bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toll-like receptor 2 is associated with house dust mite-induced inflammatory response in human bronchial epithelial cells (91.1)
Authors: Teng Fang , Xu Jimmy Peining , San Mateo Lani 
Published: January 2023

Abstract
Exposure of the respiratory tract of an atopic individual to allergens such as D. pteronyssinus (DP) house dust mite is associated with the development of allergic asthma. In the study, we explored the role of Toll-like receptors (TLRs) in allergen-induced inflammatory responses of human bronchial epithelial cells. Our results showed that DP induced production of G-CSF, GM-CSF, CXCL1, IL-6, CXCL8, and CCL2 in BEAS-2B (immortalized human bronchial epithelial cells) in a dose-dependent manner. An inhibitory peptide against MyD88 significantly inhibited the allergen-induced cytokine response, while monoclonal antibodies (mAbs) against TLR2 showed some (but not significant) inhibitory effects. Analysis of mRNA transcripts by qPCR revealed an increased expression of MyD88 at 1 hr post-stimulation with DP. DP stimulation also induced increased expression of TLR1, TLR2, TLR3, TLR5, TLR8, and TLR9, as well as IFNβ. HKLM, a TLR2 agonist, along with DP showed a synergistic effect on cytokine response of BEAS-2B and the response was inhibited by anti-TLR2 mAb. HEK293 cells expressing TLR1/2, TLR2/6 or TLR4/CD14/MD2 showed increased cytokine response to allergens, while anti-TLR2 inhibited the response in HEK293 cells expressing TLR1/2 or TLR2/6. These data demonstrate a link between DP allergen-induced inflammatory response and TLR2-mediated signaling in airway epithelial cells and contribute to our understanding of the role of innate immunity in allergic diseases.
TLR4/MyD88-induced non-migratory myeloid cells suppress Th2 effector function in the lung (91.15)
Authors: Arora Meenakshi , Poe Stephanie , Oriss Timothy , Krishnamorthy Nandini , Yarlagadda Manohar , Billiar Timothy , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
Bacterial lipopolysaccharide (LPS) is immunostimulatory at a low dose but immunosuppressive at a high dose in the respiratory tract as observed in animal studies. Relevant to LPS-mediated immunosuppression in the lungs of animals is the protective effect of high doses of LPS in allergic diseases such as asthma in humans. Our study investigated the impact of a high dose of LPS on cells of the innate immune system in the lung to elucidate the basis of LPS-mediated immunosuppression. A high LPS dose blunted house dust mite-induced airway eosinophilia and Th2 cytokines production. Conversely, adoptively transferred Th2 cells were unable to mount allergic airway inflammation in LPS-treated lungs. The high LPS dose promoted the development of a lung-resident myeloid cell type in a TLR4- and MyD88-dependent fashion that suppressed lung DC-mediated reactivation of primed Th2 cells. Adoptive transfer of these myeloid cells suppressed allergen-induced airway inflammation. These data suggest that LPS-induced non-migratory myeloid cells might contribute to the protective effects of LPS in allergic airways disease by dampening Th2 effector functions in the lung. RO1 HL060207 (P.R.), RO1 HL077430 (A.R.), RO1 HL084932 (A.R. and P.R.) and AHA 0865379D (M.A.)
The role of CD1d-restricted type II NKT cells in the pathogenesis of inflammatory bowel disease (93.10)
Authors: Liao Chia-Min , Zimmer Michael , Cho Hoonsik , Choi Hak-Jong , Cardell Susanna , Yu Hoon-Tsen , Wang Chyung-Ru 
Published: January 2023

