bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction with Secretory Component Stimulates Effector Functions of Human Eosinophils But Not of Neutrophils
Authors: Motegi Youichi , Kita Hirohito 
Published: December 2022

AbstractEosinophils and their products are important in the pathophysiology of allergic inflammation in mucosal tissues. Secretory component bound to IgA mediates transepithelial transport of IgA and confers increased stability on the resultant secretory IgA; however, the effect of secretory component on the biologic activity of IgA is unknown. Here, we report that secretory IgA and secretory component preferentially activate human eosinophils. When eosinophils were stimulated with immobilized secretory IgA, degranulation and superoxide production were two- to threefold greater than when stimulated with serum IgA. In contrast, neutrophils responded similarly to secretory IgA and serum IgA. Flow cytometric analysis showed that eosinophils bound to purified secretory component. The binding of 125I-labeled secretory component was inhibited by unlabeled secretory component or secretory IgA but not by serum IgA. Superoxide production by eosinophils stimulated with cytokines or IgG was enhanced synergistically by immobilized secretory component; secretory component showed no effect on neutrophil activation. Finally, anti-CD18 mAb abolished eosinophil superoxide production stimulated with secretory IgA or secretory component but not with serum IgA, suggesting a crucial role for β2 integrins in eosinophil interactions with secretory IgA or secretory component. Thus, secretory component plays important roles in activating eosinophil functions but not neutrophil functions. This preferential interaction between secretory component and eosinophils may provide a novel mechanism to regulate mucosal tissue inflammation.
Oxidized α2-Macroglobulin (α2M) Differentially Regulates Receptor Binding by Cytokines/Growth Factors: Implications for Tissue Injury and Repair Mechanisms in Inflammation
Authors: Wu Sean M. , Patel Dhavalkumar D. , Pizzo Salvatore V. 
Published: December 2022

Abstract
α2M binds specifically to TNF-α, IL-1β, IL-2, IL-6, IL-8, basic fibroblast growth factor (bFGF), β-nerve growth factor (β-NGF), platelet-derived growth factor (PDGF), and TGF-β. Since many of these cytokines are released along with neutrophil-derived oxidants during acute inflammation, we hypothesize that oxidation alters the ability of α2M to bind to these cytokines, resulting in differentially regulated cytokine functions. Using hypochlorite, a neutrophil-derived oxidant, we show that oxidized α2M exhibits increased binding to TNF-α, IL-2, and IL-6 and decreased binding to β-NGF, PDGF-BB, TGF-β1, and TGF-β2. Hypochlorite oxidation of methylamine-treated α2M (α2M*), an analogue of the proteinase/α2M complex, also results in decreased binding to bFGF, β-NGF, PDGF-BB, TGF-β1, and TGF-β2. Concomitantly, we observed decreased ability to inhibit TGF-β binding and regulation of cells by oxidized α2M and α2M*. We then isolated α2M from human rheumatoid arthritis synovial fluid and showed that the protein is extensively oxidized and has significantly decreased ability to bind to TGF-β compared with α2M derived from plasma and osteoarthritis synovial fluid. We, therefore, propose that oxidation serves as a switch mechanism that down-regulates the progression of acute inflammation by sequestering TNF-α, IL-2, and IL-6, while up-regulating the development of tissue repair processes by releasing bFGF, β-NGF, PDGF, and TGF-β from binding to α2M.
Complement-Induced Expression of Chemokine Genes in Endothelium: Regulation by IL-1-Dependent and -Independent Mechanisms
Authors: Selvan Rathinam S. , Kapadia Homi B. , Platt Jeffrey L. 
Published: December 2022

