bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constitutive expression of IL-6 receptors and their role in the excessive B cell function in patients with systemic lupus erythematosus.
Authors: Nagafuchi H , Suzuki N , Mizushima Y , Sakane T 
Published: January 2023

Abstract
Excessive B cell function including autoantibody production is a common feature of SLE and considered to be intimately associated with spontaneous lymphokine secretion by themselves. To clarify roles of IL-6/IL-6 receptor autocrine activation pathway in autoantibody production observed in patients with SLE, we studied expression and function of IL-6 receptors in comparison with those of IL-2 receptors, Tac on SLE B cells. IL-6 receptors and IL-2 receptors have been detected on B cells in the blood without any in vitro stimuli in most patients with SLE. The introduction of anti-IL-6 receptor antibody, which inhibits binding to the receptors of IL-6, and anti-IL-2 receptor antibody, anti-Tac to the cultures of SLE B cells resulted in potent inhibition of spontaneous production of polyclonal Ig and anti-DNA autoantibodies. In addition, fresh SLE B cells secreted high levels of IL-6 without any in vitro stimuli. These results indicate that constitutive expression of IL-6 receptors on B cells in conjunction with spontaneous IL-6 production by B cells induces autocrine B cell activation, which may lead to B cell hyperactivity and autoantibody secretion in SLE patients. Dysregulation of B cell activity observed in patients with SLE could thus be, at least in part, independent of T cell help.
Further characterization of the interaction between the C1q subcomponent of human C1 and the transmembrane envelope glycoprotein gp41 of HIV-1.
Authors: Thielens N M , Bally I M , Ebenbichler C F , Dierich M P , Arlaud G J 
Published: January 2023

Abstract
Previous studies have provided evidence for activation of the human C1 complex by HIV-1, resulting from direct interaction between C1q and the external portion of the viral transmembrane envelope protein, rsgp41. The present study was undertaken to locate more precisely, within C1q and rsgp41, the sites involved in the C1/HIV-1 interaction. Using a solid phase binding assay, we showed that 125I-labeled C1q binding to rsgp41 was dose dependent, saturable, and comparable with binding of C1q to IgG-OVA immune complexes. The globular and, to a lesser extent, the collagen-like regions of C1q both bound to rsgp41. In contrast, the globular region of C1q inhibited the C1q/rsgp41 interaction, whereas the collagen-like region of C1q did not. A series of peptides covering the putative C1q-binding site on gp41 (positions 590-613 of gp160) were synthesized and used as competitors in the C1q-rsgp41-binding assay. Peptide 601-613 (GIWGCSGKLICT) inhibited C1q binding the most efficiently, with 50% inhibition at a concentration of 100 microM. This peptide also inhibited binding of C1q to rsgp36, the protein of HIV-2 homologous to rsgp41. The inhibitory effect of this peptide was dependent in part on the presence of the S-S bridge normally connecting Cys 605 to Cys 611 because reduction of this bond significantly reduced its efficiency. These data suggest that the C1q/HIV-1 interaction involves a site on C1q located within the globular regions, and a major site located within the immunodominant domain of HIV-1, which shares homology with the corresponding region of HIV-2.
Alterations in Fc epsilon RI induced by protoporphyrin plus long-wavelength ultraviolet light in mouse bone marrow-derived mast cells.
Authors: Yen A , Liu F T , Barrett K E , Gigli I 
Published: January 2023

Abstract
As previously reported, protoporphyrin plus long-wavelength UV light (PP/UVA) inhibits IgE-mediated degranulation of mouse bone marrow-derived mast cells, as assessed by measurement of the release of beta-hexosaminidase. This inhibitory effect was seen with cells sensitized with IgE either before or after PP/UVA treatment (57.8 and 55.3% inhibition, respectively). PP/UVA did not dissociate IgE already bound to cells as assessed either by measuring release of bound 125I-IgE or by flow cytometric analysis. Results from immunoadsorption followed by SDS-PAGE analysis suggested that PP/UVA treatment may cause stable conjugation of IgE to its receptor. In unsensitized cells, PP/UVA did not cause conjugation of the unoccupied Fc epsilon RI to other proteins in the plasma membrane. Nevertheless, Scatchard analysis revealed that PP/UVA decreased the number of Fc epsilon RI per cell by 37% (0.95 x 10(5) vs 1.51 x 10(5)/cell), whereas affinity of the receptor for IgE was comparable between PP/UVA-treated and untreated cells (3.40 nM vs 3.27 nM). Flow cytometric analysis also confirmed the decrease in Fc epsilon RI number in PP/UVA-treated unsensitized mouse bone marrow-derived mast cells. Although 84% of PP/UVA-treated and 82% of untreated cells expressed positive fluorescence when stained with FITC-conjugated IgE, fluorescence intensity was reduced by 40% after PP/UVA treatment. We conclude that PP/UVA alters the conformational structure and/or number of Fc epsilon RI expressed on the mast cell surface. This effect could potentially explain the ability of PP/UVA to inhibit mast cell secretory function and may be related to an ability of PP/UVA to alter the properties of the plasma membrane.
Cyclosporin A-induced autoimmune disease in mice.
Authors: Bucy R P , Xu X Y , Li J , Huang G 
Published: January 2023