Abstract
CD1d is an MHC class Ib molecule that is specialized to present lipid antigens to NKT cells. Two subsets of NKT cells have been identified: type I NKT cells express an invariant TCR α chain while type II NKT cells express a more diverse TCR repertoire. Recent studies have shown that a specific pattern of CD1d expression is required for proper development and function of type I NKT cells. However, little is known about the regulation and selection of type II NKT cells as there is no method for direct detection of these cells. To address whether changes in CD1d expression patterns can regulate the function of type II NKT cells, we have generated a double transgenic mouse model, CD1dTg/24αβTg, that expresses high levels of CD1d as well as a TCR isolated from the type II NKT cell clone 24αβ. Total numbers of 24αβ T cells are significantly reduced in CD1dTg/24αβTg mice, suggesting that type II NKT cells undergo negative selection when engaged by abundant self-antigen. The remaining 24αβ T cells exhibit an altered surface phenotype and produce increased levels of inflammatory cytokines compared to equivalent cells that develop in a wild type B6 background. Interestingly, CD1dTg/24αβTg mice spontaneously develop inflammatory bowel disease (IBD) characterized by extensive colonic inflammation. Our studies highlight the importance of CD1d expression levels in the regulation of type II NKT cells and reveal a potential role for type II NKT cells in the pathogenesis of IBD.
Low copy-number of complement C4A, the presence of HLA-DR3, and the presence of HLA-DR2 are independent and additive risk factors for human systemic lupus erythematosus (SLE) (93.13)
Authors: Wu Yee , Lundstrom Emeli , Liu Chau-Ching , Yang Yan , Gunnarsson Iva , Svenungsson Elisabet , Zhou Bi , Jones Karla , Nagaraja Haikady , Higgins Gloria , Spencer Charles , Brunner Hermine , Birmingham Dan , Rovin Brad , Tsao Betty , Ahearn Joseph , Hebert Lee , Padyukov Leonid , Yu C. 
Published: January 2023

Abstract
The major histocompatibility complex (MHC) in chromosome 6p21.3 has the strongest genetic association with human SLE. This study aims to dissect the roles of MHC genes HLA-DRB1 and complement C4 in SLE. The study population includes 744 SLE patients and 760 unrelated healthy controls of European ancestry. Genomic Southern blot analyses and qPCR were used to determine the gene copy-numbers of total C4, C4A and C4B. Two-digit genotypings for HLA-DRB1 were performed by SSP-PCRs. The copy-numbers for total C4, C4A and C4B vary from 2 to 6, 0 to 5, and 0 to 4, respectively. Lower C4A copy-number (p=2.4x10-13), and increased frequencies of HLA-DRB1*03 (DR3; p=1.5x10-10) and HLA-DRB1*15 (DR2; p=0.032) are associated with SLE. Zero, 1 and ≥2 copies of C4A strongly correlate with homozygous, heterozygous and non-DR3, respectively, in controls (r2=0.435,χ2=374.0; p=1.2x10-79) and in SLE (r2=0.381, χ2=463.9; p=4.2x10-99). Comparing to subjects with non-low C4A (i.e. ≥2 copies), non-DR3 and non-DR2, the odds for SLE with low C4A only (i.e. &lt;2 copies) was 2.22 (95% CI: 1.11-4.43; p=0.031), DR3+ only was 1.81 (1.21-2.71; p=0.004), and DR2+ only was 1.65 (1.26-2.16; p=0.0002). Notably, the odds increased to 2.80 (2.09-3.76; p=3.6x10-12) among subjects with low C4A and DR3, and 2.71 (1.10-6.64; p=0.037) among subjects with low C4A and DR2. In conclusion, low C4A gene copy-numbers, the presence of HLA-DR3 or HLA-DR2 are each independent risk factors with additive effects for SLE.
Activating KIR genes act as risk factors for Crohn’s Disease (93.34)
Authors: Samarani Suzanne , Almalte Zaema , Iannello Alexandre , Debbeche Olfa , Amre Devendra , Ahmad Ali 
Published: January 2023

Abstract
Activating Killer-cell Immunoglobulin-like Receptor (KIR) genes constitute a subset of KIR family. The genes are expressed as activating receptors on the surface of NK cells as well as on a subset of T cells. The receptors interact with poorly defined ligands and decrease the activation threshold of these cells. Overall, they increase immune reactivity of the individuals. The activating KIR genes, like other KIR genes, are highly polymorphic. Furthermore, KIR haplotypes differ from each other with respect to the number of activating genes. Some haplotypes have no activating genes while others may carry upto seven such genes. Consequently, humans differ from each other with respect to the number of inherited activating KIR genes. Activating KIR genes have been associated with autoimmune diseases. However, little is known about their association with Crohn’s Disease. We have investigated the potential association of these genes with this disease in Canadian children of the French origin. Our results show that these genes act as risk factors for developing CD in these children. An increased number of inherited activating KIR genes correspondingly increased the risk for the disease. These results were also replicated in the Canadian (Caucasian) children of non-French origin. Collectively, our results suggest that activating KIR genes act as risk factors in developing CD in humans. The study was supported by the Crohn’s and Colitis Foundation of Canada (CCFC)
Self-organized criticality theory for the cause of autoimmunity (93.39)
Authors: Tsumiyama Ken , Miyazaki Yumi , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We here investigated the cause of autoimmunity from different angle, i.e., the defect in immune ‘system’, and discovered that overstimulation of immune system beyond its self-organized criticality leads to autoimmunity. Results: Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells by repeated immunization with antigen led to the development of a fully-matured autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction to immunizing antigen, and subsequently overstimulated CD8+ T cells, driving them to become MHC class I-restricted, antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE). Autoimmune tissue injury did not appear in CD8+ T cell-deficient mice. Further, inhibition of antigen-cross presentation by treating with chloroquine abrogated the generation of CTL and autoimmune tissue injury. Conclusion: Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality.
Bacille Calmette Guérin (BCG) can induce Kawasaki disease like features in Programmed death-1 gene knockout mice (93.8)
Authors: Chun Jin-Kyong , Kang Dong-Won , Jeon Bo Young , Kim Dong Soo 
Published: January 2023

