bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of high-fat diet on B1 B cells in obesity-associated inflammatory diseases (54.28)
Authors: Hall Matthew , Zhu Andrew , Lovell John , Aprahamian Tamar , Rifkin Ian , Zhong Xuemei 
Published: January 2023

Abstract
Objective: High-fat diet (HFD)-induced abdominal obesity is a major risk factor for diabetes and atherosclerosis, yet the immunological mechanisms underlying these associations are still unclear. B1 B lymphocytes reside in the peritoneal cavity and omentum in direct contact with abdominal visceral adipose tissue. Their physiological location and functions make them an ideal intermediary for obesity-induced inflammatory disease. This study aimed to dissect the B1 B cell response to HFD-induced obesity in diabetes and atherosclerosis. Methods: gld/ApoE-/- mice fed a high-fat Western diet (WD) were used to model diet-accelerated atherosclerosis and autoimmunity. Wild type C57BL/6 mice fed a HFD were used to model diet-induced obesity and diabetes. Control mice from each group were fed with a low-fat control diet (CD). Cells from the peritoneal cavity and omentum were studied using flow cytometry. Hematoxylin/Eosin and immunohistochemistry stainings were performed on paraffin-embedded tissues. Results: Compared to their CD-fed counterparts, WD-fed gld/ApoE-/- mice exhibited enlarged omental milky spots and decreased peritoneal B1 cells. HFD-fed C57BL/6 mice demonstrated enlarged omental milky spots and reduced peritoneal B1 B cells compared to CD-fed counterparts. Conclusion: The similar B1 B cell response pattern to diet in both gld/ApoE-/- and WT mice indicates that HFD has a profound influence on the B1 B cell immune response regardless of genetic susceptibility.
Determination of the Proinflammatory Potential of Spores from Different Basidiomycetes Species with a Human Whole Blood Assay. (55.13)
Authors: Rivera-Mariani Félix , Vysyaraju Kranthi , Levetin Estelle , Hartung Thomas , Breysse Patrick 
Published: January 2023

Abstract
Airborne fungal spores could pose a proinflammatory risk when inhaled by susceptible individuals. Most studies have examined fungal spores from mitosporic fungi (e.g. Aspergillus sp, Penicillium sp., Alternaria sp.). Less is known about the proinflammatory potential of spores from basidiomycetes (meiotic fungi). In this study, we evaluated the proinflammatory potential of spores (basidiospores) from three species of basidiomycetes (Chlorophyllum molybdites, Pluteus cervinus, and Coprinus micaceus) in a human whole blood (HWB) system. This system provides the flexibility to evaluate the proinflammatory potential of a given sample based on the release of proinflammatory cytokines (e.g. IL-1β) by leukocytes. Different concentrations (100 ug, 10 ug, 1.0 ug) of spore deposits from each basidiomycete were incubated (18 hrs) with human whole blood from healthy subjects, and the release of IL-1β determined with ELISA. HWB was also incubated with endotoxin as a positive control. Similar to endotoxin, the basidiospores induced the release of IL-1β in a dose-dependent manner. In most cases, there were no significant differences between the response of endotoxin and that of the basidiospores. To our knowledge, this is the first study to evaluate the proinflammatory potential of basidiospores in a HWB system. Our results suggest that basidiospores could pose a proinflammatory inhalation risk comparable to that of endotoxin in subjects with respiratory diseases.
Brucella melitensis induces the Unfolded Protein Response in macrophages (55.14)
Authors: Khan Mike , Magnani Diogo , Harms Jerome , Liu Yi-Ping , Splitter Gary , Smith Judith 
Published: January 2023

