bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoreactive IgA antibodies are high prevalent and associated with clinical manifestations in systemic lupus erythematosus, systemic scleroderma and idiopathic inflammatory myositis
Authors: Li Quanzhen , Wei Junxia , Luo Hui , Zhu Honglin , Zhu Chengsong 
Published: November 2024

Abstract
Systemic lupus erythematosus (SLE), systemic scleroderma (SSc) and idiopathic inflammatory myositis (IIM) are autoimmune diseases characterized by a broad range of autoreactive antibodies (AutoAbs). In this study, we measured the serum IgA AutoAbs against 120 self-antigens in a cohort of 128 SLE, 73 SSc, 75 IIM and 140 healthy controls (HC), using OmicsArray™ antigen microarrays. We found IgA AutoAbs are highly prevalent in SLE and SSc compared with IIM and NC. 58.4% SLE and 41.7% SSc have 5 or more IgA AutoAbs compared with 16% in IIM and 14.1% in NC. 9 IgA AutoAbs most significantly elevated in SLE were anti-DNA antigens including dsDNA (54.7%), ssDNA (51.1%), and chromatin (46%). 32 IgA AutoAbs were significantly increased in SSC with highest reactivity to Scl-70 (55.6%). IIM showed lower IgA prevalence in general with highest in anti- Jo-1 (20%), anti-muscarinic receptor (8%) and anti-B2-microglubulin (6.7%). Significant correlation was observed between IgA and IgG isotypes on most AutoAbs. 3 IgA autoAbs (anit-gDNA, anti-C1q and anti-dsDNA) positively correlated with SLEDAI Score, but only anti-C1q was significantly elevated in lupus nephritis. 14 anti-nuclear IgA AutoAbs negatively correlated with serum complement C3 and/or C4 levels. Our study indicated that autoreactive IgA against nuclear components, in parallel with IgG, are highly prevalent in SLE and SSC patients. IgA AutoAbs could be used as biomarkers for diagnosis and prognosis of systemic autoimmune diseases.
The Effect of Weight Cycling on Myelopoiesis
Authors: Martinez-Navarrete Wenceslao , Kalev-Altman Rotem , Guha-Ray Aleepta , Wiseman Destini , Weinstock Ada 
Published: November 2024

Abstract
Inflammation is a hallmark of obesity and is associated with many complications, with myeloid cells being major culprits. Weight loss improves obesity-related comorbidities, however, subsequent weight regain, known as weight cycling (WC), has been linked to worsening of obesity-related diseases. Therefore, it is critical to understand how WC impacts inflammation. We hypothesize that mice undergoing WC will have greater myeloid cell production with heightened inflammatory capacity. To test this hypothesis, we characterized immune cell populations in bone marrow (BM) and blood using multi-parametric flow cytometry in mice undergoing acute and long-term WC compared to non-WC mice. Our results indicate WC increases the frequency of inflammatory Ly6Chi monocytes and lowers pro-resolving Ly6Clo monocytes in the BM. Additionally, WC increases circulating monocytes. The increase in monocytes are coupled with expansion of their bone marrow progenitors, suggesting that WC heightens myelopoiesis. We will further examine inflammatory capacity by stimulating bone marrow derived macrophages with lipopolysaccharide and measuring cytokine secretion. Furthermore, hematopoietic progenitor differentiation will be tested through colony forming assays. Combined RNA/ATAC-seq will be used to understand the transcriptomic and epigenetic changes occurring in progenitors with WC. This study will provide novel insight into how WC worsens disease, and the basic mechanisms regulating myelopoiesis.
Excessive expression of TIM-3 on myeloid cells leads to inflammation in the lungs
Authors: Kim Ki Sun , Lee Chanju , Kim Hyung-Seok , Gu Su Jeong , Yoon Hee Jung , Won Su Bin , Kane Lawrence P , Park Eun Jung 
Published: November 2024

