bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms underlying the mollusk hemocyanin processing and presentation through MHC-dependent pathways in antigen presenting cells of mammals
Authors: Becker María Inés , Salazar Michelle L , Díaz-Dinamarca Diego , Vásquez Abel E , Villar Javiera , Alvarado Alejandra , Castillo Byron , Navarro Daniel , Salazar Fabián , Manubens Augusto 
Published: January 2023

Abstract
Hemocyanins are oligomeric glycoproteins widely used as immunomodulators because they bias immunity towards a Th1 profile when inoculated in mammals. We have demonstrated that hemocyanins are internalized through receptor-mediated endocytosis, and TLR4 and C-type lectin receptors (MR, DC-SIGN, MGL) participate in the hemocyanin-mediated proinflammatory response in mouse and human dendritic cells (DCs). However, despite the massive use of hemocyanins, their intracellular processing route for MHC presentation to T lymphocytes has been scarcely studied. Therefore, we hypothesized that hemocyanins follow the MHC-II pathway as a classical T-cell-dependent antigen. Interestingly, our results analyzing the processing pathway of hemocyanins in mouse DCs showed that hemocyanins from Fissurella latimarginata (FLH) and Megathura crenulata (KLH) co-localized with Rab5+, Rab7+, and Lamp-1+ compartments. This observation strongly suggests that hemocyanins could be cross-presented by MHC-I molecules. Furthermore, DCs incubated with FLH showed an increase in the percentage of MHC-I+ cells versus the control cells.
FLH-induced cytokine secretion decreased in J774.2 macrophages treated with pharmacological inhibitors of both MHC-II and MHC-I pathways, supporting our previous results on hemocyanin cross-presentation but also the MHC-II pathway. Furthermore, immunoblot confirmed different FLH proteolysis patterns in macrophages treated with MHC-I and MHC-II pathway inhibitors. Hence, we postulate that hemocyanins undergo both MHC-I and MHC-II dependent antigen presentation pathways in antigen-presenting cells. These findings offer molecular clues to underlying hemocyanin processing and presentation mechanisms.
Supported by grants from FONDECYT N° 1151337 and N° 1201600 (MIB), ANID/Beca Doctorado Nacional N° 21210946 (MLS) and N° 21200880 (DDD).
B cell-mediated antigen presentation is required to induce functional pathogenicity of CD4 T cells in a proteolipid protein mouse model of multiple sclerosis.
Authors: Boyden Alexander W , Wilhelm Connor R , Updahye Mohit , Karandikar Nitin J 
Published: January 2023

Abstract
Given the success of B cell depletion therapy in multiple sclerosis (MS), deeper understanding of pathogenic B cells will be key in developing novel treatments. Notably, B cell depletion therapy leaves plasma cells and immunoglobulin levels largely intact, indicating that B cells provide pathogenic functions beyond antibodies. To better understand this, we recently developed a novel B cell-dependent, antibody-independent experimental autoimmune encephalomyelitis (EAE) mouse model of MS featuring immunoreactivity to the extracellular domains of myelin proteolipid protein (PLPECD). In contrast to a B cell-independent EAE model, we demonstrate here that PLPECD induced EAE in WT but not B cell-depleted mice, and that established disease was ameliorated by B cell depletion. We tested antigen presentation by B cells through mixed bone marrow chimeras and demonstrate that mice in which MHC II deficiency is restricted to B cells alone failed to exhibit EAE compared to MHC II sufficient mice. Given that HLA class II is the largest molecular link to MS incidence and CD4 T cells are causative in EAE, we tested B cells’ influence on CD4 T cells. In the absence of B cells, we observed not only lower activation and proliferation of CD4 T cells, but also noted a lower proinflammatory functional profile amongst the activated cells. Further, adoptively transferred CD4 T cells derived from B cell-depleted donors induced significantly less EAE compared to those from B cell-sufficient donors. These results demonstrate that antigen presentation by B cells plays a critical role in the activation, proliferation, function and pathogenicity of autoreactive CD4 T cells in demyelinating disease.
Supported by grants from NIAID/NIH AI156123 and US Veterans Affairs I01BX003677.
A specific 25-mer peptide from the cysteine protease of P. gingivalis is the epitope of humoral immune response in rheumatoid arthritis
Authors: Tsay Gregory J , Peng Hsin-Yi , Xue Ting-Yin , Hsieh Fei-Hung , Chen Yi-Ko , Yin Mei-Chin , Chao Che-Yi , Tsai Shu-Yao , Lin Chung Ping , Huang Po-Hao , Yeo Kai-Jieh , Huang Chien-Chung , Chen Jiunn-Horng , Huang Chung-Ming , Chen Der-Yuan , Lan Joung-Liang 
Published: January 2023

Abstract

Objective
Several lines of evidence suggest that the pathobiont Porphyromonas gingivalis is involved in the development and/or progression of rheumatoid arthritis. This bacterium produces cysteine proteases, such as gingipain RgpA, endowed with the potential to induce significant inflammation in patients with periodontitis and rheumatoid arthritis. Both diseases involve chronic inflammation with the production of pro-inflammatory cytokines, connective tissue breakdown and bone erosion.

