bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myd88 activation in immune cells governs distinct disease manifestations in primary Sjögren’s syndrome
Authors: Kiripolsky Jeremy , Kasperek Eileen M , Zhu Chengsong , Li Quan-Zhen , Wang Jia , Yu Guan , Kramer Jill M 
Published: February 2023

Abstract
Studies in mice and humans identify Myd88 activation as an important driver of autoimmune disease, although the role of this adapter molecule in primary Sjögren’s syndrome (pSS) is poorly understood. In pSS, patients exhibit exocrine gland dysfunction along with serious systemic disease manifestations. Although Myd88-dependent signaling networks are essential for pSS disease pathogenesis, these pathways remain incompletely understood in the context of pSS. The objective of this study was to establish the contribution of Myd88 activation in immune cells to local and systemic pSS manifestations. To this end, we generated a novel conditional knockout pSS mouse model lacking Myd88 in the hematopoietic compartment. We found that ablation of Myd88 in immune cells altered inflammatory mediators in salivary tissue, but did not affect the degree of lymphocytic infiltration in exocrine glands or salivary production. Nephritis was diminished and pulmonary inflammation was increased in mice lacking Myd88 in hematopoietic cells. Finally, we found total IgM titers and autoreactive IgM and IgG were attenuated in pSS mice lacking Myd88 in immune cells. Thus, we demonstrated that Myd88 activation in the hematopoietic compartment is essential for distinct aspects of disease. This study establishes a rationale for design of targeted therapeutics that modulate Myd88 activation in a tissue-specific manner to ameliorate salivary inflammation and systemic disease manifestations characteristic of pSS.
The enzymatic function of IDO2 is not required for its proinflammatory role in driving autoantibodies and disease in preclinical arthritis
Authors: Mandik-Nayak Laura , Merlo Lauren MF , Peng Weidan , DuHadaway James B , Montgomery James D , Prendergast George C , Muller Alexander J 
Published: February 2023

Abstract
IDO2 is one of two closely related tryptophan catabolizing enzymes induced under inflammatory conditions. Although originally thought to be functionally redundant with IDO1, recent studies using IDO1 and IDO2 genetically deficient mice demonstrated a specific pathogenic role for IDO2, but not IDO1, in mediating autoantibody production and inflammatory joint disease in the KRN model of autoimmune arthritis. In humans, there are two single nucleotide polymorphisms in IDO2 that severely impair enzymatic function: Y359X, a nonsense mutation that leads to a stop codon and R248W, a missense mutation that disrupts substrate recognition. These inactivating polymorphisms are common, with only 25% of normal individuals expressing a homozygous wild-type (wt) configuration of the gene conferring full catalytic potential. This, together with IDO2’s weak enzymatic activity, suggests IDO2 may have a non-enzymatic function. To determine if the enzymatic activity of IDO2 was required for its pro-arthritic effect, we generated IDO2 knock-in mice that express catalytically inactive IDO2 (R248W or Y359X) and bred them onto the KRN model. Strikingly, R248W KRN mice developed high levels of autoantibodies and robust arthritis, indistinguishable from mice expressing wt IDO2. In contrast, Y359X KRN mice developed attenuated disease that was correlated with reduced stability of the truncated IDO2 protein, consistent with the effect of IDO2 deficiency in this model. These data confirm IDO2 as an important mediator of autoimmune arthritis and demonstrate that tryptophan catabolism is not the mechanism by which IDO2 drives disease. Taken together, our studies suggest a completely novel function for IDO2, independent of its enzymatic activity.
MDA5 expression impacts immune cell activation during T1D development
Authors: Blum Samuel I , Burg Ashley R , Chen Yi-Guang , Tse Hubert M 
Published: February 2023