AbstractActivation of complement in the vicinity of endothelium is thought to contribute to the tissue manifestations of inflammatory and immune responses. Endothelial cells contribute to these processes in part by the elaboration of chemokines that activate various leukocytes and direct their migration into tissues. We investigated the mechanisms by which activation of complement on endothelial cell surfaces might influence the expression of chemokine genes in endothelial cells. In a model for the immune reaction occurring in a xenograft, human serum, as a source of xenoreactive anti-endothelial Abs and complement, induced expression of the monocyte chemotactic protein-1 (MCP-1), IL-8, and RANTES genes. The MCP-1 and IL-8 genes were expressed within 3 h as a first phase and at &gt;12 h as a second phase. The RANTES gene was expressed in porcine endothelial cells only 12 h after exposure to human serum. The expression of these genes required activation of complement and assembly of membrane attack complex, as it was inhibited by soluble CR1 and did not occur in the absence of C8. The early phase of MCP-1 and IL-8 gene expression did not require de novo protein synthesis. The late phase of MCP-1, IL-8, and RANTES gene expression predominantly required the production of IL-1α as an intermediate step. The results indicate that the expression of chemokine genes in endothelial cells occurs as a function of differential responses to complement and may in part be conditioned by the availability of IL-1α.
Detection of HIV-1-Specific CTLs in the Semen of HIV-Infected Individuals
Authors: Quayle Alison J. , Coston Wanda M. P. , K. Trocha Alicja , Kalams Spyros A. , Mayer Kenneth H. , Anderson Deborah J. 
Published: December 2022

AbstractCTLs play an important role in controlling cell-associated HIV. Since the majority of HIV infections are acquired through sexual transmission, we investigated whether antiviral CTLs were present in the male urogenital tract using semen as a source of T cells. We were able to establish anti-HIV cytolytic lines in five of five HIV-infected men with CD4 counts of &gt;500/μl, although cloning efficiencies were lower than with peripheral blood-derived T cells. CTLs generated from the semen of three men were analyzed in detail and showed a broadly active response, recognizing gag, env, and pol proteins. Detailed analysis of two gag-specific clones from one of the individuals demonstrated HLA class I restriction and recognition of the same p24 epitope (EQASQEVKNWMT). In summary, our results demonstrate the presence of a broad CTL response to HIV in the urogenital tract and provide a rationale for further studies of local enhancement of genital mucosal responses by anti-HIV immunization.
IL-10 Impacts Autoimmune Diabetes Via a CD8+ T Cell Pathway Circumventing the Requirement for CD4+ T and B Lymphocytes
Authors: Balasa Balaji , Davies Joanna D. , Lee Jae , Good Augusta , Yeung Brian T. , Sarvetnick Nora 
Published: December 2022

AbstractIL-10 is essential for an early phase of diabetes in nonobese diabetic (NOD) mice, but later becomes protective against its development. The mechanism by which IL-10 mediates the pathway to diabetes in these mice is unknown. Herein, we dissected the cellular and costimulation requirements for diabetes in transgenic (tg) NOD mice that expressed IL-10 in their pancreatic islets (IL-10-NOD mice). We found that IL-10 alone did not cause diabetes because the offspring (IL-10-NOD-scid mice) from backcrosses of IL-10-NOD mice with NOD-scid mice had no diabetes. Moreover, these IL-10-NOD-scid mice were free of lymphocytic infiltration. Treatment of IL-10-NOD mice with depleting anti-CD4 mAb or control mAb had no effect on diabetes. Surprisingly, depletion of CD8+ T cells by treatment with the corresponding mAb inhibited diabetes without attenuating insulitis, demonstrating a critical role for CD8+ T cells in the disease process. Interestingly, B cell-deficient IL-10-NOD mice readily developed diabetes with kinetics and incidence similar to those observed in wild-type mice, demonstrating that B lymphocytes as APCs were not required in the disease process. Administration of anti-CD40 ligand (CD40L) mAb did not prevent disease, indicating that CD40/CD40L costimulation is not required for diabetes in IL-10-NOD mice. Immunization of IL-10-NOD mice with CFA or heat-shock protein 65, known to block diabetes in NOD mice, had no effect on their diabetes. We demonstrate that IL-10 contributes early to the pathology of diabetes via a CD8+ T cell pathway, eliminating the requirement for B lymphocytes and CD40-CD40L costimulation. Our findings provide a mechanism for the participation of IL-10 in the early development of diabetes.
Cutting Edge: Senescent BALB/c Mice Exhibit Decreased Expression of λ5 Surrogate Light Chains and Reduced Development Within the Pre-B Cell Compartment
Authors: Sherwood Erin M. , Blomberg Bonnie B. , Xu Wei , Warner Cynthia A. , Riley Richard L. 
Published: December 2022

