bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maresin-1 attenuates neuroinflammation in EAE via metabolic reprogramming of disease-associated cell types
Authors: Zahoor Insha , Nematullah Mohammad , Ahmed Mohammad Ejaz , Fatma Mena , Mir Sajad , Rattan Ramandeep , Giri Shailendra 
Published: November 2024

Abstract
Inflammation resolution is dysregulated in people affected with multiple sclerosis (MS) due to impaired metabolism of docosahexaenoic acid (DHA). We hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in a preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Administration of the resolution agonist MaR1 mediated resolution and improved neurological outcome in the relapsing-remitting (RR) model of EAE. MaR1 induced metabolic changes in CD4, macrophages, microglia, and oligodendrocytes. It modulated the phenotype of disease-associated cell types by regulating their effector functions. It restored the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. MaR1 is a potential interventional candidate to attenuate dysregulated inflammation to restore neurological deficits in EAE and other autoimmune diseases.
Efficacy evaluation of B cell targeting drugs and the involved mechanism of action study in humanized BAFF transgenic SLE mice model
Authors: Liang Juan , Xu Shuxin , Xu Qiuping , Zhang Yuxi 
Published: November 2024

Abstract
The B cell activating factor (BAFF) functions as a crucial factor in B cell survival, and heightened BAFF expression can augment the presence of autoreactive B cells, thereby fostering autoimmunity like Systemic Lupus Erythematosus (SLE). This study introduces transgenic mouse strains with human BAFF overexpression, offering insights into SLE mechanisms and B cell-targeting therapies.
Human BAFF overexpression in B6-hBAFF mice led to a substantial rise in Igs and anti-dsDNA levels from 6 weeks of age, persistently escalating with time compared to wild-type mice. A heightened population of B cells but a reduced ratio of T cells was observed. At week 25 of age, B6-hBAFF mice developed lupus nephritis.
Belimumab, a BAFF antibody administrated to BAFF transgenic mice demonstrated the effectively reduced serum antibody levels after 16 weeks of dosing. Belimumab ameliorated kidney function by decreasing urine albumin-to-creatinine ratio and IgA deposition after 20 weeks of treatment. Mice were also treated with Enpatoran (TLR7/8 inhibitors) and BTK inhibitor Orelabrutinib. Only the BTK inhibitor Orelabrutinib significantly eliminated serum Igs levels. Enpatoran exhibited a similar ability to Orelabrutinib in reducing T follicular helper cell and plasma cell populations spleen and lymph nodes.
In summary, the humanized BAFF transgenic SLE model proves to be a valuable tool for preclinical efficacy studies in SLE treatment and understanding pathogenesis.
Pharmacological activation of LANCL2 ameliorates disease severity and decreases inflammation in a preclinical model of rheumatoid arthritis
Authors: Tubau-Juni Nuria , Hontecillas Raquel , Leber Andrew , Bassaganya-Riera Josep 
Published: November 2024

Abstract
Lanthionine synthetase C-like 2 (LANCL2) is a novel immunoregulatory therapeutic target for the treatment of autoimmune diseases. Activation of LANCL2 enhances Treg responses through engagement of immunometabolic pathways and interactions with IL2/CD25 signaling, while downregulating effector cell subsets. An impaired Treg compartment has been proposed as one of the key contributors to the pathogenesis of rheumatoid arthritis (RA). We have developed NIM-1324, an oral, once-daily, highly systemically distributed small-molecule first-in-class therapeutic that selectively activates LANCL2 with a benign safety profile. We evaluated the therapeutic efficacy of oral NIM-1324 in a collagen-induced arthritis (CIA) mouse model of RA. Oral daily treatment with NIM-1324 significantly reduced disease activity, including paw redness and swelling, and pathology compared to the vehicle group. Furthermore, activation of LANCL2 by NIM-1324 decreased systemic inflammation, reducing IL-17+ and IL-21+ CD4+ T cells plus TNF-producing myeloid cells while the Tregs compartment was enhanced. LANCL2 deficiency in mice resulted in increased disease severity, inflammatory pathology and frequency of inflammatory subsets, including Th17 and Th1 cells. In human peripheral blood mononuclear cells, NIM-1324 decreased secretion of inflammatory mediators. This data supports that the pharmacological activation of LANCL2 by NIM-1324 is a promising therapeutic approach for the treatment of RA.
GAIA-102 cells, an off-the-shelf and highly activated NK-like cell product, elicit endogenous immune cell responses in solid tumor model
Authors: Zheng Situo , Harada Yui , Morodomi Yosuke , Yonemitsu Yoshikazu 
Published: November 2024

