bluuebunny/crossref_metadata_2025_split huggingface dataset:
What is (in)significant? The Pathway Semantics Algorithm reveals complex immune response changes over time. (58.18)
Authors: Csencsits-Smith Keri , McGuire Mary , Nguyen Trinh , Pascual David 
Published: January 2023

Abstract
Results obtained from hypothesis-driven research may not represent the complex interactions between cells and cytokines required for the development of an acquired immune response. We applied a novel algorithm to measure change in immune response over time in a mouse model of anti-Factor VIII (FVIII) antibody formation in hemophilia A. Splenocytes isolated from FVIII injected mice treated with PBS or an experimental tolerogen (CFA/1) were cultured for 72 hours and cytokine concentrations determined via multiplex analysis at days 7 and 14. The concentrations of 22 individual cytokines were compared between the control and CFA/1-treated groups, and 3 cytokines statistically differentiated the two groups at day 7 and 5 cytokines at day 14. Median cytokine concentrations/group of each significance set were converted to pmol/L and Ingenuity Pathway Analysis was used to generate likely biological network pathways. Network graphs were converted to matrices and linear algebra was used to compare treatment groups. Sixteen different molecules were predicted to occur in PBS vs. CFA/1 groups at day 7. We validated the presence of two predicted outcomes - expression of TLR 4 and secretion of IL-25. At day 14, the predicted outcomes were similar between the treatment groups, despite being evoked from a larger significance set, suggesting that statistical differences in cytokine secretion do not consistently represent biologically relevant changes in immune response over time.
Development of IL-17A promoter-based reporter cell line and activation of the cell line by exogenous expression of RORγ and RORγt. (59.12)
Authors: Singh Sujay , Lee Hyun-Ku , Singh Gita , Luo Yi Feng , Chitta Sriram , Rosenberg Jonathan 
Published: January 2023

Abstract
As one of the six known IL-17 family members, IL-17A is a proinflammatory cytokine secreted by innate and adaptive immune cells. Especially IL-17A has been characterized as a key cytokine produced in a new CD4+ T helper subset, Th17 cells, which play an important role in host defense against specific pathogens. Effect of IL-17A is also implicated with pathogenic role of Th17 cells in autoimmunity and the chronic activation of IL-17-producing T helper cells can lead to autoimmune diseases. Indeed, increased levels of IL-17 have been observed in patients with autoimmune diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis as shown by researchers. Hence development of a targeted therapeutic means or molecule that can effectively control IL-17 induction is crucial to prevent the initiation of IL-17-producing cell-mediated autoimmune diseases. In response to this, we have developed the IL-17A Prom/LUCPorter™ HEK 293 cell line, in which Renilla luciferase reporter gene is under control of the inducible IL-17A promoter. This cell line has been validated by exogenous expression of RORγ or RORγt construct, which can induce the IL-17A promoter activity leading to expression of luciferase reporter protein. This cell line is suitable for screening of antagonists for IL-17A induction which can be utilized as the therapeutic target molecules to control IL-17-producing cells.
Identification of a novel secreted molecule expressed by Th17 cells: potential association with inflammatory diseases. (59.3)
Authors: Valle-Rios Ricardo , Burkhardt Amanda , Hevezi Peter , Zlotnik Albert 
Published: January 2023