Abstract
Brucella melitensis is a facultative intracellular bacterium that causes brucellosis, the most prevalent zoonosis worldwide. As no current vaccine is available, and current therapy suboptimal, a better understanding of how Brucella establishes an intracellular replicative niche is necessary. Brucella fuses with the endoplasmic reticulum (ER) in order to replicate, and thus may provoke an ER stress response called the Unfolded Protein Response (UPR). In this study, we found upregulation of the UPR target genes BiP and CHOP, as well as XBP1 mRNA splicing in both RAW 264.7 murine macrophages and bone marrow macrophages infected with B. melitensis. These data indicate activation of all 3 major axes of the UPR. BiP and CHOP upregulation was MyD88 independent. Furthermore, upregulation of BiP, CHOP and the XBP1 target ERdj4 was ablated in the heat killed and VirB (ER fusion) Brucella mutant. Finally, taurodeoxycholic acid, a UPR inhibitor, significantly impaired Brucella replication. The JNK inhibitor SP600125 also suppressed replication, consistent with previous reports implicating the IRE-1-dependent UPR pathway. Together, these results suggest Brucella induces the UPR to aid in its intracellular replication, and that the UPR could be a novel therapeutic target for treatment of brucellosis.
Epithelial STAT3-induced antimicrobial protein, Reg3γ is required for host defense against MRSA pneumonia in mice (55.15)
Authors: Choi Sun-Mi , McAleer Jeremy , DeLeo Frank , Hooper Lora , Qin Shulin , Reinhart Todd , Ouyang Wenjun , Kolls Jay 
Published: January 2023

Abstract
Incidence of community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia has increased and is associated with high mortality rates. Patients with Hyper IgE Syndrome (HIES), resulting from mutations in signal transducer and activator of transcription 3 (STAT3), are susceptible to recurrent SA pneumonia. USA300 (2x107 CFU), the most prevalent pneumonia-causing strain, was oropharyngeally administered to C57BL/6 (WT) and various knockout mice. Bacterial burden, gene expression, and protein levels were determined in the lung 20 hours post-infection. Although, Rag2γc-/- mice clear SA as well as WT mice, GP130 or STAT3 inhibited mice had increased bacterial burden. USA300 infection leads to IL-6 induction. IL-6 binds to GP130 and activates STAT3 in lung epithelium during infection as seen by IHC. IL-6 induction also occurred in Rag2γc-/- mice indicating that B, T, NK, and NK T cells are dispensable for this response. IL-6 induces STAT3 signaling and Reg3γ production by mouse lung epithelial (MLE12) cells. Furthermore, STAT3-dependent Reg3γ limits USA300 growth in vitro. Therefore, STAT3 signaling is necessary for host defense against MRSA pneumonia. Although, HIES patients have decreased Th17 cells, recurrent SA pneumonias are likely due to impairment of STAT3 signaling in innate immune and epithelial cells. Reg3γ, with antimicrobial activity against USA300, may be the basis for new therapies for CA-MRSA pneumonia.
Production of an NKT cell stimulatory glycosphingolipid by a prominent member of the human gut microbiota (55.22)
Authors: Penaranda Cristina , Wieland Brown Laura , Kashyap Purna , Clardy Jon , Kronenberg Mitchell , Sonnenburg Justin , Comstock Laurie , Bluestone Jeffrey , Fischbach Michael 
Published: January 2023

Abstract
While the human gut microbiota are suspected to produce diffusible small molecules that modulate host signaling pathways, few of these molecules have been identified. Species of Bacteroides and their relatives, which often comprise &gt;50% of the gut community, are unusual among bacteria in that their membrane is rich in sphingolipids, a class of signaling molecules that play a key role in modulating the host immune response. Although known for more than three decades, the full repertoire of Bacteroides sphingolipids has not been defined or linked to immune modulatory activity. We report that Bacteroides fragilis produces the glycosphingolipid α-galactosylceramide (α-GalCerBf), which is structurally related to a sponge-derived glycosphingolipid (α-GalCer, KRN7000) that is the prototypical agonist of CD1d-restricted natural killer T (NKT) cells. We demonstrate that α-GalCerBf binds to CD1d and stimulates the production of cytokines by both mouse and human NKT cells. In vivo, we show that α-GalCerBf stimulates NKT cells to induce the activation markers CD25 and CD69, secrete IFN-γ in a CD1d-dependent manner and can prevent cyclophosphamide-induced diabetes. These data suggest that NKT cells directly sense an endogenous antigen produced by a prominent human gut symbiont, uncovering a new mechanism by which the gut microbiota modulate a subset of immune cells relevant to pathogen response and autoimmune disease.
The Macrophage galactose-specific lectin (MGL) recognizes Taenia crassiceps antigens and plays a role in resistance to the infection (55.3)
Authors: Terrazas Luis I , Montero Daniel , Vera-Arias Laura , Terrazas Cesar A , Gomez-Garcia Lorena , Ledesma-Soto Yadira 
Published: January 2023

