bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD8 follicular T cells provide helper and cytolytic function in the B cell follicule during antibody-mediated autoimmunity
Authors: Hoyer Katrina K , Valentine Kristen M , Mullins Genevieve , Davalos Oscar A , Seow Lek Wei 
Published: February 2023

Abstract
CXCR5+ CD8 T cells arise during situations of chronic antigen and inflammation, including chronic viral infection, cancer, and antibody-mediated autoimmunity. In some conditions CXCR5 expression facilitates CD8 T cell homing to B cell follicles, while some studies find persistent CCR7 expression prevents follicle entry. Despite robust research within this fairly new field variance in tissue localization, expression profiles, inflammatory conditions and developmental stages limit comparisons between existing CXCR5+CD8 T cell studies. We demonstrate that CXCR5+PD-1+ CD8 T follicular (Tfc) cells comprise a functionally non-redundant subset of CXCR5+ CD8 T cells in systemic autoimmune disease. CD8 Tfc develop in the absence of functional Tregs and expand during lymphoproliferation. CD8 Tfc acquire the capacity to produce helper cytokines including co-expression of IL-21 and IL-4, and maintain capacity for cytolytic function expresing granzyme B and TNFα, suggesting the potential for functional mechanisms that diverge from CD4 Tfh cells. IL-4+IL-21+ CD8 Tfc localization in the follicle and germinal center suggest that CD8 Tfc may promote B cell activities in either location during autoimmune disease. B cell activities influenced by CD8 Tfc cells are not fully defined such as regulating somatic mutation, memory and plasma cell differentiation, and germinal center movement. However CD8 T cells promote plasma cell differentiation and antibody class switch, but do not alter germinal center B cell numbers. CD8 Tfc position coupled with cytokine production in the germinal center and follicle, and induction of activation-induced cytidine deaminase by B cells suggest a dominant helper-like role with cytolytic potential.
Evaluation of Anti-nuclear Antibodies (ANA) Patterns for aging population in Hong Kong
Authors: Lau Kwun Hung , Do Yan Tung , Chan Yat Hung , Fong Wing Long , Chau Sui Ching , Cheng Wai Wan , Chan Pui Yu , Yau Kin Nam 
Published: February 2023

Abstract

Objective
Our aim was to investigate the association among aging population, sex and Antinuclear Antibody (ANA) patterns expressed in Hong Kong population for improving the autoimmune diagnosis by using ANA HEp-2 slides under fluorescent microscope.

Methods
A total of 50 blood samples from aging population in both males and females were collected and examined under fluorescent microscope. In this research, a HEp-2 complete Kits (Bio-Rad Kallestad) with the methodology of indirect fluorescent antibody (IFA). Positive ANA patterns classified in International Consensus on ANA Patterns (ICAP) are distinguished.

Results
In this experiment, we obtained that the number of positive samples was 43 (86%), the number of suspected (weak) positive samples was 9 (21%) and the number of negative samples was 7 (14%). In 43 positive samples, 24 out of 27 females (88.9%) and 19 out of 23 males (82.6%) were aged between 70 – 91. 21 in 43 positive samples in the result were within age group 70–78 (48.8%). 17 in 43 positive samples in the result were within age group 80–88 (39.5%). 5 in 43 positive samples in the result were within age group 90–92 (11.6%). The most frequent positive ANA patterns included AC10 – (7 patients, median age = 81, 20%), AC19 – (6 patients, median age = 82, 17%), and AC7 – Few Nuclear Dots (5 patients, median age = 84, 15%). We found that ANA positivity rate was significantly higher in female than the male in Hong Kong (6.3%).

Conclusion
Our data indicated that female aged 70–78 is more likely to result higher positivity rate of ANA than male. According to data of our study, this significantly supports the further study of the trend in the aging population who are easier to have an ANA related autoimmune disease to take better care for elderly in Hong Kong.
BTLA signaling is needed in newly generated T cells to block autoimmunity
Authors: Adegoke Adeolu , Thangavelu Govindarajan , Anderson Colin C 
Published: February 2023

