bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testing the susceptibility of mice with normal microbial experience to induction of allergic airway disease
Authors: Block Katharine E , Masopust David , Kita Hirohito , Hamilton Sara E , Jameson Stephen C 
Published: January 2023

Abstract
Allergic asthma is a large and growing medical problem in the developed world. The hygiene hypothesis posits that improved sanitation, vaccination programs, and increased antibiotic use have limited our exposure to natural infections, leading to immune systems that are more vulnerable to pathological responses. It has been difficult to test whether these advancements in public health can explain some of the increased incidence in allergic asthma, partly because laboratory mice commonly used in research are housed in a clean and highly controlled environment (known as specific pathogen free, or SPF). Cohousing SPF laboratory mice with mice from pet stores leads to acquisition of natural mouse pathogens through physiological animal-to-animal transmission. Our research group has demonstrated that this normal microbial experience dramatically alters the immune system, making it more similar to the immune system of adult humans. We used this “dirty” cohousing mouse model to test the effect of physiological microbial exposure on susceptibility to allergic airway disease. SPF and cohoused mice were sensitized and challenged intranasally with house dust mite (HDM) extract. Exposure to HDM induced eosinophilic airway inflammation and immune cell infiltration in SPF mice that resembles airway pathology of asthmatic patients. Serum levels of IgE and IgG1 antibodies to HDM were also elevated. Immune cell populations infiltrating the lung and activation of antigen-specific CD4+ T cells were also analyzed. We are currently investigating the immune response to this allergen exposure model in cohoused mice. Results from these studies will help explain the impact of environmental and microbial experience on susceptibility to allergic asthma.
Scavenger receptor class B type I (SR-BI) modulates glucocorticoid mediated lymphocyte apoptosis in asthma
Authors: Reece Sky W. , Kilburg-Basnyat Brita , Madenspacher Jennifer H. , Luo Bin , Capen Amanda , Fessler Michael B. , Gowdy Kymberly M. 
Published: January 2023

Abstract
Asthma is a heterogeneous airway disease that has increased significantly in recent decades. Clinical studies have shown a positive correlation between serum large high-density lipoprotein (HDL) levels and airway protective effects in asthma. However, how cholesterol communicates with the lung during asthma is still not well understood. Scavenger receptor class B type I (SR-BI) is an HDL receptor that has also been shown to regulate glucocorticoid production. SR-BI has also been shown to regulate lymphocyte apoptosis in models of sepsis and atherosclerosis. Recently, we reported that SR-BI dampens the pulmonary innate immune response, but the role of SR-BI in asthma is unknown. Therefore, SR-BI+/+ and SR-BI−/− mice were sensitized with 10 μg house dust mite (HDM) or PBS by oropharyngeal aspiration on day 0, 7, and challenged with 2 μg HDM on day 14, 15, 16. Airway inflammation, cytokines, and serum corticosterone levels were quantified on day 17. SR-BI−/−mice had increased pulmonary neutrophils and lymphocytes after HDM challenge when compared to SR-BI+/+ mice. SR-BI−/− mice had consistently lower levels of serum corticosterone after HDM or PBS exposure. To determine the role of glucocorticoid production in asthma, SR-BI+/+ and SR-BI−/− mice were supplemented with corticosterone in their drinking water during HDM exposure. SR-BI−/− mice with corticosterone treatment had a decrease in pulmonary lymphocytes after HDM exposure. The observed decrease in lymphocytes may be due to glucocorticoid induced apoptosis which was absent in SR-BI−/− mice not treated with glucocorticoids. Our study has shed new light on how cholesterol receptors such as SR-BI play an important role in glucocorticoid mediated lymphocyte apoptosis in asthma.
Age-associated changes in intrathymic B cell function
Authors: Cepeda Sergio , Cantu Carolina , Xiao Yangming , Griffith Ann 
Published: January 2023

