bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic activity between IL-15 signaling and checkpoint blockade drives enhanced NK cell expansion and tumor control in ovarian cancer
Authors: Felices Martin , Bendzick Laura , Kodal Behiye , Hinderlie Peter , Miller Jeffrey S , Geller Melissa 
Published: January 2023

Abstract
Survival in ovarian cancer patients has not improved in the past 40 years, stressing a need for new lines of therapy. NK cell immunotherapy in ovarian cancer has not been extensively explored due to limited data showing defective NK cell function in these patients. Our previous work shows that an IL-15 super-agonist (NANT N-803 (formerly ALT-803)) can bypass some of the deficiencies. However, we show here that though N-803 enhances NK cell activation, it also induces NK PD-1 expression and inflammatory cytokines secreted by the NK cells induce PD-L1 expression on ovarian tumors. To bypass this negative feedback we combined N-803 with an anti-PD-L1 antibody (Avelumab) and show a potent increase in NK cell activation and long-term real-time in vitro tumor killing. Furthermore, combined N-803/Avelumab induces robust killing of ovarian cancer tumor spheroids, not seen with individual treatments. To evaluate the benefits of this combined treatment in vivo we tested them in a xenogeneic model of ovarian cancer containing human ovarian cancer cells (MA148lucs or OVCAR8lucs) and human NK cells. Our data clearly shows reduced tumor burden, by bioluminescent imaging, and potently increased NK cell expansion with the combined treatment when compared to individual treatments. Since Avelumab is capable of driving antibody dependent cell-mediated cytotoxicity (ADCC) we wanted to evaluate the impact of checkpoint signals in the synergy excluding ADCC using an anti-PD-1 antibody (Pembrolizumab). Combination of N-803 with Pembrolizumab yielded similar tumor control and NK cell expansion in the in vivo model, indicating that the synergy lies in checkpoint signals and IL-15 signaling, and not just in amplification of ADCC via N-803.
Pathology of B cell and neutrophil infiltration in the YUMMER1.7 mouse model of spontaneous melanoma tumor regression
Authors: Blenman Kim RM , Wang Jake , Cowper Shawn , Bosenberg Marcus 
Published: January 2023

Abstract
We evaluated the spontaneous and immunotherapy-induced histological changes in the tumor microenvironment of a mouse melanoma regression model consisting of C57BL/6J mice implanted with syngeneic YUMMER1.7 melanoma cells. We found common themes to the host response to cancer irrespective of mode of regression. Theme 1: Three regression phenotypes were identified: (1) nonregression, (2) regression, and (3) mixed regression. In nonregression, melanoma cells were epithelioid shaped and tightly packed. In regression, melanoma cells were spindle shaped and discohesive. Theme 2: In nonregression, B220+ B cells were small and located peritumor. In regression, B220+ B cells were intratumor and were plasmablasts/plasma cells. B cell numbers and distribution increased over time in spontaneous regression and was enhanced with immunotherapy. Theme 3: Ly6B.2+ neutrophils were in direct contact with dead/dying melanoma cells. The cytoplasm of the contacted melanoma cells displayed low/intermediate levels of Ly6B.2 protein, which suggested a role in melanoma cell death. Theme 4: At the peak of the adaptive immune response, in the regression tumors, most of the tumor mass were immune cells. Differentiators: The most striking difference between the two modes of regression was the presence of neutrophil extracellular traps (NETs)-like formations and geographic necrosis after immunotherapy treatment. Our preliminary data from patients with metastatic melanoma treated with anti-PD-1 therapy show that higher numbers of tumor-infiltrating B cells corresponded with longer progression-free survival. Beyond tumor regression, the increase in the B cell and neutrophil response could play a role in immunotherapy-induced adverse reactions.
The Human NK Cell Receptor KIR2DS4 Detects a Conserved Bacterial Epitope Presented by HLA-C
Authors: Long Eric O , Sim Malcolm J. W. 
Published: January 2023

