bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired resistance to superantigen-induced T cell shock. V beta selective T cell unresponsiveness unfolds directly from a transient state of hyperreactivity.
Authors: Miethke T , Wahl C , Heeg K , Wagner H 
Published: December 2022

Abstract
TCR V beta selective T cell activation and systemic release of T cell-derived lymphokines causing lethal shock in D-galactosamine (D-Gal)-sensitized mice depicts only one facet of in vivo challenge with the superantigen staphylococcal enterotoxin B (SEB). An immediate second major aspect represents the induction of peripheral unresponsiveness in SEB-reactive V beta 8+ T cells. SEB causes in vivo within 4 h resistance to an otherwise lethal challenge with SEB plus D-Gal, as well as to a challenge with the heterologous ligand toxic shock syndrome toxin 1 plus D-Gal. Contrary to the first challenge, no serum-borne IL-2 and TNF are discernible during the second challenge. On the other hand, kinetic analyses in vitro of LN cells draining the site of the first in vivo challenge indicate that SEB-reactive T cells develop via a transient state of hyperreactivity into a profound state of ligand-specific unresponsiveness. Yet unresponsive V beta 8+ T cells express IL-2R and are responsive to the growth-promoting effect of IL-2. Cyclosporin A does not impair sequential induction of hyperreactivity and unresponsiveness with concomitant IL-2R expression, but effectively blocks systemic IL-2 and TNF release during the initial hyperreactive phase. Taken together, the in vitro data imply that ligand-specific hyperreactivity followed immediately by ligand-specific unresponsiveness represents a hallmark of in vivo challenge with the superantigen SEB. The in vivo data suggest the existence of additional suppressive elements masking the ligand specificity of the state of unresponsiveness induced by SEB.
IL-1 receptor antagonist affects the plasma protein response of Hep 3B cells to conditioned medium from lipopolysaccharide-stimulated monocytes.
Authors: Damtew B , Rzewnicki D , Lozanski G , Kushner I 
Published: December 2022

Abstract
The availability of the IL-1R antagonist (IL-1ra) has made it possible to assess the specific contributions of IL-1 to the acute phase changes induced by complex mixtures of cytokines. We utilized IL-1ra to define the contribution of IL-1 to the effects of conditioned medium from LPS-stimulated monocytes on production of the positive acute phase proteins C-reactive protein, serum amyloid A, fibrinogen, alpha 1-protease inhibitor, complement component C3, alpha 1-antichymotrypsin, alpha 1-acid glycoprotein, and ceruloplasmin and the negative acute phase proteins albumin and transferrin in Hep 3B cells. Induction of C-reactive protein and serum amyloid A was essentially abolished, induction of complement component C3 and alpha 1-acid glycoprotein was moderately decreased and induction of fibrinogen was enhanced. In contrast, there was no significant effect of IL-1ra on induction by conditioned medium of alpha 1-protease inhibitor, alpha 1-antichymotrypsin, or ceruloplasmin. IL-1ra partially blocked the down-regulatory effects of conditioned medium on both of the negative acute phase proteins we studied--albumin and transferrin. These findings enhance our understanding of the contribution of IL-1 to the acute phase response. In addition, they indicate that IL-1ra in vivo may influence synthesis of both positive and negative acute phase proteins.
Complement factors H and I synthesized by B cell lines function to generate a growth factor activity from C3.
Authors: Vĕtvicka V , Reed W , Hoover M L , Ross G D 
Published: December 2022