Abstract
Although senescent BALB/c mice (∼2 years old) have reduced numbers of small pre-B cells, early pre-B cells (CD43+CD25+B220+) are present in comparable numbers within the bone marrow of both young (3–6-month-old) and senescent BALB/c mice. The transition of CD43+ pre-B cells to the CD43− pre-B cell compartments is dependent on proliferation and clonal maturation dictated by the pre-B cell receptor (μ/λ5/VpreB). In vivo, senescent CD43+B220+ pro-B/early pre-B cells demonstrated reduction of λ5 mRNA, by RT-PCR analysis, and of both surface and cytoplasmic λ5 protein. Decreased λ5 protein expression was also seen among pro-B/pre-B cells derived from senescent bone marrow after stimulation in vitro with IL-7. We propose that diminished expression of the λ5 surrogate light chain results in decreased pre-B cell receptor formation and contributes to reduced recruitment of nascent CD43+ pre-B cells into the CD43− large and small pre-B cell compartments.
Cutting Edge: Thymic Positive Selection and Peripheral Activation of Islet Antigen-Specific T Cells: Separation of Two Diabetogenic Steps by an I-Ag7 Class II MHC β-Chain Mutant
Authors: Kanagawa Osami , Vaupel Barbara A. , Xu Guan , Unanue Emil R. , Katz Jonathan D. 
Published: December 2022

AbstractThe diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II β-chain. Transgenic expression of a mutant I-Ag7, substituting histidine and serine at position 56 and 57 of β-chain with proline and aspartic acid (I-Ag7PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-Ag7PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-Ag7PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC β-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.
Cutting Edge: Rapid Induction of Mitogen-Activated Protein Kinases by Immune Stimulatory CpG DNA
Authors: Yi Ae-Kyung , Krieg Arthur M. 
Published: December 2022

AbstractUnmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) rapidly activate B cells and monocyte-derived cells; however, the intracellular signaling pathways involved in this process are unclear. Here, we demonstrate that CpG DNA induces the activation of c-Jun NH2-terminal kinase and p38 but does not activate the extracellular receptor kinase in murine B and monocyte-like cell lines. CpG DNA also induces the phosphorylation of activating transcription factor-2, c-Jun, and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 as well as the activation of activator protein-1 (AP-1) DNA binding. Inhibition of p38 led to the suppression of CpG DNA-induced AP-1 DNA-binding activity and cytokine production, indicating that the p38 pathway is required for mediating these immune stimulatory effects of CpG DNA. Chloroquine, an endosomal acidification inhibitor, selectively abolished CpG DNA-mediated MAPK activation. Our results indicate that CpG DNA activates the p38 and c-Jun NH2-terminal kinase MAPK and leads to the activation of AP-1 via a pathway which is sensitive to chloroquine.
Dendritic Cell Immunization Breaks Cytotoxic T Lymphocyte Tolerance in Hepatitis B Virus Transgenic Mice
Authors: Shimizu Yukihiro , Guidotti Luca G. , Fowler Patricia , Chisari Francis V. 
Published: December 2022

Abstract
Hepatitis B virus (HBV) transgenic mice that are immunologically tolerant to HBV-encoded Ags represent a model of chronic HBV infection suitable for the development of therapeutic immunization strategies before testing in humans. Five lineages of HBV transgenic mice were immunized with plasmid DNA that encodes hepatitis B surface Ag (HBsAg) or with cytokine-activated bone marrow-derived dendritic cells (DCs) in an attempt to break tolerance to HBsAg at the B and T cell levels. DNA immunization stimulated an Ab response but not a cytotoxic T lymphocyte response to HBsAg in two of the five transgenic lineages studied. In contrast, infusion of activated transgenic or nontransgenic DCs stimulated a splenic CTL response in all three transgenic lineages immunized in this manner at precursor frequencies comparable to those in nontransgenic mice, indicating that DC function is normal, and HBsAg-specific CTLs are present but functionally silent in these transgenic animals. Importantly, none of the animals developed hepatitis or displayed suppressed viral gene expression or replication following either DNA immunization or DC administration even in the presence of anti-hepatitis B surface (HBs) Abs and HBs-specific CTLs. These results indicate that Ag presentation by cytokine-activated DCs can break tolerance and trigger an anti-viral CTL response in HBV transgenic mice, and they suggest that this strategy is more efficient than DNA immunization in this setting. Nonetheless, more efficient immunization strategies are needed to stimulate an immune response of sufficient quality and magnitude to achieve an immunotherapeutic antiviral effect.
Longitudinal Analysis of the Acute Sendai Virus-Specific CD4+ T Cell Response and Memory
Authors: Topham David J. , Doherty Peter C. 
Published: December 2022

