bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cleavage of CD23 by ADAM proteins is regulated by beta-2 adrenergic receptor stimulation on B cells (91.14)
Authors: Padro Caroline , Sanders Virginia 
Published: January 2023

Abstract
The level of IgE is often associated with the severity of allergic asthma. Beta-2 adrenergic receptor (β2AR) agonists alleviate bronchoconstriction by targeting the β2AR on bronchiolar smooth muscle cells, triggering airway relaxation. The β2AR is also expressed on B lymphocytes. In vitro data from our laboratory showed that β2AR stimulation on a CD40L/IL-4 activated B cell increases the level of IgE produced per cell, without affecting class switch recombination. We also found that surface CD23 expression remained constant, while CD23 mRNA, total CD23 protein, and CD23 cleavage increased. We know that soluble CD23 positively regulates IgE production. Therefore, β2AR stimulation may worsen bronchoconstriction over time, while relieving it in the short term. We hypothesized that the primary sheddase of CD23, ADAM10, was regulated by β2AR stimulation on the activated B cell. However, we found that β2AR stimulation was unable to affect the level of ADAM10 protein or mRNA in an activated B cell as compared to activated cells alone. Our recent data indicated that ADAM8 and ADAM28 might instead be involved in the β2AR-associated shedding of CD23. The differential β2AR-associated ADAM protein cleavage of CD23 may provide a potential molecular target to prevent a β2AR agonist-induced increase in IgE, which may counteract the therapeutic effect to relieve bronchoconstriction. Funded by NIH-AI-37326 and T32-AI55411
Dual Roles of Inositol Phosphatase SHIP-1 in Active and Passive Systemic Anaphylactic Responses (91.16)
Authors: Zhu Zhou , Oh Sun-Young , Wu Fan , Zheng Tao 
Published: January 2023

Abstract
SHIP-1 is a negative regulator of signaling pathways triggered by antigens and cytokines. We reported that SHIP-1 knockout (KO) mice develop a spontaneous allergic pulmonary inflammation. To determine the roles of SHIP-1 in innate and adaptive immune responses, we examined IgE-dependent passive (PSA) and OVA-induced active systemic anaphylactic (ASA) responses in mice deficient in SHIP-1. Heterozygous SHIP-1 (hSHIP) mice were compared with C57BL/6 wild type (WT) mice. For PSA, 24 h after passive immunization with 5 µg anti-DNP IgE, mice were challenged i.v. with 1 mg of DNP-HSA. For ASA, mice were immunized i.p. once or twice with 50 µg of OVA/Alum on day 1 and 7 and then challenged with 1 mg of OVA on day 14 or 21. The core body temperature was monitored and blood was collected for serum immunoglobulins. Compared to WT controls, hSHIP mice developed significantly enhanced IgE-dependent PSA, but surprisingly, with one-time sensitization, hSHIP mice developed diminished ASA responses. Serum OVA-specific IgE and IgG1 were significantly lower but OVA-specific IgG2a was significantly higher in hSHIP mice. These studies demonstrate that SHIP-1 deficiency leads to enhanced PSA by increased mast cell response but diminished ASA, possibly due to impaired Th2 response to allergen and decreased production of IgE and IgG1. Thus, in contrast to its role as a negative regulator in innate immunity, SHIP-1 may play a critical role in the Th2 adaptive immunity as a positive regulator.
Involvement of HIF1α in mediating VEGF-dependent epithelial cell growth and overexpression in chronic rhinosinusitis with nasal polyposis (91.4)
Authors: Kim Jean , Lee Hyun 
Published: January 2023