Abstract
The immunosuppressive drug cyclosporin A (CsA) disrupts the process of thymic ontogeny and repertoire selection in the alpha beta T cell population. Although treatment with this agent does not cause overt abnormalities in adult animals by itself, in lethally irradiated rats reconstituted with syngeneic bone marrow cells, CsA treatment results in an autoimmune syndrome. In this report, a modified protocol is described to obtain a similar, but distinctive, pathologic syndrome in mice. The key elements of this protocol are stringent elimination of mature T cells from the bone marrow cells used to reconstitute the irradiated recipients and the use of high doses of CsA over a long course (6 wk) after irradiation. CsA treatment inhibits both the positive and negative selection of alpha beta thymocytes in normal young mice as well as in irradiated, T cell-deficient bone marrow-transplanted mice. An increased frequency of "forbidden" V beta 11 T cells is detected in these animals, but it is not clear that these cells are the actual initiators of the inflammatory lesions. In mice of several inbred strains treated by this protocol, striking inflammatory lesions develop in the colon, with less intense, but significant lesions in liver, stomach, and pancreas. Unlike allogeneic graft-vs-host disease, no lesions are found in the small intestine. Examination of these lesions by immunohistochemistry demonstrates that the lesions are composed primarily of T cells and macrophages, with focal aggregates of small B cells present. The same pattern of inflammatory lesions can be adoptively transferred with lymphoid cells from the CsA-treated animals at the peak of lesion development to irradiated syngeneic recipients. The transfer of active lesions is blocked by the co-transfer of normal syngeneic T cells to these recipients. Although similar to the previously described system in rats, these findings emphasize several novel features. In mice, we find an absolute requirement for the elimination of mature T cells from the bone marrow source to develop active inflammatory lesions. The particular tissues affected are also distinctive, especially the unusual feature of severe inflammation in the colon, but no involvement of the small intestine. The mechanism by which the presence of normal T cells suppresses the development of active autoimmunity in this model may have implications for the etiology of localized inflammatory lesions in general.
Autoanti-red cell antibodies synthesized by patients with infectious mononucleosis utilize the VH4-21 gene segment.
Authors: Chapman C J , Spellerberg M B , Smith G A , Carter S J , Hamblin T J , Stevenson F K 
Published: January 2023

Abstract
A significant proportion of patients with B cell tumors secrete IgM mAb that recognize a carbohydrate autoantigen (li) on the red cell surface. The majority bear an idiotope (Id) that arises from heavy chains encoded by the VH4-21 gene segment, indicating unusual restriction of autoantibody specificity to a single VH gene. Polyclonal anti-li antibodies are also synthesized transiently by normal B cells following certain infections, and we have analyzed the role of the VH4-21 gene in encoding these antibodies. Levels of Id in sera of patients following infection with EBV or Mycoplasma pneumoniae were significantly raised (p &lt; 0.01), and the Id-positive Ig reacted with patients' red cells. Id-positive B cell clones were established from four EBV-infected patients, and 6/6 of the IgM-Id agglutinated red cells. Nucleotide sequence analysis revealed involvement of the VH4-21 gene in all cases, with remarkably little change from the germ-line sequence. However, D segments were heterogeneous, and light chains differed. These results indicate that the same VH gene is used both by polyclonal autoantibodies produced in response to infection, and by B cell tumors. However, the lack of mutations would not appear to give an opportunity for Ag selection to drive affinity maturation of these autoantibodies.
Humanized Mik beta 1, a humanized antibody to the IL-2 receptor beta-chain that acts synergistically with humanized anti-TAC.
Authors: Hakimi J , Ha V C , Lin P , Campbell E , Gately M K , Tsudo M , Payne P W , Waldmann T A , Grant A J , Tsien W H 
Published: January 2023