Abstract
CD4 T cells (Th cells) play an important role in adaptive immune responses. These processes are controlled in part by a pattern of soluble molecules (cytokines) secreted by different types of Th cells. Here we describe a novel secreted molecule which we have called barrier tissue and activated T cell-associated molecule (BATAM). Using a comprehensive database of human gene expression that comprises more than 115 tissues or organs of the body, we identified a secreted protein that is produced by activated CD4 T cells as well as skin and various mucosal tissues. BATAM encodes a ~60 KD protein that contains a thrombospondin type 1 repeat (TSR) and the adhesion associated domain AMOP, which are known to mediate cell adhesion and are also present in various proteins involved in inflammation. We confirmed the BATAM expression pattern by qPCR in mouse tissues. The production of BATAM by activated spleen CD4 T cells is significant but not strong. We therefore hypothesized that BATAM may be preferentially produced by a polarized subset of Th cells. To investigate this possibility, we polarized CD4 T cells into Th1, Th2, Treg and Th17 in vitro. The results indicate that BATAM expression is highly associated with Th17 cells. We have also confirmed that it is a secreted protein. Using recombinant BATAM, we are currently probing its biological activity. We conclude that BATAM is a novel pro-inflammatory molecule that may be associated with diseases mediated by Th17 cells.
T helper cytokines expression in leprosy forms and reactional states: serum and in situ analysis (59.9)
Authors: Trombone Ana Paula , Belone Andrea , Guidella Cassio , Fachin Luciana , Ramuno Natalia , Soriani Michelle , Ura Somei , Soares Cleverson , Garlet Gustavo , Rosa Patricia 
Published: January 2023

Abstract
Leprosy is a chronic infectious disease of the skin and peripheral nerves characterized by a broad spectrum of clinical forms, namely tuberculoid (TT) and lepromatous (LL), the borderline forms (BB, BT and BL) and the reverse reaction (RR) and erythema nodosum leprosum (ENL) reactional states. Since the immunological basis of leprosy is still unclear, we analyzed the profile of T helper (Th1, Th2, Th17, Treg) cytokines, in serum (ELISA) and in situ (qPCR), of 72 leprosy patients and 10 healthy controls. ELISA data shows that the frequency of IL-10, IL-6 and IL-22 detection was significantly higher in patients than in controls, while TGF-b was detected in all the samples from both groups. IFN-g, IL-4 and IL-17 levels were not detectable in the serum of both controls and patients. Comparing the leprosy subgroups, IL-6 was higher in ENL patients when compared to paucibacillary (BT/TT) and multibacillary (BB/BL/LL); while IL-10 was higher in multi versus paucibacillary forms. qPCR analysis demonstrated that IL-17, IFN-g, IL-6 and TGF-b prevail in diseased sites versus controls, but no significant differences were found between the clinical forms. Our results suggest that a broader analysis of cytokine profile can contribute to a better characterization of leprosy forms than the traditional Th1/Th2 archetype, and a larger sample must be evaluated in order to confirm these findings.
Complexed BCR-TLR9 stimulation induces an activation associated cell death in B cells which is rescued by BLyS (60.12)
Authors: Oropallo Michael , Green Nathaniel , Kiefer Kerstin , Moody Krishna , Marshak-Rothstein Ann , Cancro Michael 
Published: January 2023

Abstract
Combined B cell receptor (BCR) and Toll-like receptor 9 (TLR9) signaling has been associated with the T cell Independent (TI) activation of autoreactive B cells in the presence of self-DNA. However, TLR9 knockout models of humoral autoimmunity have increased disease severity, suggesting the receptor has a more complex role. We have recently found that while both WT and AM14 RF producing B cells stimulated with complexed BCR-TLR9 agonists indeed proliferate, they die rapidly within 48-72hrs of initial stimulus, implying that combined BCR:TLR9 signaling has a role in limiting the T cell independent activation of B cells. Importantly, this activation associated cell death is unique to complexed BCR-TLR stimulation, as BCR agonist (anti-IgM) alone, TLR9 agonist (CpG ODN) alone, or both BCR + TLR9 agonists uncomplexed induces cells to continue to survive and proliferate robustly within this time frame. Further, this apoptosis involves the intrinsic mitochondrial cell death pathway, as it involves cleavage of caspase 9, occurs independently of caspase 8, and is rescued by the presence of a BCLxL transgene. Finally, we have found that addition of the survival cytokine BLyS rescues B cells proliferating in response to complexed BCR-TLR9 from cell death through BLyS binding to BR3, providing insight into how increased BLyS titers contribute to the onset of autoreactive B cell activation.
High salt induces pathogenic Th17 cells and exacerbates autoimmune diseases (60.13)
Authors: Kleinewietfeld Markus , Manzel Arndt , Wu Chuan , Titze Jens , Kuchroo Vijay , Linker Ralf , Muller Dominik , Hafler David 
Published: January 2023