Abstract
B lymphocytes and transformed B lymphoblastoid cell lines express CR2 (CD21, C3d/EBV-receptor) that is specific for C3 fragments generated by cleavage of C3b or spontaneously hydrolyzed native C3 (C3i) by the serum enzyme factor I and its cofactor, factor H. It had been shown previously that the Raji B cell line could be cultivated in serum-free medium supplemented with only transferrin and either OKB7 anti-CR2 mAb, C3d, or C3d-derived peptides containing the CR2 binding site. Because these agents appeared to function through ligation of CR2, it was unclear how native C3 could also serve as a growth factor, because C3 does not bind to CR2. It appeared possible that Raji cells might be able to use endogenous factors H and I to generate a CR2 ligand from C3, because previous studies had shown that Raji cells synthesized factor H and probably also synthesized factor I. PCR analysis was used to demonstrate factor I mRNA in Raji cells. Secretion of Raji cell factor I protein was confirmed by a sensitive mAb ELISA. Several B cell lines were examined for C3-dependent growth. Raji cells required both C3 (or OKB7) and transferrin for growth, whereas Wil-2 cells grew with transferrin alone and C3 enhanced the growth-promoting activity of transferrin. Two other B cell lines (Daudi and U698M), the T cell line 8402, and the U937 monocytoid cell line could not be sustained with transferrin plus C3. The C3-dependent growth of Raji cells was inhibited almost completely by either OX-23 anti-factor H or 052.11.3 anti-factor I mAb that also blocked the activity of serum-derived factor H or I, respectively. By contrast, there was no inhibition of growth by either OX-24 anti-factor H or OX-21 anti-factor I mAb that did not block factors H and I activity. After the spontaneous hydrolysis of native C3 to C3i, it is hypothesized that Raji cells convert C3i to iC3i with endogenous factors H and I, and then this iC3i serves as a growth factor by binding to membrane CR2.
Diverse T cell receptor V beta gene usage in the central nervous system in experimental allergic encephalomyelitis.
Authors: Bell R B , Lindsey J W , Sobel R A , Hodgkinson S , Steinman L 
Published: December 2022

Abstract
The repertoire of TCR V beta genes transcribed and expressed within the central nervous system was determined in mice with experimental allergic encephalomyelitis. Disease was induced in (PL/J x SJL/)F1 mice by immunizing with myelin basic protein-acetylated peptide 1-11, and mice were sacrificed at intervals from day 3 postimmunization to 3 wk after recovery from disease. Transcription of V beta genes was determined by reverse transcriptase polymerase chain reaction on RNA extracted from spinal cord, and expression of the V beta gene products was detected by immunohistochemistry with mAb specific for various V beta proteins. Multiple V beta genes were found to be transcribed and expressed in the central nervous system starting 7 days after immunization, and continuing up to 3 wk after clinical recovery. Preferential utilization of a single TCR V beta gene was not detected in the central nervous system at any time in the course of disease.
Age-related resistance to experimental autoimmune myasthenia gravis in rats.
Authors: Graus Y M , Verschuuren J J , Spaans F , Jennekens F , van Breda Vriesman P J , De Baets M H 
Published: December 2022

Abstract
The influence of age on the induction of experimental autoimmune myasthenia gravis (EAMG) was investigated. Immunization with acetylcholine receptor (AChR) or injection of varying amounts of anti-AChR mAb 35 into young adult (10-12 wk) BN rats induced severe signs of EAMG including weight loss and decrement of muscle action potential, whereas aged BN rats (120-130 wk) did not show any clinical signs of EAMG. Serum anti-AChr mAb titers were not significantly different in young and aged rats up to 24 h after administration of mAb. No significant AChR loss was demonstrated in aged rats, whereas similarly treated young rats showed extensive AChR loss. In contrast to young rats, no degradation of the postsynaptic membrane could be demonstrated by electron microscopy in aged rats. C component C3 and C5b-9 membrane attack complex could be demonstrated at the neuromuscular junction in both young and aged mAb-treated rats. However, infiltrating macrophages and necrotic muscle fibers were seen only in young rats. These results suggest that the postsynaptic membrane in aged rats is resistant to autoantibody attack. AChR degradation by antigenic modulation may be less efficient in aged rats as a result of altered AChR density and distribution or rigidity of the postsynaptic membrane. Age-related resistance in the EAMG model can provide more information about the factors that determine the severity of myasthenia gravis. Manipulation of AChR density or lipid composition of the postsynaptic membrane may be of therapeutic interest in myasthenia gravis.
Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice.
Authors: Picarella D E , Kratz A , Li C B , Ruddle N H , Flavell R A 
Published: December 2022