Abstract
Mik beta 1 is a mouse mAb directed at the beta-subunit of the human IL-2R (Tac) that inhibits IL-2 binding and inhibits IL-2 induction of large granular lymphocytes (LGL). Mik beta 1 alone does not inhibit IL-2-induced T-cell proliferation, but acts synergistically with anti-Tac to inhibit IL-2-induced proliferation of activated T cells. To evaluate these effects for possible therapy in humans, we constructed two humanized Mik beta 1 antibodies by combining the complementarity-determining regions of the murine antibody with human framework and constant regions. Compared with murine Mik beta 1, the two humanized Mik beta 1 antibodies, which differ in their degree of humanization, had similar affinities for IL-2R beta. The murine Mik beta 1 and one of the humanized Mik beta 1 antibodies were equivalent in competing for IL-2 binding to IL-2R beta and inhibiting IL-2 induction of LGL cytotoxicity. The activity of the second humanized antibody was significantly reduced. The three Mik beta 1 antibodies act synergistically to varying degrees with humanized anti-Tac to prevent IL-2-induced proliferation of activated T cells. This capacity to synergize paralleled their abilities to inhibit IL-2 binding. In addition, both humanized antibodies directed antibody-dependent cell-mediated cytotoxicity. We hope that humanized Mik beta 1 in combination with humanized anti-Tac will provide a new immunosuppressive therapy for the treatment of autoimmune diseases, graft-versus-host disease, and prevention of allograft rejection.
Detection and epitope analysis of autoantigen-reactive T cells to the U1-small nuclear ribonucleoprotein A protein in autoimmune disease patients.
Authors: Okubo M , Yamamoto K , Kato T , Matsuura N , Nishimaki T , Kasukawa R , Ito K , Mizushima Y , Nishioka K 
Published: January 2023

Abstract
T cells that recognize autoantigens might play an important role in autoimmune diseases. To analyze "autoantigen-reactive T cell" in patients with an autoimmune disease, a human lymphocyte proliferation assay using soluble recombinant autoantigens has been conducted. PBMC from mixed connective tissue disease and SLE patients who possessed anti-U1-small nuclear ribonucleoprotein (snRNP) A autoantibodies responded to a recombinant U1-snRNP A protein. In contrast, PBMC from healthy subjects or autoimmune disease patients not possessing anti-U1-snRNP A autoantibodies did not show such responses. In addition, this proliferative response was inhibited by anti-CD4 mAb. Limiting dilution analyses revealed that the autoantigen-reactive T cells exist in relatively high frequency (1 of 4,065 to 1 of 23,256) in the mixed connective tissue disease patients. Moreover, by T cell epitope mapping, the T cell epitope area was found to be located in the C-terminus of the U1-snRNP A protein, overlapping the B cell epitope area that has been reported. These findings suggest the presence of autoantigen-reactive T cells in such patients, and when these T cells are activated, they may play a central role in the autoantibody generation.
The age-associated increase in IFN-gamma synthesis by mouse CD8+ T cells correlates with shifts in the frequencies of cell subsets defined by membrane CD44, CD45RB, 3G11, and MEL-14 expression.
Authors: Ernst D N , Weigle W O , Noonan D J , McQuitty D N , Hobbs M V 
Published: January 2023

