bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenesis of flares in liver inflammation in hepatitis B virus-infected women during and after pregnancy
Authors: Fukutomi Keisuke , Nishio Akira , Hasan Sharika , Shah Pir A , Ali Mukarram J , Campoverde Reyes Karen J , Badger Jonathan H , Trinchieri Giorgio , Lau Daryl T Y , Rehermann Barbara 
Published: August 2023

Abstract
Women with chronic hepatitis B (CHB) are at risk of increased liver inflammation during pregnancy. To investigate the pathogenesis of these hepatic flares we studied immune responses and gut microbiota in 19 women with CHB (12 without and 7 with antiviral (NUC) treatment) and 3 uninfected controls in each trimester and at two and six months postpartum. Increased serum alanine aminotransferase (ALT) activity as a liver inflammation marker was defined as a value greater than the upper limit of normal and twice the baseline value.
While increased plasma levels of soluble CD163, inflammatory cytokines and chemokines generally occurred during episodes of liver inflammation, increases of IL-22 and IFN-γ levels during pregnancy preceded a postpartum ALT increase. In contrast, levels of IL-27, a cytokine produced by the trophoblast, increased also in women with normal ALT levels.
The fecal microbiota of HBV-infected patients with and without NUC treatment had lower α-diversity (inverse Simpson index) than those of uninfected controls. 16srRNA amplicon analysis and PCA showed patient-specific clustering of microbiota. To identify factors predictive of a postpartum ALT increase, we compared 16srRNA DNA data from patients with a postpartum ALT increase to those with normal postpartum ALT levels (four patients per group). Combining all time points, the gut microbiota of those with postpartum ALT increase differed significantly from those with normal ALT activities (UMAP, PERMANOVA p&lt;0.003).
In conclusion, the composition of the fecal microbiota was patient-rather than time point-specific and differed between patients with and without postpartum ALT increase.
Supported by NIH Bench-to-Bedside Award (B.R. and D.T.Y.L.)
Shedding LIGHT and TL1A on Pulmonary Fibrosis
Authors: Steele Hope , Cheng Jason Liang , Willicut Ashley , Dell Garrison , Breckenridge Joey , Ghastine Andrew , Herro Rana 
Published: August 2023

Abstract
Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis (PF) and tissue remodeling in the clinic. Despite the advancements made in understanding the molecular pathways driving PF, there is still an unmet need to develop innovative and effective anti-fibrotic drugs. Our lab has identified two novel mediators of fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Using a well characterized mouse model of PF driven by bleomycin, we showed that blocking LIGHT or TL1A signaling in isolation, by genetic ablation or antibody-mediated neutralization, significantly reduces PF. In gain of function studies, the in vivo administration of LIGHT or TL1A in isolation recapitulated fibrosis symptoms reminiscent of human disease. Furthermore, our data suggest that LIGHT promotes thymic stromal lymphopoietin (TLSP) expression by epithelial cells, whereas TL1A activates fibroblasts to promote periostin expression. Both TSLP and periostin are drivers of PF. Importantly, we observed an upregulation of LIGHT and DR3 (the receptor for TL1A) in human lung biopsies of patients suffering SSc and IPF. We have found that LIGHT and TL1A can drive fibrosis independently of one another and that the in vivo co-administration of these TNFSF members synergize to maximize inflammation and collagen deposition. Using antagonistic fusion proteins to neutralize LIGHT and TL1A signaling, we will monitor PF in vivo and check whether greater efficacy is achieved when LIGHT and TL1A are targeted concomitantly post-disease onset. The relevance of this work on PF associated with ILDs in humans is tremendous.
Improving lymphatic flow in SLE mice induces fibroblastic reticular cell survival via lymphotoxin beta receptor signaling
Authors: Howlader Mir , Lu Theresa 
Published: August 2023