Abstract
Coxsackievirus B3 (CVB3) infection has been associated with triggering Type 1 diabetes (T1D), potentially due to direct β-cell damage and bystander activation of autoreactive T cells. CVB3-infection of Non-Obese Diabetic (NOD) mice accelerates T1D onset, in part due to melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses. However, the role of MDA5 on immune cells during T1D remains unclear. By using mice that contain an in-frame deletion within the helicase 1 domain of MDA5 (ΔHel1) or lack MDA5 expression (KO), we can test the hypothesis that reduced MDA5 expression impairs IFN-α/β synthesis, immune cell activation, and T1D onset. NOD and KO mice develop T1D equally, but ΔHel1 mice exhibit delayed spontaneous and CVB3-accelerated T1D. During spontaneous T1D, 12-week-old ΔHel1 mice had a significant reduction in TNF+ F4/80+ macrophages (MΦ) (1.6-fold), perforin+ CD8+ T cells (13.1-fold), and IFNγ+ CD4+ T cells (6.1-fold), compared to NOD and KO mice. ΔHel1 mice had a significant reduction in pancreatic IFN-α (2.2-fold) and IFN-β (3.1-fold) levels compared to NOD mice following CVB3-infection. CVB3-infected ΔHel1 mice had a significant decrease in pancreatic TNF+ F4/80+ MΦ (2-fold) compared to NOD and KO mice. However, ΔHel1 and KO mice had reduced pancreatic perforin+ CD8+ T cells (2.5-fold) and IFNγ+ CD4+ T cells (1.8-fold) compared to NOD mice following CVB3 infection. The ΔHel1 mutation decreased basal and CVB3-responsive MΦ and T cells within the pancreata thereby delaying T1D onset. Yet, loss of MDA5 expression failed to delay T1D indicating MDA5-dependant responses may be required to prevent T1D. Future studies will determine if T1D onset is dictated by MDA5 dsRNA binding and/or ATPase activity.
Abnormal C5 production and activation contributes to the mortality of COVID-19 patients
Authors: Fang Zhou , Li Xiang , Cheng Tzu Hsuan , Desikan Shreya , Worah Samrat , Foronjy Robert , Salvani Jerome , Kaiser Ryan , Bendo Audree , Dimaculangan Dennis , Wlody David , Velickovic Ivan , Diaz Geraldine , Santana Jeans , White Seth , Shevde Ketan , Zhang Ming 
Published: February 2023

Abstract
Elucidating the pathogenesis of COVID-19 is vital for treating the disease. Recent clinical studies have suggested that the complement system may play an important role in the course of infection. We investigated the correlation between complement C5, a critical factor in the complement common pathway, and the mortality of COVID-19. Thirty-seven COVID-19 patients were consented for this study. Serial blood samples were collected at different time points from 27 patients who recovered during hospitalization, and 10 patients who did not survive during hospitalization. Circulating native C5 was analyzed by Western Blot to detect α-chain and β-chain of intact C5. The activated C5a levels were detected by an ELISA kit. The levels of C5 β-chain and C5a were significantly higher in the non-survivors than in the survivors. Multivariate regression analyses showed that abnormal levels of C5 β-chain and C5a could independently predict the mortality. Therefore, our results suggest that in COVID-19 patients, the abnormal C5 production and activation may contribute to the systemic inflammation thus affect survival.
Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome
Authors: Porritt Rebecca A , Paschold Lisa , Rivas Magali Noval , Cheng Mary Hongying , Bahar Ivet , Binder Mascha , Arditi Moshe 
Published: February 2023

Abstract
Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares many clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. The superantigen specificity for binding different Vβ-chains results in Vβ-skewing, whereby T cells with specific Vβ-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Beta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels. Further analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanding TRBV11-2 clones revealed extensive junctional diversity, indicating a superantigen-mediated selection process for TRBV expansion. In silico modelling indicates that polyacidic residues in TCR Vβ11-2 engage in strong interactions with the superantigen-like motif of SARS-CoV-2 spike glycoprotein. Overall, our data indicate that the immune response in MIS-C is consistent with superantigenic activation.
Uncovering the underlying immune perturbations that determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection
Authors: Xu Wenxi , Snell Laura M. , Guo Mengdi , Boukhaled Giselle , Macleod Bethany L. , Li Ming , Tullius Michael V. , Guidos Cynthia J. , Tsao Ming-Sound , Divangahi Maziar , Horwitz Marcus A. , Liu Jun , Brooks David G. 
Published: February 2023