Abstract
The mouse model system was used to evaluate age-associated changes in the subset composition and function of the splenic CD8+ T cell pool. In response to stimulation with plate-bound anti-CD3 epsilon mAb, CD8+ cells from old C57BL/6NNia mice produced greater levels of IFN-gamma than cells from young-adult controls. This age-associated difference was apparent at the levels of both IFN-gamma mRNA accumulation and cytokine release, and was established within the first major cell cycle in culture. In addition, the capacity to produce IFN-gamma appeared to increase gradually with age as evidenced by studies on CD8+ cells from intermediate aged mice. In contrast to these findings, the peak S-phase responses by stimulated CD8+ cells from old mice were significantly reduced relative to young-adult controls. Immunophenotypic analyses of membrane CD44, CD45RB, 3G11, and MEL-14 expression by splenic CD8+ cells from young-adult, intermediate-aged, and old mice revealed an age-associated decrease in the frequencies of cells that expressed low levels of CD44 and high levels of CD45RB, 3G11, and MEL-14, whereas the reciprocal phenotypes increased with age. The correlated analysis of all four subset markers identified a composite phenotype (CD44loCD45RBhiMEL-14hi3G11lo/hi) which, based on past functional studies, is a candidate phenotype for naive cells. This "naive" phenotype dominated the CD8+ cell pool of young-adult mice but decreased in frequency with age. In contrast to the CD44lo cell group, the CD44hi cell fraction, which is associated with preactivated/memory CD8+ cells, was found to be uniformly 3G11lo but expressed heterogeneous levels of CD45RB and MEL-14, perhaps defining multiple subsets within the memory population. All of these latter subsets increased in frequency with age. Finally, we found that when CD8+ cells were fractionated based on CD44 expression the capacity to release measurable levels of IFN-gamma segregated entirely with the CD44hi fraction, irrespective of donor age. Together, these findings support the hypothesis that aging is accompanied by dramatic shifts in the subset compositions of splenic CD8+ cell pools, which contribute significantly to their increased capacity to produce IFN-gamma at the population level.
IL-4, but not tumor necrosis factor-alpha, increases endothelial cell adhesiveness for lymphocytes by activating a cAMP-dependent pathway.
Authors: Galéa P , Thibault G , Lacord M , Bardos P , Lebranchu Y 
Published: January 2023

Abstract
IL-4 and TNF-alpha increase endothelial cell adhesiveness for PBL by promoting the expression of adhesion molecules. We investigated the intracellular cAMP involvement in the increased endothelial cell adhesivity induced by IL-4 or TNF-alpha. We showed that both IL-4 and TNF-alpha increased intracellular cAMP in endothelial cells (EC). Furthermore, dibutyryl-cAMP and forskolin (which increased intracellular cAMP) increased basic EC adhesivity for PBL. The co-stimulation of EC with cAMP elevating agents and TNF-alpha, but not IL-4, resulted in an additive increase in EC adhesiveness. 2',5' dideoxyadenosine, an inhibitor of adenylate cyclase, decreased PBL adhesion to IL-4- but not TNF-alpha-treated EC. Similarly, HA1004, a protein kinase A inhibitor, totally reversed the IL-4 but not TNF-alpha effect on EC adhesiveness, whereas H7, a protein kinase C inhibitor, did not antagonise cytokine-enhanced EC adhesivity. These results indicate that IL-4, but not TNF-alpha, uses a cAMP-dependent pathway to increase PBL adhesion. Furthermore, we showed that cAMP elevation in EC did not induce vascular cell adhesion molecule 1, the only identified adhesion molecule induced by IL-4, indicating that a rise in cAMP in EC promotes an as yet unidentified adhesion pathway. Our results show that IL-4 increases EC adhesiveness for PBL through activation of protein kinase A by promoting an unidentified adhesion pathway.
Cognate peptide-induced destruction of CD8+ cytotoxic T lymphocytes is due to fratricide.
Authors: Su M W , Walden P R , Golan D B , Eisen H N 
Published: January 2023

Abstract
In the absence of other cells, cloned CTL in culture can undergo massive destruction upon the addition of a peptide that is recognized, in association with the CTL's class I MHC proteins, by the CTL's Ag-specific TCR. To determine whether the destruction is a result of the individual CTL's recognition via its own TCR of peptide-MHC-I complexes on its own surface ("suicide"), or to cytolytic attack by some CTL on others in the same culture ("fratricide"), we compared the rate of peptide-induced cell death in conventional cultures, where CTL are free to establish cell-cell contacts, with other cultures in which individual CTL were prevented from forming cell-cell contacts by encasing them individually in agarose gel microdrops. The differences were dramatic: in the presence of high concentrations of peptide (10 millionfold greater than is necessary to support 50% lysis of conventional target cells by these CTL) cell death was linear over 0 to 8 h in conventional cultures, at a rate of about 10% per hour, whereas in the presence of the same high concentration of peptide over the same time course, no death was detected among the cells encased in agarose gel microdroplets. The results demonstrate an absolute requirement for cell-cell contact in the destruction of cloned CTL in culture with their cognate peptides at high concentration. Using an increase of intracellular calcium ion concentration ([Ca2+]i) as a measure of T-cell activation, we also found that peptide-dependent activation of CTL likewise depends upon cell-cell contact.
A kinetic study on the deletion of thymic, peripheral, and gut-associated V beta 6+ T cells in an Mls-1b BALB/c colony infected with an exogenous mouse mammary tumor virus.
Authors: Tucek C L , Desaymard C , Papiernik M 
Published: January 2023

