bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-4 induces Fas resistance in B cells.
Authors: Foote L C , Howard R G , Marshak-Rothstein A , Rothstein T L 
Published: December 2022

Abstract
Activated B cells express Fas (CD95) and are targets for apoptosis induced by CD4+ Th1 effector cells that kill in a Fas-dependent fashion. We report here that IL-4 reverses the susceptibility to Fas-mediated apoptosis that characterizes CD40-stimulated primary B cells. IL-4-induced Fas resistance is not associated with an alteration in the elevated level of Fas expression produced by CD40 ligand and does not depend on additional receptor-mediated signals. However, IL-4-induced resistance to Th1 cell-mediated cytotoxicity (Th1-CMC) develops more slowly than resistance mediated by surface Ig and is not affected by protein kinase C depletion, unlike anti-Ig-induced Fas resistance. By these two criteria, IL-4-and anti-Ig-induced resistance to Th1-CMC appear to be driven through distinct mechanisms; in keeping with this, suboptimal doses of IL-4 and anti-Ig act in synergy to induce marked protection against Th1-CMC. An important role for IL-4-induced Fas resistance is suggested by the observation that sera from IL-4-overexpressing transgenic mice contain autoreactive Abs.
Expression and presentation of endogenous mouse mammary tumor virus superantigens by thymic and splenic dendritic cells and B cells.
Authors: Ardavín C , Waanders G , Ferrero I , Anjuère F , Acha-Orbea H , MacDonald H R 
Published: December 2022

Abstract
Tolerance against superantigens (SAgs) encoded by endogenous mouse mammary tumor virus (Mtv) loci involves the intrathymic deletion of SAg-reactive T cells expressing a particular TCR V beta-chain, presumably upon presentation of the SAg by specialized APC. However, although the role of dendritic cells (DC) in the induction of tolerance against conventional Ags has been demonstrated, little is known about the role played by DC in tolerance induction against Mtv SAgs. Moreover, there is conflicting evidence concerning the capacity of DC to express and present Mtv SAgs. In this report we have analyzed the expression of Mtv SAgs in highly purified thymic and splenic DC and B cells by reverse transcriptase-PCR, using primers amplifying Mtv SAg-specific spliced mRNAs. DC express Mtv SAgs at levels comparable to B cells, but display a differential expression pattern of the various Mtv loci compared with B cells. Furthermore, our results show that DC are able to induce the deletion of SAg-reactive thymocytes in an in vitro assay, indicating that Mtv SAgs are functionally expressed on the DC surface. Collectively, our data are consistent with the hypothesis that DC play a role in the induction of intrathymic tolerance to Mtv SAgs.
Durable mixed allogeneic chimerism and tolerance by a nonlethal radiation-based cytoreductive approach.
Authors: Colson Y L , Li H , Boggs S S , Patrene K D , Johnson P C , Ildstad S T 
Published: December 2022

Abstract
For over 40 years, the association between hemopoietic chimerism and donor-specific tolerance for allografts has been recognized. However, toxicity associated with lethal conditioning has prevented the clinical application of bone marrow (BM) chimerism to induce tolerance. We previously demonstrated that engraftment could be achieved with less than total recipient myeloablation (700 cGy) and that the incidence of engraftment correlated with the dose of total body irradiation (TBI). Administration of cyclophosphamide (CyP) on Day +2 reduced the minimum TBI dose sufficient to permit engraftment to 500 cGy. In the current study, addition of antilymphocyte globulin (ALG) to the TBI/CyP-based conditioning approach reduced the radiation required for engraftment to &lt; or = 300 cGy. B10 (H-2b) mice conditioned with ALG on day -3, 300 cGy of TBI with transplantation of B10.BR (H-2k) or BALB/c (H-2d) BM on day 0, and CyP on day +2 exhibited evidence of donor chimerism (49.6 +/- 3.7% and 38.2 +/- 2.4%, respectively) in 97% of recipients. ALG eliminated CD4+ and CD8+ cells and decreased NK1.1+ cells in the peripheral circulation at the time of transplantation. Moreover, T and NK cells in the host BM were significantly decreased compared with cells of recipients conditioned with TBI alone. CyP delayed repopulation of host thymocytes, providing time for the establishment of donor chimerism before production of mature T cells. Chimeric animals exhibited stable multilineage chimerism and donor-specific tolerance to skin grafts and in in vitro assays. This model may provide a clinically acceptable approach for the induction of donor-specific transplantation tolerance.
Conversion of low antibody responders into high responders by up-regulating the T cell response to a selective epitope.
Authors: Mikszta J A , Kim B S 
Published: December 2022