Abstract
Interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) play a pivotal role in autoimmune diseases. Apart from their importance for the control of certain pathogens, IL-23 dependent Th17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE). Moreover, genetic risk factors associated with multiple sclerosis (MS) are linked to the IL23/Th17 pathway. Besides genetic factors, the increased incidence of autoimmune diseases like MS in developed countries is also believed to be related to environmental risk factors. However, how environmental risk factors such as changes in diet, sun exposure or medications could directly influence the development of pathogenic Th17 cells is not well established. Here we show that increased salt (sodium chloride; NaCl) concentrations dramatically boost the induction of murine and human Th17 cells in vitro. Moreover, mice fed with a high salt diet develop a very severe form of EAE, dependent on the induction of highly pathogenic Th17 cells. The generation of Th17 cells under high salt conditions is well regulated on the molecular level and seems to be dependent on specific pathways. Thus, increased salt intake, which may represents one of the biggest contributors to changes in diet during the last half century and accounts for cardiovascular disease, might also represent an environmental risk factor for autoimmune diseases through the exacerbated induction of pathogenic Th17 cells.
Autoreactive CD4+ Th1 cells activate monocytes to support Th17 responses in inflammatory arthritis (60.8)
Authors: Simons Donald , Oh Soyoung , Garcia Victoria , Kropf Elizabeth , Caton Andrew 
Published: January 2023

Abstract
Th17 cells have been implicated in a number of autoimmune and inflammatory disorders, yet signals that can lead to a Th17 response in vivo are poorly understood. We have analyzed this question using a transgenic mouse model in which autoreactive CD4+ T cells recognizing a ubiquitously expressed surrogate self-antigen (influenza HA) induce inflammatory arthritis by an IL-17-dependent mechanism. Arthritis development is accompanied by an accumulation in the joint draining lymph nodes of inflammatory monocytes (iMOs) that have an enhanced capacity to support Th17 responses in vitro. The accumulation of iMOs in the LNs is preceded by an autoreactive CD4+ Th1 cell response, and by the upregulation of MHCII on iMOs in the spleens of pre-arthritic mice. Adoptive transfer of HA-specific CD4+ T cells into mice that expressed HA as a self-antigen similarly led to the formation of Th1 cells and of MHCII+ iMO that could support Th17 cell formation in vitro, and significantly, the accumulation of these iMOs in the LNs was blocked by IFNγ neutralization. Collectively, these studies provide a basis by which autoreactive CD4+ Th1 cells directed to a systemically distributed self-antigen can promote a regional inflammatory disease (arthritis) by promoting the formation of Th17-trophic iMO and driving their recruitment into the LNs.
Annexin A1 mediates the anti-inflammatory effects during the granulocytic differentiation process in all-trans retinoic acid-treated acute promyelocytic leukemic cells (63.2)
Authors: Hsu Hui-Chi , Tsai Wen-Hui , Chien Hong-Yu , Shih Chung-Hung , Lai Shu-Lien , Li I-Ting , Hsu Shau-Chieh , Kou Yu Ru 
Published: January 2023

Abstract
Annexin A1 (AnxA1) originating from neutrophils and their microparticles (MPs) plays an important anti-inflammatory role. The role of AnxA1 during the process of granulocytic differentiation is still unknown. All-trans retinoic acid (ATRA) can induce differentiation of acute promyelocytic leukemic(APL) cells into mature granulocytes. We investigated whether or not AnxA1 contributed to the anti-inflammatory properties of ATRA-treated APL (NB4; ATRA-NB) cells. We found that ATRA was able to enhance the surface expression of AnxA1 and its receptor (FPR2/ALX) and the release of AnxA1-containing MPs from ATRA-NB4 cells. Further studies demonstrated that exogenous AnxA1 could inhibit ATRA-NB4 cells in their transmigratory and adhesive activity. In addition, the transmigratory activity of ATRA-NB4 cells can be significantly enhanced by pretreatment with a FPR2/ALX neutralizing antibody, suggesting that endogenous AnxA1 may contribute to the anti-migratory effects. Finally, ATRA-NB4-derived MPs could also inhibit recipient cells in their transmigratory and adhesive activities and these anti-inflammatory effects could be inhibited by pretreatment of MPs with an anti-AnxA1 antibody. Further studies demonstrated that FITC-labeled AnxA1 could be transport from MPs to the membrane of recipient ATRA-NB4 cells. We conclude that biologically active AnxA1 may play a role in the anti-inflammatory properties of ATRA-APL cells during the process of granulocytic differentiation.
Double knockout of Id2 & Id3 in developing T cells promotes the development of CD4-CD8- αβ T cell (63.3)
Authors: Li Jia , Zhuang Yuan 
Published: January 2023