AbstractThe development and persistence of Sendai virus-specific CD4+ T cell memory has been analyzed following respiratory infection of C57BL/6J mice by determining the prevalence of IL-2-producing Th cell precursors (Thp). Frequencies as high as 1:40 virus-specific CD4+ T cells were found in the regional lymph nodes and spleen during the acute phase of the host response and persisted at levels ≥1:500 for 2 to 3 mo. Thereafter, these CD4+ T cells tended to distribute more to the spleen than to the lymph nodes, a pattern that persisted for the life of the animals. From 3 to 12 mo after infection, virus-specific Thp were always detectable, although the numbers were diminished relative to those measured during the acute phase. Thereafter, however, in both contemporary and cumulative assays, there was a progressive increase in both the frequency and number of Thp. These increases were especially apparent for mice more than 2 years of age. This may reflect enrichment of the CD4+CD44high memory set due to the gradual diminution of the naive CD4+CD62LhighCD44low component. Analysis of DNA staining profiles for the CD4+ T cells showed high levels of cycling for the acute phase of the response, whereas the rate of T cell turnover measured for the CD4+CD44high population by bromodeoxyuridine incorporation indicated a pattern of stable, continuing proliferation throughout life. Virus-specific CD4+ T cell memory resulting from a single exposure to a readily eliminated RNA virus is thus maintained indefinitely in laboratory mice.
Autoimmunity Develops in Lupus-Prone NZB Mice Despite Normal T Cell Tolerance
Authors: Wither Joan , Vukusic Brian 
Published: December 2022

AbstractNZB mice spontaneously develop an autoimmune disease characterized by production of anti-RBC, -lymphocyte, and -ssDNA Abs. Evidence suggests that the NZB mouse strain has all of the immunologic defects required to produce lupus nephritis but lacks an MHC locus that allows pathogenic anti-dsDNA Ab production. The capacity to produce diverse autoantibodies in these mice raises the possibility that they possess a generalized defect in self-tolerance. To determine whether this defect is found within the T cell subset, we backcrossed a transgene encoding bovine insulin (BI) onto the NZB background. In nonautoimmune BALB/c mice, the BI transgene induces a profound but incomplete state of T cell tolerance mediated predominantly by clonal anergy. Comparison of tolerance in NZB and BALB/c BI-transgenic mice clearly demonstrated that NZB T cells were at least as tolerant to BI as BALB/c T cells. NZB BI-transgenic mice did not spontaneously produce anti-BI Abs, and following antigenic challenge, BI-specific Ab production was comparably reduced in both BI-transgenic NZB and BALB/c mice. Further, in vitro BI-specific T cell proliferation and cytokine secretion were appropriately decreased for primed lymph node and splenic T cells derived from NZB BI-transgenic relative to their nontransgenic counterparts. These data indicate that a generalized T cell tolerance defect does not underlie the autoimmune disease in NZB mice. Instead, we propose that the T cell-dependent production of pathogenic IgG autoantibodies in these mice arises from abnormal activation of T cells in the setting of normal but incomplete tolerance.
A Mouse Carrying Genetic Defect in the Choice Between T and B Lymphocytes
Authors: Tokoro Yayoi , Sugawara Takehiko , Yaginuma Hiroyuki , Nakauchi Hiromitsu , Terhorst Cox , Wang Baoping , Takahama Yousuke 
Published: December 2022