Abstract
We recently reported that VEGF is overexpressed in chronic rhinosinusitis (CRSwNP) and functions to promote nasal epithelial cell hyperplasia, a key feature of sinus polyposis, by regulating autocrine epithelial cell growth. However, the upstream signals regulating this process remain unclear. Hypoxia-inducible factor-1α (HIF1α) is a known regulator of VEGF. Therefore we examined whether HIF1α may regulate VEGF dependent cell growth in nasal epithelial cells. Immunohistochemical analysis of sinonasal surgical tissue showed significantly increased staining for HIF1α in epithelium in polyps of CRSwNP subjects as compared to normal control sinus tissue (p&lt; 0.001, n=5). Culture of human primary nasal epithelial cells (PNEC) from CRSwNP subjects demonstrated abundant expression of HIF1α by realtime PCR (Ct=19+/-2, n=5). To implicate a role of HIF1α in regulation of VEGF in CRSwNP, we performed siRNA knockdown of HIF1α in PNEC from CRSwNP subjects. This resulted in specific inhibition of VEGF mRNA by 77% (p&lt;0.01, n=3). ELISA of PNEC cell supernatants confirmed inhibition of soluble VEGF expression by 47% (p&lt;0.01, n=3). In addition, silencing of HIF1α resulted in 56% reduction of cell growth rate comparable to that of PNECs from normal control subjects, as measured by DNA binding growth assay (p&lt;0.01, n=3). These data suggest that HIF1α regulates VEGF in perpetuating hyperplastic epithelial cell growth observed in CRSwNP.
The role of CCR7 in CD8 T cell egress from the lung during influenza A virus infection. (92.17)
Authors: Jennrich Silke 
Published: January 2023

Abstract
The migratory capacity determines T cell effector function in vivo. Memory/effector T cells efficiently enter extralymphoid sites from blood and subsequently leave the tissue via the afferent lymph. While exit of resting T cells from uninflamed extralymphoid tissue is regulated by their expression of the chemokine receptor CCR7, it is unclear whether effector T cells exit from acutely infected sites. Here, we found that IFN-g expressing in vitro polarized (CD8+) Tc1 cells expressed functional CCR7 and were cytotoxic in vitro. Importantly, upon adoptive transfer, Tc1 cells were able to rescue mice infected with a lethal dose of influenza A virus. Transferred Tc1 cells did egress from infected lungs and could be recovered from draining lymph nodes. The pulmonary egress of Tc1 cells during acute infection required their expression of CCR7, demonstrating that egress from the inflamed lungs is an active, regulated process. Our data support a model, in which T cell retention in and egress from infected tissue is controlled by the regulated expression of CCR7, thereby affecting local T cell effector function and the efficiency of host defense.
Investigating original antigenic sin responses to H5N1 influenza viruses (92.19)
Authors: Masseoud Feda , Skountzou Ioanna , Temperton Nigel , Jacob Joshy 
Published: January 2023

Abstract
H5N1 influenza A virus remains a global threat since its outbreak in 1997. Its re-emergence in 2003 spread from Asia to Europe, the Middle-East and Africa, raising concerns of a possible pandemic. While stockpiling of H5N1 prepandemic vaccines has been initiated, strain prediction is difficult due to the emergence of distinct clades/subclades. Antigenic variation between vaccine and pandemic strains may confer cross-protection or result in antigenic sin, in which the immune response is directed against the original strain rather than the novel protective antigenic determinants. Observed between strains that have undergone antigenic drift, this misdirected response may compromise protective immunity. This study was carried out to determine the extent to which antigenic sin interferes with immune responses to the potentially pandemic influenza H5 subtype. We immunized mice with a DNA vaccine encoding the full length HA from influenza A/Vietnam/1194 followed by a vaccine encoding HA of drifted H5N1 strains, ranging in genetic identity from 100%- 88%. We are currently assessing responses directed against either the primary or the drifted strain by microneutralization using a pseudotyped lentivirus bearing HA from the respective H5N1 strains. By examining antigenic sin due to H5N1 viruses, we can better understand the behavior of the virus as it circulates in the human population, and therefore improve preparedness in the context of H5N1 vaccine development and pandemic planning.
An inducible antigen system to study endogenous CD8 T cell tolerance (93.11)
Authors: Jellison Evan , Turner Michael , Lefrançois Leo 
Published: January 2023