Abstract
Mls-1a expression results in the deletion of T cells bearing V beta 6 chains of the TCR. However, V beta 6+ T cells are also deleted in Mls-1b BALB/c mice that have been infected with an exogenous mouse mammary tumor virus (swiss mice) via maternal milk intake, and whose open reading frame region is markedly similar to that of the provirus Mtv-7. In this report we describe the kinetics of V beta 6+ T cell deletion in the thymus, spleen, lymph nodes, and gut-associated lymphoid populations of these BALB/c mice from the early weeks of life to 6 mo of age. Deletion of V beta 6+ T cells within the CD4+ T cell population was more obvious in the thymus than in the spleen at 8 wk of age. However, the earliest incidence of deletion was observed in the gut intraepithelial lymphocyte population at 5 wk of age. Furthermore Mtv-7 (SW) transcripts were only found in the gut in the first wk of life, whereafter they could be detected in the thymus, spleen, and lymph nodes. This report suggests that after entering the intestinal tract of host mice, mouse mammary tumor virus (swiss mice) is subsequently transferred to the thymus and peripheral lymphoid organs resulting in the deletion of CD4+V beta 6+ T cells in that order.
V gene analysis of anticardiolipin antibodies from MRL-lpr/lpr mice.
Authors: Kita Y , Sumida T , Ichikawa K , Maeda T , Yonaha F , Iwamoto I , Yoshida S , Koike T 
Published: January 2023

Abstract
We analyzed the VH and V kappa genes of 14 hybridomas producing anticardiolipin antibodies (aCL) from MRL-lpr/lpr mice, in an attempt to address the question of whether aCL are generated by Ag-driven stimulation or by polyclonal B cell activation. Five of six aCL from one mouse and both aCL from the other mouse carried 98 to 100% homologous VH and V kappa genes, respectively, thereby indicating that aCL were derived from the oligoclonal B cell precursor in that individual mouse. Of nine clones, six (67%) used the VH gene of the J558 family, and three (43%) of seven clones used the V kappa gene of the V kappa 23 group. Three to five somatic mutations were detected in all VH and V kappa genes of the examined aCL. These results suggest the possibility that usage of VH/V kappa genes in aCL is not random and that aCL consist of somatically mutated Ig genes.
Inability of truncated recombinant Osp A proteins to elicit protective immunity to Borrelia burgdorferi in mice.
Authors: Bockenstedt L K , Fikrig E , Barthold S W , Kantor F S , Flavell R A 
Published: January 2023

Abstract
The murine immune response to Borrelia burgdorferi (Bb), the etiologic agent of Lyme disease, is characterized by the development of antibodies reactive with the outer surface protein (Osp) A. It has been demonstrated that passive immunization of mice with at least some Osp A antibodies, including an Osp A mAb (CIII.78) that binds to a conformational epitope in the carboxyl-terminus of Osp A, provides protection against Bb challenge. Active immunization of mice with Osp A also confers protection, making Osp A a candidate for a vaccine Ag. To determine the regions of the Osp A protein that can elicit protective immunity, we immunized boosted mice with overlapping recombinant truncated fragments of Osp A, then challenged them with Bb. All groups of mice developed IgG Osp A antibodies detectable by immunoblotting with sera diluted at least 5000-fold. As expected, vaccination with full-length recombinant Osp A protected mice from challenge infection. In contrast, none of the mice vaccinated with the truncated Osp A proteins demonstrated immunity, even those immunized with an Osp A fragment binding the neutralizing mAb CIII.78. Osp A antibodies contained in the truncated Osp A antisera also failed to immunoprecipitate in vitro translated full-length Osp A and did not bind, as demonstrated by indirect immunofluorescence, to live or acetone-fixed Bb. Taken together, these results suggest that neutralizing Osp A antibodies are induced by vaccination with the full-length recombinant Osp A protein but not by vaccination with recombinant fragments.