Abstract
C-type lectins are multifunctional sugar-binders on dendritic cells (DCs) and macrophages that internalize antigens for processing and presentation. MGL recognizes galactose and N-acetylgalactosamine and it is expressed on immature DCs and alternatively activated macrophages (AAM). Helminth parasites contain large number of glycosilated components which appears to play a role in the immuneregulation induced by such infections. To address whether MGL may influence the immune response and resistance to T. crassiceps we infected i.p. MGL deficient (MGL-/-, C57BL/6 background) and wildtype mice (MGL+/+) with 15 non-budding T. crassiceps metacestodes. Parasite burden, cellular and humoral responses were measured during 8 wks of infection. mMGL-/- DCs displayed lower ability to bind T. crassiceps antigens. Compared with wild-type mice, mMGL-/- mice failed to produce significant levels of inflammatory cytokines during the first two weeks of Taenia infection. MGL-/- mice developed a Th2-dominant whereas wild-type mice developed a Th1-dominant immune response after Taenia infection. Associated with the insufficient production of early inflammatory cytokines, mMGL-/- mice harbored significantly higher numbers of parasites whereas WT mice were resistant. Finally, FACS analysis showed overexpression of IL-4Rα, PDL1 and PDL2 on macrophage surface in MGL-/- group unrevealing AAM phenotypes. Thus, MGL may be involved in T. crassiceps recognition and subsequent innate immune activation.
Signaling via an adapter molecule CARD9 is essential for the host defense to infection with Cryptococcus neoformans (55.5)
Authors: Yamamoto Hideki , Nakamura Yuri , Takahashi Yurie , Sato Ko , Yamamoto Natsuo , Ishii Keiko , Hara Hiromitsu , Kawakami Kazuyoshi 
Published: January 2023

Abstract
CARD9 is a critical adaptor molecule signaling for NF-κB activation triggered via C-type lectin receptors (CLRs), which recognize carbohydrate structures of microbes. Cryptococcus neoformans, a yeast-like fungus is recognized by some CLRs, such as mannose receptor or DC-SIGN, whereas the role of CLRs or CARD9 in the host defense to this infection remains to be elucidated. In this study, we analyzed the role of CARD9 in the protective immune response to C. neoformans infection. C57BL/6 and CARD9KO mice were infected intratracheally with C. neoformans (B3501). The number of live microbes, histopathological findings and cytokine synthesis in lungs and the cytokine response of paratracheal lymph node (LN) cells upon antigenic re-stimulation were evaluated. CARD9KO mice were highly susceptible to infection with C. neoformans, as shown by increased number of live microbes in lungs compared to control, which was associated with less marked granulomatous response and remarkable multiplication of yeast cells in the alveolar spaces. Expression of RORγt and IL-17A mRNA and intracellular expression of IL-17A by T, NKT and γδ T cells were strongly attenuated in the lungs of CARD9KO mice. IL-17A production by the re-stimulated LN cells was mostly abrogated in these mice. By contrast, Th1-cytokine response was not much affected. These results suggest that CARD9 is a key molecule in the Th17 response to C. neoformans, which is associated with the host defense against this infection.
GM-CSF-Induced Regulatory T cells Selectively Inhibit Anti-Acetylcholine Receptor-Specific Immune Responses in Experimental Myasthenia Gravis (56.1)
Authors: Sheng Jianrong , Prabahakar Bellur , Meriggioli Matthew 
Published: January 2023

Abstract
We and others have demonstrated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to suppress autoimmunity by increasing the number of CD4+CD25+ regulatory T cells (Tregs). In the current study, we have explored the critical role of induced antigen specific Tregs in the therapeutic effects of GM-CSF in murine experimental autoimmune myasthenia gravis (EAMG). Specifically, we show that Tregs from GM-CSF treated EAMG mice (GM-CSF/AChR-induced-Tregs) adoptively transferred into animals with EAMG suppressed clinical disease more potently than equal numbers of Tregs from either GM-CSF untreated EAMG mice or healthy mice treated with GM-CSF. In addition, GM-CSF/AChR-induced-Tregs selectively suppressed antigen specific T cell proliferation induced by AChR relative to that induced by an irrelevant self antigen, (thyroglobulin) and failed to significantly alter T cell proliferation in response to an exogenous antigen (ovalbumin). These results are consistent with the hypothesized mechanism of action of GM-CSF involving the mobilization of tolerogenic dendritic cell precursors which, upon antigen (AChR) capture, suppress the anti-AChR immune response through the induction/expansion of AChR-specific Tregs.
Use of Fungal-like Particles to probe Dectin-1 Responses in Innate Immunity (58.12)
Authors: Khan Nida , Tam Jenny , Mansour Michael , Vyas Jatin 
Published: January 2023