Abstract
Autoimmune disease affects approximately 3% of the U.S. population and is the leading cause of death among young and middle-aged women. Susceptibility to autoimmune disease generally increases with age in both sexes; however, mechanisms linking aging and increased susceptibility are incompletely understood. One hallmark of the aging immune system is atrophy of the thymus, the primary site of T lymphocyte generation. We recently showed that in addition to size, critical thymic functions are lost with age, including expression of tissue restricted self-antigen (TRA) genes. Thymic TRA expression allows clonal deletion of potentially auto-reactive T cells, and loss of TRA expression during aging represents a potential mechanism for age-associated increases in autoimmunity. Until recently, only epithelial cells were known to express TRAs within the thymus, but it is now clear that IgM-IgD-intrathymic B lymphocytes can also be induced to express Aire (Autoimmune Regulator), a factor critical for TRA expression, as well as downstream Aire-dependent TRAs. Here, we find that B cell frequency increases 5-fold in the aged murine thymus, concomitant with a shift from an IgM-IgD-to an IgM+IgD+ phenotype. Using next-generation RNA sequencing, we show significant decreases in Aire and TRA gene expression in aged intrathymic B cells. Our findings indicate that age-associated changes in intrathymic B cells inhibit their ability to negatively select auto-reactive T cells, revealing a novel potential mechanism linking aging with increased susceptibility to autoimmune disease.
Identification of novel plasma cell subsets in a mouse model of SLE
Authors: Rosean Timothy R , Loo William , Erickson Loren D 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease driven by the secretion of anti-nuclear antibodies (ANA) from a subset of terminally differentiated B cells, called plasma cells (PC). PC persist in the bone marrow for the lifetime of the host, posing challenges for the development of therapies for SLE and other autoimmune diseases. The mechanisms of long-term persistence of PC are poorly understood. Utilizing the congenic New Zealand Black Autoimmunity 2 (NBA2) mouse strain, which develops IgG ANA similar to SLE, our lab has identified novel subsets of mature bone marrow PC. which are highly heterogeneous in both phenotype and function. We have characterized these populations of PC based on the expression of CD93 and CXCR3. While CD93+ PC are largely quiescent, CXCR3+ PC are highly proliferative in the bone marrow. In addition, CXCR3+ PC are highly enriched for IgG secretion, while CD93+ PC are enriched for IgA secretion. CD93+ PC are detected in the bone marrow of B6 mice at early time points after immunization with KLH, whereas CXCR3+ PC are nearly absent in the bone marrow yet are present in the spleen. In contrast, significant numbers of both CD93+ and CXCR3+ PC are found in both the spleen and bone marrow of NBA2 mice. Characterization of transcription factors reveals that all PC populations express high levels of BLIMP-1 and IRF-4, demonstrating their commitment to a mature PC fate. These data suggest that distinct subpopulations of PC may be responsible for the pathogenesis of SLE. Current research is focused on elucidating the mechanism by which distinct PC subsets give rise to ANA.
The role of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 2 (IDO2) in initiation, development, and treatment of autoimmune disorders
Authors: Merlo Lauren MF , Grabler Samantha , DuHadaway James B , Manley Kaylend , Prendergast George C , Muller Alexander J , Laury-Kleintop Lisa D , Mandik-Nayak Laura 
Published: January 2023

Abstract
The tryptophan catabolizing enzymes indoleamine 2,3-dioxygenase (IDO) 1 and 2 lie at the interface between metabolism and immunity. Recently, we identified a unique functional role for IDO2 in modulating the initiation and severity of autoimmune arthritis in a murine model of disease. We find that IDO2, but not its better-studied counterpart IDO1, acts as a pro-inflammatory mediator affecting autoantibody production and T helper cell function in the KRN preclinical model of arthritis. Reciprocal adoptive transfer experiments demonstrate that IDO2 acts by a B-cell intrinsic mechanism to regulate inflammation. IDO2 function in B cells was contingent on a cognate, antigen-specific interaction to exert its immunomodulatory effects on arthritis development. Alterations in costimulatory molecules and associated cytokines involved in cross-talk between B and T cells suggest that IDO2 acts at the T:B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Given the paucity of novel therapies for rheumatoid arthritis and related autoimmune disorders, IDO2 should be considered as a potential novel therapeutic target for modulating disease pathways leading to autoimmunity. However, therapeutically targeting IDO2 has been challenging due to the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. To this end, we have recently begun development and characterization of approaches that ameliorate disease by specifically targeting IDO2. We find that we are able to recapitulate the reduction in arthritis seen in genetic knockouts with IDO2-targeted therapies in preclinical models of disease.
Single cell analysis of transitional B cells reveals autocrine IFNβ sustains a dynamic type I IFN network in lupus
Authors: Hamilton Jennie A , Yang PingAr , Liu Shanrun , Li Jun , Wu Qi , Luo Bao , Walter Mark R , Sanz Ignacio , Fish Eleanor N. , Chatham Winn , Hsu Hui-Chen , Mountz John D 
Published: January 2023

