bluuebunny/crossref_metadata_2025_split huggingface dataset:
The transcriptional regulator Bcl-3 impaires the function of regulatory T cells leading to the development of intestinal inflammation (BA6P.131)
Authors: Reissig Sonja , Nikolaev Alexei , Waisman Ari , Hoevelmeyer Nadine 
Published: December 2022

Abstract
The oncoprotein and transcription factor Bcl-3 (B cell leukemia-3) is a member of the IkB family of NF-κB inhibitors and was originally identified as a component of a chromosomal rearrangement in some B cell lymphomas. In contrast to other IkB proteins, Bcl-3 associates with p50 and p52 homodimers and is predominantly a nuclear protein involved in regulating nuclear NF-kB activity. To understand more about the effects of Bcl-3 on T cells, we have generated a new mouse model, where Bcl-3 is overexpressed specifically in T cells. We could show that mice overexpressing Bcl-3 solely in T cells developed spontaneous colitis accompanied by a massive cell infiltration into the colon. Interestingly, the TCRgd+ T cell population was dramatically increased in the colonic IEL population of the Bcl-3 overexpressing mice. By examing Tregs in these mice, we found that overexpression of Bcl-3 strongly impairs Treg cell function, which was accompanied by decreased expression of CD25, Foxp3 and the co-inhibitory molecule CTLA-4. Hence, the loss of suppression of Bcl-3 overexpressing Tregs might result in the development of severe spontaneous colitis. Our data emphasize a novel pathway in the maintenance of viability and suppressive function of Tregs in the gut that critically involves Bcl-3 as a negative regulator, qualifying this protein as an interesting pharmacological target for the treatment of IBD.
Specific variations in the protocol for the induction of collagen-induced arthritis in mice improve reproducibility of disease severity and incidence in an SPF facility (BA6P.136)
Authors: Strait Richard , Thornton Sherry 
Published: December 2022

Abstract
Collagen-induced arthritis (CIA) is a widely used model for studying inflammatory arthritis (IA). CIA incidence and severity (I&S) varies between labs. Factors effecting induction include; adjuvant, # of collagen type II (CII) immunizations (imm), use of LPS and environmental hygiene. A better understanding of the effects of variations in protocols/environment on the I&S of CIA would improve the quality use this model. Method: Mice in conventional (con) and specific-pathogen free (SPF) facilities were compared. Mice were imm with 2 doses CII in complete (CFA) or incomplete (IFA) Freund’s adjuvant. LPS and/or CII were given at specific intervals following the 2nd imm. IA was evaluted using established scoring systems. Result: Following CII/CFA imm, con-housed had higher I&S of IA than SPF-housed mice. For SPF-housed mice, LPS 3 d after the 2nd CII/CFA imm modestly increased IA I&S. Unlike LPS or CII alone, additional LPS+CII 14 and 28 d later resulted in severe IA in all mice. Substitution of IFA for CFA along with LPS/CII at 14 and 28 d allowed for development of moderately severe IA in 80% of mice. Conclusion: Specific variations in use of CII, CFA, IFA and LPS can induce a range of IA I&S in a SPF facility . Thus, distinct experimental settings may be designed for robust assessment of factors that either exacerbate or inhibit arthritis pathogenesis. These protocols provide a practical and humane benefit of reducing cost, time and mice necessary for experimental assessment.
TNFR2 regulates gut commensal microbiota tocontrol sex-biased spontaneous experimental autoimmune encephalomyelitis (BA6P.138)
Authors: McKarns Susan , Miller Patrick 
Published: December 2022

Abstract
Host-commensal interactions influence the development and plasticity of gut-associated T helper (Th) and T regulatory (Treg) cells. In mice, the gut commensal segmented filamentous bacteria (SFB) modulate TH17 and FoxP3+ Treg differentiation to enhance host protection against external pathogens. However, in the context of a susceptible genetic background, SFB has the potential to augment the development of autoimmunity, including multiple sclerosis (MS). We have previously demonstrated that greater than 90% of female, but few male, tumor necrosis alpha receptor type 2 (TNFR2)-deficient mice crossed onto the myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG35-55)-specific T cell receptor (TCR) transgenic background rapidly develop spontaneous experimental autoimmune encephalomyelitis (EAE). We now report that oral administration of trimethoprim/sulfamethoxazole, an antibiotic which has broad spectrum of activity against a variety of bacteria prevents the development of spontaneous EAE in TNFR2-deficient 2D2 TCR Tg mice. We have further combined Illumina MiSeq sequencing and RT-PCR to demonstrate a sex-biased microbiome profile in TNFR2-deficient MOG35-55-specific TCR mice, including increased SFB expression in the females relative to their male cohorts. Collectively, these findings suggest a role for TNFR2 in regulating commensal microbiota in the context of myelin autoantigen to control autoreactive T cells and autoimmune demyelination.
The gut microbiota regulates K/BxN autoimmune arthritis independent of Th17 and IL-17 (BA6P.121)
Authors: Block Katharine , Huang Haochu 
Published: December 2022