Abstract
Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection, yet how they alter the pulmonary microenvironment to foster coinfection and worsen disease severity is unclear. We developed a coinfection model in mice with chronic lymphocytic choriomeningitis virus and Mtb coinfection that recapitulated the central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination and heightened mortality. These long-term disease consequences were not due to chronic virus-induced immunosuppression or exhaustion, but instead were determined by early alterations in immune surveillance of Mtb coinfection. Mechanistically, increased chronic virus induced TNFα production initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lung-draining lymph nodes (LNs) and allowing bacterial sanctuary. The inhibited antigen arrival to LNs delayed CD4 T cell priming, allowing Mtb to replicate to higher set-points before T cell mediated control could be initiated. Once primed, Mtb-specific CD4 T cell differentiation skewed away from the Th1 responses associated with Mtb control, and instead toward Th17 differentiation. The elevated IL17 increased pulmonary neutrophil influx that decreased the long-term survival of coinfected mice. Therapeutically correcting the timing of CD4 T cell priming re-established CD4 Th1 over Th17 dominance, diminished pulmonary neutrophilia, and enabled enhanced Mtb control in the presence of chronic viral coinfection. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function and foster long-term coinfection.
Respiratory syncytial virus-induced high mobility group box 1 secretion modulates innate immune response to promote inflammation
Authors: Hosakote Yashoda Madaiah , Kempaiah Kempaiah Rayavara , Garofalo Roberto P , Kurosky Alexander 
Published: February 2023

Abstract
Respiratory syncytial virus (RSV) is the single most common human pathogen responsible for ~ 60% of all acute lower respiratory tract infections in young children, and is a major cause of severe respiratory morbidity and mortality in the elderly, and the immunocompromised. Yet, no vaccine or efficacious treatment is available. Although the mechanisms of RSV-induced acute airway disease are not fully understood, lung inflammatory and immune events are key. Our studies show that RSV induces increased extracellular secretion of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern family member that alerts the immune system to potential damage and trigger immediate response. The goal of this study is to investigate the molecular mechanisms of RSV-induced HMGB1 release in the activation of innate immune response in promoting lung inflammation. Studies were conducted in BALB/c mice as well as human lung epithelial cells including A549 and normal small alveolar epithelial cells. To determine the role of HMGB1 in the activation of innate immune signaling, BALB/c mice and airway epithelial cells were infected with RSV in the presence or absence of recombinant HMGB1 or HMGB1 monoclonal antibody and measured RIG-I-dependent interferon-mediated innate antiviral immune response. Our studies demonstrated an important role of HMGB1 in cellular protection and the activation of innate immune signaling cascades to promote inflammation. Our studies indicate that HMGB1 acts as a signaling molecule to induce an increased inflammatory response in the lung, thus contributing to RSV pathogenesis. Modulation of proinflammatory function of HMGB1 may attenuate RSV-induced lung inflammation.
LUBAC suppresses IL-21-induced apoptosis in CD40-activated murine B cells and promotes germinal center B cell survival and the T-dependent antibody response
Authors: Xu Zhenming , Wang Jingwei , Li Tianbao , Zan Hong , Rivera Carlos Eduardo , Yan Hui 
Published: February 2023

Abstract
B cell activation by Tfh cells, i.e., through CD154 engagement of CD40 and IL-21, and survival within GCs are crucial for the T-dependent Ab response. LUBAC, composed of HOIP, SHARPIN and HOIL-1, catalyzes linear ubiquitination (Linear M1-Ub) to mediate NF-kB activation and cell survival induced by TNF receptor superfamily members, which include CD40. As shown here, B cells expressing the Sharpin null mutation cpdm (Sharpincpdm) could undergo proliferation, CSR and SHM in response to immunization by a T-dependent Ag, but were defective in survival within GCs, enrichment of a high-affinity BCR mutant and production of specific Abs. Sharpincpdm B cells stimulated in vitro with CD154 displayed normal proliferation and differentiation, marginally impaired NF-kB activation and survival, but markedly exacerbated death triggered by IL-21. While activating the mitochondria-dependent apoptosis pathway in both Sharpin+/+ and Sharpincpdm B cells, IL-21 induced Sharpincpdm B cells to undergo sustained activation of caspase 9 and caspase 8 of the mitochondria-dependent and -independent pathway, respectively, and ultimately caspase 3 in effecting apoptosis. These were associated with loss of caspase 8 inhibitor cFLIP and reduction in cFLIP Linear M1-Ub, which interferes with cFLIP poly-ubiquitination at Lys48 and degradation. Finally, the viability of Sharpincpdm B cells was rescued by caspase inhibitors, but virtually abrogated – together with Linear M1-Ub and cFLIP levels – by a small molecule HOIP inhibitor. Thus, LUBAC controls cFLIP expression and inhibits the effects of caspase 8 and IL-21-activated caspase 9, thereby suppressing apoptosis of CD40 and IL-21-activated B cells and promoting GC B cell survival.
Elucidating the role of ATM in BER and MMR during B cell CSR
Authors: Sible Emily , Attaway Mary , Chwat Tzippora , Fiorica Giuseppe , Rahman Sadia , Velez Kristel , Vuong Bao 
Published: February 2023

