bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel anti-inflammatory function of Thy1 stromal cells in colitis
Authors: Torres-Huerta Alvaro , Boger-May Antonia , Ruley Haase Katelyn , Reed Theodore , Mysore Rajashekara Arpitha , Hiller Morgan , Mayer Lauren , Frech Maddy , Kenney Kaylee , Kane Grace Rowe , Elliott Kyle , Schmidt Annie Cate , Boone David 
Published: November 2024

Abstract
Background: Inflammatory Bowel Disease (IBD) is a complex immune disorder affecting the gastrointestinal tract. Stromal cells play a crucial role modulating the immune response. We evaluated the function of the Thy1 positive stromal population, specifically elucidating its role in the context of the innate immune system within the framework of IBD.
Methods: We created a mouse model that develops 100% penetrant, early-onset colitis in the absence of adaptive immunity. Transgenic mice expressing the TNFAIP3 (A20) gene under the villin promoter, (Villin-tgA20), crossed with RAG1-/- mice (villin-tgA20 x RAG1-/-; aka TRAG) develop innate colitis. To study ILCs and Thy1 functions in colitis we used IL2Rg-/- and Thy1-/- mice, crossed with TRAG (IL2Rg-/- x TRAG, and Thy1-/- x TRAG). IL2Rg-/- x TRAG, and Thy1-/- x TRAG were injected with anti-Thy1 antibody and assessed for prevention of colitis.
Results: In absents of ILCs (IL2Rg-/- x TRAG) and Thy1 (Thy1-/- x TRAG) colitis persists. Treatment with anti-Thy1 antibody prevents colitis in TRAG and IL2Rg-/- x TRAG, but not in Thy1-/- x TRAG, mice. Colitis in TRAG, IL2Rg-/- x TRAG, and Thy1-/- x TRAG, is characterized by an abundance of neutrophils and inflammatory monocytes. In the colon of IL2Rg-/- x TRAG mice we observed a Thy1 positive population that expressed podoplanin but not CD31. Thus, Thy1 is a functional molecule and stimulation of stromal cell Thy1 induces an anti-inflammatory response that prevents IBD.
IL-33-mediated mast cell function is female dominant
Authors: Maldonado Tania , Ryan John , Kee Sydney , Ching John 
Published: November 2024

Abstract
Allergic asthma is a common chronic disease characterized by airway inflammation and bronchoconstriction. Asthma is more common and more severe in women than in men. One component of allergic inflammation is IL-33, a cytokine released by airway epithelium when these cells are damaged by allergens. Using two models of IL-33-mediated inflammation, we have found that IL-33 elicits a stronger response in female mice than males. These differences are reversed when using castrated mice. Castrated females show reduced IL-33 responses than controls, while castrated males show enhanced responses. IL-33 is a potent mast cell activator in these models. We find that mast cells cultured from female mice respond more strongly to IL-33 than male mast cells. These data support the hypothesis that IL-33-mediated inflammation exhibits female-dominant sexual dimorphism. Further this dimorphism is linked to sex hormones and may be partly explained by IL-33 effects on mast cells.
IL-27 signalling increases lung injury in murine beta-coronavirus and Influenza infection
Authors: Worley Matthew , Gong Henry , Carver Kyle , Deng Jane 
Published: November 2024

Abstract
Introduction: IL-27 is elevated during COPD, ARDS and high levels are predictive of severe SARS-CoV-2 infection. Despite the association with severe pulmonary outcomes, little is understood on how it affects lung injury or cellular recruitment early in viral pulmonary infection.
Methods: C57BL/6 (WT) and IL-27ra-/- mice were infected with 500,000PFU of murine beta-coronavirus (MHV-1) or 500PFU of Influenza (H1N1) and evaluated for survival. At days 3 and 5 post infection kinetics of cellular recruitment, viral load and markers of lung injury were evaluated.
Results: IL-27ra-/- mice have increased survival compared to the WT mice when infected with MHV-1 (p= 0.0184) and H1N1 (p=0.0305). Despite no differences in viral load, the IL-27ra-/- had decreased lung injury at days 3 and 5 post infection (p&lt;0.05) for both MHV-1 and H1N1. IL-27ra-/- mice had significant neutrophilia during infection at day 3 and 5 (p&lt;0.05) but with altered neutrophil phenotypes (adhesion, activation and maturation markers) including decreased expression of TLR3, TLR4 and CD49d (p&lt;0.05 for all).
Conclusion: The IL-27ra-/- mice are resistant to pulmonary infection with MHV-1 and H1N1 with increased survival but no differences in viral load. Despite high pulmonary neutrophilia in both infections, the IL-27ra-/- mice paradoxically have decreased lung injury. This study highlights IL-27 as a potential early target for altering neutrophil phenotypes to limit lung injury during respiratory viral infections.
Activation of S1P/SK2 pathway in classical monocytes enhances anti-PD-1 immunotherapy
Authors: Krieg Carsten , Ball Lauren , Orgetmen Besim , Hardiman Gari , Gan Wenjian , Robinson Mark , Guglietta Silvia 
Published: November 2024