Methods
A 25-peptide named BR1 from Porphyromonas gingivalis was synthesized for the study. Serum samples from patients with RA, early arthritis, other rheumatic diseases, and normal controls were used in the study. A monoclonal antibody named BR2mAb was derived from BALB/c mice immunized with the 25-mer peptide was produced as the control. Anti-BR1, ACPA and RF were detected by ELISA.

Results
Anti-BR1 were detected in 56.0% (59/106) of RA patients and were found in 63.8% (23/36) of RA patients without both RF and/or ACPA. The serological positive rates with the two tests of RF and ACPA and with the three tests of anti-BR1, RF, and ACPA were 66% and 84.2%, respectively. Anti-BR1 were detected in 60.0% (9/15) of patients with early arthritis, but neither RF nor ACPA was detected in this group of patients. The sensitivity and specificity for RA were 60.1% and 95%, respectively. The BR2 mAb reacted to Porphyromonas gingivalis as well.

Conclusions
A specific 25-mer peptide from the cysteine protease of P. gingivalis is the epitope for humoral immune response in rheumatoid arthritis. The anti-25-mer peptide antibody test is an excellent new test for the diagnosis of patients with RA and early arthritis.
This study was supported by grants from the Ministry of Science and Technology, Taiwan (MOST-104-2314-B-039-045, MOST-105-2911-I-039-504, MOST-105-2314-B-039-047, MOST-106-2911-I-039-501, MOST-107-2314-B-039-050, MOST-108-2314-B-039-019), and from China Medical University Hospital (DMR-106-188, DMR-108-183, DMR-109-206).
The development of a gut-specific immune response to an oral antigen is dependent on α4β7 mediated lymphocyte trafficking
Authors: Sang Allison L , Redhu Naresh S , Lee Dooyoung , Dhang Fyonn , Bonesteel Raegan , St. Gelais Sarah , Zhong Cheng , Cui Dan , Harrison Bryce , Troast Dawn , Bursavich Matthew G , Lippa Blaise , Rogers Bruce N , Ray Adrian S , Wong Jamie 
Published: January 2023

Abstract

Objective
Vedolizumab has been shown to reduce the antibody response to an oral cholera, but not intramuscular hepatitis B vaccine in healthy subjects (Wyant, Gut 2015). The generation of an immune response to an oral antigen (Ag) begins at inductive sites such as Peyer’s patches (PP) followed by cell migration to effector sites in the gut. The integrin α4β7 is known to play a major role in cell trafficking to gut-associated lymphoid tissues. This study assessed whether MT-102, a potent and selective small molecule α4β7 inhibitor has similar effects on immunizations to those reported in the clinic for vedolizumab.

Methods
An in vivo immunization model system was established to determine the effects of MT-102, dosed via osmotic minipump, on the development of a gut-specific immune response. Mice were orally immunized with cholera toxin (CTX), and anti-CTX antibodies were quantified in fecal and plasma samples. The impact of MT-102 on lymphocytes within the PP of immunized mice was determined by flow cytometry.

Results
MT-102 delayed the production of anti-CTX IgA and IgG antibodies as measured in fecal samples without perturbing total gut IgA levels. Furthermore, MT-102 also inhibited the levels of Ag-specific antibodies in the plasma following repeated CTX oral immunizations. Blocking α4β7 induced a decrease in the frequency of B cells in the PP of treated mice compared to the control group.