Abstract
[Background] We have developed a novel method for generating highly activated NK-like cells (GAIA-102) from mixed peripheral blood mononuclear cells. Currently, three Phase I clinical trials are being conducted on patients with solid tumors. In preclinical studies, GAIA-102 has demonstrated two anti-tumor mechanisms in preclinical studies: significant mass reduction and the establishment of anti-tumor-acquired immunity. However, the underlying mechanism remains to be elucidated. This study aims to understand the interaction between GAIA-102 and the host immune response. [Methods]CT26-GFP cells were intraperitoneally injected into Balb/c mice, followed by intraperitoneal administration of GAIA-102 with IL-2. After one or three treatment cycles, spleens were harvested and manually dissociated and then analyzed by flow cytometry to evaluate antigen-presenting cells(APCs) , including conventional dendritic cells (cDC) and macrophages. Additionally, CD4+ and CD8+T cells were isolated for CT26-specific T cell response Enzyme-Linked Immunospot (ELISPOT) assay. [Results]The treatment with GAIA-102 resulted in a substantial increase in cDC counts and induced a shift in the M1 macrophage phenotype. ELISPOT assays demonstrated dose-dependent enhancements in CT26-specific T lymphocytes(CTLs) response in GAIA-102 treated mice. [Conclusion] GAIA-102 therapy can stimulate the recruitment of effector APCs and enhance the CTLs response, aligning with our preclinical findings.
Complement signaling as a T-cell checkpoint in the ovarian cancer (OC) tumor microenvironment (TME)
Authors: Giridharan Thejaswini , Suzuki Sora , Khan ANM Nazmul , Emmons Tiffany , Yaffe Michael , Kolev Martin , Deschatelets Pascal , Kemper Claudia , McGray AJ Robert , Zsiros Emese , Segal Brahm 
Published: November 2024

Abstract
T cell checkpoint pathways are barriers to anti-tumor immunity and critical therapeutic targets. We use ascites fluid supernatants (ASC) from patients with newly diagnosed OC as an authentic component of the TME. We previously showed that complement activation is increased in ASC versus paired serum and induces a suppressor phenotype in normal neutrophils characterized by inhibition of critical proliferative, signaling and metabolic pathways in normal human T cells. ASC by itself dramatically inhibited CD3/CD28-stimulated T cell cytokine production (IL-2, IFN-γ, and IL-10) and glucose consumption, but not proliferation. We hypothesized that complement activation in the TME delivers an inhibitory stimulus to T cells that suppresses stimulated cytokine responses required for activation and expansion. Peptide C3 inhibitors (compstatins) restored CD3/CD28-stimulated T cell cytokine responses and glucose consumption. Inhibition of Factor B, a component of the alternative pathway (AP), also rescued cytokine responses, while inhibition of C3aR, C5aR, and C7 had no significant effect. C3b/iC3b deposition on T cells was increased with ASC exposure and reduced by C3 inhibition. Addition of recombinant complement receptor-1 (CR-1) as a decoy of C3b binding to membrane-bound CR-1 fully abrogated the suppressive effect of ASC, while recombinant CD46 had variable effects among different ASC samples. Our results show a novel AP- and CR1-dependent checkpoint of T cell activation in the TME.
Longitudinal Analysis of HIV-1 Fusion Peptide-Directed Neutralizing Response in a Vaccinated Macaque Following SHIV Infection
Authors: Hwang Juyun , Wang Hua , Dal Santo James , Howe Colin , Cheng Cheng , Doria-Rose Nicole , Shaw George , Koup Richard , Mascola John , Kwong Peter , Pierson Theodore 
Published: November 2024