Abstract
Systemic lupus erythematosus (SLE) patients are photosensitive, where ultraviolet radiation (UVR) exposure can induce skin inflammation and also trigger systemic disease flares. The link between photosensitive skin and systemic autoimmunity is not well understood. Skin communicates with the immune system via lymphatic vessels that carry lymph into the conduit system of lymph nodes (LNs), which is ensheathed by fibroblastic reticular cells (FRCs). FRCs play critical roles in limiting T and B cell responses. Dendritic cells (DCs) interact both with lymphatic fluid and with FRCs and can modulate FRC survival and numbers via a DC-lymphotoxin beta receptor (LTβR)-FRC axis. We have recently shown dysfunctional lymphatic flow in human SLE and SLE mouse models exposed to UVR and that improving lymphatic flow via manual lymphatic drainage (MLD) reduces skin photosensitivity and LN plasmablast responses, while increasing FRC numbers. In this study, we aim to delineate the mechanism by which MLD induces FRC alterations, hypothesizing that it is via the DC-LTβR-FRC axis. Currently, we have found that MLD increases FRC survival of UVR exposed mice. However, treatment with antagonist LTbR-Ig reverses this FRC survival, suggesting that MLD induces FRC survival via LTbR signaling. Ongoing experiments are targeting the importance of DCs and DC-derived LTβ in modulating MLD-induced changes to FRCs. The novelty of this study is in showing that lymphatic flow from the skin can influence stromal cell populations in SLE. These findings will improve our understanding of the relationship between photosensitivity and systemic autoimmunity.
Microenvironment regulates antibody secretion by IgA+ plasma cells
Authors: Zoccoli-Rodriguez Victoria E , Coombs Wanda , Harris Joshua , Delaney Mara , Wilmore Joel 
Published: August 2023

Abstract
IgA secreting plasma cells (PCs) provide a critical supply of antibodies for barrier functions against pathogens. These cells express unique tissue-driven transcriptional profiles in their respective niches in the bone marrow (BM) and gut. We previously demonstrated that both tissues sustain long-lived IgA+ PCs, but the cell intrinsic and extrinsic signals responsible for survival and function in the gut remain largely unknown. Understanding how the microenvironment regulates tissue resident IgA+ PC functions has implications for maintaining intestinal homeostasis and protection from disease. We found that BM IgA+ PCs functionally differ from gut IgA+ PCs as they secrete significantly more antibody. To assess if this phenotype could be due to metabolic consequences, we profiled IgA+ PCs in both tissues. BM and gut IgA+ PCs have similar glucose and fatty acid uptake. However, BM IgA+ PCs have increased mitochondrial dependence, while gut IgA+ PCs have increased glycolytic capacity. We next altered the composition of the microbiome to determine the role of gut microbes in regulating tissue resident PCs. Our initial experiments used C57BL/6J mice with a well-defined low-complexity microbiome (from Jackson Labs). Co-housing Jax mice with animals containing a more diverse set of microbes led to an increase in antibody secretion. Herein, we identified that the tissue microenvironment and gut microbiome influences PC function. We aim to dissect the mechanisms involved in microbiome driven changes in PC phenotype. Ultimately, understanding how the microenvironment regulates intensity of PC antibody secretion provides a tool in targeting induction of systemic and mucosal responses and will improve vaccine design and development.
Supported by grants from NIH (R35 GM147560, R03 AI156481)
Kinetics of endogenous thymic regeneration following chemotherapy-induced involution
Authors: Lagou Maria K , Carpenter Randall S , Anastasiadou Dimitra P , Hardas Alexandros , Garcia Raquel Vallejo , Argyris Dimitris G , Chondronikola Anastasia-Aristoteleia , Licausi Francesca , Briceno Andrea , Guzik Hillary , DesMarais Vera , Branch Craig A , Cui Min-Hui , Poutahidis Theofilos , Angelopoulou Katerina , Maryanovich Maria , Karagiannis George S 
Published: August 2023