Abstract
The presence of multiple types of carbohydrate moieties on fungal cell walls prohibits elucidation of the exact immunological response to pathogen-derived carbohydrate epitopes. To dissect the immunological mechanisms used to recognize pathogens, a system of “fungal like particles” was developed that consisted of polymer beads, which mimicked the three dimensional shape of the fungus, coated covalently with purified b-1,3-glucan (BG) derived from S. cerevisiae. The morphology of the BG layer was examined by immunofluorescence, flow cytometery, and immuno-transmission electron microscopy. The covalent linkages of the BG to the polystyrene surface were stable after subjecting the beads to detergents. By pre-treating BG beads with laminarinase the reactivity of the anti-BG antibody was abrogated in comparison to treatment with proteinase K indicating that the coating of these beads was predominantly BG. TNF-a was also measured by stimulating bone-marrow derived macrophages with the BG beads and showed a dose dependent response. Finally, BG beads were incubated with GFP-Dectin-1 expressing macrophages and imaged using confocal microscopy. BG beads were taken up within minutes and retained Dectin-1, the major receptor for BG, to the phagosome as compared to uncoated beads. This data describes a unique fungal-like particle system that will permit immunologists to probe the critical steps in early recognition of pathogen-derived fungal carbohydrate antigens by innate immune cells.
Enhancement of MICA affinity for NKG2D by combining multiple rational design strategies (58.17)
Authors: McFarland Benjamin , Henager Samuel , Hale Melissa 
Published: January 2023

Abstract
We increased the affinity of MICA for the dominant immunoreceptor NKG2D by 50-fold using seven rationally designed mutations found through a stepwise process similar to affinity maturation. First we evaluated the stability of amino acid mutations in MICA located beneath the interface with NKG2D using RosettaDesign. These mutations were near a flexible region that folds when NKG2D binds. Sets of mutations predicted to mildly destabilize this region of MICA also increased its affinity for NKG2D as measured by surface plasmon resonance, with the best results from three mutations that increased affinity by 20-fold. The second design strategy optimized MICA residues that contact NKG2D. Ten single mutations proposed by RosettaDesign increased MICA-NKG2D affinity by 2-fold to 8-fold by SPR. Most combined surface mutants tested had subadditive effects on binding, but some enhanced binding through enthalpic stabilization. A combination of four of the five best single mutants increased affinity by 19-fold from wild-type. These sets of three and four mutations were combined in a MICA variant that bound NKG2D with 50 nM affinity. This variant in complex with NKG2D persisted through a size-exclusion column under conditions where the wild-type complex fell apart. These mutants were purified and tested in the context of undergraduate biochemistry courses in large quantities, so samples of purified recombinant high-affinity MICA are readily available for more tests.
Altered Th17 and Th1 cells responses in patients with primary Sjogren syndrome (59.10)
Authors: Kang Gi Soo , Kim Sang Hyun , Bunin Viviane , Shin Min Sun , Lee Naeun , Parke Ann , Kang Insoo 
Published: January 2023

Abstract
Primary Sjogren syndrome (pSS) is a systemic autoimmune disease characterized by dry eyes, dry mouth and extraglandular abnormalities, of unknown etiology. IL-17 produced largely by CD4+ Th17 cell is a major proinflammatory cytokine involved in host defense and development of inflammatory disease. We analyzed CD4+ Th17 and Th1 cells in peripheral blood from patients with pSS (n=16) and healthy subjects (n=14). We also measured cytokines, including IL-1β, IL-6, IL-7, IL-10, IL-12 and IL-23, in supernatants of lipopolysaccharide- and zymosan- stimulated PBMCs. The frequency of CD4+ T cells producing IL-17 (Th17) and IFN-γ (Th1) was significantly higher in patients with pSS than in healthy subjects. In measuring Th17-polarizing cytokines, levels of IL-1β, IL-6 and IL-23 were not different between the two groups. However, patients with pSS had higher production levels of IL-7, which could also promote Th17 response, compared to healthy subjects. In addition, the Th1-polarizing cytokine IL-12 was produced at higher levels in patients with pSS. Of interest, production levels of the anti-inflammatory cytokine IL-10 were lower in patients with pSS than in healthy subjects. In conclusion patients with pSS had an increased frequency of Th17 and Th1 cells in peripheral blood, which could be related to increased IL-7 and IL-12 production as well as to decreased IL-10 production from innate immune cells.
IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation (59.8)
Authors: Takahashi Kentaro , Hirose Koichi , Kawashima Saki , Niwa Yusuke , Wakashin Hidefumi , Iwata Arifumi , Tokoyoda Koji , Nakayama Toshinori , Nakajima Hiroshi 
Published: January 2023

