bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased tolerance to endotoxin by granulocyte-macrophage colony-stimulating factor-deficient mice.
Authors: Basu S , Dunn A R , Marino M W , Savoia H , Hodgson G , Lieschke G J , Cebon J 
Published: December 2022

Abstract
The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-gamma, IL-1alpha, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-alpha in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-alpha persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-alpha and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1alpha and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-alpha production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-gamma, IL-1alpha, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.
In vivo IL-12 administration induces profound but transient commitment to T helper cell type 1-associated patterns of cytokine and antibody production.
Authors: Rempel J D , Wang M , HayGlass K T 
Published: December 2022

Abstract
There is much interest in the utility of exogenous IL-12 as a biologic adjuvant in immediate hypersensitivity and infectious or parasitic diseases where the induction of Th1 responses is strongly associated with protective immunity. Using an immediate hypersensitivity model in which C57Bl/6 mice immunized with OVA (alum) normally generate Th2-dominated responses, we examined the ability of rIL-12 to direct and maintain OVA-specific cytokine and Ab responses in a Th1 direction. Exogenous IL-12 administered coincident with OVA immunization stimulated elevated serum IFN-gamma levels, enhanced IFN-gamma synthesis, and inhibited IL-4 synthesis in bulk culture; 80 to 99% inhibited primary Ag-specific serum IgE and IgG1 responses; and 15- to 20-fold enhanced IgG2a synthesis. However, each of these effects was highly transient, as exogenous IL-12, given at levels up to those associated with serious toxicity, failed to have a lasting impact on the OVA-specific T or B cell response. This transience was evident in primary bulk culture cytokine synthesis; in limiting dilution analysis of the frequency of OVA-specific IFN-gamma-, IL-4-, or IL-10-producing CD4 T cells; and, most importantly, in vivo effector responses such as IgE production to secondary and tertiary OVA immunization. The finding that the intense Th1-like phenomena seen following in vivo administration of rIL-12 with this exogenous Ag are highly transient and are not associated with alterations in the allergen-specific CD4 T cell repertoire to Th1-like patterns suggests a need for caution in the enthusiasm for the use of this cytokine as a biologic adjuvant.
Structure-function analysis of the integrin beta 7 subunit: identification of domains involved in adhesion to MAdCAM-1.
Authors: Tidswell M , Pachynski R , Wu S W , Qiu S Q , Dunham E , Cochran N , Briskin M J , Kilshaw P J , Lazarovits A I , Andrew D P , Butcher E C , Yednock T A , Erle D J 
Published: December 2022

Abstract
Beta 7 integrins serve special roles in mucosal immunity. Alpha 4 beta 7-mediated adhesion to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs lymphocyte homing to the gut, and alpha E beta 7 mediates binding of lymphocytes to E-cadherin on epithelial cells. Since alpha 4 beta 7 mediates adhesion to MAdCAM-1 but alpha 4 beta 1 does not, we used beta 7/beta 1 chimeras to directly assess the importance of specific regions of beta 7 in MAdCAM-1 binding. We found a region of beta 7 (residues 46-386) that accounts for specificity of alpha 4 beta 7 binding to MAdCAM-1. We also used human/mouse and human/rat chimeric beta 7 subunits to map epitopes recognized by fifteen anti-beta 7 mAbs. Six of seven Abs that block adhesion to MAdCAM-1 and E-cadherin (Fib 21, 22, 27, 30, 504; Act-1) mapped to amino acid residues 176-250. Residues 176-250 lie within the region of beta 7 that specifies MAdCAM-1 binding and also within a region that has a predicted structure homologous to the metal ion-dependent adhesion site (MIDAS) domains of the integrin subunits alpha L and alpha M. Three new Abs that recognize beta 7 in the presence of Mn2+, but not Ca2+, and promote adhesion to MAdCAM-1, mapped to amino acids 46-149. One blocking and five other Abs mapped to other regions (amino acids 387-725). We conclude that a MIDAS-like domain serves a critical role in beta 7 integrin-mediated adhesion.
Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease.
Authors: Paul S , Li L , Kalaga R , O'Dell J , Dannenbring R E , Swindells S , Hinrichs S , Caturegli P , Rose N R 
Published: December 2022