Abstract
Our previous studies have shown that hen egg-white lysozyme (HEL), structurally modified by diazonium-linked conjugation with a simple hapten such as phosphorylcholine (PC), induces more efficient T cell stimulation than the native Ag in low/non-responder C57BL/6 mice. In the present study, we examined whether such a structural modification could have any effect on the Ab response to native HEL in low- and high-responder mice. Surprisingly, C57BL/6 mice immunized with PC-HEL generated a markedly enhanced anti-HEL Ab response, while high responders failed to exhibit such an enhancement. T cell-proliferative responses to a single epitope, HEL47-61, were enhanced exclusively in the PC-HEL-immunized low/non-responder strain. To directly investigate whether a T cell response to this particular epitope is sufficient to induce anti-HEL Ab, peptide priming experiments were performed. Interestingly, C57BL/6 mice directly primed with HEL47-61 generated strong Ab responses against HEL upon immunization with non-immunogenic native HEL, whereas a different HEL epitope (HEL74-88) failed to induce such responses. Further analyses indicated that HEL47-61 induces strong Th2 (in addition to Th1)-type priming required for the IgG1 Ab response, whereas HEL74-88 stimulates only Th1. These results strongly suggest that individual T cell epitopes within the same protein Ag can induce qualitatively different types of T cell responses and that the up-regulated T cell response to a selective epitope, through altered Ag processing or direct priming, can lead to the conversion of low Ab responders into high responders.
Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells.
Authors: Oshimi Y , Oda S , Honda Y , Nagata S , Miyazaki S 
Published: December 2022

Abstract
The cytotoxicity of NK cells has been thought to be mediated mainly by the perforin-dependent pathway. We investigated the involvement of Fas-mediated pathway in the killing activity of purified human CD3-, CD16+ NK cells. Fas ligand mRNA was expressed in freshly isolated NK cells. Apoptosis, which was identified by the fragmented chromatin in individual cells, was induced in the cells that expressed high levels of Fas via direct NK-to-target cell interaction or Ab-dependent cell-mediated cytotoxicity, even in Ca(2+)-free medium, in which perforin pores are known not to be formed. Apoptosis in both the presence and absence of external Ca2+ was inhibited by Fab of an anti-Fas mAb. Transfection of the Fas gene in target cells facilitated the induction of apoptosis, compared with the parental cell line. The function of the Fas-mediated pathway in the coexistence of the perforin-dependent pathway was examined in 10 cell lines expressing different levels of Fas by Ca2+ imaging and morphologic observation of single cells. With a certain boundary level, low or high levels of Fas expression in target cells were correlated to a great degree with either acute necrosis due to severe membrane damage after NK-target cell contact or apoptosis at a later period, respectively. We concluded that Fas ligand/Fas interaction is present and plays a significant role in the human NK cell-induced apoptosis.
B7 costimulation and autoantigen specificity enable B cells to activate autoreactive T cells.
Authors: Roth R , Nakamura T , Mamula M J 
Published: December 2022

Abstract
This study examines the role of B cells as auto-APCs in activating autoimmune T cells responses. Mice immunized with their own cytochrome c (cyt c) elicit no detectable B or T cell responses. However, mice first primed with a cryptic self peptide, mouse cyt c 81-104, followed at 3 wk with a boost of whole cyt c, elicit autoreactive T cells specific to self cyt c. T cell autoimmunity is not elicited in similarly immunized B cell-deficient (mu MT) mice. The expression of the B7-2 and/or B7-1 costimulatory molecules, as well as specificity to a self Ag, cyt c, enabled B cells to activate T cells to proliferate and to express IFN-gamma, IL-4, IL-5, and IL-10 cytokine mRNAs. In contrast, neither adoptively transferred B7- B cells nor nonspecific B7+ B cells were able to activate naive T cells. Moreover, anti-B7-2 treatment of mice prevented the in vivo expression of the IL-4, IL-5, and IFN-gamma cytokine mRNA responses. Our results suggest a major role of autoantigen-specific, B7-bearing B cells in breaking T cell tolerance to self Ag.
Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig.
Authors: Topham D J , Tripp R A , Hamilton-Easton A M , Sarawar S R , Doherty P C 
Published: December 2022

