bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibigens™ drive pro-tumor responses and may act through non-classical inhibitory mechanisms
Authors: DeVault Victoria L , Starobinets Hanna , Arnold Julie , Rinaldi Stephanie , Odeh Osaruese , Nguyen Cindy , Flechtner Jessica B , Lam Hubert 
Published: February 2023

Abstract
The ATLAS™ platform screens a patient’s tumor mutanome with autologous T cells and antigen presenting cells to identify targets for cancer immunotherapy. Tumor mutations that lead to increased T cell responses are deemed stimulatory (neoantigens), while those rendering decreased responses are defined as Inhibigens. In B16F10 mouse melanoma, therapeutic neoantigen vaccination resulted in durable protection, while Inhibigen co-administration resulted in a remarkable reversal of protection and abrogation of anti-tumor responses. The Inhibigen-related pro-tumor effects were not reduced by αPD-1 therapy, and administration of αCTLA-4 resulted in modest benefit, suggesting that Inhibigen-specific responses can overpower current standard-of-care immunotherapies. The tumor microenvironment of Inhibigen-vaccinated mice was immune cold, with dramatic decreases in infiltrating T cells and myeloid cells relative to controls. Inhibigen effects were not associated with classical inhibitory mechanisms such as an overabundance of CD4+CD25+Foxp3+Tregs, MHC competition or downregulation. In addition, T cell proliferation appeared unaffected by Inhibigen administration. Time course experiments revealed that Inhibigen-specific phenotypes (e.g. defective T cell IFNγ production) occur as early as 4 days post vaccination, suggesting deficiencies related to T cell priming. RNAseq analyses showed distinct changes in T cell transcriptional patterns between neoantigen and Inhibigen-experienced T cells. Taken together, these data reveal a potential non-classical inhibitory mechanism by which responses to naturally occurring cancer mutations may promote tumor growth and reverse beneficial anti-tumor immune responses.
Novel immunotherapeutic Albumin-Flt3L enhances antigen-specific immunity and tumor control following chemoradiation: An analysis of underlying mechanism
Authors: Kung Yu Jui , Lam Brandon , Lin John , Wu T.C. , Hung Chien-Fu 
Published: February 2023

Abstract
CD8+ cells are essential to anti-cancer immunity following chemoradiation and immunotherapy. The induction of tumor specific T cells depends on the presentation of tumor associated antigens/neoantigens. This generates a bottleneck to effective antitumor immunity, where only antigens efficiently presented on MHCI can serve as CD8 T cell targets. To bypass this, we have developed a novel immunotherapeutic by fusing albumin to Flt3L (Alb-Flt3L), a cytokine known to enhance cross-presenting cDC1s, and described its function. Previously, we observed that MC38-tumor bearing mice treated with Alb-Flt3L + radiotherapy engenders neoantigen-specific T cells by tetramer staining. Now we have expanded this analysis to query the breadth and depth of CD8+ TILs by TCRb sequencing. Sorted and sequenced ADPGKneo-specific CD8 T cells encompassed a multitude of unique rearrangements, suggesting polyclonal neoantigen coverage, and bulk CD8+ cells showed a greater Diversity Index in Alb-Flt3L + radiotherapy treated mice compared to controls. We also sought to investigate the mechanism of tumor control following treatment with Alb-Flt3L + chemoradiation. The role of Batf3, a cDC1 transcription factor, type-I-interferons, cytokines essential to immune activation following chemoradiation, and pDCs, an Alb-Flt3L-tropic cell type also capable of cross-presentation, were investigated using knockout mice or antibody depletion in tumor bearing mice treated with cisplatin. This study confirmed the role of these factors in Alb-Flt3L-mediated responses, as worse tumor control was observed in the absence of Batf3, pDCs, or type-I-interferon signaling. Altogether, we were able to characterize mechanisms mediating Alb-Flt3L’s antitumor effects.
Determining Adenosine Deaminase 1 (ADA-1) Impact on Immune Memory and Durability as a Molecular Adjuvant in a SARS-CoV-2 DNA Vaccine Formulation.
Authors: Cusimano Gina , Gary Ebony N. , Bell Matt , Connors Jennifer R , Tursi Nicholas J. , Zhang Shiyu , Canziani Gabriela , Warner Bryce , Ali Ali R. , Taramangalam Bhavani , Chaiken Irwin C. , Wootton Sarah , Weiner David , Kobasa Darwyn , Kutzler Michele A. , Haddad Elias K. 
Published: February 2023

Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease of 2019 (COVID-19), has infected millions of people causing a global pandemic. SARS-CoV-2 vaccines candidates have demonstrated acute immunogenicity and protection however, it has yet to be demonstrated whether natural or vaccine induced immunity against SARS-CoV-2 induces long term, protective immunity. In this study we sought to understand if adenosine deaminase (ADA), as a molecular adjuvant, can enhance immune memory and durability in the context of a SARS-CoV-2 DNA vaccine. Mice were immunized with a plasmid encoding for SARS-CoV-2 spike alone or in combination with plasmid encoded ADA. Subsequent B and T cell responses were measured until d60pi. In mice co-immunized with ADA, there were increased concentrations of spike receptor binding domain (RBD)-specific IgG in the sera which were found to bind RBD at an increased affinity as well as exhibit increased neutralization capability against SARS-CoV-2 pseudotyped viruses. Additionally, ADA co-immunized mice exhibited increased frequency of RBD specific memory B cells. In regard to T cell responses, mice co-immunized with ADA exhibited increased spike-specific IFN-γ, TNF-a and IL-2 as measured by flow cytometry and ELISpot. The ADA-enhanced anti-spike antibody durability over time was associated with increased frequencies of T follicular helper cells (TFH). Preliminary analysis supports that co-immunization with pADA impacts viral load in a SARS-CoV-2 infection model. These data suggest that ADA enhances immune memory and durability and supports further study with translational focus for enhancement of vaccines.
BCG-derived peptides induce T cell cross-reactivity to Sars-CoV-2 homologues
Authors: Eggenhuizen P J , Ng Boaz H , Chang Janet , Fell Ashleigh L , Ooi Joshua D 
Published: February 2023

Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently-discovered beta coronavirus capable of infecting humans and causing Coronavirus Disease 2019 (COVID-19). COVID-19 causes a variety of pathologies that are still being understood. While vaccines specific for COVID-19 are being developed and deployed throughout the world, another vaccine called Bacillus Calmette–Guérin (BCG) vaccine is being trialled to test whether it has a protective effect against COVID-19. Epidemiological studies have identified a negative correlation between BCG vaccination regime and COVID-19 severity and mortality. However, the mechanism by which a vaccine for a bacterium can protect against a virus is not well understood. Here we have identified a number of homologous peptide sequences shared between BCG and SARS-CoV-2. Using in vitro human T cell recall assays, we found that pre-sensitisation to BCG-derived peptides can induce T cell cross-reactivity to SARS-CoV-2 peptides. These findings assist in explaining the molecular mechanism behind the protective effect conferred by BCG vaccination in COVID-19, and supports the clinical trials exploring BCG vaccine as an integral part of the global effort to vaccinate against COVID-19.
Effect of SARS-CoV-2 vaccine on the breastmilk antibody response among lactating healthcare workers
Authors: Stafford Lauren Stewart , Luaces Vivian Valcarce , Neu Joseph , Cacho Nicole , Parker Leslie , Burchfield David , Li Nan , Larkin Joseph 
Published: February 2023

Abstract
In 2019, a deadly virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, emerged. Two mRNA-based COVID-19 vaccines were approved for use in December 2020 in the US and have begun providing immunity to those receiving the vaccination. Certain vaccines given to pregnant and lactating mothers provide immunity to infants through transmission across the placenta and umbilical cord (IgG) and breast milk (IgA). Breastmilk produced by mothers with a history of COVID-19 infection has found to be a source of anti-SARS-CoV-2 IgA and IgG. This study aimed to determine the presence of specific SARS-CoV-2 IgA in the breastmilk of lactating women after the COVID-19 vaccine administration. As such, lactating healthcare workers who received the SARS-CoV-2 mRNA vaccine (Pfizer-BioNtech or Moderna) made up a sample group. Plasma and breast milk were collected at three time points (pre-vaccination, 14–28 days post first dose of vaccine, and 7 days post second dose of vaccine). SARS-CoV-2 specific IgA (breastmilk) and IgG (plasma) concentration were then measured by ELISA. We found consistent secretion of SARS-CoV-2 specific IgA in breast milk after COVID-19 vaccination. The second dose of the SARS-CoV-2 vaccine was necessary to elicit IgA response in breastmilk detectable by ELISA. There is a correlation of the level of SARS-CoV-2 specific IgG in blood with SARS-CoV-2 specific IgA in breastmilk. Our results show that the mRNA-based COVID-19 vaccines from Pfizer-BioNTech and Moderna induce SARS-CoV-2 specific IgA secretion in breastmilk. Further studies are needed to determine the duration of this immune response and a possible passive immunity transfer of SARS-CoV-2 specific IgA to breastfeeding infants.
T cells in relapsing-remitting multiple sclerosis demonstrate diminished expression of LAG-3
Authors: Jones Britta E , Maerz Megan D , Somasundaram Ashwin , Buckner Jane H 
Published: February 2023