Abstract
Peripheral tolerance induction is critical for deterrence of autoimmunity. Most self-reactive T cells are developmentally deleted in the thymus. This deletion process is not absolute and self-reactive T cells can escape. These T cells must either be deleted or regulated in the periphery to prevent autoimmunity. To study these processes, we generated mice in which SIINFEKL expression can be tightly controlled in small intestinal epithelial cells or dendritic cells by administration of doxycycline. Our system provides the unique ability to examine endogenous T cell responses to tissue-specific and developmentally regulated self antigen. Importantly, the transgenic mice are ignorant of antigen prior to induction. Antigen induction in either the small intestine or dendritic cells caused tissue-specific activation of transferred TCR transgenic OT-I T cells. Antigen induction also resulted in activation and expansion of endogenous SIINFEKL-specific CD8 T cells that expressed PD1, but did not express KLRG1 or CD127. Antigen induction impaired a SIINFEKL-specific CD8 response to concomitant VSV OVA infection. However, in the absence of antigen induction, SIINFEKL-specific effector and memory CD8 T cell responses were generated, but the resultant memory CD8 T cells did not respond to subsequent self antigen induction. Characterization of immune responses in these antigen-inducible mice will provide key insights into mechanisms controlling tolerance versus autoimmunity.
Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic neuroautoimmune response (93.19)
Authors: Fu Haiyan , Killedar Smruti , DiRosario Julianne , Popovich Phillip , McCarty Douglas 
Published: January 2023

Abstract
Mucopolysaccharidosis (MPS) IIIB is an autosomal recessive lysosomal storage disease with severe progressive neurological manifestation. Detailed mechanisms of neuropathology of MPS IIIB are unclear, though the primary pathology is known to be the lysosomal storage of heparan sulfate. Recently, using a mouse model of MPS IIIB, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. Here, we show for the first time, that lymphocytes isolated from MPS IIIB mice cause a mild paralytic disease when they are injected systemically into naïve wild-type mice. This disease is characterized by mild tail and lower trunk weakness with delayed weight gain. The MPS IIIB lymphocytes also trigger neuroinflammation within the CNS of recipient mice characterized by up-regulation of IL2, IL4, IL5, IL17, TNFα, IFNα, and Ifi30, glial activation and intraparenchymal lymphocyte infiltration. Together, these data suggest that an autoimmune response, especially T-cell autoimmunity, directed at CNS proteins contributes to MPS IIIB neuropathology independent of lysosomal storage pathology.
Identification of specific single-nucleotide polymorphisms that modify alternative splicing in a lupus-associated haplotype of complement receptor 2 (93.26)
Authors: Lough Kara , Douglas Katherine , Homme Carissa , Ulgiati Daniela , Tsao Betty , Boackle Susan 
Published: January 2023

Abstract
A haplotype formed by the minor alleles of three single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene is associated with decreased risk of systemic lupus erythematosus (SLE). Two of these SNPs (rs1048971 and rs17615) are in exon 10 and the third (rs4308977) is in the alternatively spliced exon 11, which is differentially expressed on follicular dendritic cells (FDC). The minor alleles of these three SNPs and a fourth SNP in exon 11 (rs17616) decrease the splicing efficiency of exon 11 in vitro and ex vivo, but the specific SNP responsible for this is not known. An exon-trapping vector (pL53In) in which genomic DNA spanning introns 9 to 12 of CR2 had been cloned was modified by site-directed mutagenesis to generate vectors containing various allelic combinations of these SNPs. After transient transfection into the Raji B cell and HK FDC lines, the relative amount of vector-derived mRNA transcripts including or excluding exon 11 was measured by quantitative RT-PCR. The presence of the minor allele at rs17615, rs4308977, or rs17616 partially reduced splicing efficiency of exon 11, whereas the presence of the minor allele at both rs17615 and rs17616 reduced it to same extent as when all four SNPs were minor. These data suggest that the minor alleles at rs17615 and rs17616 modify the secondary structure of the CR2 pre-mRNA, interfering with splice site recognition by regulatory proteins that could serve as targets for therapeutic intervention.
IL-21/IL-21R interactions on host B cells but not on donor CD4 cells are critical for the development of autoimmune features in chronic graft versus host disease. (93.9)
Authors: Nguyen Vinh , Tegla Cosmin , Luzina Irina , Rus Horea , Rus Violeta 
Published: January 2023

