bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid and systemic innate immune responses to an adenoviral HIV vaccine (45.27)
Authors: Andersen-Nissen Erica , Zak Daniel E , Duerr Ann C , Peterson Eric R , Robertson Michael N , DeRosa Stephen C , McElrath M. Juliana , (HVTN) and the NIAID-sponsored HIV Vaccine Trials Network 
Published: January 2023

Abstract
Understanding innate immune responses to candidate HIV vaccines will guide vaccine design. We assessed the early innate response in volunteers enrolled in HVTN 071, a trial of intramuscularly delivered Merck adenovirus serotype 5 (MRKAd5) gag/pol/nef- the same vaccine used in the Step trial. Samples were collected pre-vaccination and at 4-6 hours, days 1, 3, and 7 (n=11) post-vaccination or at day 1 post-vaccination (n=24). Cytokine and chemokine levels in the serum were measured by multiplex assay and cell populations were analyzed by multiparameter flow cytometry. Serum levels of IP-10, MCP-1, TNF-α, IL-6, IL-1RA, IFN-γ, and IL-10 were similar at baseline and 4-6 hours post-vaccination, showed up to 10-fold increases over baseline on day 1 post-vaccination, and returned to baseline levels by day 3. Dendritic cell concentrations increased in 4 hours; monocytes increased gradually and peaked at day 3. In contrast, T, B, and NK cell blood concentrations decreased sharply at day 1 post-vaccination, suggesting massive trafficking to the vaccination site. Moreover, PBMC gene expression analysis by microarray consistently revealed strong induction of inflammatory and antiviral genes. Together, these data demonstrate robust early immune activation after vaccination. Future studies of innate immune responses to other candidate HIV vaccines may elucidate why the vaccine used in the Step trial did not show efficacy.
Reduced Th17 cells in a patient with recurrent staphylococcal disease and neutralizing autoantibodies against IL-6 (47.33)
Authors: PUEL Anne , de Beaucoudrey Ludovic , Chrabieh Maya , Picard Capucine , Gendrel Dominique , Casanova Jean-Laurent 
Published: January 2023

Abstract
We investigated a patient presenting with two severe episodes of staphylococcal cellulitis and abscesses. We identified in the patient's serum high titers of autoantibodies against IL-6, able to specifically almost completely neutralized IL-6 ex vivo and in vitro. The existence of a relationship between IL-6 deficiency and susceptibility to S. aureus recently gained credence from the identification of patients with STAT3 deficiency and an autosomal dominant form of the hyper-IgE syndrome, as these patients often present recurrent staphylococcal skin abscesses and show defective responses in particular to IL-6 and IL-10. A defect in the Th17 population differentiation has been reported in STAT3 deficient patients. In order to determine the role of IL-6 in Th17 differentiation in human, we investigated the presence of this population ex vivo and in vitro in our patient. We observed a strong decrease of Th17 positive cells both ex vivo and after differentiation in vitro, strongly suggesting an important role of IL-6 in Th17 development in vivo in human
Clinical-electrophysiologic-pathologic correlations in severe murine experimental autoimmune neuritis (48.14)
Authors: Ubogu Eroboghene E , Yosef Nejla , Xia Robin H 
Published: January 2023

Abstract
Severe murine experimental autoimmune neuritis (sm-EAN) is a reliable animal model of Guillain-Barré Syndrome. There is insufficient data characterizing the inflammatory infiltrates in this model or correlating neuromuscular severity with electrophysiological parameters. Sm-EAN was induced in 8-12 week old female SJL/J mice as previously published. Disease onset occurred at 9-13 days, with maximal severity between 26-32 days post-induction (p.i.). There was residual mild weakness &gt;2 months p.i. Severe multifocal or diffuse demyelination with some mild axonal loss was observed at peak severity, associated with mononuclear cell infiltrates (F4/80+ macrophages, CD3+ and CD4+ T-lymphocytes and CD19+ B-cells). There was increased expression of CCL2-CCR2, CCL5-CCR1, CCR5 and CXCL10-CXCR3 at peak severity. Residual infiltrates and rudimentary 'onion bulb' formation were seen during the recovery phase. Serial electrophysiological studies of the dorsal caudal tail nerve and bilateral sciatic nerves showed statistically significant reductions in mean compound motor action potential (CMAP) amplitudes and conduction velocity and increases in mean CMAP durations compared to controls. Regression analyses demonstrated correlations (r2=0.78-0.99) between neuromuscular severity and the above parameters, with stronger correlations seen with the dorsal caudal tail motor nerve responses.
Targeted depletion of lymphotoxin-alpha-expressing Th1 and Th17 cells inhibits autoimmune disease (48.22)
Authors: Grogan Jane L , Chiang Eugene , Yu Xin , Kolumam Ganesh 
Published: January 2023