Abstract
αβ T cell development is regulated by sequential rearrangement and expression of TCRβ and TCRα genes at the DN (CD4-CD8-) and DP (CD4+CD8+) stage, respectively. Expression of TCRβ paired with preTα at the DN stage leads to αβ lineage commitment and differentiation into the DP stage. DP cells undergo TCRα gene rearrangement, resulting in expression and the selection of functional αβTCR. Id3 has been shown to be an important sensor downstream of both preTCR and TCR signals. However, Id3 knockout only leads to a partial block in αβ lineage development, suggesting functional compensation from other Id proteins. To further investigate functions of Id proteins at the preTCR and TCR checkpoints, we simultaneously deleted Id3 and the structurally and functionally related Id2 gene at the early DN stage of T cell development. We find that removal of Id2 and Id3 failed to block T cell development at the preTCR checkpoint although imposed a strong block at the TCR checkpoint. Furthermore, deletion of both Id2 and Id3 promoted development of an aberrant population of αβ T cells that bear DN (CD4-CD8-) phenotype. This genetic system revealed a novel function of Id proteins in regulation of alternative αβ lineages during T cell development. We will present the latest information on characterization of this CD4-CD8- αβ T cell lineage associated with Id2 and Id3 disruption in developing T cells.
The role of Dectin-1 in fungal asthma (64.5)
Authors: Lilly Lauren , Metz Allison , Dunaway Chad , Schwiebert Lisa , Steele Chad 
Published: January 2023

Abstract
Sensitization to fungi, such as the mold Aspergillus fumigatus, is increasingly becoming linked with asthma severity. Although long considered a Th2 dominated disease, emerging data indicates that IL-17A and IL-22 may also contribute to asthma pathogenesis. Our laboratory has identified protective roles for Dectin-1 mediated beta-glucan recognition and Dectin-1 dependent IL-17A and IL-22 production during invasive A. fumigatus infection. Unexpectedly, in an allergic model of repeated lung exposure to live A. fumigatus conidia, we show that the absence of Dectin-1 resulted in markedly improved respiratory mechanics in the presence of reductions in multiple allergy-associated and inflammatory mediators. Intriguingly, attenuated lung IL-17A and IL-22 production in Dectin-1 deficient mice, but not Th2 cytokines, correlated with a better outcome. IL-22 deficiency reproduced the phenotype observed in Dectin-1 deficient mice after repetitive A. fumigatus exposure. We further identified IL-33 as a Dectin-1 and IL-22 dependent pro-allergic mediator. Collectively, our data suggests that during repetitive fungal exposure, beta-glucan recognition via Dectin-1 results in the generation of IL-17A and IL-22 responses as well as to the induction of IL-33 leading to the initiation of the allergic cascade. These results provide a novel link between infectious agents (fungi), new players (IL-22) and immunopathogenesis (IL-33) in severe asthma.
Identification of a novel motif in MARCH1 that affects the conformation and the E3 ubiquitin ligase activity (65.10)
Authors: Bourgeois-Daigneault Marie-Claude , Thibodeau Jacques 
Published: January 2023