Abstract
To understand the role of TNF in the regulation of inflammation and the development of autoimmune diseases such as insulin-dependent diabetes mellitus, we produced transgenic mice in which the synthesis of murine TNF-alpha was directed by the rat insulin II promoter. The expression of the TNF-alpha transgene was restricted to the pancreas, in contrast to TNF-beta expression from the same promoter, in which the transgene was expressed in the pancreas, kidney, and skin. The expression of TNF-alpha in the pancreas of transgenic mice resulted in an overwhelming insulitis, composed of CD4+ and CD8+ T cells and B220+ B cells, considerably greater than that of TNF-beta transgenics. Moreover, in contrast to the predominant peri-insulitis observed in TNF-beta transgenic mice, the majority of the infiltrate in the TNF-alpha transgenic mice was within the islet itself. These unique patterns of infiltration were observed in the F1 progeny of crosses with C57BL/6 as well as NOD. Both TNF-alpha and TNF-beta transgenic mice show elevated expression of leukocyte adhesion molecules VCAM-1 and ICAM-1 in islet endothelia and increased expression of MHC class I on islet cells. This inflammation did not result in reduced insulin content of the islets, nor did it lead to diabetes. These data suggest that additional stimuli are necessary to initiate the process of islet destruction.
Alloreactive cytotoxic T lymphocytes generated in the presence of viral-derived peptides show exquisite peptide and MHC specificity.
Authors: Alexander-Miller M A , Burke K , Koszinowski U H , Hansen T H , Connolly J M 
Published: December 2022

Abstract
The nature of alloreactivity to MHC molecules has been enigmatic, primarily because of the observation that allogeneic responses are considerably stronger than syngeneic responses. To better determine the specificity potential of allogeneic responses, we have generated alloreactive CTL specific for exogenous, viral-derived peptide ligands. This approach allowed us to critically evaluate both the peptide- and MHC-specificity of these alloreactive T cells. Exploiting the accessibility of the H-2Ld class I molecule for exogenous peptide ligands, alloreactive CTL were generated that are specific for either murine cytomegalovirus (MCMV) or lymphocytic choriomeningitis virus (LCMV) peptides bound by Ld alloantigens. Peptide specificity was initially observed in bulk cultures of alloreactive CTL only when tested on peptide-sensitized T2.Ld target cells that have defective presentation of endogenous peptides. Subsequent cloning of bulk alloreactive CTL lines generated to MCMV yielded CTL clones that had exquisitely specific MCMV peptide recognition requirement. All of the MCMV/Ld alloreactive CTL clones were also exquisitely MHC-specific in that none of the CTL clones lysed targets expressing MCMV/Lq complexes, even though Lq differs from Ld by only six amino acid residues and Lq also binds the MCMV peptide. This observation clearly demonstrates that alloreactive CTL are capable of the same degree of specificity for target cell recognition as are syngeneic CTL in MHC-restricted responses.
Activated T-cell adhesion to thrombospondin is mediated by the alpha 4 beta 1 (VLA-4) and alpha 5 beta 1 (VLA-5) integrins.
Authors: Yabkowitz R , Dixit V M , Guo N , Roberts D D , Shimizu Y 
Published: December 2022

Abstract
T lymphocytes utilize adhesion receptors in a regulated manner to interact with other cells and with components of the extracellular matrix. These cell-cell and cell-matrix interactions serve a critical role in T cell recognition of foreign Ag and in the migration of T cells to various anatomic sites in vivo. Thrombospondin is an extracellular matrix protein that is transiently expressed at high concentration in damaged and inflamed tissue. Given recent evidence implicating a role for the extracellular matrix in modulating T-cell migration and function, we analyzed T-lymphocyte interactions with thrombospondin. We show here that CD4+ T cells specifically adhere to thrombospondin predominantly via the 70 kDa core region of the thrombospondin molecule. Antibody blocking and affinity chromatography analysis suggest that T-cell adhesion to thrombospondin involves three distinct receptors: an activation-independent receptor that mediates adhesion of resting T cells, and the alpha 4 beta 1 and alpha 5 beta 1 integrins, which mediate a rapid increase in adhesion to thrombospondin upon activation. These three molecules appear to be novel thrombospondin receptors, as other receptors previously implicated in the adhesion of nonlymphoid cells to thrombospondin appear not to be involved in T-cell/thrombospondin interactions. The up-regulation of alpha 4 beta 1 and alpha 5 beta 1 functional activity upon activation is associated with the preferential adhesion of memory T cells to thrombospondin. Our results thus define three novel thrombospondin receptors, and provide additional evidence that extracellular matrix proteins play an important role in lymphocyte migration into, and retention in, inflammatory sites.
Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin.
Authors: Rodriguez M , Dunkel A J , Thiemann R L , Leibowitz J , Zijlstra M , Jaenisch R 
Published: December 2022