Abstract
Secondary immunoglobulin isotypes are produced by class switch recombination (CSR), which requires AID-dependent DNA deamination of intronic switch (S) regions within the immunoglobulin heavy chain gene. Non-canonical repair of deaminated DNA by mismatch repair (MMR) or base excision repair (BER) creates staggered DNA breaks that promote recombination between S regions. ATM-dependent phosphorylation of AID at serine-38 (pS38-AID) promotes its interaction with APE1, a BER protein, suggesting that ATM regulates CSR through BER. However, pS38-AID may also play a role in MMR during CSR, although the mechanism remains unknown. To examine whether ATM participates in MMR-mediated CSR, ATM−/− mice were bred to mice deficient for the MMR gene MSH2. Surprisingly, the predicted Mendelian frequencies of ATM−/− MSH2−/− adult mice were not obtained. To bypass the observed lethality, ATM was conditionally deleted on an MSH2−/− background using a floxed ATM allele [ATMF] and B cell-specific Cre recombinase expression. These ATMd/dMSH2−/− mice and B cells display a hypomorphic CSR phenotype comparable to ATM−/− B cells, which suggests that ATM may function genetically upstream of MSH2 and implicates a role for ATM in both MMR and BER.
Genetic regulation of nitric oxide-mediated metabolic reprogramming in dendritic cells
Authors: Snyder Julia Priscilla , Krementsov Dimitry N , Amiel Eyal 
Published: February 2023

Abstract
Dendritic cell (DC) activation is characterized by a rapid “metabolic switch” towards increased glycolysis that supports maturation. Sustained glycolysis post-activation is a requirement for survival in DC subsets that express inducible nitric oxide synthase (Nos2, iNOS), due to the production of nitric oxide (NO) which acts as an inhibitor of mitochondrial respiration. Long-term metabolic reprogramming in activated DCs has almost exclusively been studied in the strain C57BL/6J (B6), which experience loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we generated and compared DCs from B6 mice to the wild-derived genetically diverse PWD/PhJ (PWD) strain. We show attenuated iNOS induction, lowered NO production, and intact mitochondrial respiration in activated PWD DCs. To reduce genetic variability in our model, we generated DCs from a congenic mouse strain containing a genetic interval from PWD—including Nos2—on a B6 background. Activated DCs from the congenic strain produce NO at lower levels than B6, but NO production is not completely ablated as it is for pharmacologic or genetic interventions, thus this model allows for the subtle interrogation of NO-mediated metabolic reprogramming. We show that glucose-dependent carbon flux through the TCA cycle is altered in DCs with restrained NO production compared to B6 DCs, and we demonstrate that these differences are driven by NO. These studies provide a more comprehensive understanding of NO-mediated metabolic reprogramming in the murine myeloid lineage and establish a natural genetic model for investigating the contribution of NO in regulating the interplay between DC metabolism and immune function.
A role of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells
Authors: Jeon Myung-Shin , Lkhagva-Yondon Enkhmaa , Oh Ye-Na 
Published: February 2023