Abstract
The pathogenesis of Kawasaki disease (KD) is not clear, but certain genetic defects of inhibitory immune processes after infectious stimuli have been suspected as a feasible factor. In the present study, we investigated the associative roles of programmed death-1 (PD-1) gene in the pathogenesis of KD. In order to induce KD-like manifestations in young PD-1KO mice, injection of the bacilli Calmette Guérin (BCG) was performed twice with a 4 week interval. After the second injection, PD-1KO mice showed KD-like clinical features including prolonged fever for more than 5 days, erythematous swelling on soles, anal desquamation, and gallbladder (GB) hydrops. Inflammation in at least more than one coronary artery was found in all PD-1KO mice whereas scanty coronary lesion was found in wild type (WT) mice. When the PD-1KO mice were challenged twice with HSP65 as same methods of BCG, coronary arterial lesions similar to those seen after BCG injection were observed. Inflammatory reactions in other organs including hepatic arteries, renal arteries, and biliary arteries were observed in PD-1KO mice. The levels of Interferon-γ and IL-6 were significantly increased in both sera and splenocytes of PD-1KO mice compared with WT mice (P &lt; 0.05). These results suggest that KD may develop in genetically prone populations by microorganism containing HSP65, and PD-1 gene may be an important component among genetic predispositions of KD.
Crystal structure of NKp30 and identification of ligand binding site through peptide mapping and blocking antibodies (94.12)
Authors: Joyce M.Gordon , Colonna Marco , Sun Peter 
Published: January 2023

Abstract
Natural Killer cells are a group of innate immune cells which carry out continuous surveillance for the presence of virally infected or cancerous cells. These lymphocytes are activated without any prior immune priming and elicit their effects via a combination of both activating and inhibitory receptors ensuring a highly sensitive mechanism which allows the differentiation between healthy and transformed cells. NKp30 is known to be the dominant activating receptor responsible for the destruction of a number of specific tumor cell types. In addition, NKp30 has been shown to cause the activation and expansion of resting NK cells upon interaction with dendritic cells and in addition to cause the death of immature dendritic cells (imDCs). The precise mechanism of how NKp30 interacts with virus-infected, cancerous cells and imDCs initiating NK cell killing is an intriguing question and to date, a number of NKp30 interacting molecules have been proposed. These molecules are quite diverse, ranging from Heparan sulphate to a plasmodium falciparum molecule and most recently a B7 homolog protein. How NKp30 recognizes these diverse molecules is to date unknown. In order to address this question we have determined the crystal structure of the extracellular domain of human NKp30. In an attempt to understand how NKp30 binds diverse ligands, we have identified a putative ligand binding region on the surface of NKp30 through peptide mapping and competition with blocking antibodies.
Viral immune evasion: HSV-1 immediate early protein ICP0 inhibits TLR2-driven NF-kB activation (94.18)
Authors: Kurt-Jones Evelyn , vanLint Allison , Murawski Matthew , Fitzgerald Katherine , Finberg Robert , Knipe David 
Published: January 2023