Abstract
Intracerebral infection of susceptible strains of mice with Theiler's virus, a picornavirus, results in central nervous system demyelination, which is similar to multiple sclerosis. Immunogenetic experiments indicate that the MHC (H-2) and, in particular, the D region that controls class I-restricted immune responses, is an important determinant to development of demyelination. We tested whether disruption of beta 2-microglobulin (beta 2-m) would abrogate resistance to demyelinating disease normally observed in H-2b mice. All (C57BI/6 x 129)F3 mice transgenic for homozygous beta 2-m gene disruption (-/-) developed chronic demyelination after Theiler's murine encephalomyelitis virus infection, whereas none of the infected littermates with normal expression of class I MHC (beta 2-m, +/+) developed demyelination. Demyelinated lesions showed class II MHC expression, macrophages, and TNF but no class I MHC expression or CD8+ T cells. No correlation was observed between development of demyelination and delayed-type hypersensitivity responses to virus Ag. Despite the presence of demyelinating lesions, none of the infected beta 2-m (-/-) mice developed neurologic deficits. Infectious virus and virus Ag persisted in the central nervous systems of infected beta 2-m (-/-) mice but not in beta 2-m (+/+) mice. These experiments support the hypothesis that a class I immune response mediated by CD8+ T cells is important in resistance to Theiler's murine encephalomyelitis virus-induced demyelination. Development of chronic neurologic deficits as observed in immunocompetent susceptible strains of mice may be dependent on the presence of class I MHC and CD8+ T cells.
Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotoxin challenge.
Authors: Parmely M J , Zhou W W , Edwards C K , Borcherding D R , Silverstein R , Morrison D C 
Published: December 2022

Abstract
Adenosine (ADO) and its structurally related analogues are known to regulate the activities of immune and inflammatory cells, including a number of key functions of mononuclear phagocytes. In this study ADO and the synthetic ADO analogue MDL201112 inhibited TNF-alpha, but not IL-1, production by activated mouse peritoneal macrophages and the macrophage-like cell lines J774 and RAW-264. Northern blot analysis indicated that MDL201112 selectively inhibited the expression of steady-state TNF-alpha RNA in LPS+IFN-gamma-activated J774 and RAW-264 cells. This effect could not be attributed to changes in TNF-alpha RNA stability. In contrast, ADO had no effect on RNA levels for TNF-alpha and IL-1, suggesting that ADO acts at a post-transcriptional biosynthetic step. To determine whether either compound inhibited TNF-alpha-mediated inflammatory responses, mice were treated with ADO or MDL201112 and challenged with a lethal dose of endotoxic LPS and D-galactosamine, an hepatotoxin that sensitizes mice to lethal LPS challenge. A single i.p. injection of MDL201112 (100 mg/kg) protected over 90% of the mice, whether injected 1 h before or at the time of LPS challenge. MDL201112 also inhibited the appearance of TNF-alpha in the serum of LPS-challenged animals. The compound did not block D-galactosamine sensitization nor did it prevent lethality caused by the injection of rTNF-alpha. ADO failed to protect animals against endotoxin lethality, most likely due to the rapid metabolism of the nucleoside in vivo. These results establish ADO and MDL201112 as potent inhibitors of TNF-alpha biosynthesis and suggest that MDL201112 or similar analogues warrant further study as potential agents for the treatment of endotoxin shock and other diseases in which TNF-alpha plays an important pathogenic role.
Zymosan-induced tyrosine phosphorylations in human monocytes. Role of protein kinase C.
Authors: Sanguedolce M V , Capo C , Bouhamdan M , Bongrand P , Huang C K , Mege J L 
Published: December 2022