Abstract
Tumor-associated macrophages (TAMs) often impede immunotherapy success by promoting an immune-suppressive environment in the tumor. Depleting TAMs directly has shown limited success in clinics due to challenges in precise targeting and avoiding toxic side effects. An alternative approach involves targeting circulating monocytes (CMs), the precursors of TAMs. In inflammatory conditions like cancer, CMs replace exhausted tissue-resident macrophages. Our study found that anti-PD-1 responders had elevated CM numbers before treatment, correlating with increased anti-tumorigenic macrophages in tumors. Analyzing CMs revealed higher sphingosine 1-phosphate (S1P) levels in responder patients, crucial for immune cell bioenergetics. Preliminary experiments using S1P/SK2 treatment improved CM function, supporting T cell proliferation and enhancing checkpoint inhibition therapy response. Exploring the S1P/SK2 pathway's impact on CM-derived macrophages and in vivo behavior is ongoing. Targeting the S1P/SK2 pathway to reprogram CM for anti-tumorigenic macrophage generation epigenetically shows promise in enhancing cancer immunotherapy efficacy, with potential implications for treating diverse diseases beyond cancer.
The Role of Recirculating Thymic T regulatory Cells in Regulation of de novo T reg Development and Central Tolerance
Authors: Joo Sookyong , Owen David , Farrar Michael 
Published: November 2024

Abstract
AIRE+ medullary thymic epithelial cells (mTECS) play a key role in establishing immune tolerance. These cells peak 2-3 weeks after birth and then steadily decline as mice get older. The mechanism by which AIRE+ mTECs decline remains unclear. We observed that a subset of recirculating thymic T regulatory cells (RT-Tregs) accumulates in the thymus at the same time that AIRE+mTECs decline. Using scRNA-Seq we found that RT-Tregs are quite diverse and may have cytotoxic potential. We propose that RT-Tregs play an essential role in balancing the stringency of T cell selection in the thymus by regulating mTEC abundance. To test this hypothesis we injected diphtheria toxin (DT) into the thymus of FOXP3-DTR mice, which selectively deplete RT-Tregs, but not de novo generated thymic Tregs or peripheral Tregs. This treatment led to a substantial increase in the number of AIRE+ mTECs. Using previously published datasets, we observed that the TCR diversity of conventional T cells (Tconv) in lymphoid organs of AIRE-/- mice was significantly increased relative to that of WT mice. We are currently testing whether depletion of RT-Tregs results in the opposite phenotype - a less diverse Tconv repertoire. We propose that early in life AIRE+ mTECs promote self-tolerance. RT-Tregs then act in a feedback loop to signal that peripheral tolerance has been established and eliminate AIRE+ mTECs resulting in a more diverse TCR repertoire that may be more self-reactive but also more pathogen-reactive.
Autoimmune diseases (AIDs) in Côte d’Ivoire West Africa
Authors: Siransy Liliane , Moussa Y Salimata , Doris Fleur Oura Brou , Adou Honoré , Sery Jocelyne , Dasse Sery Romuald 
Published: November 2024