Abstract
Increased selection of transitional B cells reactive with nucleic acid antigens is a prominent feature of systemic lupus erythematosus (SLE). We found that transitional stage 1 (T1) B cells from both human SLE patients and BXD2 lupus mice intrinsically express significantly higher levels of IFNα and IFNβ compared to normal individuals. IFNβ expression in T1 B cells was significantly correlated with the development of mature autoreactive 9G4+ B cells in SLE patients and La+ B cells in BXD2 mice. IFNβ was also specifically required for optimal B cell survival and TLR7 responses. In single T1 B cells isolated from Ifnb−/− vs. WT B6 bone marrow chimeras, upregulation of Ifnα7 was completely abrogated in single Ifnb−/− T1 B cells, while other genes (Ifna1, Ifna4, Cd86, Tlr7) were significantly but incompletely diminished implicating both autocrine and paracrine IFNβ activity. To resolve these signals in an autoimmune environment, single cell gene expression analysis was carried out on sorted BXD2 T1 B cells. Hierarchical clustering revealed three distinct gene expression patterns. Cluster 1 cells were “IFN producers” characterized by high expression of type I IFN genes, but low co-expression of IFN receptor genes, Ifnar1 and Ifnar2. Cluster 2 “IFN responders” exhibited the highest co-expression of both Ifnar1 and Ifnar2 as well as immunomodulatory IFN response genes (Irg1, IL6, Cd69, Cd86). Cluster 3 had low expression of type I IFN and IFNAR genes. Clusters 1 and 2 exhibited the highest Tlr7 expression, while Cluster 3 had the highest expression of Baffr and Tlr9. The heterogeneity of IFN signatures at the T1 stage suggests that varying interferonogenic phenomena can differentially prime T1 B cells for subsequent responses and cell fates.
Estrogen promotes SLE serum-induced skin inflammation via the estrogen membrane receptor GPER1
Authors: Deng Guo-Min , Cai Zhenming , Xie Changhao , Guo Xuanxuan , Liu Huicheng , Li Xiaoyan , Fang Xiang , Fei Xibin , Guo Yacong , Xu Guangqiong , Dou Hui 
Published: January 2023

Abstract
Skin injury is the second most common clinical manifestation in patients with systemic lupus erythematosus (SLE). Estrogen may affect the onset and development of SLE. In this study, we investigated the role of estrogen and its membrane receptor GPER1 in SLE-related skin injury in mice treated with SLE serum in vivo, and monocytes from mouse spleen in vitro. We found that skin injury induced by SLE serum was more severe in female mice and required monocytes. Estrogen promoted these effects through the membrane receptor GPER1 located in lipid rafts and that inhibition of lipid rafts and GPER1 suppressed SLE serum-induced skin inflammation and expression of inflammatory molecules. From these studies, we conclude that estrogen promotes the development of skin injury induced by SLE serum through the membrane receptor GPER1 and that lipid rafts play an important role in the regulatory effect of GPER1 in SLE skin inflammation.
Leptin promotes plasma cell generation and exacerbates collagen-induced arthritis
Authors: CHEN QIAN , LU LIWEI 
Published: January 2023

Abstract
Plasma cells (PCs) contribute to the relapse of many autoimmune diseases, especially in patients with rheumatoid arthritis (RA) after rituximab treatment. Increasing evidence indicates a crucial role of leptin in autoimmune pathogenesis via enhancing CD4+ T cell responses, but whether and how leptin regulates PCs remain largely unclear. In collagen-induced arthritis (CIA) mice, we detected increased levels of leptin and anti-collagen II (CII) antibodies in the synovial fluid (SF) and sera of mice at acute and chronic stages of CIA. Higher percentage and cell number of plasma cells (PCs) were observed in the SF of CIA mice. Leptin receptor-deficient (db/db) mice exhibited ameliorated CIA development with reduced PCs responses and CII-specific antibody production. Intra-articular injection of recombinant leptin enhanced PCs responses and CII-specific antibody production and joint damage. Importantly, intra-articular injection of a soluble leptin blocker (ObR:Fc) deceased PCs responses, CII-specific antibody production and joint damage. Mechanistic studies revealed that leptin promoted CD138+IFR4+ PC generation from GL-7+Fas+ germinal center B cells via activating Akt-mTOR-IRF4 axis. Moreover, rapamycin treatment attenuated leptin-induced IRF4 expression and PCs generation. In RA patients, leptin levels and autoantibody production were positively correlated with disease activity (DAS28 score) with increased CD38+CD27+ plasmablasts detected in the synovium of active RA patients. Together, these findings demonstrated that leptin enhanced PCs responses via ObR-Akt-mTOR-IRF4 axis and exacerbated CIA development, indicating that leptin blockade may serve as a potential therapeutic target for the treatment of RA.
A Methodology and Application for Statistical Polarization in the Immune Response
Authors: Qeadan Fares , Dwivedi Sunita , Page Kimberly , Gravitt Patti 
Published: January 2023