Abstract
The co-inhibitory receptor lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates T cell activation, proliferation, and homeostasis. Blockade or deletion of LAG-3 in autoimmune-prone backgrounds or induced-disease models has been shown to exacerbate disease. We observed decreased surface expression of LAG-3 on T cells in subjects with rheumatoid arthritis (n=35), type 1 diabetes (n=105), or relapsing-remitting multiple sclerosis (RRMS; n=121) as compared to age and sex-matched healthy subjects (n=123). Interestingly, decreased LAG-3 expression was observed across CD4 and CD8 T cell subsets. T cell receptor stimulation on a subset of our initial cohort revealed decreased surface and intracellular LAG-3 as well as decreased LAG3 transcript in subjects with RRMS. Decreased LAG-3 in subjects with RRMS was associated with diminished IFNγ production and intracellular cleaved caspase 3; the addition of a LAG-3 blocking antibody further underscored this relationship. Despite the decreased level of LAG-3, CD8 T cells from RRMS subjects were less proliferative than healthy subjects after a low-dose viral peptide stimulation as well as after blocking LAG-3; another indication of defective T cell activation associated with LAG-3 expression. In T cells from RRMS subjects, we observe a global dysregulation of LAG-3 expression that stems from decreased transcription and persists after T cell stimulation. These findings further support the potential clinical benefits of a LAG-3 agonist in the treatment of human autoimmunity.
Two lineages of memory B cell development regulated by type I interferon and IL-4R are perturbed in systemic lupus erythematosus
Authors: Gao Min , Liu Shanrun , Lu Changming , Chen Jake Y , Chatham W Winn , Hsu Hui-Chen , Mountz John D 
Published: February 2023

Abstract
Abnormal expansion of type I interferon (IFN) stimulated B cells and T-bet+CD11c+IgD−CD27− DN2 atypical memory B cells are both hallmarks of SLE. To determine how they are interrelated, we have carried out single cell transcriptomics analysis using B cells derived from 3 SLE patients (anti-DNA+ and anti-Smith+) and 3 healthy controls (HCs)(all African Americans). We have identified that elevation of IL4R in pre-switched IGHM+/IGHD+ B cells is the opposing signature of type I IFN stimulated genes (ISGs) and DN2 B cells (TBX21, ITGAX, FCRL3, FCRL5, and ZEB2). In HCs, IGHM+/IGHD+ B cells expressed elevated IL4R. Further, activated naïve B cells (IGHM+IGHD+IGHG+) exhibited upregulation of the germinal center-oriented classical memory B-cell signature genes, CD27, TNFRSF13B (the gene encoding TACI), and GPR183 (the gene encoding EBI2). Flow cytometry analysis confirmed that down-regulation IL-4R and upregulation of intracellular IFN-β in naïve IgD+CD27− B cells correlated with the accumulation of atypical CD21−IgD−CD27−B cells and a reduction in the percentage of classical IgD−CD27+memoryB cells in SLE patients (n=47). In vitro exposure of SLE B cells to IL-4 prior to treatment with anti-Ig+IL-21+IFN-gamma+TLR7+BAFF stimulation significantly enhanced B-cell development into CD27+CD38+ plasmablasts/plasma cells as well as IgD−CD27+memoryB cells but it significantly blocked the development of DN2 B cells. Our results show that upregulation of type I IFN and down-regulation of IL-4R signaling in naïve B cells lead to the accumulation of atypical memory B cells in SLE. Type I IFN and IL-4R signaling in naïve B cells induce the development of distinct lineages of atypical versus classical memory B cells, respectively.
Human monoclonal autoantibodies in autoimmune basal ganglia encephalitis target dopamine receptors and act as drug agonists
Authors: Menendez Chandra M , Zuccolo Jonathan , Reim Sean , Swedo Susan , Kovoor Abraham , Cunningham Madeleine W 
Published: February 2023