Abstract
Radiotherapy and/or chemotherapy in cancer treatment causes lymphopenia, which favors autoimmunity. Also, coinhibitory receptor blockade triggers immune-related adverse events in more patients than it cures of cancer. Having shown that PD-1 coinhibitory receptor is required in newly generated T cells (NGTC) to prevent lymphopenia-induced autoimmunity, our objective was to determine if the coinhibitory receptor BTLA is also required to establish tolerance in NGTC during lymphopenia. NGTC from thymocytes or established T cells from splenocytes of wildtype (WT) or BTLA−/− B6 mice were adoptively transferred to lymphopenic Rag−/− B6 mice. Sorted WT or BTLA−/− CD8 or CD4 single-positive (SP) thymocytes were adoptively transferred to Rag−/− mice not expressing MHC II (CiiTA−/−) or lacking MHC I (KbDb−/−), respectively. Disease was assessed by macroscopic appearance and weight loss. About 65% (5/8) recipients of BTLA−/− NGTC developed overt autoimmunity, while 4/4 recipients of BTLA−/− splenocytes were disease-free. 10/10 recipients of BTLA−/− CD8 SP T cells showed progressive weight gain. In contrast, 11/11 BTLA−/− CD4 SP T cell recipients had diarrhea, piloerection, hunched appearance, and progressive weight loss from 3–8 weeks post thymocyte transfer (p&lt;0.0001). 3/11 BTLA−/− CD4 SP T cell recipients developed dermatitis post thymocyte transfer. Overt autoimmunity was evident in all WT Rag−/− (n=11) and Rag−/− KbDb−/− (n=4) recipients of thymocytes, but not in any of the CiiTA−/− recipients (n=4). There were no signs of disease in the recipients of WT NGTC. Our study suggests that BTLA is required to establish tolerance in NGTC. Disease in BTLA−/− thymocyte recipients was mediated by the CD4+ T cells and was dependent on MHC II.
IL-4 and IL-13 act on immune and epithelial cells to promote gastric metaplasia during autoimmune gastritis
Authors: Noto Christine N , Bockerstett Kevin A , Jackson Nicholas M , Hoft Stella G , Mollman Johnathan , Ford Eric L , DiPaolo Richard J 
Published: February 2023

Abstract
Chronic inflammation in the stomach can lead to peptic ulcers and is the highest independent risk factor for developing gastric cancer. Autoimmune gastritis (AIG) and infection with Helicobacter pylori are the two major causes of chronic gastritis. Cytokines released during chronic inflammation likely regulate the degree of tissue damage and the emergence of metaplasia, a precancerous condition believed to be the origin of gastric cancer. We recently discovered that mice with AIG that lack a receptor for IL-4/IL-13 (Il4ra−/−) developed mild gastritis but failed to develop gastric metaplasia. The objective of this study was to determine how IL-4 and/or IL-13 regulate disease development and severity. Immune assays revealed that autoantibody titers were high in control mice with AIG yet were nearly absent in Il4ra−/− mice with AIG. Epithelial cell assays revealed that both IL-4 and IL-13 also act on the gastric epithelium to promote growth and induce transcriptional changes associated with metaplasia. Finally, neutralizing antibodies to IL-4 and IL-13 were effective at ameliorating disease and preventing gastric metaplasia in mice with AIG. Together these data demonstrate that IL-4 and IL-13 play critical and complex roles in exacerbating gastric disease severity and metaplasia development by increasing production of tissue-damaging autoantibodies and inducing gastric metaplasia. These novel findings identify IL-4 and IL-13 as potential therapeutic targets for treatment of diseases induced by chronic gastritis.
RNA m6A methylation guides IL-17-driven autoimmunity through IMP2-dependent regulation of C/EBP transcription factors
Authors: Bechara Rami , Amatya Nilesh , Bailey Rachel D. , Li Yang , Aggor Felix EY , Li De-Dong , Jawale Chetan V. , Jawale Chetan V. , Coleman Bianca M. , Dai Ning , Gokhale Nandan S. , Taylor Tiffany C. , Horner Stacy M. , Poholek Amanda C. , Biswas Partha S. , Gaffen Sarah L. 
Published: February 2023