Abstract
The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The effect of the microbiota on autoimmunity has important implications, although the mechanisms are not well understood. The K/BxN mouse model of rheumatoid arthritis is dependent on the microbiota, and particularly on segmented filamentous bacteria (SFB), for the autoimmune phenotype. Because SFB potently induce Th17 cell differentiation, previous studies have suggested Th17 cells as the link between microbiota and arthritis. In this study we sought to test directly the functional significance of Th17 and IL-17 in arthritis development by genetic approaches. We utilized mice deficient for either transcription factor RORγt (which controls the Th17 program), or the cytokine IL-17A (the major cytokine of the IL-17 family) in both cell transfer and spontaneous disease models. Unexpectedly, mice without Th17 or IL-17 were not protected from disease. Germinal center B and follicular helper T cell (Tfh) populations were normal, as were levels of serum IgG against self antigen. We found no evidence for compensation in production of the related cytokine IL-17F in IL-17A deficient mice. However, antibiotic treatment prevented disease in both IL-17 deficient and sufficient K/BxN mice, and resulted in defective Tfh and germinal center B cell differentiation. We conclude that the gut microbiota promotes autoimmune development by mechanisms independent of Th17 or IL-17.
The role of susceptible HLA shared epitopes in rheumatoid arthritis: a proclivity for citrullinated and self peptides (BA7P.158)
Authors: Anderson Kirsten , Roark Christina , Portas Mary , Aubrey Michael , Freed Brian 
Published: December 2022

Abstract
Rheumatoid Arthritis (RA) is an autoimmune disorder most strongly linked to the HLA-DRB1 gene locus and associated with antibodies to joint proteins, of which many are citrullinated. Polymorphic positions in the peptide-binding groove of HLA-DRB1 correlate with RA susceptibility, suggesting that these residues mediate binding of arthritogenic peptides. We measured binding of type II collagen259-273 and native and citrullinated forms of vimentin66-78 and α-enolase11-25 to 88 HLA Class II alleles including susceptible and resistant DRB1 alleles. The most susceptible allele, DRB1*04:01, has a strong preference for citrullinated forms of vimentin66-78 and α-enolase11-25. Resistant alleles DRB1*04:02 and *08:01 had either no preference or preferred the native form of these peptides. Mutations at positions 67, 70, 71, 74 or 86 in DRB1*04:01 to the corresponding residues in DRB1*04:02 or *08:01 reduced citrullinated peptide specificity, by increased binding of the native form or decreased binding of the citrullinated. Using DRB1*04:01 restricted collagen259-273 specific T cell hybridomas, we tested the effect of the mutations on T cell response. A good correlation exists between collagen binding and the T cell response, with reduced binding also showing a reduced T cell response. However, while mutation at position 70 from a positively charged amino acid to negative still bound collagen259-273, the T cell response was eliminated.
Single-cell RNA sequencing reveals regulatory patterns of self-antigen expression by medullary thymic epithelial cells (BA8P.162)
Authors: Lonnberg Tapio , Miragaia Ricardo , Zhang Xiuwei 
Published: December 2022