Conclusion
α4β7-specific inhibitor, MT-102, effectively diminished the mucosal antibody response to an orally delivered Ag in mice. These results are consistent with what has been reported clinically in vedolizumab-treated subjects and thus establishes that potent small molecule inhibitors of α4β7 can replicate the pharmacology of an antibody.
Enteric glia regulates the expression of neutrophil inflammatory factors during acute inflammation
Authors: Padilla Rolon Darwing S , Gulbransen Brian D 
Published: January 2023

Abstract
Inflammation is an event in functional gastrointestinal disorders that has detrimental effects in the enteric nervous system. Recent advances in our understanding of the immune and enteric nervous system indicate that enteric glial cells modulate immune cells in the gastrointestinal tract. Previous single-nuclei multiomic analysis has shown that genes that encode for and influence neutrophil function, Neutrophil cytosolic factor 4 and C-X-C motif chemokine ligand 5, are changed in enteric glia during peak colitis. We hypothesize that enteric glia regulate the expression of neutrophil modulating factors during acute inflammation. We tested this using the acute dinitrobenzene sulfonic acid colitis model. Animal body weight and gross macroscopic damage were recorded as indications of overall inflammation and tissue was harvested for immunohistochemical analysis. Enteric glial cells were labeled with antibodies against Neutrophil cytosolic factor 4 and C-X-C motif chemokine ligand 5. Results suggest no significant difference in labeling for immunological markers in enteric glial cells of dinitrobenzene sulfonic acid treated mice. Results also show labeling in some neurons that may or may not be specific. Further experimentation is needed to elucidate the mechanisms of enteric neurons and glia in gut inflammation. These studies will contribute to further understand how immune responses are regulated in the gut and impact the general knowledge of gut disease processes.
This work was supported by the National Institute of Health grants R01DK103723 and R01DK120862 to BDG and DPR was supported by the National Institute of Health Bridge to the Ph.D. in Neuroscience grant 2R25NS090989.
MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration
Authors: Mendel Itzhak , Salem Yaniv , Propheta-Meiran Oshrat , Kafri Pinhas , Yacov Niva , Breitbart Eyal 
Published: January 2023

Abstract
Monocytes are innate immune cells that drive the chronicity of various inflammatory diseases, making them an attractive target for therapeutic intervention. Monocyte migration to inflamed tissues involves multiple steps of interaction with the vascular endothelium and the extra-cellular matrix (ECM), a process mainly mediated through conformational transitions in cell surface integrins. We previously described Motile sperm domain-containing protein 2 (MOSPD2) as a surface protein expressed on myeloid cells that is essential for the migration of monocytes and a key regulator of inflammatory disease pathogenesis. Therefore, a possible role for MOSPD2 in regulating adhesion and integrin activation in monocytes was assessed.
Silencing of MOSPD2 expression in THP-1 monocytic cell line significantly increased the adhesion of monocytes to various ECM ligands of integrins. Employing VB-601, a humanized anti-human MOSDP2 monoclonal antibody, on wild-type THP-1 cells or primary human CD14 monocytes similarly increased cell adhesion to ECM ligands as well as adhesion molecules. At the molecular level, silencing of MOSPD2 or blocking MOSPD2 using VB-601 led to a transition in integrin αLβ2 conformation into active high affinity binding-form and to the phosphorylation of adhesion-associated pathways. Co-precipitation experiments show that MOSPD2 binds integrin-β2, but not integrin-β1.
Our results reveal a novel regulatory mechanism on monocyte migration in which MOSPD2 governs the balance between monocyte adhesion and release from adhesion molecules and ECM. Targeting MOSPD2 has the potential to treat inflammatory diseases by stemming monocyte infiltration into inflamed tissues.
Tissue ischemia induces mobilization of pro-angiogenic neutrophils from the spleen
Authors: Leite Catarina , Parv Kristel , Seignez Cédric , Ng Henry , Lindsay Robin S , Christoffersson Gustaf , Phillipson Mia 
Published: January 2023

Abstract
Pro-angiogenic neutrophils (PAN) form a small subset of circulating neutrophils expressing CD49d+ VEGFR1hi CXCR4hi, which play a crucial role in the revascularization of transplanted islets.
To determine the role of PANs in re-establishing tissue perfusion following a large ischemic event we used the mouse model for peripheral artery disease, the hindlimb ischemia (HLI) model. We found that numbers of PANs in the affected gastrocnemius muscle increased ≈4 times 3h following ischemia induction and reached its peak 2 days following ischemia onset. Similarly, in patients undergoing surgery where peripheral perfusion is transiently clamped, numbers of circulating PANs increase ≈3 times 30 min post-HLI.
In healthy mice, PANs are found in high frequency in the spleen (spleen: 9,8% of total neutrophils, blood: 0,78%). Splenectomy prior to induction of HLI reduced recruitment of PANs to the ischemic muscle, which demonstrates that the spleen acts as a reservoir for PANs.
Furthermore, HLI downregulated the CXCR4-ligand CXCL12α in the splenic red pulp. This was prevented by chemically induced sympathectomy, resulting in increased retention of PANs in spleen, reduced PAN accumulation in the ischemic muscle and reduced blood flow recovery. Therefore, we propose that the downregulation of CXCL12α controlled by sympathetic nerve signaling pathways drives retention of PANs in the spleen, thereby regulating their release in response to HLI.
In summary, we identified that the spleen contains a peripheral pool of PANs and emphasize the pivotal role of the neuro-immune axis in the recruitment of PANs to the site of ischemia. These discoveries open new avenues for drug development to limit damage and accelerate healing following ischemic events.
This study was supported by the Swedish Research Council, Knut and Alice Wallenberg foundation, The Swedish Cancer Society, and O. E. and Edla Johansson’s foundation.
Diesel exhaust particles induced inflammatory responses are associated with executive functions deficits in juvenile mice
Authors: Torres Nicole Arianne Pagan , Rosa Hector J , Menendez Daviana L , Casillas Karla M , Mendez Loyda B 
Published: January 2023