Abstract
Aryl hydrocarbon receptor (AhR), a ligand-induced transcription factor, is known to be involved in the balance between inflammatory and suppressive/regulatory T cell activity. Mesenchymal stem cells (MSCs) possess immunomodulatory activities, including suppression of T- and B-cell activation. MSC-mediated immunosuppression occurs via nitric oxide (NO) in mice. Here, we isolated MSCs from Ahr−/− bone marrow in mice and found less immunosuppressive function compared to the wild type (WT)-MSCs. When MSCs are co-cultured with T cells in the presence of anti-CD3 and anti-CD28 antibodies, the AhR-deficient MSCs less inhibited T-cell proliferation, CD25 and CD122 expression and cytokine productions such as IFN-γ, IL-17A compared with wild type MSCs. In addition, we found AhR-deficient MSCs produce less inducible nitric oxide synthase (iNOS) and NO compared with wild type MSCs, when MSCs were stimulated with IFN-γ, TNF-α, and IL-1β. Since MSCs has been used for the treatment of graft-vs-host disease (GvHD), we injected the WT and AhR-deficient MSCs into the GvHD mice. The AhR-deficient MSCs showed less therapeutic efficacy compared to the WT MSCs. We think that the AhR is involved in the production of NO via regulating iNOS expression which is required for the therapeutic efficacy of MSCs.
Oral mucosal IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral candidiasis
Authors: Aggor Felix E.Y. , Break Timothy , Trevejo-Nunez Giraldina , Whibley Natasha , Bailey Rachel D. , Kaplan Daniel H , Naglik Julian R. , Shan Wei , Shetty Amol C. , McCracken Carrie , Durum Scott K. , Biswas Partha S. , Bruno Vincent M. , Kolls Jay K , Lionakis Michail S , Gaffen Sarah L. 
Published: February 2023

Abstract
Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans. IL-17 and IL-22 both mediate antifungal immunity yet activate distinct downstream signaling pathways. While much is known about IL-17-dependent immunity in OPC, the activities of IL-22 are less well delineated. We show that induction of Il22 is independent of Dectin-1, CARD9 and aryl hydrocarbon receptor (AhR) and is driven by IL-23 and the C. albicans pore forming peptide candidalysin. Despite similar induction requirements and cellular sources, IL-22 and IL-17 function non-redundantly during OPC and exert opposing roles in neutrophil recruitment. The IL-22 and IL-17 receptors are required in anatomically distinct locations; loss of IL-22RA1 in the oral basal epithelial layer (BEL) but not the suprabasal epithelial layer (SEL) causes susceptibility to OPC, whereas IL-17RA is needed in the SEL. Our data reveal that IL-22 is a major activator of STAT3 in the BEL during OPC. Moreover, loss of STAT3 in the BEL but not the SEL renders mice susceptible to OPC. Transcriptional profiling of RNASeq data linked IL-22/STAT3 to oral epithelial cell proliferation and survival, but also, unexpectedly, to driving an IL-17 gene signature. We show that IL-22 acts on the BEL to replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17. Consequently, IL-22 signaling in BEL ‘licenses’ IL-17R signaling in the oral epithelium, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis. This work also suggests that oral thrush in Jobs’ syndrome patients may be caused by STAT3 impairments in the oral epithelium, not just Th17 cells.
The immunomodulating enzyme indoleamine 2,3-dioxygenase 2 (IDO2) as a target for therapy in autoimmune disease
Authors: Merlo Lauren MF , Bowers Jessica , Stefanoni Tony , Gordon Gary V , Getts Robert , Mandik-Nayak Laura 
Published: February 2023

Abstract
The enzyme indoleamine 2,3-dioxygenase 2 (IDO2) is an important mediator of inflammatory autoimmune responses. Unlike its better-known counterpart, IDO1, which is thought to act primarily in an immunosuppressive manner, IDO2 acts to promote inflammation via a B-cell intrinsic mechanism. Prior work has demonstrated that genetic knockout of IDO2 can inhibit both autoantibody production and joint inflammation in the KRN.g7 murine model of arthritis. IDO2 played a similar role in driving inflammation in collagen induced arthritis and contact hypersensitivity models. Given the clear role of IDO2 in mediating autoimmunity, we have worked to find novel ways to target IDO2 in vivo. In addition to previous research successfully targeting the intracellular IDO2 protein with a novel monoclonal antibody, we have recently described an innovative, targeted DNA nanostructure-based siRNA-delivery system to specifically inhibit IDO2 function in B cells. Treatment of KRN mice with this B cell-directed anti-IDO2 siRNA nanotherapy reduced autoantibodies and attenuated arthritis, mimicking the phenotype seen with genetic knockouts. These data provided preclinical proof-of-concept that IDO2 could be effectively targeted as a treatment strategy in murine arthritis and suggested a similar strategy could be used target IDO2 in human RA. Similar to our findings using murine B cells, we found that IDO2 expression was elevated in B cells isolated from RA patients and could be silenced using anti-IDO2 siRNA in vitro. These data provide the first indication for the relevance of IDO2 in human RA and suggest nanoparticle delivery systems are a potential therapeutic strategy to inhibit IDO2 in RA patient B cells.