Abstract
Natural killer (NK) cells are innate immune effector cells regulated by many germline-encoded activating and inhibitory receptors. The DAP12-associated activating receptor KIR2DS4 has been linked with multiple disease processes including cancer, disorders of pregnancy, and resistance to HIV. However, the precise ligands for KIR2DS4 remain poorly defined and the role of this receptor in immune responses is unclear. Here we show that human KIR2DS4 is a highly peptide-specific receptor for the human MHC-I molecule HLA-C*05:01. Of over 60 different peptides tested, only two conferred strong binding to KIR2DS4. Recognition of these peptides presented by HLA-C*05:01 potently activated KIR2DS4+ NK cells to degranulate and produce IFN-gamma and TNF-alpha. A recombinant peptide:HLA-C complex was sufficient to activate KIR2DS4+ NK cells. An alignment search of the KIR2DS4 binding peptides identified an epitope in recombinase A (RecA), a highly conserved bacterial protein. RecA epitopes from Chlamydia, Campylobacter, Brucella and Helicobacter pathogens were presented by HLA-C* 05:01, bound KIR2DS4 and activated KIR2DS4+ NK cells. By sequence alignment we predict that hundreds of species of bacteria contain RecA epitopes that can be presented by HLA-C*05:01 and bind KIR2DS4. These data provide clear evidence that KIR2DS4 is a highly peptide specific activating receptor and suggest that KIR2DS4 evolved to play a role in immune defense to bacteria.
Investigating a role for HLA-DO in the development of CD4 memory cells
Authors: Song Nianbin , Welsh Robin A , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
HLA-DO (DO) is a MHC class II-encoded protein in humans (known as H2-O in mice). It is expressed only in thymic medulla, B cells and some subsets of dendritic cells. Although DO is found to form a stable complex with HLA—DM, its biological functions remain poorly understood. Based on biochemical experiments, our lab has previously proposed a model suggesting that DO enhances binding of DM-resistant peptides, and reduces the binding of DM-sensitive peptides to the HLA-DR1 molecules in vitro. We also have established that a reduced density of antigen presentation by B cells during the contraction phase of an infection, induces of anergy in CD4 memory T cells, a condition that helps memory CD4 T cell survival and effective memory response to a second challenge. Based on our model, it would be expected that in immunized DO-KO mice, presentation of altered densities of DM-resistant pMHC by B cells would fail to induce long-lived, multifunctional memory CD4 T cells. We tracked the development of DR1 restricted flu specific CD4 memory T cells three months post flu vaccine immunization in DR1+/DO-KO mice. We found that the DR1+/DO-KO mice had fewer flu specific CD4 memory T cells than DR1+/DO-WT mice. By in vitro and in vivo recall experiments, we also found that the secondary immunological responses in DR1+/DO-KO mice were compromised. In addition, we recovered fewer memory B cells from immunized DR1+/DO-KO mice. These results demonstrate that in the absence of DO, the presentation of cognate foreign antigens in the DO-KO mice is altered and can potentially hamper the proper development of memory cells after the resolution of the infection. These findings support the idea that the expression of DO might ensure the proper development of memory cells.
Parkinson’s disease related proteins PINK1 and Parkin are major regulators of the immune system
Authors: Matheoud Diana , Cannon Tyler , Voisin Aurore , Penttinen Anna-Maija , Ramet Lauriane , Fahmy Ahmed , Ducrot Charles , Laplante Annie , Bourque Marie-Josée , Zhu Lei , Le Campion Armelle , McBride Heidi , Gruenheid Samantha , Trudeau Louis-Eric , Desjardins Michel 
Published: January 2023

Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder linked to the loss of dopaminergic neurons (DN) in the substantia nigra. Although the mechanisms triggering the loss of DN are unclear, mitochondrial dysfunction and inflammation are viewed as playing a key role. PINK1 and Parkin are major regulators of mitophagy and failure in this pathway in DNs is hypothesized to enhanced oxidative stress and cause cell death. However, we showed that PINK1 and Parkin play also a role in adaptive immunity by repressing mitochondrial antigen presentation (MitAP) (Matheoud et al., Cell 2016), suggesting that autoimmune mechanisms participate in the aetiology of PD. Here, following on the finding that LPS triggers MitAP in vitro and in vivo, we present evidence that intestinal infection with Gram - bacteria in Pink1 KO mice increases the release of pro-inflammatory cytokines, activates MitAP and induces autoimmune mechanisms eliciting the activation of cytotoxic mitochondria-specific CD8+ T cells. Remarkably, infection in these mice also leads to the emergence of severe motor impairment, reversed by L-DOPA treatment, accompanied by a sharp decrease in the density of dopaminergic axonal varicosities in the striatum. These data support the role of PINK1 as a modulator of the immune system and provide a new pathophysiological model where intestinal infection acts as a triggering event in PD, highlighting the relevance of the gut-brain axis in the disease.
Polymorphism in chicken MHC-Y class I molecules that bind lipid ligands
Authors: Goto Ronald , Gugiu Gabriel , Zhang Jibin , Stadtmueller Beth , Bjorkman Pamela J , Miller Marcia M 
Published: January 2023

Abstract
Polymorphism is a major structural feature considered to set peptide-binding MHC class I molecules apart from other types of MHC class I molecules that bind other types of ligands. Most polymorphic residues in peptide-binding MHC class I molecules point into the ligand binding groove and delimit the types of peptides bound. For illustration, in an analysis of the α1 and α2 domains of 25 HLA class I sequences, most of the highly polymorphic positions (12 out of 15 positions with variability indices greater than six) have amino acids with side-chains pointing into or toward the ligand binding groove. In contrast, distribution of polymorphic positions in chicken MHC-Y class I molecules is strikingly different. An analysis of 25 MHC-Y class I molecules revealed 16 highly polymorphic positions (variability indices greater than six) in α1 and α2 domain sequences. Only seven of these have amino acids with side chains pointing into or toward the binding groove. The remaining polymorphic positions are located mostly along the α1 helix, pointing up and away from the binding groove. These findings are consistent with the MHC-Y class I binding groove being narrow and binding simple lipid ligands through hydrophobic interactions. It may be that the remaining surface polymorphism is the basis for specificity in the interactions of MHC-Y class I molecules in immune responses that remain to be defined.
Support - USDA NIFA 2016-10247 & Caltech-City of Hope Biomedical Research Initiative
Androgens may influence lupus development via an effect on the composition and metabolic activities of intestinal microbiota in BWF1 mice
Authors: Harder James W , Ma Jing , Chhabra Anita , Alard Pascale , Zhang Xiang , Yuan Fang , Ferrill Rachel , Hua Yuan , Kosiewicz Michele M 
Published: January 2023