Abstract
Dysregulated activity of IL-17 underlies many autoimmune conditions, but the molecular mechanisms by which IL-17 mediates pathogenic inflammation remain poorly understood. IL-17 regulates pathogenic inflammatory genes by two key transcription factor classes, NF-κB and CCAAT/Enhancer Binding (C/EBP) proteins. Surprisingly little is known about mechanisms that activate C/EBPs. In seeking to understand how IL-17 upregulates C/EBPs, we found that IL-17 signaling enhanced Cebpd mRNA stability, concomitant with increased levels of C/EBPδ translation. In contrast, IL-17 had only a marginal inductive effect on Cebpb mRNA, yet C/EBPβ protein was strongly upregulated. Examination of Cebpb and Cebpd noncoding sequences identified consensus sites for N6-methyladenosine (m6A) modification, an epitranscriptomic mark that influences mRNA fate. knockdown of the m6A ‘writer’ METTL3 decreased C/EBP expression, which was reversed by the ‘eraser’ FTO. Moreover, we found that loss of an unusual m6A ‘reader’ IGF2BP2 (IMP2), an RNA binding protein known to control mRNA stability, impaired IL-17 induction of C/EBPs. IMP2 bound directly to Cebps transcripts, leading to enhanced Cebpd half-life and enhanced translation of both C/EBPs. Transcriptomic analysis revealed that IMP2 regulates C/EBP-dependent genes, including IL-6 and Lcn2. Lcn2 is a biomarker of autoantibody-induced glomerulonephritis (AGN), a setting of IL-17-driven inflammatory nephritis. Imp2−/− mice were resistant to AGN, which was linked to impaired upregulation of C/EPBs and Lcn2 in kidney. Thus, IL-17-induced autoimmunity is mediated through m6A-dependent post-transcriptional regulation of C/EBP transcription factors.
Adipocyte-secreted Interleukin-9 Promotes Leukemia Development and Chemoresistance to Front-line Chemotherapies
Authors: Hamilton Jamie A.G. , Pillsbury Claire E. , Lee Miyoung , Henry Curtis J. 
Published: February 2023

Abstract

Background
Obese pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) have inferior overall survival outcomes compared to lean patients, with obese patients having a 2.5-fold increased risk of an adverse event and an almost 4-fold greater risk of death. Emerging data suggest that the presence of factors in the obese microenvironment may directly promote chemoresistance in B-ALL cells.

Objective
Given the increasing prevalence of obesity and negative impact of obesity on cancer, in this study, we sought to determine how adipocytes impact B-ALL progression and responses to front-line chemotherapies.

Results
We found that circulating IL-9 levels were significantly elevated in obese mice fed high-fat diets compared to mice fed control diets. Furthermore, treating human B-ALL cells with recombinant IL-9 (rIL-9) promoted cell cycle progression and proliferation. Interestingly, rIL-9 stimulation of human B-ALL cells activated survival pathways, which coincide with the induction of chemoresistance to methotrexate and doxorubicin.

Conclusions
Our findings demonstrate that IL-9 levels are elevated in obese microenvironments and that this cytokine promotes B-ALL pathogenesis. In ongoing studies, we are determining how antibody-mediated neutralization of IL-9 impacts disease progression and chemosensitivity in B-ALL cells.
Distinct spatial profile of inflammatory gene expression in the brain of a mouse model of neuropsychiatric lupus
Authors: Aw Ernest , Zhang Yingying , Carroll Michael 
Published: February 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease that results in central nervous system (CNS) involvement in up to 80% of patients, with clinical manifestations ranging from anxiety and fatigue to overt psychosis. However, the mechanisms and cellular components underlying these neuropsychiatric symptoms (NPSLE) remain largely unknown. An elevated type 1 interferon (IFN) signature has been commonly observed in SLE patients, particularly within the CNS of NPSLE patients (Crow et. al., 2014, Shiozawa et. al., 1992). Given the diversity of clinical CNS manifestations, we hypothesized that type 1 interferon-mediated inflammation occurs in spatially distinct regions within the CNS, resulting in differential behavioral outcomes depending on the impacted brain region. To test this hypothesis, we first characterized behavioral phenotypes in the Sle1, Yaa mouse model, and show that these mice exhibit anxiety-like, and fatigue-like behaviors consistent with the major clinical manifestations of NPSLE. To assess the spatial distribution of inflammatory gene expression, we utilized MERFISH (Moffitt et. al., 2016), a multiplexed spatial transcriptomics platform, and observed strikingly distinct patches of interferon stimulated gene (ISG) expression within the subcortical regions of Sle1, Yaa mouse brains. Preliminary single nucleus sequencing (sNuc-Seq) and in situ hybridization results implicate astrocytes and oligodendrocytes as the major cell classes enriched in these ISG patches. In summary, our results validate a mouse behavioral model of NPSLE, and show spatially distinct regions of ISG expression within the CNS, opening up a new avenue of investigation into the fundamental mechanisms of NPSLE.
Loss of isoprenylation significantly reduces IgE mediated mast cell activation
Authors: Dailey Jordan , Ballance William , Kee Sydney Ann , Jackson Kaitlyn G. , Sebti Said , Ryan John J 
Published: February 2023