Abstract
Polyreactive and thyroglobulin (Tg)-directed proteolytic activities present in the serum IgG of healthy controls and patients with autoimmune disease were studied by electrophoretic separation of 125I-labeled Tg reaction products and spectrofluorometric measurement of Pro-Phe-Arg-methylcoumarinamide cleavage at the Arg-methylcoumarinamide bond. A decrease of the polyreactive proteolytic activity accompanying an increase of the Tg-cleaving activity in IgG from autoimmune thyroiditis (ATh) and systemic lupus erythematosus (SLE) patients was evident. The Tg, a known target of autoimmune reactions in ATh, was cleaved at lower levels by Abs from patients with this disease than from SLE patients. The Tg-cleaving and Tg-binding activities of the autoantibody preparations were not correlated. Enhanced rates of cleavage at saturating substrate concentrations (Vmax), not increased Tg-binding affinities, were evident in IgG preparations with the greatest Tg-cleaving activity. Similarly, diminution of the polyreactive proteolytic activity in IgG from the autoimmune disease patients was due to decreased Vmax values, not decreased substrate-binding affinities. No cleavage of Tg by IgG from subjects with HIV-1 infection, or from mice hyperimmunized with an albumin-hapten conjugate was evident, suggesting that generation of Tg-cleaving Abs does not accompany V region affinity maturation in response to unrelated Ags. These observations establish Tg as a target of catalytic autoantibodies in SLE and ATh, suggest a transition from polyreactive proteolytic activity to autoantigen-directed activity in autoimmune disease, and open the possibility that combining site chemical reactivity is a factor driving the expression of catalytic activity by autoantibodies.
Mouse complement receptors type 1 (CR1;CD35) and type 2 (CR2;CD21): expression on normal B cell subpopulations and decreased levels during the development of autoimmunity in MRL/lpr mice.
Authors: Takahashi K , Kozono Y , Waldschmidt T J , Berthiaume D , Quigg R J , Baron A , Holers V M 
Published: December 2022

Abstract
Human complement receptors type 1 (hCR1;CD35) and type 2 (hCR2;CD21) are expressed on B lymphocytes at specific stages during differentiation and activation. These receptors play critical roles in the immune response to T-dependent Ags in addition to germinal center formation. Expression of both hCR2 and hCR1 is decreased on B lymphocytes of patients with systemic lupus erythematosus (SLE). We have studied the expression of mouse CR2 and CR1 on normal populations of mouse B lymphocytes in BALB/c mice. Our results demonstrate that expression of these receptors in the normal state closely parallels that of hCR2. During bone marrow development, expression is first detected on low B220/high IgM cells, demonstrating that complement receptors appear after central tolerance mechanisms are completed. In the splenic microenvironment the highest levels of receptor expression are found on marginal zone B lymphocytes. Mouse CR2 and CR1 are also found on peritoneal B1a and B1b cells in addition to IgA+ Peyer's patch B cells. Activation of splenic B cells under Th2 conditions results in a marked decrease in receptor expression. To determine whether the patterns of receptor expression also parallel those found in human disease, we studied the MRL lpr/lpr (MRL/lpr) model of SLE. Interestingly, we found an early decrease in complement receptor expression that is progressive and first detectable before major clinical manifestations of nephritis. We hypothesize that the early decrease in complement receptor expression such as that demonstrated by MRL/lpr mice plays an important role in the pathogenesis of murine and perhaps human SLE.
CD28-induced cytokine production and proliferation by thymocytes are differentially regulated by the p59fyn tyrosine kinase.
Authors: Ong C J , Lim A S , Teh H S 
Published: December 2022