Abstract
Aberrant autoimmune responses are often underpinned by dysregulated and uncontrolled CD4+ T helper (Th) cell subsets Th1 and Th17. We identify surface lymphotoxin-alpha (LTa) as common to Th1 and Th17 cells and employ a novel strategy to target these subsets using a depleting monoclonal antibody directed to surface LTa. A depleting anti-LTa mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of anti-LTa; inhibited disease, resulting in immunoablation of T cells expressing IL-17, IFN-g; and TNF-a, whereas a decoy LTbR fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of FcgR binding and ADCC activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1b and TNF-a within joints. These data indicate that depleting Th1 and Th17 with anti-LTa mAb may be beneficial in the treatment of autoimmune disease.
IMO-3100, an Antagonist of Toll-Like Receptors 7 and 9, Modulates Gene Expression and Regulatory Networks Induced by Ligands (48.25)
Authors: Jiang Weiwen , Bhagat Lakshmi , Yu Dong , Kandimalla Ekambar R , Agrawal Sudhir 
Published: January 2023

Abstract
In autoimmune diseases, immune complexes containing self-nucleic acids have been shown to induce inflammatory responses through TLR7 and 9. IMO-3100 is a novel DNA-based antagonist of TLR7 and 9 that is shown to inhibit TLR7- and 9-mediated immune responses. To elucidate inhibitory effects of IMO-3100 on TLR7 and 9 agonist-mediated gene expression, we treated human PBMCs with a TLR7 or TLR9 agonist with or without IMO-3100, isolated total RNA, carried out gene expression profiling on human inflammatory response and autoimmunity microarray, and analyzed data to identify changes in regulatory networks. IMO-3100 alone showed insignificant up-regulation of a small number of genes. TLR9 agonist significantly up-regulated a number of genes, including IP-10, MyD88, MCP-1, IL-6, IRF7, IL-17A, NF-κB1, and RIPK2, which regulate immune responses, NF-κB signaling, inflammation, and chemotaxis networks. TLR7 agonist showed a different gene expression profile compared with TLR9 agonist. The genes that were significantly up-regulated by TLR7 agonist include IP-10, IRF7, IFN-α1, IFN-α4, IFN-γ, IL-15Ra, IL-17A, IL-6, and TIRAP, which regulate host defense response, chemotaxis, and cytokine and chemokine signaling pathways. Co-incubation of IMO-3100 with either TLR agonist resulted in inhibition of genes that were up-regulated with either TLR agonist alone. These results indicate that TLR7 and 9 agonists induce different gene expression profiles and IMO-3100 is a potent inhibitor of these responses. IMO-3100 is a lead candidate identified for development for potential applications in autoimmune diseases.
TLR2 dependent activation of IL-6/IL-17 axis in the development of Collagen-Induced Arthritis (48.28)
Authors: Ortmann Rob , Sisk Bryan , Krogstad Aric , Kannan Krishna 
Published: January 2023

Abstract
Toll-like receptors (TLRs) are pattern-recognition receptors for foreign microbial products which initiate host defense responses. Several lines of evidence suggest that abnormal TLR signaling may lead to excess production of pro-inflammatory cytokines and development of Th-17 cells, a pathogenic T helper cell subset implicated in Collagen-Induced Arthritis (CIA). In this study, we examined the TLR2 dependent cytokine milieu that promotes Th-17 polarization and the development of disease. Using C57BL/6 (B6), DBA/1, and B6 TLR2-KO mice, we examined the role of TLR2 signaling in the development of pro-inflammatory responses during various phases of arthritis development. We observed that TLR2-KO mice were resistant to disease whereas both B6 and DBA/1 mice developed CIA 4 to 5 weeks after immunization. Ex vivo culture of spleen cells and draining lymph node cells demonstrated significantly elevated levels of IL-6, TNF-α, IFN-γ and IL-17 in response to type II collagen in DBA/1 and B6 mice as compared to TLR2 deficient animals. Importantly, IL-6 levels were elevated both before and after arthritis developed. Also, progressively higher levels of IL-17 and Th-17 cells were found as disease developed, and this increase was not seen in TLR2 deficient animals. Together, our results demonstrate a role for TLR2 mediated control of the IL-6/Th-17 axis in the development of collagen-induced arthritis.
Inhibition of TNFR1 signaling by P60 PLAD protein ameliorates skin lesions in lupus MRL/lpr mice (50.24)
Authors: Deng Guo-Min , Liu lena , Tsokos George C 
Published: January 2023