Abstract
Like many autoimmune diseases, systemic lupus erythematosus (SLE) occurs much more often in females than males in humans and spontaneous mouse models of lupus, such as NZBxNZWF1 (BWF1) mice. Castration increases disease incidence, severity, and mortality in BWF1 males, and BWF1 females are protected from disease by androgen treatment, suggesting that male sex steroids, androgens, play a protective role in lupus. Accumulating evidence suggests that microbiota dysbiosis is associated with development of autoimmune diseases, and the microbiota influences and is influenced by androgens. Our previous research has linked sex differences in microbiota to the sex-bias of SLE and differences in immunoregulation in BWF1 mice. To investigate the role of androgen in this sex-bias, we have studied the effects of androgen depletion via castration on male BWF1 mice. Fecal samples were collected from castrated and control male and female BWF1 mice, and analyzed for microbiota composition, function, and metabolites. We found that androgen-depletion induced a significant shift in the overall microbiota profile away from that found in control male mice, and toward one that was more similar to BWF1 female mice. Androgen-depletion also altered the fecal metabolite profile; 72 metabolites were altered in castrated compared to control male mice, and of these, 34 were also differentially produced in control female vs male mice. These changes in microbiota and metabolite profiles correlated with increased disease/mortality and altered immunoregulation in castrated male mice. Taken together, these data indicate that androgens have a dramatic effect on the microbiota, and it may be through the microbiota that androgens affect SLE development.
Systemic activation of B and CD4 but not CD8 cells drives early disease in lupus prone mice, while macrophages, CD4 and CD8 cells infiltrate the kidney with the exclusion of B cells
Authors: Wu Juan , Wang Hongsheng , Amo Laura , Scott Bethany , Kole Hemanta K , Bolland Silvia 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies in serum and multi-organ inflammation. Immune complex deposition in kidney can lead to lupus nephritis, which is a major risk factor for morbidity and mortality in SLE. Using FcγRIIB−/− mice as a lupus animal model, we performed a detailed time course analysis of the extent of the spontaneous leukocyte activation and expansion in spleen and in renal, inguinal, mesenteric lymph nodes. We then correlated the data with the onset of pathology and leukocyte infiltration in the kidney. In the FcγRIIB−/− mouse model, effector-memory CD4 cells and germinal centers appeared first in the spleen and renal lymph nodes, but not in other immune organs such as inguinal or mesenteric lymph nodes. As the disease progresses in these mice, lymphocytes undergo an extensive expansion that involves all immune organs in a systemic manner. At the same moment we can detect the first signs of kidney pathology, measured by histopathology and by the levels of creatinine and albumin in urine. In FcγRIIB−/− mice, the onset of kidney pathology correlates with leukocyte infiltration in kidney, detected both by parenchyma-restricted flow cytometry and histopathology. Macrophages, CD4 and CD8 cells are found both in glomerular and interstitial spaces with the exclusion of B cells, most likely suggesting a role for T cells and/or macrophage specific chemokine signals in lupus nephritic kidney.
Divergent roles for TLR7 and TLR9 in modulating the NFκB pathway in B cells
Authors: Nundel Kerstin (Kiefer) , Moses Stephanie , Shim JaeHyuck , Marshak-Rothstein Ann 
Published: January 2023

Abstract
BCR signal strength plays a key role in the fate decision of B cells with strong BCR signals promoting plasma cell differentiation and weaker BCR signals driving germinal center formation. Signals through toll-like receptors (TLRs) also influence B cell differentiation. It is still unclear how the BCR and TLR signaling cascades interface to modulate B cell responses and differentiation. To address this question, we used a BCR sdTg mouse model, AM14, in which all mature B cells have a naïve follicular phenotype. The AM14 BCR recognizes IgG2a-bound immune complexes (ICs) and B cell activation depends on TLR7 and/or TLR9. ICs formed using the auto-antibody (autoAb) PL2-3 can activate AM14 B cells through either BCR/TLR9 or BCR/TLR7, allowing us to use TLR knockout lines to dissect signaling pathways unique to each TLR. Using this system, we reported earlier that BCR/TLR7-activated AM14 B cells differentiate into short-lived plasmablasts while plasma cell development does not occur in BCR/TLR9-activated AM14 B cells. Intriguingly, we now show that BCR/TLR9 activation of AM14 B cells leads to sustained activation of the NFκB pathway. BCR/TLR7-activated AM14 B cells are unable to sustain the initial NFκB response and fail to express the non-classical IκB member, IκBζ. IκBζ is known to be important in regulating cytokine responses in T cells and macrophages. However, its role in B cells is not well defined. We find that several IκBζ regulated cytokines are expressed after BCR/TLR9 dependent signaling but not after BCR/TLR7 dependent signaling. Our results point to divergent roles for TLR7 and TLR9 in modulating the NFκB signaling cascades, leading to differential expression of NFκB target genes which may influence B cell fate decisions.
Characterization of CD11c+ B-cells from human blood
Authors: Calbo Sébastien F , Demeules Mélanie , Derambure Céline , Riou Gaetan , Vaillant Maud , Boyer Olivier , Joly Pascal , Golinski Marie-Laure 
Published: January 2023