Abstract
CD28 is a 44-kDa homodimeric receptor that is expressed on the majority of T cells. Engagement of the CD28 receptor by soluble anti-CD28 mAb in conjunction with phorbol ester (PMA) induces the production of cytokines and the proliferation of resting T cells via signal transduction pathways independent of the TCR. Evidence is provided herein that CD28 signals leading to cytokine production do not require the p59fyn (Fyn) tyrosine kinase, whereas CD28-mediated proliferation is dependent on the presence of the Fyn kinase in thymic, but not lymph node, cells. The defect in proliferation is not due to failure of IL-2R signaling, since addition of high concentrations of exogenous IL-2 can overcome the proliferative defect. Analysis of CD28-directed induction of the IL-2R alpha (CD25)-chain, which confers high affinity binding to IL-2, showed that Fyn-deficient thymocytes, but not lymph node cells, failed to up-regulate CD25 expression following anti-CD28 and PMA stimulation. Thus, the Fyn tyrosine kinase is critically required for thymic CD28-mediated CD25 expression and proliferation but not for CD28-mediated cytokine production.
CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response.
Authors: Jaiswal A I , Croft M 
Published: December 2022

Abstract
Recent data suggest that CD40 ligand (CD40L)-CD40 interactions are essential for up-regulation of costimulatory activity on APC and that efficient induction of CD40L may be pivotal to the success of a CD4 T cell response. CD40L is regulated primarily by TCR signaling, but high level expression on a naive T cell appears to require additional interactions between T cell coreceptors and APC accessory molecules. The data reported here show that resting B cells presenting peptide Ag, in contrast to both dendritic cells and preactivated B cells, induce very little CD40L on naive CD4 cells, which in turn is insufficient to promote APC costimulatory activity. We also show, however, that previously activated effector T cells have enhanced responsiveness to Ag when accessory molecule help is limiting and consequently can express high levels of CD40L after interaction with resting B cells. High level CD40L expression correlated with B cell activation and up-regulation of costimulatory activity; however, blocking studies showed that CD40L was only partially responsible for these phenomena. These studies reinforce the notion that resting B cells may be tolerogenic for naive CD4 cells in part because of inefficient CD40L induction. The data also suggest that a successful primary T cell response will only occur if either the initial interaction is with a dendritic cell followed by subsequent interactions of the effector T cells with resting APC or if nonspecific inflammatory stimuli up-regulate accessory molecule expression on resting APC before an encounter with the naive T cell.
The glycosylation of IgA produced by murine B cells is altered by Th2 cytokines.
Authors: Chintalacharuvu S R , Emancipator S N 
Published: December 2022

Abstract
We sought to determine whether selected cytokines, known to profoundly increase proliferation and/or production of Ig by B cells and their progeny, also have as yet unrecognized effects upon IgA glycosylation. For these studies, we selected CH12LX mouse B lymphoma cells, a widely used model of B cell differentiation. Glycosylation was assessed by detection with enzyme-lectin conjugates in an immunoabsorption assay and verified by profiling and sequencing of the N-linked oligosaccharides. Stimulation of B cells with IL-4 plus IL-5 significantly alters the terminal glycosylation of secreted IgA, whereas LPS has a minor effect, despite the fact that both stimuli are equipotent at inducing Ig class switching and Ig secretion. Moreover, the alteration in terminal glycosylation was more profound on IgA secreted from surface IgM+ than from surface IgA+ CH12LX cells. These results suggest that the increased production of IL-4 and IL-5 by peripheral blood lymphocytes from IgA nephropathy patients might result in the production of abnormally glycosylated IgA. In turn, this abnormally glycosylated IgA may promote deposition of IgA in glomeruli in this disease.
T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin.
Authors: Thomas J W , Kralick P M , Ewulonu U K 
Published: December 2022