Abstract
The recognition of Pathogen Associated Molecular Patterns (PAMPS) by conserved receptors of the innate immune system is a critical step in the development of anti-viral immunity. We have studied a class of innate immune receptors, the Toll-like receptors (TLRs), in the anti-viral response to viruses including Herpesviruses. We have previously shown that HSV-1 infection induces NF-kB dependent innate immune responses via TLR2. TLR2 activation by HSV-1 drives NF-kB-dependent inflammatory cytokine production which plays a critical role in the HSV-1 pathology particularly the development of lethal encephalitis. Here we describe studies of TLR2-HSV-1 interaction which reveal a complex interplay between viral gene products and the host innate immune response. Using various mutant HSV-1 viruses, we find that ICP0, an immediate early viral protein, significantly inhibited TLR2-driven responses. Further, ICP0 expression alone was sufficient to block TLR2 activation by both viral and non-viral stimuli. Expression of ICP0 reduced levels of MyD88 and Mal, two critical adaptors for TLR2 signaling. ICP0 did not affect TRIF- or TRAM-driven NF-kB, but did block MyD88- and Mal-driven NF-kB responses. Proteosomes were required to inhibit TLR2 activation as was the E3 ligase function of ICP0. Our results suggest that ICP0 promotes degradation of the TLR adapter proteins, MyD88 and Mal, thereby blocking TLR2-driven activation of NF-kB sensitive inflammatory target genes.
Role of Myd88-mediated signaling in the prevention of colon adenocarcinomas (95.10)
Authors: Salcedo Rosalba , Worschech Andrea , Cardone Marco , Jones Yava , Gyulai Zsofia , Dai Ren-Ming , Marincola Francesco , Trinchieri Giorgio 
Published: January 2023

Abstract
Signaling through the adaptor protein MyD88 promotes carcinogenesis in several chemically induced cancer models. In contrast, in the AOM/DSS model of chronic colitis induced cancer, we observed a protective role for MyD88 in the development of colitis-associated cancer (CAC). The inability of Myd88-/- mice to heal ulcers generated upon DSS treatment creates an altered inflammatory environment that induces profound early alterations in expression of genes encoding pro-inflammatory factors as well as pathways regulating cell proliferation and apoptosis. Additionally, AOM/DSS treatment induced alterations in DNA repair in MyD88 deficient mice, resulting in increased frequency of mutations and a dramatic increase in adenoma formation and progression to invasive phenotype. Others have reported that Tlr4 deficient mice share similar susceptibility to colitis as Myd88 deficient mice but, unlike the latter, are resistant to CAC. We observed that mice deficient for Tlr2 or IL-1R do not show a differential susceptibility to colitis or CAC. In contrast, AOM/DSS treatment resulted in increased susceptibility to colitis development and enhanced polyp formation in Il-18-/- mice. This indicates that the phenotype of Myd88 -/- mice is in part due to their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that differentially impact tissue homeostasis and carcinogenesis.
Mechanism of inhibition of colitis by indole-3-carbinol (96.19)
Authors: Busbee Phililp , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Colitis is an autoimmune disease characterized by acute or chronic inflammation of the large intestine. Currently there is no cure for patients suffering from colitis, and most treatments involve the use of immunosuppressive drugs that can have adverse side-effects or increased toxicity. In the current study, we investigated the effects of indole-3-carbinol (I3C), a component found in a number of cruciferous vegetables. The products of I3C activate the aryl hydrocarbon (AhR) receptor, which has been shown in our laboratory to trigger apoptosis in activated T cells. In the current study, we tested the effect of I3C on a colitis model induced by administration of dextran sodium sulfate (DSS). The data showed that I3C administration reversed the weight loss seen during DSS-induced colitis. I3C treatment also reversed the shortening of the colon caused by DSS, as well decreased the level of immune cell infiltration found in the large intestine of colitis-induced mice. Early analysis of cell populations from the mesenteric lymph node showed that I3C treatment reduced the effects the disease model had on immune cells including T regulatory cells, natural killer cells, and myeloid-derived suppressor cells. In all these immune cell subsets, I3C treatment caused a return of the proportion of these cell populations to a more normal state. Together, the current study suggests that I3C may a serve as a novel treatment modality against colitis.
In vivo Treg expansion by TNFRSF25 stimulation inhibits allergic lung inflammation (97.11)
Authors: Tsai Matthew , Schreiber Taylor , Wolf Dietlinde , Chirinos Jackeline , Gonzalez Louis , Levy Robert , Podack Eckhard 
Published: January 2023