Abstract
BACKGROUND: IL-22 functions as both a proinflammatory and an anti-inflammatory cytokine in various inflammations. However, the roles of IL-22 in the allergic airway inflammation are still largely unknown. OBJECTIVE: We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS: We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS: Antigen inhalation induced IL-22 production in CD4(+) T cells. Only one third of IL-22-producing CD4(+) T cells also produced IL-17A. Anti-IL-22 antibody administration enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of rIL-22 attenuated eosinophil recruitment. Moreover, anti-IL-22 antibody enhanced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. CONCLUSION: IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.
Development of spontaneous vitiligo in human tyrosinase reactive co-receptor independent TCR transgenic mice (60.11)
Authors: Chatterjee Shilpak , Al-Khami Amir , Nishimura Michael , Le Poole Caroline , Mehrotra Shikhar 
Published: January 2023

Abstract
Vitiligo is an autoimmune disease of the skin presenting with progressive depigmentation in approximately 0.5% of the population worldwide. Traditionally, vitiligo has been ascribed to a combination of genetic, neurologic and immune deficiencies. However, limited animal models for the disease have hampered its understanding. Clinical trial targeting melanoma has shown that destruction of melanocytes in the skin could be correlated to the presence of auto reactive T cells against melanoma-associated antigen. To gain insight into the crucial involvement of immune system in the development of autoimmune vitiligo, we generated TCR transgenic mice (h3TA2) using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient. These h3TA2 transgenic mice develop spontaneous hair depigmentation that progressed with age. Strikingly, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells in h3TA2 mice. Further our data shows that development of vitiligo in these transgenic mice strongly depends on IFN-gamma as genetic ablation of IFN-gamma controls the disease, whereas CXCR3, TNF-alpha and perforin are dispensable. Our data suggest that IFN-gamma ablation controls development of T cell mediated spontaneous vitiligo and provides a model for testing other therapeutic modalities.
Investigating the novel protein, Ttc7, and its role in transitional B cells (60.2)
Authors: Walker Jennifer , Hill Beth , Harris Kimberly , Hakker Lauren , Agris Paul , Pelsue Stephen 
Published: January 2023

Abstract
Ttc7 is a novel protein of unknown function. Ttc7fsn mutant mice develop an autoimmune phenotype that includes an increase in immature B lymphocytes and marginal zone cells. Here we show that the transitional T1 population is increased two-fold in Ttc7fsn mice and that these cells proliferate upon BCR ligation. Preliminary data also indicate that T1 cells survive BCR stimulation rather than undergo apoptosis. Thus far we've identified two signaling abnormalities in transitional B cells: elevated Erk phosphorylation and decreased CD22 expression. Together, these data suggest that autoreactive transitional B cells are inappropriately activated and allowed to survive rather than undergo clonal deletion or anergy. Results from in silico analyses reveal a number of physical and chemical changes to the Ttc7fsn protein including decreased hydrophobicity, increased polarity and net charge, and the addition of helix-breaking residues. Computational models comparing the TPR domains of Ttc7 and Ttc7fsn show that the mutation disrupts the structure of both the TPR-1 domain and the linking sequence connecting TPR-1 and TPR-2. Further evidence of structural change is provided by preliminary CD spectroscopy, which indicates that the α-helical nature of Ttc7 is altered by the fsn mutation. Based on these findings, we hypothesize that structural changes in the Ttc7fsn protein alter its function and result in faulty molecular and functional regulation of B cell development and function.