Abstract
An early or preimmune repertoire for anti-insulin B cells was examined using the T cell-independent (TI) response to insulin conjugated to Brucella abortus (BA-ins). mAbs from the BA-ins response reflect a repertoire present 7 to 10 days before the first Ab-forming cells (AFC) are detected in primary T cell-dependent (TD) responses to insulin. Although 4 of 6 BA-ins mAb express IgG2 isotype, evidence for somatic mutation is limited. A total of 9 of 12 V regions are identical with known V(H) or Vkappa genes, and consensus sequences suggest two other V genes may be in germ-line configuration. The relative avidities (50% inhibition of binding) of TI anti-insulins cover a broad range and are consistent with a germ-line anti-insulin repertoire that is functionally diverse. The V(H)s of 5 mAb are from two subsets of J558 genes (205.1 and 186.3) that dominate the B cell pool of adult mice and are different from the V(H)s used by anti-insulin mAb in primary TD responses. One IgM anti-insulin (mAb 301) uses V(H)-J606 and Vkappa1, and this mAb binds beta cells. Other TI mAb use either Vkappa5 or Vkappa19.3 genes and are similar to Vkappa genes used by anti-insulin mAb from TD responses. The data show that mutations in germ-line genes are not required for measurable insulin binding by monospecific mAb from adult mice. The recurrent use of Vkappa genes in both early (TI response) and late (TD responses) suggest that these structures are important in insulin binding.
Cytolytic T lymphocyte recognition of the immunodominant HLA-A*0201-restricted Melan-A/MART-1 antigenic peptide in melanoma.
Authors: Romero P , Gervois N , Schneider J , Escobar P , Valmori D , Pannetier C , Steinle A , Wolfel T , Lienard D , Brichard V , van Pel A , Jotereau F , Cerottini J C 
Published: December 2022

Abstract
The Melan-A/MART-1 gene product is frequently recognized by tumor-specific HLA-A2-restricted CTL. An immunodominant nonapeptide has been localized to the region spanning residues 27-35. However, the decapeptide including residues 26-35 (the nonapeptide extended NH2 terminally by one residue) appeared to be recognized as efficiently as the nonapeptide. In this study, we show that the optimal length immunodominant peptide appears to correspond to the decapeptide 26-35, as assessed by quantitative analyses of both 4 polyclonal and 13 monoclonal populations of specific CTL. Functional assays of peptide binding to HLA-A2 indicate that the decapeptide is significantly a more efficient binder than the nonapeptide. Moreover, analogues of the decapeptide including substitutions at a secondary HLA-A2 peptide anchor further improve decapeptide binding. Finally, we show that the functional (9 CTL clones analyzed) and structural TCR repertoire (7 CTL clones) of a group of specific CTL clones is rather diverse. The findings reported here may have important implications for future peptide-based melanoma vaccination trials as well as for the monitoring of specific CTL responses in vivo.
Growth of P511 mastocytoma cells in BALB/c mouse brain elicits CTL response without tumor elimination: a new tumor model for regional central nervous system immunity.
Authors: Gordon L B , Nolan S C , Cserr H F , Knopf P M , Harling-Berg C J 
Published: December 2022

Abstract
We have developed a murine model to explore the tumor-specific CTL response in the immune-privileged central nervous system using P511 mastocytoma cells. Three strains with varying degrees of histocompatibility to P511 cells (CD-1, allogeneic; BALB/c, minor histoincompatible; DBA/2, syngeneic) received tumor cells (10(4)) into the putamen 7 days after cannula implantation, when the blood-brain barrier was functionally intact. Without exception, tumor formed reproducibly by day 7 in all strains. Tumor rejection occurred in CD-1 but not in BALB/c and DBA/2 mice. Using a flank injection site, both CD-1 and BALB/c, but not DBA/2 mice, ultimately rejected flank tumors. Analysis of tumor-specific CTL in BALB/c spleens revealed that P511 administration into brain or flank elicited similar responses: no fully activated CTL were detectable but a significantly expanded population of nonkilling precursors of CTL (pCTL) were present. A P511 cell-specific pCTL population was also identified at the brain tumor site 14 days post-tumor introduction, indicating that pCTL, generated in the periphery, traffic to the tumor site in brain. These data indicate that failure to reject tumor in brain is neither due to lack of afferent stimulation nor to inability of peripheral effectors (P511 cell-specific pCTL) to reach the tumor site. We hypothesize that these effector cells are prevented from developing into fully activated CTL by conditions within the central nervous system microenvironment that down-regulate CTL development.
Hydrogen peroxide-mediated transcriptional induction of macrophage colony-stimulating factor by TGF-beta1.
Authors: Hong Y H , Peng H B , La Fata V , Liao J K 
Published: December 2022