Abstract
T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) has increasingly shown to exhibit unique characteristics and functions that differ according to the specific cell type and cell status. However, at present, little is known about the cell-specific properties of TIM-3 in pathophysiological conditions. Here, we show that TIM-3 on myeloid cells exerts essential roles in modulating inflammation and abnormality of lungs. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have a characteristic appearance of low body weight and short lifespans compared to WT mice. Interestingly, whole-body PET/CT analysis revealed that FSF-TIM3/LysM-Cre+ mice showed considerably high [18F]FDG uptake in the areas of lungs. Given that FSF-TIM3/LysM-Cre+ mice displayed abnormal features in lung areas, we next carefully examined the lungs. We observed that the lungs of FSF-TIM3/LysM-Cre+ mice were enlarged and histopathological examination showed features of disease-associated pathology compared to WT mice. Similar features were observed in a different myeloid cell-specific TIM-3 knock-in mouse (FSF-TIM3/Cx3cr1-Cre+). In addition, inflammation-related cytokines and the number of myeloid innate immune cells increased in the lungs of FSF-TIM3/LysM-Cre+ mice. Collectively, these findings suggest that TIM-3 is an important regulator of myeloid cells in the lungs and maybe a relevant therapeutic strategy against inflammation-associated lung disease.
Plasmacytoid dendritic cells are central regulators of the humoral ChAdOx1 nCoV-19 vaccine response in a human tonsil organoid model
Authors: Provine Nicholas , Pudjohartono Maria , Powell Kate , Ferry Helen , Barnes Ellie , Klenerman Paul 
Published: November 2024

Abstract
Studying human vaccine responses is limited by the difficulty of access to secondary lymphoid tissues. To overcome this, we have optimized a human tonsil organoid model to investigate the processes that regulate the humoral responses to the ChAdOx1 nCoV-19 vaccine.
Stimulation of tonsil cultures with ChAdOx1 nCoV-19 induced broad innate immune activation and cytokine secretion within 24 hours. This induced (global and antigen-specific) B cell activation and spike-specific antibody secretion over the following 14-day culture period. Stimulation with an irrelevant ChAdOx1 GFP vector did not induce spike-specific antibody secretion.
Plasmacytoid dendritic cells (pDCs) showed the highest rate of transduction and activation. Critically, pDC-depletion decreased both innate and humoral responses. IFN-⍺ blockade phenocopied pDC depletion while supplementing IFN-⍺ to pDC-depleted cultures rescued humoral responses. IL-6 was also critical for optimal humoral responses, and its production was modulated in an IFN-⍺-dependent manner even in the absence of pDCs, suggesting cross-talk of multiple key signaling pathways.
Overall, this model reveals a critical role for pDCs in inducing humoral responses to ChAdOx1 nCoV-19, primarily through IFN-⍺. IFN-⍺ appears to act directly and indirectly through IFN-induced IL-6 secretion to augment the humoral response. This model has the potential for studying other vaccine platforms.
Comparing the antibody repertoire of XBB1.5 booster immunization with mRNA or protein-based platforms
Authors: Lobo Igor , Cohn Hallie , Bozarth Bailey , Fantin Raianna , Rao Vishal , Bushfield Kaitlyn , Nardulli Jessica , Srivastava Komal , Clark Jordan , Study Group PVI , Krammer Florian , Simon Viviana , Coelho Camila 
Published: November 2024

Abstract
The SARS-CoV-2 spike (S) protein is an essential target for neutralizing antibodies, accumulating mutations, and generating variants of concern (VOC). The Omicron variant is a VOC that continues to evolve into antibody-resistant subvariants, such as XBB1.5. This led to the approval of an updated mRNA vaccine and a protein-based vaccine to target the XBB1.5 strain. However, whether these vaccines can elicit functional monoclonal antibodies specifically against this strain and how the different vaccine platforms (mRNA vs protein) shape the antibody repertoire is unknown. Here, we analyzed the antibody repertoire of five humans who either received the updated mRNA or the protein-based vaccine. We used the Immcantation framework to analyze the VDJ sequences. We assigned V, D, and J genes using IgBlast according to the Change-O pipeline. Clonal groups were defined using the SCOPer package v.1.3.0, and then we calculated somatic hypermutation (SHM) for the BCR sequences. Firstly, we reconstructed germline V and J sequences. The total number of mutations was found for the V gene using SHazaM v.1.2.0, and clonal lineage trees were built using the dowser package v.2.0. We are currently expressing human monoclonal antibodies from the participants and will assess binding, neutralization, and affinity. Our results will compare the antibody activity elicited by vaccination between protein-based (Novavax) and mRNA (Pfizer/Moderna) in humans receiving the XBB1.5 booster.
The breadth and neutralizing activity of SARS-CoV-2 antibodies among children 6 months to 4 years of age following vaccination with mRNA-1273 or BNT162b2
Authors: Williams Caitlin , Dalapat Trisha , Giorgi Elena , Hurst Jillian , Herbek Savannah , Chen Jui-Lin , Kosman Christina , Rotta Alexandre , Turner Nicholas , Pulido Natalie , Aquino Jhoanna , Pfeiffer Trevor , Rodriguez Javier , Permar Sallie , Fouda Genevieve , Kelly Matthew 
Published: November 2024