AbstractTransgenic mice with human CD3ε gene have been shown to exhibit early arrest of T cell development in the thymus. The present study shows that, instead of T cells, B cells are generated in the thymus of a line, tgε26, of the human CD3ε transgenic mice. The accumulation of mature B cells in the thymus was found only in tgε26 mice, not in other human CD3ε transgenic mouse lines or other T cell-deficient mice, including CD3-ε knockout mice and TCR-β/TCR-δ double knockout mice. Hanging drop-mediated transfer into 2-deoxyguanosine-treated thymus lobes showed that lymphoid progenitor cells rather than thymus stromal cells were responsible for abnormal B cell development in tgε26 thymus, and that tgε26 fetal liver cells were destined to become B cells in normal thymus even in the presence of normal progenitor cells undergoing T cell development. These results indicate that lymphoid progenitor cells in tgε26 mice are genetically defective in thymic choice between T cells and B cells, generating B cells even in normal thymus environment. Interestingly, tgε26 thymocytes expressed GATA-3 and TCF-1, but not LEF-1 and PEBP-2α, among T cell-specific transcription factors that are involved in early T cell development, indicating that GATA-3 and TCF-1 expressed during thymocyte development do not necessarily determine the cell fate into T cell lineage. Thus, tgε26 mice provide a novel mouse model in that lineage choice between T and B lymphocytes is genetically defective.
B Cell Deletion, Anergy, and Receptor Editing in “Knock In” Mice Targeted with a Germline-Encoded or Somatically Mutated Anti-DNA Heavy Chain
Authors: Pewzner-Jung Yael , Friedmann Dinorah , Sonoda Eiichiro , Jung Steffen , Rajewsky Klaus , Eilat Dan 
Published: December 2022

AbstractTo study the relative contributions of clonal deletion, clonal anergy, and receptor editing to tolerance induction in autoreactive B cells and their dependence on B cell receptor affinity, we have constructed “knock in” mice in which germline encoded or somatically mutated, rearranged anti-DNA heavy (H) chains were targeted to the H chain locus of the mouse. The targeted H chains were expressed on the vast majority of bone marrow (BM) and splenic B cells and were capable of Ig class switching and the acquisition of somatic mutations. A quantitative analysis of B cell populations in the BM as well as of Jκ utilization and DNA binding of hybridoma Abs suggested that immature B cell deletion and light (L) chain editing were the major mechanisms affecting tolerance. Unexpectedly, these mechanisms were less effective in targeted mice expressing the somatically mutated, anti-DNA H chain than in mice expressing the germline-encoded H chain, possibly due to the greater abundance of high affinity, anti-DNA immature B cells in the BM. Consequently, autoreactive B cells that showed features of clonal anergy could be recovered in the periphery of these mice. Our results suggest that clonal deletion and receptor editing are interrelated mechanisms that act in concert to eliminate autoreactive B cells from the immune system. Clonal anergy may serve as a back-up mechanism for central tolerance, or it may represent an intermediate step in clonal deletion.
IL-4 in Combination with TGF-β Favors an Alternative Pathway of Th1 Development Independent of IL-12
Authors: Lingnau Karen , Hoehn Petra , Kerdine Saadia , Koelsch Stephan , Neudoerfl Christine , Palm Norbert , Ruede Erwin , Schmitt Edgar 
Published: December 2022

AbstractIL-4 was found to be the essential differentiation factor for Th2 cells and simultaneously to be a potent inhibitor of Th1 development that is induced by IFN-γ and IL-12. Furthermore, it was demonstrated that TGF-β can also inhibit Th1 development. In this work, we demonstrate that polyclonal activation of Mel-14highCD4+ T cells by immobilized anti-αβTCR mAb together with a mixture of IL-4 and TGF-β can lead to the development of both Th1 and Th2 cells, depending on the concentration of these cytokines. Additional experiments revealed that Th1 induction by a combination of IL-4 and TGF-β depends on the presence of endogenous IFN-γ, and that this alternative Th1 development is further enhanced by IL-12, but is not dependent on this cytokine. Moreover, naive OVA323–339-specific Th cells that were stimulated by APCs and OVA323–339 peptide differentiated toward Th1 cells after priming in the presence of IL-4 in combination with TGF-β. Hence, this finding confirmed the results obtained by polyclonal activation of naive CD4+ Th cells and implicates that this alternative Th1 development may also occur in vivo under the influence of TGF-β and IL-4 independently of the Th1-promoting effect of IL-12.