Abstract
The role of B lymphocytes and their Ig product in the development and maintenance of virus-specific CD4+ T cells has been analyzed in mice homozygous for disruption of the Ig mu gene (mu MT). These mice lack mature B220+ B cells and do not secrete Ig, but generate normal CD8+ cytotoxic T lymphocyte responses and have no difficulty clearing the HKx31 influenza A virus from the infected respiratory tract. Sequential limiting dilution analysis of virus-specific CD4+ T cells established that the frequencies of IL-2-producing T helper cell precursors in the draining lymph nodes and/or spleen from 7 days to 6 mo after infection were essentially similar in mu MT and C57BL/6 (B6) mice. Ag presentation and processing mechanisms involving Ig or B cells are apparently not required to generate virus-specific T helper cell precursors, and Ag-Ig complexes on follicular dendritic cells are not essential for the persistence of virus-specific CD4+ T cell memory. The main difference was that the spleens of the mu MT mice were much smaller than those of the B6 controls, and greater numbers of CD4+ T cells were found consistently in the regional mediastinal lymph nodes. This could be the result of abnormal expression of the lymph node homing receptor (CD62L) on the mu MT CD4+ T cells. However, the profiles of CD62L expression over the long term were comparable for both total and virus-specific CD4+ T cells from the two groups. The diminished role of the mu MT spleen is thus more likely to reflect the absence of germinal centers and/or Ig rather than a disruption of CD62L-mediated T cell trafficking.
Ig light chains are secreted predominantly as monomers.
Authors: Dul J L , Aviel S , Melnick J , Argon Y 
Published: December 2022

Abstract
Ig light (L) chains are secreted not only as part of assembled Ab molecules, but also as free L chains, the latter process being involved in the pathology of several diseases. The secretion competence of free L chains distinguishes them from free subunits of other oligomeric proteins, which are usually retained intracellularly. We used several techniques to test the idea that secretion of free L chains is dependent on dimerization. Coexpression of pairs of L chains, differing in only one amino acid, which alters the secretory phenotype, shows that these L chains behave independently: the wild-type chains are secreted, whereas the mutants are retained intracellularly. A survey of kappa- or lambda-producing cell lines by nonreducing gel electrophoresis shows that a negligible fraction of these L chains exists as disulfide-bonded dimers. Moreover, chemical cross-linking and density gradient centrifugation demonstrate that there is no significant pool of noncovalent L chain dimers. Noncovalent heterodimers can be detected readily between a kappa-chain and a chimera consisting of a heavy chain variable domain linked to the kappa-chain constant domain. This confirms that noncovalent L chain homodimers would have been detected if they were present. These findings about the association state of free L chains are independent of the host cell, as they are observed in both myeloma cells and COS fibroblasts. We conclude that L chain dimerization is a rare event that neither facilitates secretion nor is required for it.
Staphylococcal protein A simultaneously interacts with framework region 1, complementarity-determining region 2, and framework region 3 on human VH3-encoded Igs.
Authors: Potter K N , Li Y , Capra J D 
Published: December 2022

Abstract
Staphylococcal protein A (SPA) is a B cell superantigen that binds to human VH3-encoded Igs independently of the D- and JH-encoded regions and light chain sequences. The SPA-binding structure formed by VH3-encoded Igs remains controversial. We localized the regions in a VH3-encoded Ab required for SPA binding by producing mutant Abs in the baculovirus expression system in which regions of a human-derived Ab known to bind SPA were exchanged with those from a mouse Ab of the J558 family, a family not associated with SPA binding. The pattern of SPA binding indicates not only that residues in FR1, CDR2, and FR3 are involved but also that the three regions are required to interact simultaneously with SPA for binding to occur. When any one of the three regions was replaced with the corresponding region from the nonbinding Ab, SPA binding was severely disrupted. These data indicate that SPA requires simultaneous interaction with three distinct regions of a VH3 structure, which together in three-dimensional space form an extended solvent-exposed surface. These studies more precisely define the genetic requirements for VH3-encoded Ig binding to SPA.
Human dendritic cells phagocytose and process Borrelia burgdorferi.
Authors: Filgueira L , Nestlé F O , Rittig M , Joller H I , Groscurth P 
Published: December 2022