Abstract
Body: The mRNA-based COVID-19 vaccines approved for use in children less than 5 years of age have differences that could affect vaccine immunogenicity and effectiveness. We directly compared the adaptive immune responses to mRNA-1273 or BNT162b2 in children under the age of 5.
Methods: We enrolled children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines between July and December 2022. Serum was collected from children one month after completion of the primary vaccine series. Children receiving either vaccine series developed robust and broad serum SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a prior history of SARS-CoV-2 infection or who had detectable serum SARS-CoV-2 nucleocapsid antibodies at enrollment developed significantly higher antibody binding responses and neutralization. No differences in vaccine-induced antibody responses were observed between children 6-23 months of age and 24-59 months of age.
Conclusions: Monovalent mRNA-1273 and BNT162b2 elicit similar antibody responses one month after vaccination in young children irrespective of age. Prior infection significantly enhanced the strength of antibody responses to Omicron subvariants. These findings demonstrate that both mRNA-based COVID-19 vaccines induce immune correlates of protection from severe COVID-19 among young children.
Optimization of an anti-fentanyl monoclonal antibody to improve stability
Authors: Hoppe Brooke , Hicks Dustin , Baehr Carly , Kang Jason , Pravetoni Marco , Rodarte Justas , Pancera Marie 
Published: November 2024

Abstract
Fentanyl and other synthetic opioids continue to be the primary contributors to overdose deaths despite widespread availability of FDA-approved reversal agents, highlighting the need for novel complementary therapeutics to address this epidemic. Monoclonal antibodies (mAbs) targeting fentanyl and related analogues have been shown to be promising candidates to help treat opioid overdose in preclinical models. Maintaining formulation stability is critical to the clinical utility of these immunotherapeutics. Previously, the structure of a lead anti-fentanyl mAb in complex with fentanyl was solved through X-ray crystallography, identifying a residue near the binding site that was liable to oxidation. Using a structure-guided approach, the identified amino acid residue was mutated to residues that were expected to have reduced oxidative liability. Stability of the resulting mAbs was quantified using differential scanning fluorimetry, and affinity of the mAbs for fentanyl was assessed via biolayer interferometry (BLI) and competitive enzyme-linked immunosorbent assays (ELISA). Replacing the oxidation-liable residue improved antibody stability as evidenced by an increase in Fab melting temperature. One specific mutation resulted in a 40-fold increase in affinity measured against a fentanyl hapten by BLI, and a 4-fold increase in affinity for free fentanyl by competitive ELISA. Future studies will seek to validate the improved mAb affinity in vivo relative to the parent mAb.
Elucidating the role of macrophage galactose-type lectin 1 (MGL-1) in the pathogenesis and resolution of SARS-CoV2
Authors: Perez Jaid , Puebla-Clark Lucinda , Huante Matt , Orozco Maria , Naqvi Kubra , Martinez-Martinez Yazmin , Menachery Vineet , Rajsbaum Ricardo , Stephens Robin , Endsley Mark 
Published: November 2024

Abstract
The C-type lectin receptor (CLR) family plays an important role in mediating the innate immune responses to some viruses. The Macrophage galactose-type lectin (MGL), or CLEC10, is a CLR that binds SARS-CoV-2 Spike. This binding event is dispensable for virus entry but has been implicated in an increased inflammatory response. Downstream immune responses relevant to host protection against SARS-CoV-2 are not well described. We investigated the role of MGL in disease pathogenesis by utilizing MGL-1 deficient mice (KO) and wild type (WT) control mice. Male and female mice were intranasally infected with the mouse-adapted SARS-CoV-2 strain CMA3p20 for 3 and 7-days. Lung tissues were assessed for viral load, pathology, and changes in leukocyte populations. Viral load was similar in mouse strains at 3 days post-infection (dpi), while virus persisted in MGL-1-/-, but not WT, at 7 days. This observed difference was more pronounced in female mice. Histology analysis indicated no difference in lung pathology between wild type and MGL deficient mice at 3 dpi. Immunohistochemistry and flow cytometric analysis of lung tissue for CD3 also indicated similar numbers and distribution of T cell populations. By using full spectrum flow cytometry, preliminary clustering analysis shows an increase in activated B cells and plasma cells in MGL-1-/- compared to WT mice. We are exploring the implications of altered B cell populations by investigating changes in antibody titers and isotypes.
B and T cell repertoire and gene expression differences in measles infection and vaccination revealed by longitudinal single-cell RNA/VDJ sequencing
Authors: Chan Kwan Pui , Rubens Jessica , Bartlett Maggie , Brockhurst Jacqueline , Ghimire Shristi , Griffin Diane 
Published: November 2024