Abstract
Neuropsychiatric diseases in autoimmune basal ganglia encephalitis (BGE) are associated with anti-neuronal autoantibodies which target the basal ganglia. BGE includes the group A streptococcal sequelae Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). In SC, autoantibodies against dopamine receptors 1 and 2 (D1R and D2R) are elevated, and IgG in SC sera and cerebrospinal fluid (CSF) induce excessive dopaminergic D2R signaling and dopamine release. D1R autoantibody reactivity targeting the basal ganglia is not defined. Here we demonstrate specific IgG targeting of D1R in multiple neuropsychiatric PANDAS cohorts by serum, CSF, and human-derived mAbs. Anti-D1R human mAbs and serum autoantibodies induced D1R second messenger signaling in a dose-dependent manner. The results suggest that D1R autoantibodies enhanced antibody-mediated IgG signaling activity in the presence of the neurotransmitter dopamine. D1R autoantibodies sensitized D1R and exacerbated endogenous dopamine signaling in disease. Agonistic D1R signaling was inhibited by synthetic D1R peptide epitopes derived from human D1R extracellular loops which identified the immunodominant epitopes and antibody specificity. Taken together, D2R autoantibodies in BGE lead to excessive dopamine release and chorea, while D1R autoantibodies act like dopamine on receptors leading to allosteric enhancement and neuropsychiatric disease. Collectively, our novel findings suggest dopamine receptor autoantibodies in basal ganglia disorders act like drugs and mediate hyperactive dopaminergic receptor signaling.
Role of B-cell endogenous interferon beta in lupus nephritis
Authors: Alduraibi Fatima Khalid , Hsu Hui-Chen , Fatima Huma , Chatham W. Winn , Mountz John D 
Published: February 2023

Abstract
Lupus nephritis (LN) is histologically evident yet early diagnosis can be challenging since some patients do not exhibit overt clinical manifestations until advanced stages. The objective of the present study is to determine if B-cell expression of interferon beta (IFNβ) can be a unique systemic lupus erythematosus (SLE) clinical prognostic marker and if specific histopathologic features of LN can be identified in patients with elevated B-cell expression of IFNβ. A total of 80 patients who met the ACR/EULAR classification criteria of SLE were recruited. LN was identified in 41% (N=33). Multivariate regression analysis indicated a significant positive correlation between naïve B-cell IFNβ with race (African American &gt; European American; P=0.006) and LN class (P&lt;0.0001). Patients with elevated serum anti-Smith (P=0.01) and anti-DNA (P=0.013) exhibited significantly higher naïve B-cell IFNβ. B-cell IFNβ was further compared with renal histopathology microscopy findings on light, electron microscopy, and immunofluorescence (IF) (N=23). Patients with a higher percentage of IFNβ in naïve B cells showed increased segmental scaring (P=0.046). These patients also exhibited aggressive LN class (P=0.14), membranous pattern (P=0.15), and global sclerosis (P=0.18), although the differences were not significant. B-cell IFNβ did not show significant correlation with IgG, IgM, IgA, and C1q, and C3 in situ staining. The present study suggests that B-cell endogenous IFNβ may be developed into a unique target-based marker for the development and severity of LN. IFNβ blockade may be developed into an individualized therapy for this subset of SLE patients.
Genetic studies play an important role in the correct diagnosis of congenital immunodeficiency conditions
Authors: Fazal Nadeem , Nasrullayeva Gulnara , Mammadova Vafa 
Published: February 2023