Abstract
Studies in murine models of lupus have indicated increased production of IL-21 and attenuation of autoimmune features following IL-21 blockade. IL-21 exerts an autocrine effect on T follicular B helper cells (TFH) cells and also stimulates B cell proliferation, plasma cell (PC) differentiation and germinal center (GC) expansion. To determine whether IL-21 promotes systemic lupus through effects on TFH cells or B cells, we assessed the effect of IL-21/IL-21R signaling on B cells independent from the effect on CD4 T helper cells using IL-21R-/- or IL-21R+/+ mice as donor or hosts in the P-into-F1 and Bm12-into-B6 models of cGVHD. CGVHD induced by injection of IL-21R-/- CD4 cells from B6 mice into B6D2F1 hosts was characterized by a decrease in the expansion of donor CD4, TFH and GC cells. However, other parameters of cGVHD such as host B cell expansion, MHC class II upregulation, PC differentiation and anti-ssDNA autoantibody production did not differ between groups. In contrast, when cGVHD was induced by injecting Bm12 spleen cells into IL-21R-/- B6 mice, parameters of cGVHD were markedly attenuated compared to IL-21R+/+ hosts. Specifically, MHC class II upregulation of B cells decreased by 32%, PC differentiation by 66%, GC cells by 60% and anti-ssDNA antibody level by 81%. These results suggest that IL-21R signaling on host B cells and possibly myeloid cells but not on Ag-specific CD4 T cells is critical for the initiation and progression of systemic autoimmunity in cGVHD.
Differential expression of two pathways of chemokine induction protect CD14- and TLR4-deficient mice from localized E. coli infections (94.16)
Authors: Goyert Sanna , Metkar Shalaka , Kim Kwang , Silver Jack 
Published: January 2023

Abstract
Sepsis, characterized by a systemic bacterial infection, is a life-threatening condition that can lead to multi-organ failure and death from septic shock. We have observed that CD14- and TLR4-deficient mice are resistant to death by sepsis from several different clinical isolates of E. coli injected intra-peritoneally. This resistance has been attributed to the 10-fold lower levels of the proinflammatory cytokines TNF and IL-6 induced in these mice. Surprisingly, however, neither TLR4- nor CD14-deficient mice were resistant to two closely related organisms that differed only in that they expressed a K1 polysaccharide capsule, even though these mice continued to express low levels of the proinflammatory cytokines. These and other observations suggest that the ability to limit bacterial dissemination may be equally or even more important than reducing the levels of these proinflammatory cytokines in preventing death from sepsis. We present evidence here, that the pathogenic role for the CD14/TLR4 pathway in severe infection, whereby it mediates the induction of proinflammatory cytokines, may be secondary to a more important insidious role whereby differential activation of local and systemic pathways of chemokine induction via CD14/TLR4-dependent and independent mechanisms generate chemokine gradients that prevent PMN transmigration from the blood to infected tissue and facilitates the dissemination of bacteria from a localized site of infection.
Costimulatory signals regulate the proliferative potential and effector function of NKT cells (95.14)
Authors: Sun Wenji , Oelke Mathias , Schneck Jonathan , Webb Tonya 
Published: January 2023

Abstract
Natural killer T (NKT) cells play a pivotal role in maintaining immune homeostasis. NKT cells rapidly secrete both proinflammatory and inflammatory cytokines following activation. However, the role costimulatory molecules during activation and their impact on effector functions have yet to be clearly defined. Our innovative system, which utilizes bead-based artificial Antigen Presenting Cells (aAPC), allows us to systematically evaluate the role of different costimulatory molecules on NKT cell activation and expansion. In this study, we have examined the effects of CD28, CD44, CD161, and OX-40 on NKT cell proliferation, phenotype and function. We found that the costimulatory molecules which increased NKT cell proliferation also enhanced cytokine production and cytotoxic function. These studies will enhance our knowledge of NKT cell biology and may aid in the development of novel NKT cell-based immunotherapeutic approaches for the treatment of infectious and autoimmune diseases, as well as cancer.
Regulation of anti-tumor immunity by p53 (95.2)
Authors: Singh Nagendra 
Published: January 2023

Abstract
Several pro-apoptotic molecules play an essential role in regulating oncogenesis as well as T-cell expansion during immune responses. Tumor suppressor molecule p53 regulates DNA repair, genomic integrity, cell proliferation and apoptosis. Mutations of P53 pathway is the most common genetic aberration in human tumors and as many as 50% of all the human tumors contain mutation in p53 pathway. Mice lacking p53 preferentially develops T-cell lymphomas and is susceptible to induced autoimmune dieases, suggestting a role for p53 in regulation of T cell responses. We found that p53 acts as a negative regulator of immune responses by inducing apoptosis and inhbiting T-cells proloiferation during immune responses. Furthermore, p53-deficient mice generates a robust anti-tumor cytotoxic T-cell responses and reject an implanted immunogenic tumor. These findings demonstrate an essential role of p53 in generating anti-tumor T-cell responses and suggest that a careful immunomodulation should be considered to achieve optimum results if p53 pathway is potential target of cancer chemotherapy.
Deletion of IL-6 in dnTGFβRII Mice Improves Colitis but Exacerbates Autoimmune Cholangitis (96.10)
Authors: Zhang Weici , Tsuda Masanobu , Yang Guo-Xiang , Tsuneyama Koichi , Rong Guanghua , Ridgway William , Ansari Aftab , Lian Zhe-Xiong , Flavell Richard , Gershwin M. Eric 
Published: January 2023