Abstract
Allergic disease a leading cause of chronic illness in the US and accounts for billions of dollars in healthcare costs annually. Mast cells are tissue resident innate immune cells linked to allergic disease and activated by IgE and other ligands. Upon activation they release histamine, cytokines, chemokines, proteases, and lipid mediators evoking allergic symptoms. New ways of targeting mast cells could greatly benefit allergic disease therapy. Repurposing statin drugs such as Fluvastatin as a therapeutic treatment of allergic disease showed reduced allergic symptoms using in vitro and in vivo mouse models. We found the Fluvastatin suppresses IgE mediated mast cell activation by inhibiting protein isoprenylation. However, statin suppression is dependent on genetic background. To avert genetic background dependency, we tested the hypothesis that a dual farnesyl and geranylgeranyl transferase inhibitor (FGTI 2734) would consistently suppress mast cell function. We show that FGTI 2734 reduced IgE-mediated degranulation and cytokine production similar to Fluvastatin effects, but maintained efficacy on fluvastatin-resistant genetic backgrounds. FGTI 2734 also suppressed IgE-mediated anaphylaxis in vivo on multiple genetic backgrounds. Finally, inhibition of Ras, a known target of prenylation, can mimic statin effects on IgE-mediated mast cell function. These data support the hypothesis that dual farnesyl and geranylgeranyl transferase inhibitors may be an effective therapeutic treatment for mast cell-associated diseases.
Na+/H+ exchanger regulatory factor 1 (NHERF1) enhances MRGPRX2-mediated mast cell anaphylaxis
Authors: Subramanian Hariharan , Kammala Ananth Kumar , Das Rupali 
Published: February 2023

Abstract
Anaphylaxis is a severe life-threatening allergic reaction that is caused by mast cell hyperactivity. Two different mast cell receptors play critical roles in mediating anaphylaxis: 1) the IgE receptor that is stimulated by IgE-bound allergen and 2) the MRGPRX2 receptor that can bind to several cationic molecules and FDA-approved drugs resulting in mast cell activation. Activated mast cells degranulate to release proinflammatory mediators. We have recently identified that Na+/H+ exchanger regulatory factor 1 (NHERF1) regulates IgE-dependent mast cell activation in vitro and promotes passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA) in vivo. In the current study, we investigated the role of this adapter molecule in affecting IgE-independent mast cell activation via the MrgprB2 (mouse orthologue of human MRGPRX2) receptor using a novel mouse strain, Cpa3-Cre+ NHERF1fl/fl that lacks NHERF1 in mast cells. PCA and PSA to compound 48/80 (a known MrgprB2 agonist) were significantly attenuated in the Cpa3-Cre+ NHERF1fl/fl mice as compared to control Cpa3-Cre− NHERF1fl/fl mice. In agreement with our in vivo data, peritoneal mast cells isolated from Cpa3-Cre+ NHERF1fl/fl mice showed a significant reduction in mast cell degranulation to the MrgprB2 ligands, compound 48/80 and substance P. Additionally, NHERF1-silenced human LAD2 mast cells showed decreased degranulation to these ligands as well. Collectively, our data suggests that NHERF1 promotes mast cell activation though the MRGPRX2/MrgprB2 receptor and determining the mechanisms through which NHERF1 modulates MRGPRX2 responses will lend insights into the development of new therapeutics for anaphylaxis and other allergic diseases.
A Basophil-Neuronal Axis Promotes Itch Flares
Authors: wang Fang , Trier Anna M. , Li Fengxian , Kim Seonyoung , Chen Zhen , Chai Jiani N. , Mack Madison R. , Morrison Stephanie A. , Hamilton Jennifer D. , Baek Jinok , Yang Ting-Lin B. , Ver Heul Aaron M. , Xu Amy Z. , Xie Zili , Dong Xintong , Kubo Masato , Hu Hongzhen , Hsieh Chyi-Song , Dong Xinzhong , Liu Qin , Margolis David J. , Ardeleanu Marius , Miller Mark J. , Kim Brian S. 
Published: February 2023