Abstract
A promising direction of HIV-1 vaccine research has been eliciting fusion peptide (FP)-directed broadly neutralizing antibodies. To investigate if a potent FP-directed neutralizing response could be induced, 10 macaques were infected with simian-human immunodeficiency virus (SHIV) after immunization via FP priming and envelope trimer boosting. While the FP-directed neutralizing responses for some of the macaques dramatically increased within 8 weeks of SHIV infection, another macaque, JC69, displayed a potent cross-clade neutralizing response that grew in magnitude in the year following experimental SHIV infection. To characterize the immune response in JC69, anti-FP and -trimer ELISA, FP competition neutralization, and FP-specific B cell phenotyping analyses were performed longitudinally. FP-directed neutralizing response remarkably increased from week 32 to 68 post-SHIV infection and remained high until week 136. Furthermore, the proportion of FP-specific B-cells greatly expanded from week 32 to 68 post-SHIV infection. Overall, a potent cross-clade FP-directed neutralizing response was elicited in JC69 that peaked more than 1 year after SHIV infection. To better understand the mechanism of this late response, future directions will include the characterization of FP-directed monoclonal antibodies and viral RNA sequencing to map antibody-SHIV coevolution. Immunization to elicit site-specific neutralizing antibodies may be a key component of effective HIV vaccine strategies.
Exploring the spatiotemporal cellular dynamics of draining lymph nodes during primary and secondary SARS-CoV-2 infection recovery
Authors: Oh Taehwan , Woo YoungMin , Kim Green , Baek Seung Ho , Koo Bon-Sang , Hwang Eun-Ha , An You Jung , Kim Dong-Yeon , Kim Yujin , Hong Jung Joo 
Published: November 2024

Abstract
While lymph node structures may experience compromise in severe SARS-CoV-2 infections, the extent of recovery in convalescent individuals remains a critical exploration. Our study aims to unravel the nuances of structural recovery, germinal center (GC) dynamics, and their implications for long-term immune memory in non-human primates recovered from SARS-CoV-2. Here, we utilized a Xenium In-situ (10x Genomics) to delineate the immune cell composition and mediastinal lymph node architecture in COVID-19 macaque lungs across primary infection, convalescence, and secondary infection. Noteworthy findings include an increase in follicular helper T cells, GC B cells and plasmablasts within lymphoid follicles during convalescence. In the paracortex, secondary infection results in a decrease in cytotoxic T cells but an increase in follicular helper T cells. In the medulla, a reduction in macrophages is observed, accompanied by increased conventional and plasmacytoid dendritic cells, GC B cells and plasmablasts during secondary infection. This study not only enhances our understanding of GC formation during COVID-19 recovery but also provides insights into immune cell repopulations within draining lymph nodes following secondary infection. These findings have the potential to inform the optimization of vaccine strategies and the design of precise therapeutic interventions.
Humoral correlates of protection against influenza A H3N2 virus infection
Authors: Hoy Gregory , Stadlbauer Daniel , Balmaseda Angel , Kuan Guillermina , Lopez Roger , Ojeda Sergio , Sanchez Nery , Plazaola Miguel , Krammer Florian , Gordon Aubree 
Published: November 2024

Abstract
Background: Gaps remain in our knowledge of the humoral correlates of protection against influenza A/H3N2, including the role of antibodies against the hemagglutinin stalk, a highly conserved but immunologically sub-dominant region.
Methods: Two household studies were conducted in Managua, Nicaragua. Household contacts were tested for influenza using RT-PCR. We compared pre-existing antibody levels against full-length hemagglutinin (FLHA), HA stalk, and neuraminidase (NA) measured by ELISA, along with initial HA inhibition assay (HAI) titers, between infected and uninfected participants.
Results: A total of 899 individuals participated in household activation during three A/H3N2 seasons with 329 infections occurring. A four-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (OR=0.82, 95%CI 0.68-0.98, p=0.04). In 0-14-year-olds, anti-NA antibodies (OR=0.67, 95%CI 0.53-0.85, p&lt;0.01) were associated with protection, but anti-HA stalk antibodies were not. In adults, anti-HA stalk antibodies were independently associated with protection (OR=0.72, 95%CI 0.54-0.95,p=0.02).
Conclusions: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this protection is age dependent. This supports the continued exploration of the HA stalk as a target for broadly protective influenza vaccines and suggests that the protective benefits may depend on age and influenza exposure history.
Sphingosine kinase 2 suppresses neutrophil responses while attenuating immune pathology during a persistent viral infection
Authors: Vijayamahantesh Vijayamahantesh , He Ying , Studstill Caleb , Jung Kwang Il , McKenna Savannah , Allen Lee-Ann , Hahm Bumsuk 
Published: November 2024