Abstract
There is strong evidence that the immune response to Borrelia burgdorferi (Bb) contributes to the pathogenesis of Lyme disease. Bb are transmitted by ticks to the skin, which is particularly rich in dendritic cells (DC). The initial reaction of these APCs may already set the course to immune pathogenesis. To study the role of DC, biopsies from human skin were incubated with Bb and investigated in toto with electron microscopy. In addition, DC freshly isolated from dermis (DDC) and epidermis (Langerhans cells) were compared with blood-derived DC (BDC). In situ, Bb were found in the dermal layer of the skin only, occasionally cleared by DDC. Isolated DDC and BDC, but not Langerhans cells, readily engulfed Bb preferentially using coiling phagocytosis. Internalized Bb were located free in the cytosol and inside of phagolysosomes of DDC and BDC. Intravesicular Bb Ags were colocalized with MHC class II molecules. In addition, live Bb induced IL-12 production in BDC. Bb-pulsed BDC activated naive and primed autologous Bb-specific T cells, as measured by detection of granulocyte-macrophage CSF gene transcription and proliferative response, respectively. These data indicate that human DC phagocytose, process, and present Bb Ags. The way in which DC may influence the immune response in Lyme disease, however, remains to be evaluated.
Protection against lethal viral infection by vaccination with nonimmunodominant peptides.
Authors: Oukka M , Manuguerra J C , Livaditis N , Tourdot S , Riche N , Vergnon I , Cordopatis P , Kosmatopoulos K 
Published: December 2022

Abstract
CTL response of H-2b mice to influenza PR8 virus is directed against the nucleoprotein (NP)-derived immunodominant 366-374 (NP366PR8) peptide presented by the Db molecule. However, NP has three nonimmunodominant peptides corresponding to the 17-25 (NP17), 55-63 (NP55), and 97-105 (NP97) sequences that have the Db consensus motifs and bind to the Db molecule with an intermediate (NP55) or low (NP17 and NP97) affinity. In a previous report, we have shown that NP55 peptide is naturally processed by infected cells. In the present work, we studied whether nonimmunodominant peptides can protect mice against viral infection. Antiviral protection was evaluated by measuring three parameters: survival after inoculation of a lethal dose of mouse-adapted PR8 virus, percentage of pulmonary lesions in surviving mice, and virus clearance from lungs of infected mice. Our results showed that immunization of B6 mice with nonimmunodominant peptides protected from PR8 virus infection, although less efficiently than immunization with the immunodominant NP366PR8 peptide. Protection was mediated by CD8 T cells. The efficacy of nonimmunodominant peptides correlated with their Db binding affinity; the low affinity binders NP17 and NP97 induced a weaker protection than the intermediate affinity binder NP55. A mixture of NP366PR8 and nonimmunodominant peptides gave a higher protection than NP366PR8 peptide alone. In conclusion, nonimmunodominant peptides protect against a viral infection with an efficacy that is proportional to their affinity for the restricting class I molecule.
Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice.
Authors: Thomsen A R , Johansen J , Marker O , Christensen J P 
Published: December 2022