Abstract
While wild-type measles virus (WT MeV) was demonstrated to induce immune amnesia, it paradoxically still elicited high titers of measles-specific antibodies longitudinally; and much higher than the live-attenuated measles vaccine (LAMV). In order to further understand the longitudinal B and T repertoires, clonotype evolution and gene expression difference in WT MeV and LAMV, we conducted longitudinal single-cell RNA/VDJ sequencing of peripheral blood mononuclear cells (PBMC) from WT MeV and LAMV-infected rhesus macaques (RMs) (n = 3 in each WT MeV and LAMV groups, with 4 timepoints at D0, D11, D42/56, D168/176).
Firstly, B cell subtypes (e.g. naïve, memory, activated and antibody-secreting B cells) were successfully annotated in PBMC based on key gene markers and immunogenetic information. Furthermore, preliminary analysis of 1 WT MeV and 1 LAMV revealed interesting differences in the B cell repertoire, including a more diverse usage of IGHV genes, greater isotype switching from IgD/M to IgGs, higher level of somatic hypermutation and later B cell clonal expansion peak in LAMV than WT-MeV infected RMs longitudinally. Interestingly, there was greater T cell clonotype expansion in the WT MeV than LAMV RMs.
Our study highlights the differential humoral and adaptive immune responses between LAMV and WT MeV infections, uncovering important immunogenetic understanding in natural infection and vaccination.
Electronic health record data shows immunosuppressive conditions are associated with poor outcomes in patients hospitalized for COVID-19
Authors: Guggilla Vijeeth , Pacheco Jennifer , Carvalho Alexandre , Pawlowski Anna , Whitmer Grant , Achenbach Chad , Walunas Theresa 
Published: November 2024

Abstract
We identified 10,713 adults hospitalized for COVID-19 from 03/2020 to 05/2022 in electronic health record data from Northwestern Medicine. Based on extracted diagnosis codes, we identified 214 of these adults with primary immunodeficiency (PI), 669 with history of solid organ transplant, and 183 with HIV. Assessed COVID-19 outcomes included mortality, a seven-point ordinal severity scale (1 = Death) based on maximum oxygen requirements during care, and hospitalization length. Patients with PI had a significantly higher mean hospitalization length of 11.8 days and a significantly lower mean maximum severity of 3.3 compared to 7.8 days and 3.9 in immunocompetent patients when controlling for obesity and T2DM. These effects were not significant when controlling for age. Patients with transplant had a significantly higher mean hospitalization length of 15.8 days when controlling for obesity, T2DM, and age, and a significantly lower mean maximum severity of 3.2 when controlling for obesity. Significantly higher mortalities were observed in PI and transplant (RR = 1.5, 95% CI 1.2 to 2.0; RR = 1.5, 95% CI 1.3 to 1.7), but these effects were not significant when controlling for age. There were no significant differences in any outcomes for patients with HIV. Our results suggest patients with PI or transplant hospitalized for COVID-19 may have worse clinical outcomes compared to immunocompetent patients. Meanwhile, patients with HIV had similar outcomes to immunocompetent patients.
Increased interleukin-6 correlates with LAMP1 expression in NK cells and hospital stay of patients with SARS-COV-2 pneumonia.
Authors: OSUNA ESPINOZA KENIA , Mejía Torres Manuel , Camacho Ortiz Adrian , Perez Alba Eduardo , Salinas Carmona Mario , Rosas Taraco Adrian 
Published: November 2024

Abstract
During viral infections, NK cells play an important role in virus clearance. In the course of COVID-19 pandemic, the immunologic response to viral infections gains a main interest. Despite the extensive evidence, the functional status of cytotoxic cells has remained a controversial area of interest. Here, we provide a detailed comparative analysis of immune population counts and activation markers expression (LAMP1, IFNγ, KIR2DL1 and granzyme B) in NK cells from blood by flow cytometry, and serum cytokine concentration by LUMINEX from patients with severe COVID-19 and healthy participants. A significant decrease in total lymphocyte was observed in COVID-19 patients, mainly by T-CD4+, T-CD8+ and NK cells. The expression of the activation marker LAMP1 on NK cells was significantly higher in COVID-19 patients compared with the control group (P&lt;0.05), and its expression was related to their clinical outcome. Also, IL-6 concentration was significantly higher in COVID-19 patients, correlated negatively with LAMP1 expression (r2=-0.693, P&lt;0.05) and positively with hospital stay (r2=0.752, P&lt;0.01). In conclusion, we show evidence of increased expression of the activation marker LAMP1 in NK cells, and high levels of IL-6 in COVID-19 patients, as well as, their correlation with the clinical outcome and hospital stay of the patients.
High sensitive detection and validation of neuronal specific autoantibodies in post COVID-19 patients with neurocognitive disorders
Authors: Li Quanzhen , Wei Junxia , Niu Luming , Yang Shuwei , Liang Chen 
Published: November 2024