Abstract
Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). The etiology of skin injury remains unclear. There is urgent need to understand better the pathogenesis of skin lesions and to develop effective, non-toxic therapy for cutaneous lupus erythematosus. MRL/lpr mice develop pathology similar to human SLE including skin lesions. To understand whether tumor necrosis factor (TNF) contributes to the pathogenesis of cutaneous lupus erythematosus, we treated lupus MRL/lpr mice with TNF receptor (R) defined PLAD protein. P60 PLAD inhibits the function of TNFR1, whereas P80 PLAD inhibits the function of TNFR2. We found that P60 PLAD protein significantly inhibited skin injury but P80 PLAD failed to do so in MRL/lpr mice. Both PLAD proteins promoted the development of proteinuria. Immunohistochemistry studies of skin lesions demonstrated that TNFR1 but not TNFR2 in expressed in the skin lesion of MRL/lpr mice. P60 PLAD significantly inhibited NF-kB, MCP-1 and iNOS expression by skin keratinocytes. Our results indicate that TNFR1 contributes to the development of skin lesions in lupus-prone mice suggest that it can be targeted successfully to treat cutaneous SLE.
Beneficial Therapeutic Effect of Cellcept® in Systemic Lupus Erythematosis (SLE); Suggested Mechanism of Action (50.26)
Authors: nuhaily Samer , Yei Soonpin , Zarieh Ata , Meza Miguel , Zhang Hongying (Hannah) , Incardona Francesca , Esber Henry J , Damaj Bassam B 
Published: January 2023

Abstract
Cellcept® inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation and suppresses antibody formation in B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in adhesion to endothelial cells. Although Cellcept® is prescribed "off label" to treat SLE and shows great benefits, the exact mechanism of action is not fully understood. MRL/lpr developing glomerular disease mice that exhibit similar pathology to human SLE were used to study the therapeutic effects of Cellcept®. Although Cellcept® at 100mg/kg doses significantly decreased the proteinurea levels in the treated mice, it had marginal effects on the ds-DNA antibody levels. In addition, Cellcept® reduced the levels of B cells in the spleens of treated mice consistent with its immunosuppressant benefit. Histopathological evaluation demonstrated that Cellcept® reduced glomerulonephritis but not vasculitis in kidneys of treated mice. Furthermore, it was shown that Cellcept® lowered the number of monocytes in kidneys; this is the most likely mechanism of action responsible for the less kidney damage and lower proteinurea levels. The reduction in the number of monocytes in kidneys is the first major indication that the beneficial effect of Cellcept® to the kidney function in patients with SLE might be due to the inhibition of mocnocyte infiltration responsible for the destruction of nephritic tissues and not through the action on B cells by lowering the ds-DNA antibody levels.
APLP2 Diverts MHC-Peptide Complexes to Clathrin-Mediated Endocytosis and Lysosomal Degradation (78.14)
Authors: Tuli Amit , Sharma Mahak , Capek Haley , Naslavsky Naava , Caplan Steve , Solheim Joyce 
Published: January 2023

Abstract
The amyloid precursor-like protein 2 (APLP2) is a secreted protein that is ubiquitously expressed. We have shown previously that APLP2 associates with peptide-bound forms of H-2Kd, and influences the endocytosis, surface expression, stability, and turnover of Kd. Our new findings indicate that APLP2 is internalized in a clathrin-dependent manner, as a dominant negative dynamin II mutant and the C-terminal tail of AP180 (both inhibitors of clathrin-dependent endocytosis) block its internalization. However, endocytosis of Kd is not blocked by these inhibitors, consistent with findings by others that MHC class I molecules are internalized mainly through a clathrin-independent pathway. Furthermore, the APLP2 cytoplasmic tail contains overlapping tyrosine-based motifs that can potentially bind to adaptor protein AP-2. Mutation of the tyrosine in this sequence severely impaired endocytosis of APLP2. This APLP2 mutant, unlike wild-type APLP2, failed to enhance the endocytosis of Kd molecules. Also, we found that APLP2 and Kd bind at the plasma membrane (PM) and are internalized together. Upon increased APLP2 expression, Kd molecules were predominantly directed to the lysosomes rather than recycled to the PM. These findings suggest a model in which APLP2 binds Kd at the PM, facilitates uptake of Kd in a clathrin-dependent manner, and routes the endocytosed Kd to the lysosomal degradation pathway. Thus, APLP2 has a multi-step trafficking function which influences the expression of MHC-peptide complexes at the PM. [NIH GM57428 & GM74876]
Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin (78.24)
Authors: McLachlan James B , Catron Drew M , Moon James J , Jenkins Marc K 
Published: January 2023

