenced by the finding that most of the cells present in the thymuses of CsA-treated female mice were functionally immature precursors that expressed heat-stable Ag. In male mice, CsA delayed but did not prevent the deletion of most CD4+8+ thymocytes. A few transgenic thymocytes, however, were not deleted and achieved the TCR+, CD4-8+ phenotype of positively selected cells. Therefore, for a small subset of thymocytes, CsA may convert a normally negatively selecting TCR signal to a positively selecting one.
Functional analysis of two tetanus toxin universal T cell epitopes in their interaction with DR1101 and DR1104 alleles.
Authors: Valmori D , Sabbatini A , Lanzavecchia A , Corradin G , Matricardi P M 
Published: December 2022

Abstract
In this study we have investigated the interaction between two DR11 alleles (DB*1101 and DB*1104) and two previously described tetanus toxin (tt) universal T cell epitopes P2(tt830-843) and P30(tt947-967) by means of a functional cytotoxic competition assay. Both truncation analysis and single alanine substitution analysis were performed. In addition, the capacity of truncated and single alanine substituted peptides to be recognized by human T cell clones from donors bearing the DR1101 or DR1104 alleles was assessed. In the case of truncated peptides the same binding and recognition pattern was observed with both alleles. Longer peptides were better competitors and more potent stimulators, a result that should be taken into account when these peptides are used as immunogens. None of the single alanine substitutions could abrogate or strongly diminish the inhibitory capacity of the analogues tested indicating the lack of strong "anchor residues" present in P2 and P30 and implicated in DR binding. In addition, although the original peptide sequences were presented to specific T cell clones with comparable efficiency, some of the alanine single substituted peptides were better recognized in association with one of the alleles by clones derived from individuals bearing the homologous allele. The only exception was the tt951-967 analogue ttW955A, which was preferentially recognized in association with the DR1104 allele regardless of the clone tested. This suggests that, although it binds to both alleles with comparable efficiency, the MHC-peptide complex so formed is conformationally distinguishable by specific T cell clones.
In vitro and in vivo effects of lymphokine-activated killer cells upon preattachment ovine conceptuses.
Authors: Segerson E C , Gunsett F C 
Published: December 2022

Abstract
An investigation assessed the cytolytic effect of autologous ovine lymphokine-activated killer (LAK) cells upon preattachment ovine conceptuses. For an in vitro experiment, conceptuses were recovered from six ewes on each of days 14, 16, and 19 (estrus = day 0). Dissociated conceptus cells (5 x 10(4), considered target cells) were incubated with autologous LAK cells at varying E:T ratios (5:1-200:1) and cytotoxicity was assessed by 51Cr release. In vivo, control (saline), cultured PBL (1 x 10(7)) and LAK cells (1- and 4- x 10(7)) were infused into the lumen of the uterine horn ipsilateral to the corpus luteum of mated ewes on day 14. Conceptuses were recovered on day 19 and placed within one of three morphologic categories (intact, large fragments, or highly fragmented). The numbers of mononucleated and binucleated giant cells and remaining trophoblastic cells were then quantitated within sections of conceptus tissue. Mitotic activity was also recorded. At E:T ratios of 100:1 and 200:1, respectively, percent 51Cr release for LAK cell cultures was greater (p &lt; 0.05) for day-16 and 19- than day-14 conceptus cells. The frequencies of highly fragmented conceptuses recovered from saline + cultured PBL and LAK cell-infused ewes were 0/10 and 8/13, respectively. Within tissue sections, the numbers of morphologically normal mononucleated giant and mitotic cells were less (p &lt; 0.05) for LAK cell (4 x 10(7)) than for saline-infused ewes. Data from additional in vitro and in vivo experiments revealed that supernatants from LAK cell (4 x 10(7)) cultures failed (p &gt; 0.05) to affect % 51Cr release from K-562 target cells, conceptus morphology, and numbers of conceptus cells. In conclusion, autologous LAK cells exerted in vitro and in vivo lytic damage upon preattachment ovine conceptuses. A temporal pattern was observed for the in vitro lytic responses.
Membrane vesiculation of Naegleria fowleri amoebae as a mechanism for resisting complement damage.
Authors: Toney D M , Marciano-Cabral F 
Published: December 2022