Abstract
To study the contribution of CD4+ T cells and B cells to antiviral immunity and long term virus control, MHC class II-deficient and B cell-deficient mice were infected with lymphocytic choriomeningitis virus. In class II-deficient mice, which lack CD4+ T cells, the primary CTL response is virtually intact, and the infection is initially controlled in most organ sites including the blood. However, approximately 2 mo postinfection, CTL memory cannot be detected, and recrudescence of viremia to titers as high as seen during the acute phase of the infection is observed. To investigate whether this phenomenon could reflect participation of B cells and/or Abs in long term virus control, similar experiments were performed with mice that do not have mature B cells because of a disrupted membrane exon of the mu chain gene. In these mice, the cell-mediated immune response was slightly delayed, but transient virus control was observed in most mice. However, approximately 3 mo postinfection, blood virus titers were as high as observed during the acute infection, and no CTL memory could be demonstrated. These results indicate that Abs and/or B cells are required for permanent virus control and that in their absence, the virus-specific CTL potential becomes exhausted. Together our results indicate that while CD8+ cells play a dominant role in acute virus control, all three major components of the immune system are required for long term virus control.
Induction of blister-causing antibodies by a recombinant full-length, but not the extracellular, domain of the pemphigus vulgaris antigen (desmoglein 3).
Authors: Memar O , Christensen B , Rajaraman S , Goldblum R , Tyring S K , Brysk M M , McCormick D J , el-Zaim H , Fan J L , Prabhakar B S 
Published: December 2022

Abstract
Pemphigus vulgaris (PV) is mediated by autoantibodies to desmoglein 3, the pemphigus vulgaris antigen (PVA). PVA and an extracellular domain of PVA-Ig fusion protein (PV-Ig) can completely adsorb the blister-causing Abs from PV patient sera, suggesting that the extracellular segment of PVA might be sufficient to induce pathogenic Abs. To test this, we immunized rabbits with either PVA or its extracellular domain (EPVA) expressed in insect cells in our laboratory. When Igs were passively transferred from these rabbits into neonatal mice, anti-PVA, but not the anti-EPVA, induced blisters. To understand the basis for their differential pathogenic effects, we examined the properties of these sera. Both sera showed comparable ELISA titers and indirect immunofluorescence reactivity against monkey esophagus, a source of native PVA. Moreover, EPVA, like PVA adsorbed blister-causing Abs from sera of PV patients and rabbits immunized with PVA. In contrast, when IgG preparations were incubated with fura-2-AM (acetyloxymethyl ester)-loaded human keratinocytes in culture, only IgG from anti-PVA serum induced intracellular calcium mobilization. These data showed that PVA but not EPVA can elicit Abs that induced blisters in neonatal mice and mediate intracellular signaling through calcium mobilization.
B-cell activation in vitro by helper T cells specific to region alpha 146-162 of Torpedo californica nicotinic acetylcholine receptor.
Authors: Rosenberg J S , Oshima M , Atassi M Z 
Published: December 2022

Abstract
We have previously mapped the T and B cell epitopes on the alpha-subunit of acetylcholine receptor (AChR) in human myasthenia gravis (MG) and in experimental autoimmune MG-susceptible (C57BL/6 (B6)) and nonsusceptible mouse strains. In addition to regions recognized by both T and B cells, the AChR alpha-subunit has regions that are recognized solely by T cells. An exclusive T cell epitope within residues alpha 146-162 of Torpedo californica (t), tAChR, plays an important role in experimental autoimmune MG pathogenesis in B6 mice. To study its function, we established, from tAChR-primed B6 mice, two t alpha 146-162-specific T cell lines (P14Th) which comprised Th2-type cells because they secreted IL-4 but not IL-2. P14Th did not recognize the corresponding region on mouse (m) AChR (m alpha 146-162). They caused in vitro differentiation of tAChR-primed B cells into plasma cells that secreted anti-AChR Abs directed, in decreasing order, against the following tAChR alpha regions: t alpha 122-138 &gt; t alpha 134-150 &gt; t alpha 45-60 &gt; t alpha 170-186 &gt; t alpha 56-71. Little or no Ab response could be detected against peptides t alpha 182-198 or t alpha 146-162 itself. The major enhancement was in the Abs against region t alpha 122-150 (spanning the t alpha 122-138/t alpha 134-150 overlap) that is involved in ACh binding. These Abs cross-reacted completely with m alpha 122-150, the corresponding region on mAChR. Therefore, t alpha 146-162-specific T cells, although unable to recognize m alpha 146-162, are nevertheless pathogenic because they help B cells responding to a tAChR region that is conserved in mAChR and involved in ACh binding. These Abs cross-react with the corresponding effector-binding region of mAChR, thereby disrupting the normal physiologic function of the mouse receptor.