Abstract
Polarization in the CD4+ mediated T-helper cell immune response is a very well characterized phenomenon in immunology; towards either Th1, Th2, or Th17 pathways. However, to-date, this concept has neither been developed nor demonstrated in a robust statistical framework. In this study, we provide a novel statistical methodology to facilitate the idea of polarization within a multivariate setting, and apply it to luminal fluid cytokine data of 90 women from the Peruvian Amazon. The panel of cytokines and chemokines for this study were assayed using separate BioRad Multiplex Array kits. In our application, we show that soil transmitted helminth (STH) infection induces statistically significant Th2 polarization in the female genital tract.
To provide statistical evidence of Th2 polarization in STH-infected women at the cervix, we compare the clustering of cytokines among STH-infected versus STH-uninfected women while examining the shift in the strength of correlation for Th2 cytokines with IL-4, which is seen as a central Th2 cytokine. The proposed statistical test is one that tests if, significantly, k&gt;1 for f(L1)=f(L2) where L1 and L2 are the loadings in the principal component analysis (PCA) framework for the STH-infected and STH-infected groups respectively.
The proposed method is a confirmatory one and could be supported by visual representation of the Th polarization through heat maps. It has the potential to become the reference or gold standard when studying the polarization phenomenon in immunology as it tailors the clinical characteristics and mechanisms associated with the entire panel of cytokines and chemokines in the context of a system.
IL-17c promotes peripheral nerve growth during human herpes simplex virus type 2 (HSV-2) infection
Authors: Zhu Jia , Peng Tao , Chanthaphavong Savahn , Sun Sijie , Trigilio James , Jin Lei , Vazquez Julio , O’Day Diana , Glass Ian , Knipe David , Wald Anna , Corey Larry 
Published: January 2023

Abstract
During human HSV-2 infection, peripheral nerve destruction and sensory anesthesia are rarely developed, despite frequent virus reactivation. The mechanisms underlying this clinical observation are unclear. Here, we describe a novel interaction between HSV infected keratinocytes and the peripheral nerve system via IL-17c that promotes neurite growth and neuron survival during reactivations. Skin biopsies obtained during asymptomatic human HSV-2 reactivation exhibit a higher nerve fiber density in relation to biopsies obtained during the virological and clinical quiescent phase. Keratinocytes, the peripheral targets of HSV reactivation, produce IL-17c both in vivo during HSV-2 reactivation in humans and in vitro in primary cultures. Further characterization indicates that IL17RE, the receptor specific for IL-17c signaling, is expressed on nerve endings in human skin and on nerve fibers, glia cells and sensory neurons in human dorsal root ganglia. The addition of exogenous human IL-17c promotes neurite growth and branching and provides directional guidance in a microfluidic device. Furthermore, pretreatment of IL-17c reduces apoptosis in HSV-2 infected primary neurons. Taken together, these results suggest that IL-17c might function as a neurotrophic factor to induce peripheral nerve ending growth and protect neurons from apoptosis during HSV reactivation. This interaction provides a potential mechanism for the lack of clinical nerve damage from a lifelong recurrent neurotropic viral infection. It also highlights the role of immune cytokines in regulating the functions of the peripheral nervous system.
An unadjuvanted model for oral immunization revealing complex regulatory control of gut IgA responses to soluble protein
Authors: Gribonika Inta , Schön Karin , Strömberg Anneli , Lycke Nils 
Published: January 2023