Abstract
Pathogenic and nonpathogenic Naegleria amoebae activate the alternative C pathway; however, only pathogenic amoebae are resistant to C-mediated damage. The present study was undertaken to determine the mechanism by which highly pathogenic N. fowleri amoebae resist C-mediated damage. Nomarski optics microscopy and electron microscopy of Naegleria amoebae revealed membrane blebbing on the surface of C-resistant N. fowleri, but not on C-sensitive N. gruberi, in response to incubation in normal human serum diluted 1:4 to 1:16. Immunofluorescent staining of pathogenic amoebae, by using antiserum to human C proteins comprising the membrane attack complex, C5b through C9, and FITC-labeled goat anti-rabbit IgG, confirmed that the membrane attack complex was concentrated on the membrane blebs. Binding studies with the use of radioiodinated C9 demonstrated a decrease in the 125I-labeled C9 cpm associated with N. fowleri amoebae and an increase in the 125I-labeled C9 cpm associated with the released membrane vesicles after increasing incubation periods in normal human serum. Treatment of pathogenic, C-resistant N. fowleri with cytochalasin D or cytochalasin B to inhibit actin-dependent exocytic processes increased the susceptibility of the amoebae to C damage. In contrast, incubation of nonpathogenic, C-sensitive amoebae with cytochalasins did not alter their susceptibility to C lysis. These data indicate that pathogenic N. fowleri use membrane vesiculation to remove membrane-deposited C proteins, specifically the membrane attack complex (C5b-C9). The ability to remove surface-associated membrane attack complexes serves as one mechanism by which pathogenic N. fowleri resist C lysis.
Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a T helper type 1 profile of cytokine secretion in the liver of patients chronically infected with Hepatitis B virus.
Authors: Barnaba V , Franco A , Paroli M , Benvenuto R , De Petrillo G , Burgio V L , Santilio I , Balsano C , Bonavita M S , Cappelli G 
Published: December 2022

Abstract
Highly purified CD4+ T cells isolated from liver biopsies of patients with hepatitis B virus-induced CAH had a strong cytotoxic activity and were comprised of a substantial number of cells (25%-40%) expressing CD56 surface marker. These cells were absent in CD4+ T cells from the peripheral blood of CAH patients or normal controls and these suspensions did not have cytotoxic activity. CD4+CD56+ T cells were further characterized by studies at the clonal level. A total of 71 hepatitis B envelope antigen-specific CD4+ T cell clones was investigated (23 from liver biopsies, 48 from peripheral blood of patients or normal vaccinated individuals). A total of 16 out of 23 (69.5%) of the clones from liver biopsies, but only 4.1% (2 out of 48) of those from PBLs, expressed CD56. A clone was defined as CD56+ when 40% or more of the cells expressed the marker. Production of TNF-alpha, IL-4, IL-5, IL-2, and IFN-gamma was investigated in 15 CD4+CD56+ and in 18 CD4+CD56- T cell clones, which shared the same HLA restriction element (DR2w15) and the same fine specificity (peptide 193-207 of the S region). All of the clones from the two groups released TNF-alpha and IL-2. However, all of the CD4+CD56+ T cell clones produced IFN-gamma but not IL-4 and IL-5 (Th1-like cell clones). Fourteen of the CD4+CD56- clones released IFN-gamma, IL-4, and IL-5 (Th0-like cell clones); three produced IL-4 and IL-5 but not IFN-gamma (Th2-like cell clones); and only one had a Th1 cytokine secretion profile. Cell fractionating studies within single CD4+CD56+ T cell clones showed that cells expressing high density CD56 had a stronger cytotoxic activity and produced higher levels of IFN-gamma than cells with low density CD56, thus further supporting a correlation between CD56 expression and cell functions. The results indicate that: 1) in CAH patients, cytotoxic CD4+ T cells with a Th1 cytokine secretion profile are compartmentalized in the liver, 2) these cells may be identified by the expression of CD56, 3) the expansion of these cells may be facilitated by antigenic stimulation within the inflammatory environment of the liver, and 4) CD4+CD56+ cells may play a pathogenetic role in hepatitis B virus infection.
A novel subpopulation of primed T cells in the human fetus.
Authors: Byrne J A , Stankovic A K , Cooper M D 
Published: December 2022

Abstract
Virgin and memory T cells reciprocally express high levels of the RA or the RO isoforms of CD45, respectively. In an examination of T cell expression of these two CD45 isoforms during human development, the RO+RA- "memory" T cells were infrequent in the newborn blood and spleen, but comprised approximately half of the T cells in adult tissues. These anticipated findings probably reflect the immunologic naivete of the newborn. Surprisingly, however, RO+RA- T cells were relatively abundant in fetal spleen and in cord blood samples from premature births, comprising approximately 25% and 10% of the T cells in these tissues, respectively. This early peripheral wave of RO+RA- T cells was composed of polyclonal T cells in both the CD4 and CD8 subpopulations. The fetal RO+ cells of CD4+ phenotype frequently expressed the CD25-alpha chain subunits that characterize high affinity IL-2 receptors, and were able to proliferate in response to exogenous IL-2. In further contrast with their RO+ memory T cell counterparts in adults, the fetal T cells were unresponsive to mitogenic anti-CD2 and anti-CD3 antibodies. We conclude that the data suggest an embryonic population of autoreactive T cell clones with anergic characteristics.