Abstract
The thymus is a primary lymphoid organ where T cell development occurs. Besides the naturally transpiring age-dependent involution, the thymus also undergoes acute involution from cytotoxic stimuli. Establishing thymic regeneration strategies would, thus, be immensely critical for pediatric cancer and transplantation patients receiving cytoablative chemotherapies. Several signaling pathways (e.g., KGF, BMP4) promote thymic regeneration, albeit with suboptimal therapeutic potential, mainly due to poor insight of the detailed mechanisms of endogenous thymic repair. To address this issue, we developed a mouse model of cyclophosphamide-induced thymic involution and monitored thymic reconstitution for up to 5 weeks post-treatment. Macroscopic assessment via thymic weight index and MRI-based volumetric analysis, along with histopathology, revealed that endogenous thymic regeneration is a non-linear, multistep process, consisting of a: (a) Reconstitution phase, during which recuperation occurs at an exponential rate, (b) Rebound phase, in which abnormal thymic hyperplasia is observed, and (c) Recoil phase, where thymic homeostasis ensues. Quantification of peripheral blood lymphocytes, however, revealed that thymic hyperplasia at Rebound does not correlate with restored thymic functions and output. Detailed investigation via flow cytometry revealed the stalling of T cell development at the Double Positive (CD4+ CD8+) stage, implying cortical defects during thymic repair. Currently, we employ single-cell RNA sequencing with single cell resolution imaging, to define the molecular pathways disrupting cortical Thymic Epithelial Cell (cTEC) renewal post-chemotherapy, leading to impaired thymopoiesis.
Supported by AAI’s Career in Immunology Fellowship PI’s funding supported by Albert Einstein College of Medicine: New Investigator Start-up funds
In vitro validation of Cathepsin S docking models
Authors: DeHority Riley , Gil Pineda Laura I , Cochran Kari , Bian Yuanzhi , Lemkul Justin A , Zhang Chenming 
Published: August 2023

Abstract
In dendritic cells, the dominant lysosomal protease involved in Ii chain degradation and antigen digestion is Cathepsin S, a cysteine protease in the papain family. Extracellularly, Cathepsin S also contributes to pathological processes in cardiovascular disease, cancer, and autoimmune arthritis: unlike most lysosomal proteases, it retains its activity at serum pH. In computational molecular docking studies comparing peptides from the literature, we found that Cathepsin S shows a pH-dependent specificity switch, with predicted dissociation constants for specific peptide sequences differing at lysosomal and serum pH. The aim of this study is to further characterize this specificity switch and to compare docking results to kinetic parameters of Cathepsin S digestion in vitro. We identified peptide sequences of interest from docking, including sequences from the Ii chain and elastin, and digested these peptides (LifeTein) using human Cathepsin S (Calbiochem), collecting samples for LC-MS analysis over 16 hour reaction times. We report the kinetic parameters of Cathepsin S catalysis at both lysosomal and serum pH. Digestion results are compared to docking models and the models most predictive of catalytic activity are identified. Further investigation is needed to determine whether pH-dependent catalytic activity and selectivity of Cathepsin S will enable the design of protein-based therapies and inhibitors optimized for their targeted microenvironments.
This work was partially supported by the NIDA/NIH award UG3DA048775, the USDA National Institute of Food and Agriculture, AFRI project #2021-0858, and the department of Biological Systems Engineering at Virginia Tech.
Mechanistic aspects of tapasin-mediated antigen presentation revealed by structure of a tapasin/MHC-I complex
Authors: Natarajan Kannan , Jiang Jiansheng , Taylor Daniel Kyle , Kim Ellen J , Boyd Lisa F , Dhobi Javeed Ahmad , Mage Michael G , Truong Hau , Woodward Claire , Sgourakis Nikolaos , Cresswell Peter , Margulies David H 
Published: August 2023

Abstract
T cell immunity to viruses and cancers is crucially dependent on the cell surface display of major histocompatibility complex class I (MHC-I) molecules selectively loaded with high affinity peptides. Peptide loading occurs in the ER within a multimolecular assembly known as the peptide loading complex (PLC). A critical component of the PLC is tapasin, a 45 kDa membrane glycoprotein in whose absence the expression and stability of MHC-I are greatly reduced. To determine the mechanistic basis of tapasin-mediated peptide loading, we determined the crystal structures of human tapasin in complex with HLA-B44:05 as well as tapasin complexed to each of two well-characterized antibodies. The tapasin-stabilized peptide receptive state is characterized by distortions of the peptide binding groove, destabilization of the b2-microglobulin interaction, and rearrangements of the membrane proximal Ig domains, all of which are reversed on high affinity peptide binding. Additionally, the structural footprints of the anti-tapasin antibodies confirm previous functional assays and together with the tapasin/MHC-I complex and mutagenesis data reveal dynamic aspects of tapasin function.
Supported by the Intramural Research Program, NIAID, NIH.
Cell-specific MHC class I deletion on CD11c+ APCs abrogates CD8 T Cell infiltration into the brain
Authors: Maynes Mark Andrew , Fain Cori E , Ayasoufi Katayoun , Wolf Delaney , Tritz Zachariah , Bamkole Michael A , Jin Fang , Hansen Michael J , Johnson Aaron J 
Published: August 2023