Abstract
Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders like atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. Recent discoveries have implicated type 2 cell-associated cytokines such as IL-4, IL-13, and IL-31 in directly stimulating sensory neurons to promote chronic itch in AD. However, in addition to chronic itch, patients often experience intense acute itch exacerbations. Whether this form of itch represents amplification of known itch pathways or a different mechanism remains overlooked. Herein, we show that a large proportion of patients with AD harbor allergen-specific IgE and exhibit a propensity for acute itch flares. In mice, we found that while acute itch is mediated by the classical mast cell-histamine axis in steady-state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene receptor (CysLTR2) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a novel basophil-neuronal circuit that may underlie a variety of pathological neuroimmune processes.
Dual role of CCL3 and follicular regulatory T cells in the control of germinal center response
Authors: Ke Fang , Benet Zachary , Grigorova Irina L 
Published: February 2023

Abstract
Follicular regulatory T cells (Tfrs) have been reported to play multiple roles in the control of B cells response. They repress foreign antigen-specific germinal center (GC) B cells at the peak of GC response. At the same time, under some conditions they promote GC B cell cycling in IL-10 dependent fashion and ensure optimal affinity maturation. Our previous studies suggested that CCL3 produced by GC centrocytes (CCs) promoted their direct contacts with Tfr cells and negative regulation of GC B cells at the peak of GC response. However, which fraction of CCs upregulates CCL3 expression, which receptors on Tfrs may respond to CCL3, and the long-term effect of CCL3 on GCs has been unclear. Based on the single cell and bulk qPCR analysis we found that CCL3 is upregulated in about 10% of CCs that express Myc and are undergoing positive selection. qPCR and transwell analysis revealed expression and synergistic involvement of CCR5 and CCR1 chemokine receptors on Tfr cells in their chemotaxis to CCL3. Interestingly, both an adoptive transfer and mixed bone marrow chimeras models suggest that after the peak of GC response B cell-intrinsic production of CCL3 promotes their prolonged participation in GCs and B cell affinity maturation, as well as better memory and plasmablast response. We also showed that both the negative and positive regulation of GC B cells by CCL3 was dependent on the presence of Tregs. To summarize, our studies suggest that in addition to the role of CCL3 and Tregs in the modest repression of foreign antigen-specific B cells at the peak of GC response, it is also important for optimal selection of B cells in GCs. Further studies are underway to determine the role of Tfr cells specifically in the negative and positive CCL3-mediated regulation of GCs.
Redefining the targets of the vitamin D receptor (VDR) utilizing a novel VDR reporter mouse.
Authors: Arora Juhi , Cantorna Margherita T 
Published: February 2023

Abstract
The vitamin D receptor (VDR) is a ligand-activated nuclear protein that regulates gene transcription. Vitamin D target cells are identified by the expression of VDR. Kidney and colon epithelial cells constitutively express high levels of the VDR. Immune cells also express the VDR; however, at significantly lower levels. Western blots show very low expression of the VDR in spleen, and lymph nodes. Gene expression studies in macrophage, B cells and T cells showed that activation for 24–48 hours increased the VDR mRNA levels. We have developed transgenic mice that express Cre recombinase within the VDR locus (VDRcre) and crossed these with a reporter line (Tdtomatofl/fl). Cre expression in the VDR locus results in a VDR +/− mice. The frequencies of immune cells were similar between VDR−/− and VDR +/− mice. The VDRcre expressing offspring had pink skin. Kidneys, small intestine and colon were also distinctly pink suggesting high expression of the Tdtomato-VDR reporter. Splenic T cells, activated with CD3e antibody showed upregulation of VDR mRNA and protein. Regardless of activation status, naive, effector or memory T cells had similar and high levels of the VDR reporter. VDR expression was detected at various stages of T cell thymic development with a 80% in the CD4-CD8- cells and 90% of CD4+CD8+ cells, 84% CD4+ and 88% CD8+ thymocytes. High expression of the VDR reporter in multiple T cell types and precursors suggests that the VDR is expressed throughout the life of a T cell. Future work will identify immune cells negative for the VDR reporter and the kinetics of VDR expression following activation in various cell types.