Abstract
Introduction
Autoimmune diseases (AIDs) are until now very well unknown in Africa and particularly in subsaharien countries. They were even considered non-existent .
The objective of this work is to estimate the prevalence, describe the epidemiological, clinical and biological aspects of AID in our country.
Methods
This was a descriptive retrospective study conducted from January 1, 2010 to December 31, 2020, on the files of patients hospitalized in the rheumatology department of the University Hospital of Cocody in Abidjan, Côte d’Ivoire.
Results
We studied 116 patients including 104 female patients (90%) and 12 male patients (10%). Most systemic autoimmune diseases have been observed in patients aged from 31 to 45 years.
The average age was 40.02 +/- 15.07 years (extreme 12 and 72 years). The main diagnoses retained were systemic lupus erythematosus (34%), rheumatoid arthritis (22%), mixed connectivites (27%), sclerodermia(13%) .
Of the 116 patients, 82% were not tested, 4% were negative and 14% were found positive for antinuclear antibodies, the most common biomarker in autoimmunity.
Conclusion
AIDs are prevalent in our countries with various presentation in our patients and they occur in young adults. Autoimmune disease are prevalent in our country and increasing. Further studies and a national regsitry of autoimmune disease need to be established to understand the disease and its increase in african environnement.
Mitochondrial transcription is essential for the potent antitumor stem memory T cells
Authors: Kumaresan Soundharya , Rangel Rivera Guillermo , Knochelmann Hannah , Smith Aubrey , Ruffin Ayana , Cole Anna , Wittling Megen , Wyatt Megan , Lowe Michael , Lesinski Gregory , Paulos Chrystal 
Published: November 2024

Abstract
Adoptive T cell transfer (ACT) therapy is an effective approach to treat cancer patients, where expanding the patient’s T lymphocytes and redirecting them to recognize and regress solid tumors. Unfortunately, ACT can fail in some patients due to exhaustion or impaired metabolic fitness during T cell expansion. We discovered through transcriptomic analysis that the novel mitochondrial transcription regulator REXO2 induced by regulating PI3Kδ signaling in vitro - generated stem memory T cells (TSCM) - is responsible for the antitumor potency of TSCM cells. This finding is novel, as REXO2 has never been studied in immune cells and has only recently been appreciated in regulating heart muscles during embryonic development. We found that knocking out REXO2 via CRISPR in TSCM cells impaired their mitochondrial transcription and morphology in vitro. Moreover, they had reduced metabolic fitness marked by poor spare respiratory capacity, reduced mitochondrial potential and increased production of reactive oxygen species post tumor antigen recognition. Of clinical importance, REXO2 knockout in TSCM cells impaired the antitumor potency when infused into mice. This work also has translational potential, as REXO2 could be induced in human TIL or CAR T cell products by expanding them in the presence of PI3Kδ inhibitor. Our findings reveal that REXO2 is a promising target to bolster the antitumor activity of next generation TIL and CAR T cell products to treat cancer patients.
Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism
Authors: Peralta Ronal , Delgoffe Greg 
Published: November 2024

Abstract
CD8+ T cells are critical mediators of antitumor immunity but differentiate into a state of dysfunction, known as exhaustion, after experiencing persistent TCR stimulation and metabolic stress in the tumor microenvironment (TME). The TME creates an immunosuppressive metabolic environment via reduced levels of vital nutrients and oxygen combined with increased catabolic waste products. How Texh cells survive and function in the face of this altered metabolite balance remains unclear. Here we show Texh cells upregulate a newly characterized monocarboxylate transporter, MCT11, enabling uptake of lactic acid which can drive their dysfunction. MCT11 expression requires both the core exhaustion program induced through chronic activation and metabolic stress signals, like hypoxia. Conditional deletion of MCT11 in T cells reduced lactic acid uptake in Texh cells and improved effector function and response to immunotherapy. Further, a monoclonal antibody targeting MCT11 reduced lactate uptake specifically in Texh cells, which, when used therapeutically in tumor-bearing mice, resulted in significantly reduced tumor growth, inducing complete regressions. Our data support a model in which the exhaustion program upregulates MCT11, rendering exhausted T cells sensitive to toxic lactic acid. MCT11 represents an attractive target to edit in therapeutic T cells or block using antibodies to render Texh cells impervious to lactic acid, allowing for tumor eradication.
B cell Maturation Antigen Impacts Microglia and Macrophage Phenotypes in Neuro-autoimmune disease.
Authors: Kumar Gaurav , Massey Kaylea , Ko Rose , Axtell Robert 
Published: November 2024