Abstract
The role of IL-6 in autoimmunity continues to attract attention, particularly because of the impending clinical usage of monoclonal antibodies designed to block IL-6 pathways, using antibodies to IL-6R. We have previously reported that dnTGFbRII mice develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we have generated IL-6 deficient mice on a dnTGFbRII background (dnTGFbRII IL-6-/-) and examined sera for the presence of anti-mitochondrial antibodies, levels of cytokines, as well as histopathology and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti-IL6R in inflammatory bowel disease, dnTGFbRII IL-6-/- mice manifest a dramatic improvement in their own inflammatory bowel disease. Importantly, however, autoimmune cholangitis in dnTGFbRII IL-6-/- mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells and worsening hepatic pathology. The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti-IL-6R if they have accompanying autoimmune liver disease and emphasize the need for further studies.
A novel Highly Specific Small Molecule Inhibitor for BTK Suppresses Fc Receptor Function in Macrophages and Prevents Inflammatory Arthritis (96.18)
Authors: Reif Karin , Huang Tao , Barbosa Jim , Hymowitz Sarah , Gallion Steven , Hurez Vincent , Maciejewski Patricia , Dennis Jr. Glynn , Rong Hong , Shen Fang , Diehl Lauri , DeFroge Laura , Lee Wyne , Balazs Mercedesz , Currie Kevin , DiPaolo Julie 
Published: January 2023

Abstract
Activating Fc receptors and inflammatory cytokine production by macrophages have been implicated in the development and pathology of arthritis. However, the molecular components that mediate these events are not well characterized. Here we identify Bruton’s tyrosine kinase (BTK) as an essential player not only in B-cell dependent but also in myeloid-cell dependent inflammatory arthritis using a novel highly specific small molecule inhibitor of BTK (BTK SMI). In rodent models of collagen-induced arthritis, treatment with BTK SMI inhibits disease by at least two mechanisms: preventing autoantibody production and suppressing inflammatory cytokine production. Specifically, BTK SMI treatment prevents signaling and inflammatory cytokine production in response to immune complex activation in macrophages. Pathways found in rodents translate to human as BTK SMI prevents Fc receptor induced cytokine production in human monocytes. These data indicate that BTK SMI may be beneficial for the treatment of arthritis and that BTK contributes substantially to myeloid cell-dependent disease pathogenesis.
Novel peptides ameliorate symptoms of systemic lupus erythematosus in mice (96.2)
Authors: Wormser Uri , Proscura Elena , Brodsky Berta , Shapira Elena 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance, production of auto-antibodies and inflammatory damage in multiple organs. We have tested the effect of anti-inflammatory peptide, a H2A histone fragment, termed IIIM1 on MRL/lpr mice, an animal model of SLE. Oral administration of IIIM1 at early stage of disease caused reduction in proteinuria and serum anti-dsDNA antibodies. Starting the treatment at advanced stage of disease resulted in prolonged animal survival, decreased lymphadenosis and reduced levels of pathogenic or abnormal double negative CD4-CD8- cells and B220+ cells in lymph nodes and spleen. We discovered that IIIM1 induces the production of an additional peptide, a fragment of alpha-1-antitrypsin, termed UBE. Relatively low dose (1µg/kg) of UBE reduced proteinuria and hematuria in MRL/lpr mice. The beneficial effect of the peptide was corroborated by histological examination. Furthermore, a significant reduction in serum IL17, IL12 and anti dsDNA antibodies was observed in the UBE-treated mice. Isolated CD4 cells incubated with the peptide showed similar cytokine profile. Decreased levels of double negative CD4-CD8- and B220+ cells were determined in lymph organs of UBE-treated animals. The beneficial effects of both UBE and IIIM1 suggest these peptides as potential drugs for SLE.