Abstract
TNF receptor super family member 25 (TNFR25, DR3) is constitutively and highly expressed by CD4+FoxP3+ regulatory T cells (Treg). Here we have utilized a TNFR25 agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Treg in vivo. We have previously demonstrated that signaling through TNFR25, in the absence of TCR signals, induces rapid and selective expansion of natural Treg in vivo to 30-35% of all CD4+ T cells within 4 days. TNFR25-expanded Treg remained highly suppressive ex vivo. Here we demonstrate that although certain IL-2 antibody complexes expand Treg to a similar degree, only in vivo TNFR25-expanded Treg are protective against allergic lung inflammation, a model for asthma, by reversing the T-effector to T-regulatory ratio in the lung, suppressing IL-13 and Th2 cytokine production and blocking eosinophil exudation into bronchio-alveolar fluid. Unlike TNFR25 responses by T effector cells, which require TCR engagement, expansion of Treg by TNFR25 signaling is not dependent upon stimulation by exogenous antigens. Our studies define a novel mechanism for Treg control and important functions for TNFR25/TL1A in regulating auto aggression that balance its known role in enhancing auto immunity.
Immunocomplexes down-modulate the induction of food allergy in mouse. (97.12)
Authors: Alves de Araujo Claudia , Clay Bryan , Ganeshan Kirthana , Bryce Paul , Sperling Anne 
Published: January 2023

Abstract
Food allergy is an adverse Th2 response whose incidence has been increasing dramatically over the past decade. We have demonstrated that signaling triggered by immunocomplexes (IC) through CD16 (FcgRIII) in conjunction with TLR4 prime dendritic cells (DCs) to drive Th2 responses. To address our hypothesis that IgG plays a role in the pathogenesis of food allergy in a murine model, we investigated the contribution of CD16 signaling. Wild type (WT) or CD16-/- mice were sensitized by gavage for 8 weeks with SEB, SEB+OVA or SEB+OVA-IC and challenged on the 9th week. To analyze the systemic responses, blood eosinophilia and OVA-specific serum IgE and IgG1 levels were measured. We found that CD16-/- had reduced responses compared to WT, however, both SEB+OVA-IC-immunized WT and CD16-/- mice had lower responses compared to SEB+OVA immunized controls. To investigate the effect of IC in DC functions, naïve WT and CD16-/- BMDCs were stimulated with SEB with either OVA or OVA-IC, and DC maturation and survival were determined. Compared to SEB-OVA stimulation, SEB+OVA-IC-stimulated WT and CD16-/- BMDCs have similar maturation, but a decrease in late apoptotic cells. Our findings suggest that ICs down-regulate the allergic response in the gut of WT and CD16-/- mice leading to lower systemic responses, and yet preserves DC functions. Thus, IC might induce a regulatory network in the gut mucosal that allows sensitization, but fails to trigger an exacerbated inflammatory response.
Allergic Airway Disease is Inhibited by Transfer of Lung Tissue CD8+ T Cells from Tolerant Mice (97.4)
Authors: McNamara Jeff , Secor Eric , Guernsey Linda , Schramm Craig , Lefrancois Leo , Thrall Roger 
Published: January 2023

Abstract
CD8+ T cells can play both a pro and anti inflammatory role in asthma, which we have examined using a biphasic model of allergic airway disease (AAD). Acute delivery (7-14 days) of ovalbumin (OVA) aerosol to sensitized animals results in AAD, while continued delivery of OVA (42days) results in local inhalational tolerance(LIT). During AAD the number and percentage of antigen specific CD8+ T cells continued to increase in the bronchoalveolar lavage(BAL) and lung tissue past the peak of BAL eosinophilia. After the chronic delivery of allergen high percentages of OVA specific cells were still found in the BAL, whereas lower levels were identified in the lung tissue. There were phenotypic changes in the BAL and lung tissue cells at LIT, including lower CD27, CD127 and granzyme b expression and higher expression of the inhibitory NK2GA molecule. Negatively selected CD8+ T cells from the lung tissue from LIT animals were transferred into sensitized animals. Subsequently, these mice received 6 days of OVA aerosol and then were examined for disease. Mice receiving LIT Lung Tissue CD8+ T cells had significantly fewer eosinophils in the BAL (9±5 x105 eosinophils) than mice receiving saline (47±14), or LIT lung tissue CD8- T cells (37±7 p = 0.05 by ANOVA). These data suggested that CD8+ T cells from the lung tissue may play an important role in the establishment of tolerance in AAD. What role the altered phenotype of OVA specific cells play in this inhibition is yet to be determined.