Abstract
We have identified a unique mouse model in which oral immunization with soluble protein, without a potent mucosal adjuvant, is highly effective at stimulating strong gut IgA responses. In fact, cholera toxin (CT), which is the gold standard for oral adjuvants, did not enhance the gut IgA response to ovalbumin (OVA) in this model. As we dissected the mechanism allowing for an unadjuvanted strong gut IgA response we found that adoptively transferred OVA-peptide-specific TCR Tg DO11.10 CD4 T cells into nude Balb/c mice were sufficient to promote the gut IgA response. However, only CD4 T cells with a rearranged TCR a-chain, reactive to unknown, but possibly microbial, antigens in the gut, were effective, because SCID DO11.10 CD4 T cells failed to support a gut IgA response. Co-transfer of wild-type CD4 T cells with DO11.10 CD4 T cells into nude Balb/c hosts completely obliterated the response, but not if the CD4 T cells were isolated from IL-10−/− mice. Hence, the gut IgA response was under strict regulatory CD4 T cell control. By contrast, if CT adjuvant was admixed with OVA we completely rescued the gut IgA response following oral immunization. Thus, oral CT adjuvant primarily exerted a modulating effect on the regulatory CD4 T cell control in Peyer’s patches (PP), impacting on the balance between follicular helper and regulatory T cells. While both Th17 and CD25+ Tregs, have been claimed sufficient for supporting gut IgA responses, our model clearly suggests that the regulatory environment in PP is more complex, as will be discussed.
The microbiota-derived metabolite indole is an endogenous regulator of autophagy
Authors: Hunt Carrie , Zhao Xiao , Crisp Zeni , Choi Kyungoh , de Figueiredo Paul , Jayaraman Arul , Karpac Jason , Alaniz Robert Christopher 
Published: January 2023

Abstract
Autophagy is an evolutionarily conserved cellular mechanism that is crucial for promoting cell survival, pathogen clearance, and homeostasis. Dysregulated autophagy destabilizes GI tract homeostasis, promotes Crohn’s Disease, and perturbs the microbiota, a prominent feature during gut inflammation. Classically, energy substrate starvation induces cellular autophagy, yet host dietary intake makes the GI tract nutritionally abundant. Thus, the discrete gut signals able to induce autophagy and overcome the cues from a fully energy replete environment remain largely unknown. Here we demonstrate that indole, a strictly microbiota-derived metabolite, induces autophagy at a level comparable with the canonical autophagy-inducer rapamycin.
Consistent with the induction of autophagy, indole-conditioned dendritic cells exhibited increased LC3-II expression and puncta formation, enhanced bacterial killing, and reduced inflammasome activity. Indole effects were largely similar to rapamycin yet also distinct, suggesting a complementary mechanism of action for these molecules. Both indole and rapamycin suppressed mTOR signaling and IL-1beta production, suggesting a functional link. Unlike rapamycin, we have reported indole is a ligand of the aryl hydrocarbon receptor (AhR), yet regulation of autophagy by indole was AhR-independent. To our knowledge, this is the first evidence of a tryptophan microbiota metabolite functioning as a regulator of autophagy. These findings reveal novel biology by which the microbiota regulates gut autophagy and has therapeutic implications in inflammatory and autophagy-mediated disorders.
The differentiation and maintenance of RORγt+ Tregs respectively require integrin αvβ8 expression by dendritic cells and commensal microbiota
Authors: Chen Zhengtao , Wang Meixiang , Zhang Zhongyun , Liu Weixiu , Song Wengang , Tang Hua 
Published: January 2023

Abstract
The generation of RORγt+ regulatory T cells (Tregs), which regulate type 2 immune respond, is dependent on dendritic cells and microbiota, but mechanisms are poorly understood. Here we show that the differentiation of RORγt+ Tregs was critically dependented on integrin αvβ8 expressed in DCs. In mice, lack of αvβ8 in DCs resulted in loss of RORγt+ Tregs in the small intestine and mesenteric lymph nodes. Moreover, we also report that the maintenance of RORγt+ Tregs needs the existence of commensal bacteria but not DCs in small intestine. The percentage and the proliferation of RORγt+ Tregs were decreased after treated with antibiotic while these were unaffected by the absence of DCs in a short time. These date demonstrate that αvβ8 expressed in small intestinal DCs play a critical role in the induction of RORγt+ Tregs and microbiota act as a key factor on maintenance of RORγt+ Tregs, respectively. Our results may help to explain the mechanisms of oral tolerance via αvβ8 in DCs and commensal microbiota regulate the generation of RORγt+ Tregs to suppress type 2 immune respond.