Abstract
More than 350 kinds of PID (Primary Immunodeficiency disorders) related gene defects have been found, which lead to multiple clinical manifestations including repeated infection or opportunistic bacterial infections, autoimmune and malignant tumors. The 6-year-old boy was born from third pregnancy and not related parents. His oldest brother died at the age of 3 from unknown disease, second sibling, 11 years old, is alive. Until the age of 3 patient developed normally, when he started exhibiting swelling in the lymph node and temperature increased to 38–40°C. Lymph node biopsy showed tuberculosis. Bilateral pneumonia and the swollen right ankle, right and left elbow with purulent abscesses in the ankles and elbows. Surgical treatment gave a short-term relieve. At the age of 5, the disease recurred and all treatments were ineffective. CBC, biochemical, serological, immunological analysis and X-ray, US, MRT were done. Genetic sequence analysis of the 207 genes listed in the Genes Analyzed section (Invitae Primary Immunodeficiency Panel) was carried out. On objective examination, the anterior cervical lymph node and the axillary lymph nodes were swollen on both sides. Aplasia of tonsils, “high palate”, hepatomegaly and splenomegaly were detected. Lab results showed severe anemia and high CRP (60 mq/l), however, HbsAg, HCV, Anti-Syphilis, Brucella antibodies were negative. Genetic examination: heterozygous mutations in CASP10, CLPB, CSF3R, CTPS1, IL17RC, LRBA, NLRP12, RFX5 genes were found. Diagnostic genetic testing to clarify the severity of disease and assistance with a personalized treatment may help management of patient.
A novel variant in CoQ biosynthesis highly prevalent in Papua New Guinea children increases mortality following bacterial pneumonia
Authors: Walker Emma C , Todd Elizabeth M. , Ramani Rashmi , Anaya Edgar , Javati Sarah , Matlam John-Paul , Pomat William , Morley Sharon Celeste 
Published: February 2023

Abstract
To identify immune variants predisposing to severe pneumonia, we performed whole exome sequencing in a pediatric population highly susceptible to acute lower respiratory infections, identifying a candidate novel variant in the CoQ biosynthetic pathway. To evaluate the effect of this variant on immune function during bacterial pneumonia, we generated a mouse line using CRISPR-Cas9 that expresses the homologous variant in the enzyme COQ6. Interestingly, we found that the variant does not result in CoQ deficiency, as other known variants in biosynthetic proteins do, however intra-tracheal S. pneumoniae infection leads to increased bacteremia and mortality in mutant mice. Mechanistic studies show that mutant macrophages have reduced pneumococcal killing in vitro, showing an intrinsic defect in innate immune function conferred by the COQ6 mutation. Variant macrophages have decreased mitochondrial respiratory capacity both at baseline and following stimulation with LPS, as well as an inability to induce mitochondrial reactive oxygen species (mROS) in response to stimulation despite increased mROS at baseline. Thus, the novel variant in a CoQ biosynthetic enzyme leads to changes in macrophage mitochondrial function and an intrinsic inability to kill internalized bacteria. As alveolar macrophages are the first responders in the lung to bacterial challenge, the inability of these macrophages to mount a sufficient immune response leads to the observed increase in mortality following bacterial pneumonia. This work describes a novel susceptibility locus to severe childhood pneumonia, and also represents the first known pathogenic variant in a CoQ biosynthetic protein that does not cause pathology resulting from CoQ deficiency.
Crosstalk of TDP-43 and Optineurin in in vitro and ex vivo Models of Amyotrophic Lateral Sclerosis
Authors: Munitic Ivana , Prtenjaca Nikolina , Rob Matea , Peradinovic Josip , Buratti Emanuele 
Published: February 2023

Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease marked by protein aggregation and neuroinflammation. Protein aggregates in &gt;95% of ALS cases are cytoplasmic and contain ubiquitinated and phosphorylated TAR DNA binding protein 43 kDa (TDP-43). Mutations in a ubiquitin-binding adaptor protein optineurin have recently been found in a subset of ALS cases. Its mutations are thought to act by loss of function, leading to disbalanced inflammatory signaling and/or impaired disposal of aggregated proteins by autophagy. Here we addressed the putative link between TDP-43 proteinopathy and loss of optineurin and/or its function. To this end we generated optineurin knockout (KO) neuronal and microglial cell lines by CRISPR/Cas9 technology, and (2) primary cells from a mouse optineurin insufficiency model lacking the ubiquitin-binding region (Optn470T). Elevated TDP-43 protein levels were found in optineurin-deficient BV2 microglial cell line, and in primary Optn470T bone marrow-derived macrophages (BMDM) and microglia. No differences were detected at TDP-43 mRNA levels, arguing for post-translational regulation. Elevated TDP-43 protein levels were not caused by autophagy blockade, and were specific to myeloid cells as they were not observed in neuronal NSC-34 and Neuro2A optineurin-deficient cell lines. Upon lipopolysaccharide (LPS) stimulation, TDP-43 levels increased in WT BV2 cells and BMDM, but in BV2 KO and OPTN470T BMDM they remained at the same elevated state as in basal conditions. Our results show that optineurin directly influences basal TDP-43 protein levels in myeloid but not in neuronal cells. Further studies are needed to determine if this could be a mechanistic link to protein aggregation in ALS.