Abstract
Cerebral malaria (CM) is a severe complication of P. falciparum infection and a leading cause of death, globally. Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice serves as a murine model of CM called experimental cerebral malaria (ECM) due to the neurological and neuropathological features that simulate the infection of human CM. A putative mechanism of disease in human CM requires CD8 T cell to infiltration into the brain and blood-brain barrier disruption. The specific antigen-presenting cell type(s) that prime this CNS infiltrating CD8 T cell response capable of inducing lethal blood-brain barrier disruption has not been defined. To answer this, single class I expressing Kb loxP transgenic mice were generated. Crossing these mice to class I deficient CD11c-cre or LysM-cre mice created the LysM-cre Kb cKO and CD11c-cre Kb cKO mice, respectively. PbA infected Kb loxP and LysM-cre Kb cKO were susceptible to ECM. In contrast, CD11c-cre Kb cKO mice survived acute PbA infection and avoided neurological manifestations. We therefore employed spectral flow cytometry to analyze splenocytes and brain infiltrating immune cells during acute PbA infection in these genotypes. We observed a reduction in activated CD8 T cells in the spleens of PbA infected CD11c-cre Kb cKO mice versus the Kb loxP mice and the LysM-cre Kb cKO. This reduced peripheral CD8 T cell activation in PbA infected CD11c-cre Kb cKO mice also corresponded with reduced brain infiltration of CD8 T cells. We conclude a CD11c+ APC is therefore required for priming and potentially recruitment of CD8 T cells to the brain during lethal ECM pathology.
5R01NS103212-06
Xeno-interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes
Authors: Sun Yi , Papadaki Georgia , Devlin Christine , Danon Julia , Young Michael , Winters Trenton , Burslem George , Procko Erik , Sgourakis Nikolaos 
Published: August 2023

Abstract
Immunological chaperones Tapasin and TAPBPR play key roles in antigenic peptide optimization and quality control of nascent MHC-I molecules. The polymorphic nature of MHC-I proteins leads to a range of allelic dependencies on chaperones for assembly and cell-surface expression, limiting chaperone-mediated peptide exchange to a restricted set of human HLA allotypes. Here, we demonstrate and characterize xeno-interactions between a chicken TAPBPR ortholog and a complementary repertoire of HLA allotypes, relative to its human counterpart. We find that TAPBPR orthologs recognize empty MHC-I with broader allele specificity and facilitate peptide exchange by maintaining a reservoir of receptive molecules. Deep mutational scanning of human TAPBPR further identifies gain-of-function mutants, resembling the chicken sequence, which can enhance HLA-A* 01:01 expression in situ and promote peptide exchange in vitro. These results highlight that polymorphic sites on MHC-I and chaperone surfaces can be engineered to manipulate their interactions, enabling chaperone-mediated peptide exchange on disease-relevant HLA alleles.
This work was supported by NIAID (5R01AI143997), NIDDK (5U01DK112217), NIGMS (5R35GM125034), and NIGMS (R35GM142505).
Hexavalent coronavirus vaccine elicits both humoral and cellular immune responses in mice
Authors: Gröhn Stina , Soppela Saana , Iakubovskaia Alina , Pasternack Arja , Lampinen Vili , Ritvos Olli , Hankaniemi Minna 
Published: August 2023

Abstract
Coronaviruses have caused three deadly human outbreaks over the last 20 years, the latest causing the COVID-19 pandemic which has now lasted over three years. The animal reservoir of coronaviruses is extensive, and history has shown that coronaviruses are able to crossover from animals to humans. Thus, there is a clear need for a universal coronavirus vaccine. In this study, we produced S1 subunits of spike proteins of six different human coronaviruses fused to the antibody Fc fragment in HEK293 cells. In addition, we produced another coronavirus protein (CP) in High Five™ insect cells. The vaccine compositions included either the six S1-Fc or the six S1-Fc together with CP, and mice were immunized either intranasally or with a combination method utilizing both subcutaneous and intranasal injections. Our results showed that both vaccine compositions elicited both humoral and cellular immune responses in mice. Antigen-specific IgG levels were higher in mice immunized solely intranasally but using a combination of different immunization routes seemed to boost cellular immune responses. As a conclusion, all the vaccine compositions were highly immunogenic and generated both antibody and T cell responses in mice. Further studies are needed to optimize the immunization scheme. Additionally in the future, in order to better characterize the T cell responses generated by intranasal immunization, the nasal associated lymphoid tissue and cervical lymph nodes from the mice will be collected and analyzed.
Supported by a grant from The Research Foundation of the Pulmonary Diseases (Finland)
The role of intestinal intraepithelial lymphocytes in resistance against coccidiosis in chickens
Authors: Nazmi Ali , Hamad Shaimaa K , Majeed Shuja 
Published: August 2023