Abstract
The crucial capability of T cells for discrimination between self and non-self peptides is based on rigorous negative selection of developing thymocytes by medullary thymic epithelial cells (mTECs). The mTECs purge autoreactive T cells by apparently stochastic expression of cell-type specific genes referred to as tissue-restricted antigens (TRAs). The expression of many TRAs is promoted by the autoimmune regulator (AIRE) protein, while others are induced by yet unknown factors. Despite its tremendous immunological significance, the regulation of TRA expression in mTECs is incompletely understood. Recently developed single-cell RNA-sequencing enables systematic dissection of such genome-wide patterns for the first time. Here we present analysis of 152 murine mTEC transcriptomes, revealing a regulatory hierarchy within the highly diverse population of TRA genes. We find that TRAs dependent on AIRE exhibit distinct transcriptional dynamics, with high degree of genomic clustering and characteristic transcriptional burst profiles. We show that expression of other, AIRE-independent TRAs, is likely to be secured by regulatory pathways promoting differentiation of the mTEC cells from the TEC progenitors. The TRA repertoire is further shaped by the maturation of the mTECs to MHCIIhigh state. We further show that certain subsets of TRAs are neglected by the mTEC population, and that mTEC-driven negative selection of thymocytes may have intrinsic leakiness.
Expression and function of IL-1R complex governing human Th17 responses (BA8P.167)
Authors: Kim Dong Hyun , Cho Sunjung , Chung Yeon-Ho , Lee Won-Woo 
Published: December 2022

Abstract
The IL-1 receptor signaling is essential for differentiation, commitment, and maintenance of Th17 cells by induction of RORγt, a Th17 lineage-specific transcriptional factor. Due to its immunological significance, IL-1 receptor signaling is tightly regulated by expression of a functional IL-1 receptor type I (IL-1RI), a decoy IL-1RII, and IL-1R antagonist. However, underlying mechanism for their expressions still remains to be clarified. We aimed to investigate how the expression of IL-1RI and II is modulated by CD4 T cells and how their expression affects human Th17 responses. IL-1RI expression was identified by a part of CD4 T cells, whereas no CD4 T cells in resting state express IL-1RII. Upon TCR stimulation, IL-1RII was however induced by CD4 T cells but the underlying mechanism seemed to be different in naive and memory subsets. In naive CD4 T cells, IL-6 was a critical cytokine for synergizing TCR-induced IL-1RII expression. However, its expression in CD4 memory T cells was largely dependent upon TCR signaling and cytokine effect was minimal. Of note, the IL-1RI and II expressions were higher in Foxp3+ CD4 T cells in response to TCR stimulation as compared with Foxp3- T cells, suggesting a possible role of IL-1R signaling in newly identified IL-17-producing Foxp3+ T cells. Our findings suggest that the regulatory mechanism for IL-1RI and IL-1RII expression is important for fine-tuning IL-1 signal and Th17 responses thereby affecting the pathogenesis of autoimmunity.
IL-22 reduces the pulmonary injury and lethality of influenza infection (CCR4P.201)
Authors: Pociask Derek , Yan Xiaoqiang , Kolls Jay 
Published: December 2022

Abstract
Influenza A hospitalization and mortality are often due to fulminant inflammation/acute respiratory failure (ARDS) or the development of secondary bacterial infections. Epithelial injury is a critical component of ARDS, thus identifying ways to attenuate inflammation while promoting epithelial integrity are vital in improving recovery after infection. We have identified IL-22 as an epithelial specific cytokine that is integral in lung epithelial repair, leading us to hypothesize that IL-22 has therapeutic potential during Influenza infection. To test this, mice infected with an LD90 or LD50 dose of H1N1(PR8/8/34) were treated with IL-22:Fc. While IL-22 treatment did not reduce viral load, It caused a significant reduction in inflammartion, neutrophilia, and lung leak. Importantly, this led to improved health outcomes (reduced weight loss, greater activity scores) and decreased mortality. This effect was specific to the IL-22Ra1 signaling as EIIa-cre x IL-22Ra1fl/fl mice (a global receptor knockout) were non-responsive to IL-22 treatment. Further, we believe IL-22Ra1 signaling is critical in the lung, as albumin-cre X IL-22Ra1fl/fl mice (liver specific) did not have reduced lung pathology with IL-22:Fc treatment. Taken together these data lead us to believe IL-22 is an important cytokine for improving recovery after influenza infection. We are currently working to identify the mechanisms and key IL-22ra1+ cells required for the therapeutic efficacy of IL-22.
Myeloid cells are primed for anti-inflammatory STAT6 signaling during inflammation (CCR4P.210)
Authors: Wermeling Fredrik 
Published: December 2022