Abstract
During chronic virus infections, the functions of immune cells are often suppressed which may restrict immune pathology but lead to viral persistence. However, the underlying mechanisms are incompletely understood. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phosphate, a bioactive lipid mediator, and mediates diverse cellular processes. We have recently found that SphK2-deficient mice succumb to infection by lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl 13) due to immune pathology associated with nephropathy. Heightened T cell immunity was crucial for infection-induced mortality of SphK2 KO mice. However, in addition to T cell immunity, a notable increase of neutrophils was observed in multiple tissues as well as blood of LCMV-infected SphK2 KO mice. Importantly, SphK2-deficient neutrophils expressed substantially lower levels of the immune suppressive marker CD244 and produced higher amounts of ROS compared to SphK2-sufficient neutrophils upon infection. Depletion of neutrophils from SphK2 KO mice increased the viability of infected mice. Further, adoptively transferred SphK2-deficient neutrophils improved virus-specific T cell responses in wild type mice when compared to the transferred SphK2-sufficient neutrophils. The results indicate that SphK2 inhibits neutrophil expansion and function, contributing to the immune regulation during a persistent virus infection. The study may help to design new immune therapeutics to control viral diseases.
A virtual memory T cell–originated CD44s-hiCD49dlo CD8+ T cell subset confers immune protection against respiratory viral infections
Authors: Cho Sung-Dong , Choi Yunseo , Kim Hawon , Seok Joon , Shin Eui-Cheol , Park Su-Hyung 
Published: November 2024

Abstract
Virtual memory CD8+ T (TVM) cells, exhibiting a memory phenotype without foreign antigen exposure, exert protective immunity against viral and bacterial infections. However, a TVM-originated distinct CD8+ T cell subset (CD44super-hi (s-hi)CD49dlo CD8+ T cells) induces pathogenesis of a chronic inflammatory disease (alopecia areata (AA)) by NKG2D-mediated innate-like cytotoxicity (Nat. Immunol. 24(8):1308-17 (2023)). Notably, these pathogenic cells were also residing in the lungs. Therefore, in this study, we aimed to investigate the distinct immune characteristics of lung-infiltrated CD44s-hiCD49dlo CD8+ T cells in AA mice and their protective roles against respiratory viral infections.
In AA mice, the lung-infiltrated CD44s-hiCD49dlo CD8+ T cells exhibited tissue-resident features, lower NKG2D expression, and less cytotoxicity than those in the skin. In AA mice with influenza A virus infection, the lung CD44s-hiCD49dlo CD8+ T cells showed increased NKG2D expression and cytotoxicity. Finally, CD44s-hiCD49dlo CD8+ T cells in the lungs of AA mice conferred immune protection against influenza virus infection, evidenced by a significantly improved survival rate and less body-weight loss.
Collectively, our results elucidate the two-sided roles of TVM cells. The ambivalent aspects of CD44s-hiCD49dlo CD8+ T cells originated from TVM cells provide a solid rationale for the continuing investigation of TVM cells in immune protection and disease.
PD-1 mediates brain resident memory T cell formation and virus control
Authors: Butic Arrienne , Lauver Matthew , Lukacher Aron 
Published: November 2024

Abstract
Programmed cell death protein 1 (PD-1) is upregulated in T cells of patients with progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by infection of the central nervous system (CNS) by JC polyomavirus (JCPyV). Studies have exhibited variable success in treating PML with PD-1 blockade, denoting a need to understand the function of PD-1 in polyomavirus CNS infection. PD-1 is highly expressed on functional CD8 T cells in the brain after intracerebral inoculation of mouse polyomavirus (MuPyV), which we use to model JCPyV CNS infection. We hypothesized that PD-1 signaling on CD8 T cells regulates the differentiation of virus-specific brain resident-memory T cells (bTrm). Using an inducible global PD-1 knockout mouse model, we show that deleting PD-1 during acute MuPyV infection results in the transition of virus-specific CD8 T cells toward a more resident-memory-like phenotype. PD-1 deletion during persistent infection results in higher T cell counts as well as reduced viral loads. To clarify the effects of CD8 T cell-specific PD-1 signaling, we adoptively transferred inducible PD-1 knockout CD8 T cells into recipient mice. In contrast to global deletion, CD8 T cell-specific loss of PD-1 led to a lower frequency in resident-memory-like cells. These data suggest that acute global PD-1 loss promotes bTrm formation, which may be independent of PD-1 signaling on CD8 T cells, and that PD-1 loss during persistent infection may promote better viral control.
Molecular mechanism of CD14+ human monocyte/macrophage activation by Ebola virus protein VP40
Authors: Singh Karnail , Le Hung , Ding Lingmei , Waggoner Stephen , Spearman Paul 
Published: November 2024