Abstract
Coccidiosis is a critical enteric disease that costs more than $14.5 billion in annual cost to world poultry industry. It is caused by different Eimeria species that invade and replicate within the intestinal epithelium in a site-specific manner. The Eimeria infection induces local intestinal damage, reduces feed consumption, feed utilization, and growth performance, and increasing mortality rate. With the recent antibiotic ban including anticoccidial drugs in chicken production, the live vaccination become widely used to control coccidiosis. However, the live vaccines are expensive, require time to circulate in the host to induce a protective immunity, and process a high-risk factor for necrotic enteritis caused by clostridium perfringens. Therefore, there is a high demand for development of safe, protective, and inexpensive vaccines against coccidiosis which require better understanding of host immune responses to Eimeria parasites. The aim of this study is to elucidate the protective role of intestinal intraepithelial lymphocytes (IELs) during the Eimeria infection. At 3 week of age, SPF white-leghorn chicks were divided into 3 groups. Each group (n=50) was orally inoculated with 20,000 oocytes of Eimeria (E) acervuline or E. maxima, or mock-inoculated with PBS. At 2 day post-infection (dpi), 7 dpi and 14 dpi, the frequency and the number of small intestinal IEL populations were determined by a flow cytometry. Eimeria infection induced the number of TCRγδ+, TCRβ+, TCRneg, TCRβ+CD4+, TCRβ+CD4+CD8α+, TCRβ+CD8αβ+, TCRβ+CD8αα+, and iCD8α IELs compared to the control group at 14 dpi. However, there was no difference among groups at 2 and 7 dpi. More experiments are underway to determine the effector and function of each subset of IELs.
Startup funding, The OSU
Human BH3-only protein, Noxa, is a major contributor to proliferative metabolism and apoptosis in the CD8+T cell immune response
Authors: Yang Tingyuan , Sharma Himani , Pennell Christopher A , Kelekar Ameeta 
Published: August 2023

Abstract
Human Noxa, the smallest BH3-only Bcl-2 protein, was originally identified as pro-apoptotic, but has since also been shown to promote cell growth in both malignant and activated normal T cells by facilitating proliferative metabolism (Lowman et al., 2010, Mol Cell, 40, 823–33; Hanse et al., 2017, Oncogene, 36, 3915–3924). To investigate the contribution of Noxa to the T cell immune response, we tracked its expression in primary human CD8+T cells in an in vitro anti-CD3/CD28 co-stimulation model. Noxa is undetectable in naïve CD8+T cells but is induced upon co-stimulation and remains highly expressed during the differentiation phase and through the onset of apoptosis. The viable cells that remain following apoptosis at the end of the immune response are ‘memory-like’, as determined by flow cytometry, harboring large mitochondria with robust spare respiratory capacity. These cells no longer express Noxa, but rapidly upregulate it upon re-stimulation. We observe that Noxa protein expression in CD8+T cells, upon stimulation, is directly dependent on glutamine and unaffected by glutaminase inhibitors, while the entry of glutamine carbons into the TCA cycle, in turn, requires Noxa. CD8+T Noxa KO cells, moreover, show reduced dependence on glutamine and significantly higher viability at the end of the immune response. CD8+T cells expressing an apoptosis deficient Noxa BH3 domain point mutant similarly presented an extended effector phase. The fundamental contributions of human Noxa to both activation-associated metabolic reprogramming and apoptosis in a prototypic immune response, makes this protein an attractive tool to manipulate the expansion, effector function, and longevity of CD8+T cells for immunotherapy.
R21 AI148876