Abstract
TGF-beta1 and macrophages are important regulators of tissue fibrosis and remodeling. Here we show that TGF-beta1 induces the expression of macrophage-CSF (M-CSF) in vascular endothelial cells via a signaling pathway(s) involving hydrogen peroxide (H2O2). In a time-dependent manner, TGF-beta1 produced a 10- and a 6-fold increase in M-CSF mRNA and protein levels after 12 h, respectively. This increase in M-CSF expression was attenuated by a nitric oxide donor, S-nitrosoglutathione (GSNO), and by a nonspecific oxidase inhibitor, diphenylene iodonium. Furthermore, the TGF-beta1-induced M-CSF mRNA expression was inhibited by catalase, but not by superoxide dismutase, suggesting that H2O2 rather than superoxide anion (O2.-) is the primary mediator of the effects of TGF-beta1. Transient transfection studies using deletional M-CSF promoter constructs demonstrated that TGF-beta1 produced a 13-fold induction in M-CSF promoter activity that was repressed by &gt;85% with GSNO and catalase, in part through inhibitory effects on kappaB cis-acting elements. Electrophoretic mobility shift assays revealed that the activation of nuclear factor-kappaB by TGF-beta1 was also inhibited by GSNO and catalase, but not by superoxide dismutase. In a concentration-dependent manner, treatment with exogenous H2O2 produced 14- and 4.6-fold increases in M-CSF promoter activity and mRNA expression, respectively. These results indicate that the generation of H2O2 and activation of NF-kappaB by TGF-beta1 are required for the induction of M-CSF gene transcription.
Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.
Authors: Labow M , Shuster D , Zetterstrom M , Nunes P , Terry R , Cullinan E B , Bartfai T , Solorzano C , Moldawer L L , Chizzonite R , McIntyre K W 
Published: December 2022

Abstract
IL-1alpha and IL-1beta are potent inflammatory cytokines that contribute to a number of normal physiologic processes and to the development of a number of inflammatory diseases. Two IL-1R, the type I and type II receptors, have been identified. This work describes the derivation and characterization of mice deficient in expression of the type I IL-1R (IL-1RI). IL-1RI-deficient mice were viable and fertile, but failed to respond to IL-1 in a variety of assays, including IL-1-induced IL-6 and E-selectin expression and IL-1-induced fever. Similar to IL-1beta-deficient mice, IL-1RI-deficient mice had a reduced acute phase response to turpentine. In contrast, IL-1RI-deficient mice had a reduced delayed-type hypersensitivity response and were highly susceptible to infection by Listeria monocytogenes. These data demonstrate that the IL-1RI is essential for all IL-1-mediated signaling events examined, and that both IL-1alpha and IL-1beta are critical to the animals' response to injury and infection. These data also demonstrate that IL-1 function is not required for normal development or homeostasis.
Immunodominance is independent of structural constraints: each region within hen eggwhite lysozyme is potentially available upon processing of native antigen.
Authors: Moudgil K D , Sekiguchi D , Kim S Y , Sercarz E E 
Published: December 2022

Abstract
T cell responses to different protein Ags have been shown to focus on a few ("immunodominant") determinants. We have addressed three major, interrelated questions regarding immunodominance. First, can each area within hen eggwhite lysozyme (HEL) serve as an immunodominant focus in different inbred mouse strains or are there structural constraints that limit the utilization of certain segments of the molecule? Second, in MHC-congenic mice with identical non-MHC genes, is response to HEL restricted to one or more members of a set of HEL determinants owing to processing constraints imposed by the background genes? Third, does a truncated TCR repertoire influence the immunodominance of certain determinants of HEL? Our results in 19 strains of mice, representing 11 different MHC haplotypes, demonstrate that the immunodominant determinants within HEL are distributed all over the molecule, suggesting that there is no inherent structural constraint imposed on certain regions to be always immunorecessive. However, in different mouse strains, the emergence of identical regions of HEL as immunodominant sites strictly correlates with the identity of their MHC haplotypes but not genetic background (non-MHC) genes. We attribute this relationship to "MHC-guided processing" of native Ag. Finally, our results demonstrate that a truncated TCR repertoire can result not only in the loss of response to certain immunodominant determinants, but can also result in a gain. These results should contribute significantly to further understanding of the mechanism of immunodominance.