Abstract
Epidemiological studies have reported associations between exposure to ambient particulate matter (PM) and neurocognitive impairments. Children are particularly vulnerable to the effects of PM since their CNS is still in development, especially in regions related to executive functions (EFs). Toxicological studies have reported oxidative stress and neuroinflammatory responses in mice exposed to different types of PM. However, most studies have focused on prenatal, perinatal, and adult PM exposures. The goal of this study was to assess if PM exposure impairs the postnatal development of EF. We hypothesized that exposure to diesel exhaust particles (DEP) will impair EFs by inducing inflammatory responses in the CNS and lungs. To test this hypothesis, female and male C57BL/6J mice (n=14/group) were exposed intranasally to either saline or increasing doses of DEP during postnatal days (PND) 25 to 33. General cognitive abilities and executive function were evaluated on PND 36–38 with the Puzzle Box paradigm. Mice were euthanized on PND 39 and the tissue was collected to measure the concentration of proinflammatory cytokines in the CNS and assess inflammatory cell influx into the lungs. In the brain, the levels of IL-6 and GM-CSF, but not TNFα, significantly increased in a dose-dependent manner. In the lungs, a dose-dependent influx of inflammatory cells was also observed. The results showed that mice exposed to DEP had concomitant deficits in cognitive processes related to executive functions and inflammatory responses in the brain and lungs. This suggest that DEP induced pro-inflammatory responses might be associated with deficitis in the postnatal development of EFs. In the future, the role of microglia activation will be explored.
Supported by Puerto Rico IDeA Network of Biomedical Research Excellence 5P20GM103475-18.
An unexpected role for IRF8 during human T cell development.
Authors: Taghon Tom N , Liang Kai Ling , Lavaert Marieke , Roels Juliette , Strubbe Steven , Lambrechts Nina , De Vos Tamara , Boehme Lena , Van Hulle Jolien , Oatman Nicole , Putteman Tom , Velghe Imke 
Published: January 2023

Abstract
Lineage tracing studies or other genetic approaches have allowed investigators to obtain detailed insights into the molecular mechanisms that control T cell development in the mouse. However, our understanding of how this process is regulated in human has remained unclear. Using various genome-wide approaches, such as bulk RNAseq, ATACseq, ChIPseq and scRNAseq, we have recently obtained important novel insights into the molecular mechanisms through which human hematopoietic progenitor cells are converted into T-lineage committed precursors, and further into the TCRαβ and −γδ lineages. Specifically, we identified two distinct populations of thymus seeding precursor cells (TSPs) of which one population, TSP2, expressed IRF8, a transcription factor that is mainly associated with dendritic cell development. Consistently, IRF8-expressing TSPs have both T− and DC-linage potential and are characterised by the coexpression of CD127 and CD123. We discovered that Notch activation, the main initiator of T-lineage specification, induces IRF8 expression in human ETPs, in contrast to in mouse, and that IRF8 is transiently expressed during early human T cell development. As T cell precursors commit to the T-cell lineage, IRF8 is repressed by GATA3, while IRF8 levels rise for ETPs that differentiate into plasmacytoid dendritic cells. Importantly, IRF8 is required for the generation of CD34+ CD127+ CD123+ T/DC precursors and low level IRF8 activity enhances their generation from hematopoietic progenitors. Thus, using these approaches, we have identified an IRF8-dependent T cell precursor subset and revealed unique molecular events that control early T cell development in human.
Supported by grants from the Fund for Scientific Research Flanders (FWO), the Foundation Against Cancer (STK), the Chan Zuckerberg Initiative (CZI) and Ghent University (BOF Ugent).
Ezrin promotes antigen receptor diversity during B cell development by supporting immunoglobulin heavy chain variable gene recombination
Authors: Aysola Varun , Labib Christina , Gupta Neetu 
Published: January 2023