Abstract
Some members of the MARCH family of RING-type E3 ubiquitin ligases target important players of immune responses. Of these, MARCH1 prevents the cell surface accumulation of MHC class II molecules and regulates antigen presentation in response to IL-10 in human primary monocytes (Thibodeau et. al., Eur JI 2008). Structure-function analysis of mouse MARCH1 showed the presence of two functional tyrosine-based endosomal sorting motifs in the C-terminal cytoplasmic part of the protein. We investigated the importance of the corresponding motifs in human MARCH1. Site-directed mutagenesis of these tyrosines did not reduce the activity of MARCH1 in transfected cells. However, a reporter molecule fused to the C-terminal cytoplasmic domain of MARCH1 was expressed less efficiently at the plasma membrane. A series of deletions were made in the C-terminal part of MARCH1 and a new functional motif was discovered. BRET experiments revealed that this motif is important for the spatial organisation of the two cytoplasmic domains of MARCH1. Interestingly, this motif is also present in others RING-type E3 ubiquitin ligases such as Parkin and its alteration is linked to the development of the disease in certain patients.
Histamine 2 receptor mediates IL-4-dependent class switching to IgE in B cells (65.5)
Authors: Swartzendruber Julie , Bryce Paul 
Published: January 2023

Abstract
Histamine is a critical mediator of allergic disease and signals through four receptors. We recently showed that histamine 2 receptor (H2R) is essential for IL-4 mediated eosinophil recruitment and that H2R deficient mice are protected from allergic airway inflammation. Additionally, we observed an inability to generate IgE in these mice. This was not due to a sensitization defect, since the mice are capable of generating antigen specific IgG1. However, the functions of H2R on B cells are unclear. Here we show that H2R is not required for B cell development and proliferation and that H2R deficient mice are capable of generating antibodies to the T independent antigens NP FICOLL and NP LPS. However, H2R deficient B cells were unable to class-switch to IgE in vitro. This was further characterized by an absence of epsilon specific post-switch transcripts in H2R deficient B cells. The upregulation of CD23 in response to IL-4 was also impaired in H2R deficient B cells. STAT6 phosphorylation in IL-4 treated B cells from H2R deficient mice was also reduced. These findings suggest that histamine is vital in permitting IL-4 signaling to mediate STAT6 phosphorylation and for the switch to IgE that occurs in B cells.
CD200R1 regulates synovial inflammation through neutrophil LTB4 (66.3)
Authors: Vaine Christine , Primo Valeria , Nikolic Boris , Calderone Nicholas , Nigrovic Peter , Soberman Roy 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a debilitating disease afflicting over 2 million Americans. The K/BxN model of synovial inflammation shares several key aspects of pathology in common with human RA, and is an accepted model of synovial inflammation. The 5-lipoxygenase (LO) pathway product leukotriene (LT)B4, generated by polymorphonuclear leukocytes (PMNs) and macrophages, plays a requisite role in this model by initiating and amplifying the recruitment and activation of PMN in joints. Mechanisms that down-regulate LTB4 synthesis have the potential to play a major role in inhibiting synovial inflammation and provide novel therapeutic targets. To explore the role of the inhibitory CD200:CD200R1 axis in this process, we developed CD200R1-/- mice and examined them in the K/BxN arthritis model. We observed that CD200R1-/- mice show increased severity as compared to CD200R1+/+ mice. Synovial fibroblasts were found to express CD200 and are in close proximity to CD200R1-expressing macrophages in inflamed ankle sections. Finally, CD200R1-/- PMN generated approximately 50% more LTB4 in response to C5a or to a combination of GM-CSF and C5a. Together, these observations indicate that CD200R1 plays a key role in regulating LTB4 synthesis and synovial inflammation in the K/BxN model of RA.
Reconciling heterogeneous differentiation of CD4+ T cells by systems-level modeling (66.4)
Authors: Hong Tian , Xing Jianhua , Li Liwu , Tyson John 
Published: January 2023

Abstract
CD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Here, we propose a systems frame work to demonstrate how heterogeneous differentiation can be initiated by a dynamic signaling motif composed of competing master regulators common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. This framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cell, and it can be helpful for interpreting experimental results. This mathematical model makes specific testable predictions that may that may advance our understanding of the complex molecular network regulating T helper cell differentiation.