Abstract
Effector (Teff) and regulatory (Treg) T cells produce cytokines that balance immunity and immunopathology at sites of infection. It is not known how this balance is achieved. Here, we show that Treg and Teff cells specific for the same foreign peptide:major histocompatibility complex II (pMHCII) ligand accumulated preferentially in a subcutaneous site injected with the relevant antigen plus an adjuvant. Some of the Treg cells in this site were producing IL-10 twelve days after injection while a similar fraction of the Teff cells were producing IFN-γ. Acute ablation of Treg cells increased the fraction of IFN-γ-producing Teff cells, indicating that Teff function was limited by the Treg cells. Production of cytokines by both populations was driven by pMHCII presentation by local CD11bhigh dermal dendritic cells. Therefore, balanced production of microbicidal and suppressive cytokines in inflamed skin is achieved by simultaneous dendritic cell antigen presentation to Teff and Treg cells.
Regulation of Th1 and Th2 phenotypes by γ-secretase inhibitor in an animal model for asthma (79.10)
Authors: Kang Jin Hyun , Kim Do Jin , Park Choon-Sik , Chung Il Yup 
Published: January 2023

Abstract
γ-Secretase inhibitor (GSI) has been used to effectively block Notch signaling, which is implicated in the differentiation and functional regulation of T helper (Th) effector cells. We investigated a therapeutic potential of GSI against development of Th2-mediated inflammatory airway disease and the possible mechanism. Intranasal administration of GSI led to inhibition of asthma phenotypes including airway inflammation, goblet cell metaplasia, and airway hyperresponsiveness. When BAL cells from inflamed airways of mice were stimulated via TCR- or non TCR-pathways in the presence of GSI, Th2 cytokine production was decreased while Th1 cytokine production was increased. Furthermore, GSI treatment of CD4+ T cells that were purified from BAL cells resulted in markedly elevated IFN-g production and declined IL-5 production. However, this analogy was not exactly applied to splenic CD4+ T cells isolated from both naïve and asthma-induced mice: both IL-5 and IFN-g productions were inhibited by GSI, indicating that CD4+ T cells differentially responded to GSI depending on places where they reside. These data suggest that GSI is of therapeutic benefit against asthma by modulating Th effector responses.
Alternatively activated macrophages participate in the recruitment of eosinophils to the lung in a murine model of allergic lung inflammation (79.2)
Authors: Ford Andrew Q. , Smith Elizabeth , Noben-Trauth Nancy , Keegan Achsah D. 
Published: January 2023

Abstract
The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and is involved in IL-4 and IL-13 signaling, allowing it to influence various pathological components of allergic lung inflammation. We've previously reported that IL-4Rα expression on both bone marrow derived and non-bone marrow derived cells contributes to the severity of allergic lung inflammation. We found a correlation between the expansion of cells expressing the IL-4Rα, CD11b, and IAd and the degree of eosinophilia in ovalbumin challenged mice, suggesting a possible role for monocytes in the development of disease. To determine the role of CD11b+ cells in allergic lung inflammation, CD11b cells were developed in vitro from IL-4Rα positive and negative mice and transferred to IL-4RαxRAG2 knockout mice; TH2 cells were provided exogenously. Mice receiving IL-4Rα+, CD11b+ cells showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4Rα-, CD11b+ cells. Furthermore, an increase in cells expressing the macrophage marker F4/80 and the alternatively activated macrophage marker Ym-1 were recruited to the lungs of mice receiving IL-4Rα+, CD11b+ cells. These results suggest that stimulation of macrophages through IL-4Rα leads to their alternative activation and participation in the recruitment of eosinophils to the lung. (PHS AI38985)
Epicutaneous antigen challenge of orally sensitized mice elicits allergic dermatitis by redirecting α4β7 gut homing T cells to the skin (79.7)
Authors: Oyoshi Michiko K , ElKhal Abdallah , Scott Jordan E , He Rui , Wurbel Marc , Campbell James , Geha Raif S 
Published: January 2023