Abstract
Impaired functions of many innate immune cells have been implicated in Ebola virus disease (EVD) pathogenesis. Previously, we reported that CD14+ accessory cells are required for the optimal Ebola virus protein VP40-induced activation of human natural killer (NK) cells. In the current study, we explored the molecular mechanism(s) of VP40-induced activation of CD14+ accessory cells and their role in triggering NK cell activation. Human PBMCs, purified CD14+ myeloid cells or CD14+ cell and CD56+ NK cell co-cultures were incubated with VP40, mCherry-VP40 fusion protein or virus-like particles (VLPs) containing it and binding, internalization, and distribution of VP40 analyzed by flow and confocal microscopy. Molecular pathway(s) triggered in CD14+ cells and the resulting gene expression changes were analyzed by flow, western blotting, luminex and RNA-Seq. Ebola VP40/VLPs bound to and were internalized by classical, intermediate and non-classical monocytes but to varying degrees. VP40 triggered activation of NF-kB and inflammatory pathways in CD14+ cells resulting in their enhanced secretion of multiple cytokines and factors. IL-12 or IL-18 blockade partially abrogated VP40-induced, CD14+ cell dependent activation of NK cells. Taken together, our data suggests that activation of CD14+ cell by Ebola VP40/VLPs can rapidly trigger NK cells that, in turn, may eliminate Ebola virus infected host cells, findings that may help in designing better anti-Ebola countermeasures.
T-bet+ B cell-deficiency enhances obesity-driven autoantigen- and T-dependent humoral immunity
Authors: Leadbetter Elizabeth , Vanz Carlo , Enslow Benjamin , Liendo Nathaniel , Dudley Elizabeth 
Published: November 2024

Abstract
The recent pandemic provided a stark example of the deadly consequences of humoral immune suppression during infection or following vaccination in obese patients. Unfortunately, the mechanism of this inhibition remains unknown. We recently showed that T-bet+ B cells increase in lymphoid organs and adipose tissue during obesity and exacerbate metabolic dysfunction through antibody production, especially in female mice. Here, we report that autoreactive IgG antibodies in obese mice exist largely as autoantigen-bound immune complexes. T-bet+ B cells express elevated levels of antigen presenting molecules and scavenger receptor CD36, positioning them to efficiently uptake lipid antigens and productively engage T helper cells. Flow cytometry shows that during obesity CXCR5+ TFH and CXCR5- TPH cells expand in the spleen and liver, respectively, providing a ready source of help. T-bet+ B cell-deficient obese mice lack IgG2a but have expanded IgG2b and IgG3 antibody titers. Unexpectedly, they also develop expanded GC B cells, class switched B cells, and antibody secreting B cells compared to intact obese or lean controls. Furthermore, T-bet+ B cell deficient mice also make an enhanced humoral GC B cell response to NP-KLH/alum vaccination, suggesting that obesity-expanded T-bet+ B cells skew the immune response away from protective immunity. This may provide a much-needed explanation for reduced humoral immunity observed in obese patients.
IL-22 binding protein promotes macrophage phagocytosis during lung injury.
Authors: Chakawa Mazvita , Zhang Zhe , Allen Michaela , Pociask Derek 
Published: November 2024

Abstract
Interleukin 22 binding protein (IL-22BP) is a soluble receptor predominantly produced by myeloid and epithelial cells. While the only documented function of IL-22BP is regulation of IL-22 activity, our new data suggests IL-22BP is involved in macrophage function and phagocytosis independent of IL-22.
We found that IL-22BP knock out (IL-22BPKO) mice had greater pulmonary injury and elevated inflammatory macrophages compared to wildtype mice in a bleomycin injury model. Clodronate ablation of macrophages demonstrate limited ablation in IL-22BPKO mice. In-vitro phagocytic assays using fluorescent beads revealed a phagocytic defect in IL-22BPKO macrophages. This defect appeared independent of IL-22 as there were no differences in bead uptake in macrophages derived from IL-22 receptor knock out mice. Immunohistochemistry showed less foamy macrophages in IL-22BPKO mice compared to wildtype mice. Foamy macrophages are important in clearance of cellular debris during lung injury. We assessed expression of lipid recognition receptors using RT-qPCR. Our data shows reduced expression of macrophage scavenger receptor 1, scavenger receptor 1, lectin type oxidized LDL receptor and transcription factor peroxisome proliferator-activated receptor gamma in IL22BPKO mice.
Taken together, these data suggest lipid uptake is compromised in IL-22BPKO-derived macrophages and demonstrates that IL-22BP may have a novel role in lipid recognition and macrophage function.