Abstract
Genome-level rearrangements of immunoglobulin genes during B cell development are critical for generation of a diverse repertoire of B cell antigen receptors (BCRs) that bind to a multitude of foreign antigens and some self-antigens. Bone marrow B cell development involves a variety of cell-cell interactions, cell migration and receptor signaling that likely benefit from the activity of membrane-cytoskeletal reorganizing proteins. However, the specific contribution of such proteins towards BCR repertoire diversification is poorly understood. Ezrin is a membrane-cytoskeletal linker protein that regulates mature B cell activation through spatial organization of the BCR. We employed next generation sequencing to investigate if Ezrin plays a role in immunoglobulin heavy chain rearrangements and generation of BCR diversity in developing bone marrow B cells. BCR repertoire development occurred stochastically in B cell progenitors from both control and B cell conditional Ezrin-deficient mice. However, the loss of Ezrin resulted in fewer unique CDR3s in the BCRs and reduced Shannon entropy. Ezrin-deficient pro-, pre- and immature B cells utilized similar number of joining (J) genes but significantly fewer variable (V) genes, thereby decreasing V-J combinatorial diversity. V-J junctional diversity, measured by CDR3 length, nucleotide additions and deletions, was also altered in Ezrin-deficient pro-, pre- and immature B cells. Mechanistically, Ezrin-deficient bone marrow B cells showed a marked decrease in RAG1 gene expression, indicating a less efficient DNA recombination machinery. Overall, our results demonstrate a novel role for Ezrin in shaping the BCR repertoire through combinatorial and junctional diversification.
Supported by grants from NIH (R01 AR067705) to N.G.
Epigenetic Regulation During Maternal Schistosomiasis Results in Aberrant B cell Maturation and Tolerance
Authors: Gibbs Lisa C , Oviedo Juan Marcos , James Kimra , Fairfax Keke C 
Published: January 2023

Abstract
Maternal helminth infections are a global public health concern that correlate with altered infant immune responses to childhood immunizations and infection. A mechanistic understanding of how maternal infection and inflammation alters the immune responses of offspring is lacking but is critical to decrease childhood morbidity and to understand the consequences of specific long-lived immunity defects. Using our model of maternal Schistosoma mansoni infection, we have shown that murine pups born to mothers chronically infected with Schistosoma mansoni have reduced responses to vaccinations, corresponding to what has been reported in humans. To determine the origin of this humoral immunity defect, we began investigating the plasticity and functionality of progenitors of lymphoid cells critical for a protective humoral response. We found an increase in the common lymphoid progenitors (CLPs) in the bone marrow of pups from Schistosome infected mothers, but a marked decrease in immature and transitional B cells in male mice, indicating sex-specific limitations during B cell maturation. Using single cell V(D)J sequencing, we found only male pups from infected mothers have a more restricted repertoire compared to male mice from uninfected mothers after immunization, leading to decreased antigen-specific B cells in the germinal center of the draining lymph node. We hypothesize that epigenetic regulation of key immune genes is the mechanistic root of long-lived defects in humoral immunity to foreign antigens during maternal Schistosomiasis.
Supported by a grant from NIH (R01 AI135045)
Transcription factor TFII-I fine tunes innate properties of B lymphocytes
Authors: Kaila Mary , Singh Amit , De Supriyo , Mazan-Mamczarz Krystyna , Sen Ranjan , Roy Ananda 
Published: January 2023

Abstract
The ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation and, germline deletion of the Gtf2i gene leads to embryonic lethality. To delineate the physiological role of TFII-I in murine B cells, we carried out conditional deletion of Gtf2i. Here we report a surprising phenotype that suggests a role for TFII-I in homeostasis of innate properties of B lymphocytes. B cell transcriptome and chromatin landscape is skewed towards myeloid like features in the absence of TFII-I. Gtf2i ablated B cells also demonstrate enhanced sensitivity towards LPS induced transcription and proliferative capacities, features associated with innate immune cells. Finally, increased IgG3 switching, which is normally associated with inflammation, was observed in the absence of TFII-I. These results suggest an unexpected role for TFII-I in maintaining immune homeostasis and provide further clues for GTF2I polymorphism associated with B cell dominated autoimmune diseases.
This work was supported in part by the intramural program of the NIH, National Institute on Aging (NIA)