Abstract
Patients with atopic dermatitis (AD) can develop skin flares after ingestion of food allergens or cutaneous contact with these antigens. We examined the mechanism by which cutaneous exposure to allergens in orally sensitized individuals may elicit allergic skin inflammation. Wild-type (WT) or CC chemokine receptor (CCR)4-/- mice were fed intragastrically once a week for eight weeks 5 mg ovalbumin (OVA) and 10 μg cholera toxin (CT) in 200 μL saline or with CT alone in saline. Mice were then epicutaneously (EC) challenged with 100 μg OVA or saline. Mice were sacrificed a week later and analyzed for allergic skin inflammation. For adoptive transfer, CD4+α4β7+ T cells were purified from mesenteric lymph node (MLN) of orally sensitized WT or CCR4-/- mice and administered to WT recipients followed by EC challenge with OVA. Mice orally immunized with OVA then EC challenged with OVA developed allergic skin inflammation characterized by dermal infiltration with eosinophils and CD4+ T cells and upregulation of Th2 cytokines mRNA expression. In contrast to WT mice, orally immunized CCR4-/- mice failed to develop allergic skin inflammation in response to EC challenge. Purified CD4+α4β7+ T cells from MLN of orally immunized WT mice, but not CCR4-/- mice, transferred allergic skin inflammation to WT recipients. These results suggest that CD4+α4β7+ T cells educated in the gut can be reprogrammed in vivo to home to the skin in a CCR4 dependent manner and cause allergic skin inflammation in response to cutaneous antigen exposure.
Funded by The Atopic Dermatitis and Vaccinia Network NIH/NIAID contract N01 AI40030
Flow cytometric cellular analyses on the developmental, activation, and proliferation states of B cells in rainbow trout (81.3)
Authors: Barr Maggie , Mott Katrina , Rosato Pamela , Zwollo Patty 
Published: January 2023

Abstract
Teleosts, including rainbow trout, provide an important animal model for the immunologist as they lack bone marrow and lymph nodes and utilize the kidney, spleen, and blood as immune organs. The developmental, activation, and proliferation stages of trout B cells and the location of these processes within the immune tissues are not well defined. Expression patterns of B cell transcription factors can be used as markers to investigate the B cell stages. In this study, the transcription factors Pax5 and XbpI, as well as RAG1, total IgM, secreted IgM, and BrdU incorporation were used as markers in trout B cells. Pax5 is expressed in early B cell development through the plasmablast stage, but is absent from plasma cells. In contrast, XbpI is induced in activated B cells and is expressed throughout plasmablast and plasma cell stages. Trout immune cells were LPS-activated in culture, fixed and permeabilized, and stained cells were analyzed by flow cytometry. Preliminary data suggests that each of the immune organs contains a plasmablast (Pax5+/XbpI+/total IgM+/ BrdU+) population either prior to, or upon LPS activation in culture. In the spleen, most of such cells are present at day 4, while blood has most plasmablasts on day 2. Both anterior and posterior kidney contain relatively high frequencies of plasmablasts immediately after isolation, but frequencies decrease upon culturing. This study supports the concept that flow cytometric analysis can be used to determine the location and differentiation state of B cells within the immune organs of the rainbow trout. This research was funded by a grant from the NIH.
Alternative splicing of Pax5 in immune tissues of rainbow trout (Oncorhynchus mykiss) (81.4)
Authors: Talauliker Raaj M , Harman Alice , Zwollo Patty 
Published: January 2023

Abstract
Pax5 is a master regulator of B cell development and regulates gene expression of a host of genes involved in cell maturation and activation. Previous studies on alternative splicing of Pax5 have reported on different isoforms that differ in DNA binding (encoded by exons 2 and 3) and trans-activation (TA) potential (encoded by exons 7-10). Our lab explores alternative splicing of Pax5 as a viable way of regulating downstream gene targets and hence, progression of the B cell program in rainbow trout. cDNAs from four trout immune tissues (anterior and posterior kidney, spleen and blood) were screened by nested PCR to search for alternatively spliced Pax5 transcripts. Several splice forms, lacking exons 2, 8 or 9, were uncovered. Using quantitative real-time PCR, the change in expression of each isoform is currently being analyzed in immune tissues stimulated in culture with LPS. This study will set the framework to better understand how alternative splicing can potentially regulate expression of target genes during B cell differentiation. This research is supported by a grant from the NIH and a graduate research grant from the A&S GSA.