Abstract
BAFF and APRIL, crucial to B cell function, play a role in multiple sclerosis (MS), with therapeutic blockade linked to worsened disease. These cytokines signal through the receptors: BAFFR, TACI, and BCMA. BCMA stands out in MS due to elevated soluble levels in the cerebrospinal fluid. Our prior study using EAE revealed increased disease severity in BCMA knockout mice. Additionally, BCMA showed divergent roles in response to anti-CD20 and TACI-Fc treatments in EAE, enhancing anti-CD20 therapy responsiveness but diminishing TACI-Fc efficacy. The contrasting effects of BCMA on these treatments led us to explore its function in cell types beyond B cells. Here, we report that BCMA is highly expressed on microglial cells, and infiltrating Ly6C+ myeloid cells in the CNS of wildtype mice with EAE. Additionally, we found that BCMA-/- mice exhibited altered CD86 expression on microglial cells and elevated iNOS on infiltrating macrophages, suggesting a role in skewing towards an M1 phenotype in the CNS during EAE. In the lymph nodes, we also observed a similar effect on the M1-type macrophages in BCMA-/- mice compared to BCMA+/+ mice. These findings offer evidence of a novel role for BCMA in modulating microglia and macrophage function, providing additional insights into the intricate role that BAFF and APRIL play in neuroautoimmune diseases.
DB-2304, a Duality Immune Modulating Antibody‒Drug Conjugate (DIMAC) targeting BDCA2, displays strong potency in the suppression of pDC functions.
Authors: Li Xi , Li Bing , Yao Jun , Liu Shenxue , Shi Rong , Zhang Yu , Zhu Zhongyuan , Qiu Yang , Hua Haiqing 
Published: November 2024

Abstract
Study Objective: BDCA2 is specifically expressed on plasmacytoid dendritic cells (pDCs), whose overproduction of type I IFN is crucial in SLE pathogenesis. Combining anti-BDCA2 mAB with glucocorticoids (GCs) has shown clinical efficacy. Previous studies revealed superior anti-inflammatory effects of anti-BDCA2 antibody‒drug conjugate (ADC), motivating the development of DB-2304, an anti-BDCA2 ADC using a novel glucocorticoid receptor agonist as a payload. This study assessed the preclinical efficacy and safety of DB-2304.
Methods: A novel BDCA2 mAB, Hu033-03, was developed and conjugated with the DIMAC payload to generate DB-2304. The inhibitory potency of DB-2304 was evaluated in human PBMCs in vitro. The PK and safety profile and pDC function suppression were characterized in cynomolgus monkeys.
Results: Hu033-03 exhibited high affinity for BDCA2, inducing rapid internalization upon binding. DB-2304 showed enhanced suppression of IFNa production and a broader spectrum of proinflammatory cytokines in human PBMCs without cytotoxicity. Reduction in pDC cytokine production capability and surface BDCA2 level occurred in an ADC serum concentration-dependent manner. DB-2304 exhibited a favorable safety profile, with an HNSTD of 125 mg/kg in cynomolgus monkeys.
Conclusions: DB-2304 has demonstrated potent in vitro and in vivo anti-inflammatory effects on type I IFN genes and proinflammatory cytokines in pDC. These findings strongly support future clinical investigations of DB-2304.
Preclinical evaluation of Janus Kinase inhibitors in atopic dermatitis: Insights from an oxazolone-induced mouse model
Authors: Zhang Xiaotuan , Wang Jingjing , Zhang Ya , Lu Dan , Gu Qingyang , Zhang Qiyao 
Published: November 2024

Abstract
Atopic dermatitis (AD) is a prevalent inflammatory skin condition affecting a substantial proportion of the population. However, the lack of robust preclinical evidence of Janus kinase (JAK) inhibitors in AD treatment necessitates the development of more effective therapies, including those repurposed from other indications. Thus, we aimed to establish a preclinical evaluation system targeting JAK inhibitors to explore their effectiveness and mechanism of action in AD mouse model.
We utilized an oxazolone (OXA)-induced AD mouse model to assess the effects of JAK inhibitors. Ear thickness, IgE and MPO levels were measured regularly. At the end of study, spleen weights were measured, and ear tissues were processed for cytokine analysis and pathological evaluation. Additionally, flow cytometry was utilized to analyze immune cells in auricular draining lymph nodes (DLN).
Following OXA challenge, temporal changes in the immune system were observed, characterized by increased pro-inflammatory cytokines, immune cell infiltration in auricular DLN, and elevated IgE and MPO levels. Treatment with JAK inhibitors led to a reduction in AD-associated features and resulted in decreased immune cell infiltration and alterations in specific molecular features.
Our study successfully established a preclinical mouse model for AD, facilitating a comprehensive understanding of skin inflammation, immunomodulation, and the pharmacodynamics of test articles in the context of AD.
Inhibition of p38α MAPK-MK2 axis alleviate inflammatory response in various inflammation-related disease models
Authors: Han Tian , Han Tian , Fu Donglin , Hu Zhilong , Xia Yuanfeng , Yang Fanglong 
Published: November 2024