Abstract
Protein tyrosine phosphorylations are involved in the proliferation and secretory responses of immune cells, but their role in phagocytes is poorly understood. The ability of unopsonized zymosan to induce protein tyrosine phosphorylations was investigated in human monocytes. The addition of zymosan to monocytes resulted in an increase in tyrosine phosphorylation of several endogenous proteins including 28-, 33-, 38-, 42-, 47-, 55- to 60-, 62-, 68-, 90-, 105-, 116-, and 120-kDa proteins; 55- to 60-kDa proteins were the predominant phosphoproteins. Moreover, we studied the effects of tyrphostin 23, a specific tyrosine kinase inhibitor, on stimulated tyrosine phosphorylations and early secretory responses of monocytes, i.e., arachidonic acid release and oxidative metabolism. We showed that tyrphostin inhibited zymosan-stimulated tyrosine phosphorylations and arachidonic acid release, but that it did not affect superoxide generation induced by zymosan. Zymosan binds mainly to CR3 receptor on human monocytes, and CR3 is devoid of intrinsic tyrosine kinase activity. It was predictable that zymosan stimulated a tyrosine kinase distal to the receptor or associated with it. We observed that PMA mimicked zymosan-induced tyrosine phosphorylations, thus suggesting that both agonists used a common transductional pathway implicating the serine/threonine kinase, protein kinase C. The antagonists of protein kinase C, sphingosine and calphostin C, inhibited zymosan-stimulated tyrosine phosphorylations. We suggest that, in human monocytes, zymosan-induced tyrosine phosphorylations are involved in cell responses such as the release of arachidonic acid, and that they require the sequential activation of protein kinase C and cellular protein tyrosine kinases.
Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro.
Authors: Hanson D F 
Published: December 2022

Abstract
Fever is a common sign of clinical disease but its biological purpose is unclear. Several cytokines mediate fever as well as the regulation of immune responses, and it was previously shown that murine thymocyte proliferative responses to IL-1 and IL-2 are exquisitely temperature-sensitive. The present studies were performed to determine whether such a high degree of temperature sensitivity was also a property of the primary in vitro immune responses of mature, murine splenic T cells. Using a physiological range of temperatures spanning those of normal skin (29 degrees C) to those of febrile core tissues (39 degrees C), primary murine spleen cell proliferative responses to either Con A, solid-phase anti-CD3 antibody, specific Ag, or allogenic cells were all found to display a high degree of temperature sensitivity. A similar pattern of strong temperature sensitivity was found for the capacity of primary MLR cultures to generate allospecific effector CTL. All of these forms of T-cell temperature sensitivity are expressed both in terms of the absolute degree of the response and in terms of its kinetics, the warmer temperatures up to 35 degrees C to 37 degrees C giving larger responses sooner than the lower physiological temperatures of 29 degrees C to 33 degrees C, at which these responses are markedly inhibited relative to those at 37 degrees C. In contrast, the effector cytolytic activity of a previously formed population of CTL is remarkably insensitive to the same temperature changes that strongly regulate the generation of those effector cells. The temperatures that usually define fever are those appropriate to the core tissues of a febrile animal, yet temperature changes in this range (37 degrees C-39 degrees C) had little stimulatory effect upon the T-cell responses studied, and were, in some cases, actually inhibitory. Temperature changes appropriate to the peripheral tissue temperatures in an animal becoming febrile (29 degrees C-37 degrees C) appear to be the ones that strongly regulate mature primary T-cell responses. These results suggest that one purpose of either fever or local tissue inflammation may be to temporarily ablate the cooler portions of normal thermal gradients, thereby selectively amplifying the emergence of T-cell immunity in peripheral tissues.
Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection.
Authors: Orme I M , Roberts A D , Griffin J P , Abrams J S 
Published: December 2022

Abstract
The results of this study, in which CD4 T cells were harvested from mice at various times during the course of a virulent Mycobacterium tuberculosis infection and examined for their secretion of cytokines during culture in vitro with bone marrow-derived macrophages presenting mycobacterial Ag, provide evidence for the existence of two separate waves of cytokine-producing CD4 cells. The first, which peaks at the time at which protective immunity was maximally expressed, was characterized as a IFN-gamma-secreting cell population that preferentially recognized macrophages presenting mycobacterial culture filtrate proteins, or that were infected with the live organism. A second population, which emerged 20 to 40 days later at a time when the infection had been contained, secreted IL-4 in response to the filtrate proteins, but also reacted particularly strongly to the 65-kDa (hsp60) heat shock protein molecule of M. tuberculosis. These data indicate that acquired immunity to tuberculosis infection involves the production of both Th1- and Th2-like cell populations that differ in terms of their kinetics of emergence and loss, and in terms of their Ag specificity.