Abstract
Intravenous Immunoglobulin (IVIG) is an anti-inflammatory drug used to treat various autoimmune conditions. Using the K/BxN model for rheumatoid arthritis we’ve shown that the therapeutic activity of IVIG depends on STAT6 signaling. Here we show that the anti-inflammatory activity of IL-4Rα induced STAT6 signaling takes place directly in LysM+ myeloid cells. However, in naïve mice these cells express low levels of the IL-4Rα. Exploring this discrepancy we found that during KBxN-mediated inflammation, IL-4Rα is highly up-regulated selectively on myeloid effector cells. This regulation is seen during several types of inflammation, and subsequently the cells respond to IL-4 with increased STAT6 phosphorylation. This regulation can be transferred both in vitro and in vivo using serum from mice with ongoing inflammation. Furthermore, transfer experiments show that the responsible (proteinase K-sensitive) factor is released by bone marrow derived non-lymphoid cells found in several organs, including the lungs and in fat. In conclusion, during ongoing inflammation, anti-inflammatory STAT6 signaling is specifically targeted to myeloid effector cells. This is mediated by regulation of the STAT6 signaling pathway by a secreted acute-phase reactant. We propose that this regulation is part of a homeostatic mechanism trying to limit excessive inflammation and tissue damage. IVIG, thus, exploits an endogenous feedback loop that could be further targeted for therapeutic purposes.
Altered soluble mediator levels and systemic lupus erythematosus-specific Connective Tissue Disease Screening Questionnaire (CSQ) scores differentiate unaffected relatives of lupus patients from healthy individuals with no family history of SLE (CCR4P.214)
Authors: Munroe Melissa , Young Kendra , Fessler Jennifer , Fife Dustin , Kamen Diane , Guthridge Joel , Niewold Timothy , Weisman Michael , Ishimori Mariko , Wallace Daniel , Karp David , Harley John , James Judith 
Published: December 2022

Abstract
Identifying populations at risk of SLE who remain unaffected would provide insights for potential disease prevention. Using a unique resource of SLE patient family members, first degree relatives (FDRs) of SLE patients (n = 154) with plasma samples available from previous genetic studies and who remained unaffected at follow-up evaluation (mean time = 6.8 years) were matched to healthy individuals unrelated to SLE patients (Controls). FDRs and Controls provided clinical and demographic information, and completed screening questionairres at baseline (BL) and follow-up (FU). BL and FU plasma samples were assessed for autoantibody production and soluble mediators. FDRs had significantly higher BL and FU CSQ scores (p&lt;0.0001), but no difference in the number of positive autoantibodies compared to Controls. FDRs had significant (p &lt; 0.01) increases in 38 (of 52) soluble mediators at BL and FU, including IFN-associated chemokines, TNFR ligands, and regulatory mediators (p&lt;0.002). Levels of MIP-1α (p=0.008), MIG (p=0.019), GROα (p=0.001), ICAM-1 (p=0.007), and VEGF (p=0.004), along with CSQ scores (p=0.010), best distinguished FDRs from Controls in logistic regression models. These alterations are present despite lack of progression to classified SLE, suggesting that multiple perturbations in immune-mediated inflammatory processes present in FDRs of SLE patients may be offset by inhibitory factors.
Use of social media like Facebook in learning and teaching immunology at college of pharmacy: synergy or rivalry? (EDU1P.217)
Authors: Fazal Nadeem , Arabian Elnaz , Cheptene Elena 
Published: December 2022

Abstract
It is proven that today’s students spend majority of their time on Facebook. To help students stay more focused on studying a Facebook group about Immunology was created. It was hypothesized that Facebook will create an interest and impulse for first year pharmacy students to help increase participation in the class and help understand key concepts of Immunology. For those students that are visual learners and seem to struggle with understanding key concepts of immunology, uploading videos can help them with grasping this knowledge.The purpose of this project was to determine if creating a Facebook group would be beneficial for the Pharmacy Year 1 (P-1) class to help them get a better understanding of the Immunology through videos. The P1 class had the option of watching the videos and completing the surveys. While the results were promising in the first week, they slowly depleted as the study proceeded. After the second week there were numerous surveys completed that were not in favor of the videos or topic discussions. This trend continued until the last week of the study where it was not approved by the vast majority of the students. Based upon this research we concluded that Facebook did create an initial interest especially for visual learners but that seemed to wane away over time. Students were unable to remain focussed over time during the length of Immunology course. They preferred textbook reading and interactive discussion among small groups more than Facebook.
Differential response of hematopoietic stem cells to type 1 interferon signaling in nonobese diabetic mouse strain at non-diabetic and diabetic stages (HEM5P.234)
Authors: Xia Changqing , Butfiloski Edward , Clare-Salzler Michael 
Published: December 2022