Abstract
Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated by p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. Preclinical studies indicate that targeting MK2 may be a much safer approach than blocking p38a MAPK activation because that dissect the pathway downstream of p38α MAPK without affecting additional cellular functions. 141-A was identified as a highly potent and selective p38α MAPK-MK2 allosteric inhibitor that exhibited nanomolar-level inhibition on p38α MAPK activation of MK2 while sparing the p38α MAPK activation of ATF2 and PRAK. 141-A potently reduced various cytokine production (TNFα, IL-1β, IL-6, IL-8 and IL-17) in human peripheral blood mononuclear cells (PBMC) and displayed excellent efficacy in adjuvant-induced arthritis (AIA), psoriasis and MSU-induced air pouch rat models with 1/6 of the systematic exposure of CDD450. The compound exhibits favorable physicochemical and pharmacokinetic properties, along with an excellent preclinical toxicity profile, which may enhance therapeutic efficacy without causing side effects. 141-A is currently under IND-enabling studies and P1 trial is planned in early 2025.
CD11d, an NK cell ally in their fight against tumours
Authors: Bourel Capucine , Al Khaldi Maher , Dubuissez Marion , Chabot-Roy Geneviève , Mullins-Dansereau Victor , Guimont-Desrochers Fanny , Coderre Lise , Lombard-Vadnais Félix 
Published: November 2024

Abstract
NK cells participate in viral clearance and tumour control. They differentiate from bone marrow precursors and undergo a series of guided differentiation steps to acquire various functional properties. We previously showed that pre-mNK cells represent one of these precursors and that a locus on mouse chromosome 7 is linked to pre-mNK abundance. As pre-mNK cells are associated with a heightened anti-tumour activity, we sought to identify genes within this locus that influence their number, and could thus affect NK cell-mediated tumour growth. Through a candidate gene-based approach, we identify Itgad, encoding for CD11d, a member of the ß2 integrin family. We find that the absence of CD11d affects the expression of the other ß2 integrin subunits, particularly on NK cells. This led us to investigate the functional outcome of the loss of CD11d expression in NK cells. Although NK cells from CD11d-KO mice show unabated expression of effector proteins in vitro, their anti-tumour activity is impaired in vivo. Indeed, the growth of NK-sensitive RMA-S lymphoma is significantly accelerated in CD11d-KO mice. This increase in tumour growth was associated with a reduction in the number of NK cells in the tumours, suggesting a role for ß2 integrins in NK cell migration. Altogether, our candidate gene-based approach determined that expression of ß2 integrin subunits are co-regulated in NK cells and revealed an important role for CD11d in NK cell-mediated anti-tumour activity.
Single-cell RNA sequencing unveils metabolic and transcriptional dynamics in CD8+ T cells of Autoimmune Hepatitis murine model, offering insights into potential therapeutic targets.
Authors: Dolasia Komal , Centa Monica , Giotti Bruno , Ughetta Mimi , Alexandropoulos Konstantina , Tsankov Alexander 
Published: November 2024

Abstract
Autoimmune hepatitis (AIH) is a chronic liver disorder characterized by immune-mediated hepatocellular damage, potentially leading to liver failure, and necessitating liver transplantation if uncontrolled. Current treatments, primarily immunosuppressive drugs, are hampered by variable efficacy, significant adverse effects, and risks of non-responsiveness or relapse, underscoring the need for novel therapeutic strategies. In AIH, the inflammatory liver infiltrate predominantly consists of α/β T cells; moreover, recent findings highlight a significant contributory role of CD8+ T cells in AIH pathogenesis. Utilizing Traf6ΔTEC mice that exhibit a liver-centric autoimmune response characterized by mTEC (murine thymic epithelial cells) depletion due to conditional Traf6 deletion in thymic epithelial cells, we conducted a single-cell RNA sequencing (scRNA-seq) analysis of CD8+ T cells. This analysis elucidated diverse cellular states and functional dynamics within these cells and a preponderance of exhausted CD8+ T cells. Furthermore, flow cytometry was employed to confirm the presence of identified CD8+ T cell subtypes. Our study identified unique metabolic profiles and transcription factors differentially expressed in CD8+ T cells, shedding light on potential disease-driving mechanisms. These insights lay the groundwork for the discovery of new therapeutics aimed at modulating specific metabolic and transcriptional pathways in autoimmune hepatitis.