Abstract
COVID-19 has affected tens of million patients worldwide and a significant portion of COVID-19 patients experience post-COVID syndrome characterized by a variety of persistent, debilitating symptoms including profound neurological symptoms. Studies have demonstrated the association between autoantibodies and the severity of COVID-19. but the role of autoantibodies in post-COVID-19 patients with neurological disorders has not yet well established. We screened the levels of anti-neuronal antibodies in 120 serum and CSF samples from 60 post-COVID-19 patients using an OmicsArray™ antigen panel containing 83 neuronal specific antigens (NSA). We identified 7 anti-NSA antibodies which were significantly elevated in serum of at least 1 post-COVID-19 patient with neurocognitive symptoms, including anti-CASPR2, anti-GAD65, anti-RCVRN, anti-mGluR2, anti-MuSK, anti-CSPG4 and anti-ELAVL2 (HuB). 3 anti-NSA antibodies (anti-MOG, anti-GAD65 and anti-mGluR2) were also detected positive in CSF samples of neurocognitive patients. Pre-incubation of the patient serum samples with the purified antigens inhibited the binding of the antibody with the specific NSA on array, validated the specificity of antigen array results. We further confirmed that anti-MuSK antibody in patient serum was targeting the extracellular domain of the MuSK protein using peptide array. Our results suggest anti-NSA antibodies may play a role in post-COVID neurological syndrom and warrant further study.
Epigenetic drug screen of natural killer cells identified compounds controlling immune training and tolerance
Authors: Geanes Eric , Fraley Elizabeth , Pierce Stephen , McLennan Rebecca , Bradley Todd 
Published: November 2024

Abstract
Natural killer (NK) cells are cytotoxic innate lymphocytes that provide defense against pathogens and malignancy. New evidence identified that NK cells are capable of memory-like immune responses in certain settings. This innate immune memory is thought to be imprinted through epigenetic modifications. However, precise epigenic pathways or strategies to modulate long-term NK cell activity are not well defined. In this study, we performed a screen of an epigenetic library containing 160 drug compounds with well-characterized epigenetic regulatory mechanisms, to identify drugs and pathways that could train or tolerize NK cell activation. One compound that we identified was the H3K27 methyltransferase Ezh2, which regulated NK cell lineage commitment from bone marrow hematopoietic stem cells and altered the phenotype of differentiated NK cells to increased cytotoxicity. This outcome provides an option to train or induce stronger cytotoxic effects on NK cells. In contrast, another compound we identified was the histone deacetylase inhibitor, Givinostat, which did not alter NK cell commitment from bone marrow stem cells, but significantly decreased NK cell function in the periphery resulting in a more tolerant innate immune state to secondary NK cell stimulation. Identification and exploration of these epigenome altering drugs may offer further insight into downstream pathways of NK cell function or provide novel therapies for tolerizing or priming innate immune responses.
Regulation and activity of Runx2 in CD8+ T cells responding to infection promotes long-term survival
Authors: Michaels-Foster Mary , Berg Leslie 
Published: November 2024

Abstract
Constitutive expression of Runx family proteins in CD8 T cells and maintenance of accessibility surrounding Runx motifs in regulatory regions of lineage-specific loci suggest that they may play a role in establishing and maintaining the epigenetic state of CD8 T cells. Additionally, Runx proteins possess a highly homologous DNA binding domain, leading not only to redundancies, but also potential competition between Runx proteins for the same genomic binding sites. While Runx1 and Runx3 have well known roles in the development of CD8 T cells, the function of Runx2 is not well established. To further explore the function of Runx2, our lab utilizes a model of retroviral overexpression and CRISPR knockout of Runx proteins in OT-1 CD8 T cells. Adoptive transfer of Runx2 overexpressing or knockout cells followed by ovalbumin-expressing Listeria monocytogenes (LmOva) infection suggests that Runx2 activity is important for the expression and maintenance of genes needed for long-term survival and function, such as Tcf7 and Il7ra. Data analyzed from the literature and chromatin analyses from our lab suggest that Runx proteins may compete for binding sites and drive opposing transcriptional and epigenetic profiles in CD8 T cells after infection. Preliminary data also give insight into the mechanisms controlling Runx2 expression, suggesting that the signals received during priming may affect the balance of Runx protein activity.