Abstract
Nonobese diabetic mouse exhibits heightened type I IFN signaling in dendritic cells and it has been demonstrated that type I IFN signaling drastically influences hematopoiesis. In this study, we seek to determine whether heightened type I IFN signaling takes place in NOD hematopoietic stem cells (HSC) and whether HSC functioning alters after onset of diabetes. Lin-Sca-1+c-kit+ (LSK) was used to define HSC within which CD48-CD34- cells were defined as dormant HSCs. In contrast to B6 mice, NOD LSKs was much higher, but the Sca-1 levels on HSCs were significantly lower. No significant difference was found between the two strains in terms of dormant HSCs. Notably, there were much higher numbers of CD34+CD48+ HSCs in NOD mice than in B6 mice. NOD HSCs responded to type I IFN-inducing agent, poly I:C at much higher levels than those of B6 mice, showing higher expression levels of Sca-1. The effect of Poly I:C on Sca-1 up-regulation in HSCs was inhibited by anti-IFNR antibodies in both the NOD and B6 mice. Interestingly, NOD HSCs lose their type I IFN-responding capability after onset of diabetes, which could be recovered after normalization of blood glucose, suggesting that hyperglycemia may impact on HSCs in diabetic animals. Our study demonstrates that heightened type I IFN signaling takes place in HSCs of autoimmune diabetes mouse model NOD mice, and hyperglycemia in diabetes may alter HSC functioning.
Hematopoietic crippling by chronic TLR4 ligand requires cell-intrinsic TLR4 and compromises both murine and human HSPCs in vivo (HEM5P.227)
Authors: Borghesi Lisa , Liu Ailing , Wang Yujuan , Ding Ying , Baez Ineavely , Payne Kimberly 
Published: December 2022

Abstract
The classical model for blood cell replenishment is changing with the unexpected realization that hematopoietic stem and progenitor cells (HSPCs) directly sense and respond to pathogens via toll-like receptors (TLRs). For the first time, we show that human HSPCs are severely compromised by repeated exposure to low dose TLR4 ligand as assessed in vivo in humanized mice. CD34+ HSPCs are reduced 50% with concomitant hyperproliferation. Downstream bone marrow lymphoid precursors and peripheral B cells are virtually ablated to the benefit of the myeloid cells. In the mouse model, reciprocal chimeras reveal that numerical and functional hematopoietic stem cell (HSC) defects following repeated exposure to TLR4 ligand require hematopoietic-derived TLR4. Selective deficiency of TLR4 on hematopoietic cells alleviates HSC hyperproliferation and myeloid skewing while cell non-autonomous TLR4 is largely dispensable. Finally, within uncommitted progenitor compartments, we show that HSC and downstream non-renewing multipotent progenitors (MPP) respond directly to TLR4 ligand. Thus, while transient TLR stimulation is thought to enable replenishment of the innate immune compartments that are rapidly consumed through acute infection, chronic TLR stimulation is detrimental to both murine and human HSPC integrity in vivo. These findings have broad implications as persistent exposure to TLR4 ligand occurs in individuals suffering from each chronic infection and obesity.
The Isolation of a Serum Lipid Which Inhibits Serologic Reactions
Authors: Volkin Elliot 
Published: December 2022

Conclusions and Summary
The inhibitory activity of the human plasma fraction IV-1, remains unaffected by extraction with ether but disappears after subsequent extraction with ethanol.

It has been possible to isolate from the ethanol extract an active inhibitory fraction which by its solubility behavior in acetone, CdCl2 and BaCl2, and by its nitrogen/phosphorus ratio, has been identified as a human serum lecithin.
Quantitative serologic titrations have shown that this human serum lecithin fraction exerts inhibitory activity toward euglobulin fractions of biologic false positive origin in appreciably lower concentrations than does the whole serum fraction IV-1. However, comparative measurements have indicated that the inhibitory activity of the latter is more specific than that of the former, as evidenced by their respective actions toward euglobulin fractions of syphilitic origin. It appears, therefore, that the specificity of the whole fraction IV-1 may be attributed to the firm combination of the serum lecithin with the protein.
While egg lecithin has no specific inhibitory activity, purified beef heart lecithin exhibits the same inhibitory pattern as human serum lecithin.