Abstract
Different B cell subpopulations with immuno-regulatory properties have been recently identified. We previously reported a CD11c+ B-cell subset that was not able to produce IL-10 even under optimal conditions (1). Interestingly, despite the fact that CD11c+ B-cells are detected in the blood of healthy individuals, they have been reported to be increased in autoimmune diseases. We aimed to characterize CD11c+ B cells from healthy humans by flow cytometry, microarray analysis, in vitro functional assays, and by measuring their frequency in patients with autoimmune diseases. Here we report that CD11c+ B cells are a distinct subpopulation of B cells, even if their phenotype is heterogeneous, with overexpression of genes involved in B cell activation and antigen presentation. Moreover, upon activation, CD11c+ B cells can differentiate into plasma cells and CD11c could be up-regulated in CD11c− B cells. Finally, we showed that patients with pemphigus, an autoimmune disease mediated by B cells, have a decreased frequency of CD11c+ B-cell after treatment, relative to baseline. Our findings could help to identify a B-cell population that may represent novel targets for immunotherapy.
Analysis of age-associated B cells (ABCs) in Systemic Lupus Erythematosus (SLE) patients
Authors: HERNÁNDEZ VÍCTOR ANDRÉS SOSA , Navarro-Hernandez Itze Cecilia , Torres-Ruiz Jiram José , Whitall Laura Patricia , Gómez-Martín Diana , Santos-Argumedo Leopoldo , Maravillas-Montero José Luis 
Published: January 2023

Abstract
SLE is an autoimmune disease which is characterized by the formation of auto-antibodies and loss of tolerance. In addition to the production of auto-antibodies, certain sub-populations of B cells may play a critical role in the resolution or severity of the disease.
Recently, a novel CD11c+, CD21low, and T-bet+ expressing B-cell subset has been identified as critical for the development of autoimmune diseases; the transcriptional program that develops this phenotype is induced in response to signaling by IFN-γ, TLR-9 and the costimulatory molecule CD40 and is linked to the induction of IgG2a, IgG2b, IgG3 and repression of IgG1 and IgE. However, the relationship between the presence of these cells and autoimmunity development is not yet well understood.
In this study, we analyzed blood samples from a cohort of 15 patients with SLE through flow cytometry. The frequency of this ABCs sub-population was correlated with clinical and laboratory variables such as C3, C4, antidsDNA antibodies, anti-nucleosomes antibodies, serum creatinine and total urine proteins. These data were subjected to Spearman’s correlation analyses. Interestingly, we found a positive correlation with ABCs percentages and anti-dsDNA antibodies (r=0.604, p=0.028).
These results suggest that circulating ABCs number can be potentially used as a diagnostic/prognostic marker for this autoimmune disease.
Peptides of endogenous retrovirus Gag gene variants are not agonistic ligands for autoreactive T cells in non-obese diabetic mice
Authors: Dai Yang D , Bashratyan Roman , Marquardt Kristi , Hu Wen-Yuan , Evans Leonard , Haskins Kathryn 
Published: January 2023

Abstract
Endogenous retroviruses (ERV) have been isolated from the pancreatic islets of non-obese diabetic (NOD) mice. We previously demonstrated that a murine leukemia retrovirus–like ERV Gag protein was secreted together with exosomes by an insulinoma and by primary islet mesenchymal stem cells. Here, we further demonstrated that Gag is an effective antigen to stimulate IFN-gamma production by autoreactive T cells using recombinant Gag protein or virus-like particles (VLPs) expressing the Gag gene. However, candidate peptides of this Gag protein were not effective in stimulating the T cells. Upon analyses of ERV Gag genes expressed in the islets of prediabetic NOD mice, we were surprised to find multiple Gag gene variants with complete open-reading frames. These results suggested the expression of different endogenous proviruses, or alternatively, the detection of point mutations incurred during viral replication. A new batch of altered peptides was synthesized reflecting the variations among the Gag gene variants, and a few of them induced detectable amount of cytokine secretion from the T cells. But, the levels of IFN-gamma induced by the peptides were much lower than that induced by the Gag protein and the VLPs, suggesting a low affinity activation. This weak T-cell-stimulating activity of the Gag peptides was further confirmed by testing diabetogenic T-cell clones, as well as by using MHC tetramers loaded with candidate peptides. The data suggest that ERV Gag or its gene variants may trigger autoimmunity via a pathway that could be independent from direct presentation of viral peptides to autoreactive T cells.
Molecular Targets of inflammation in pancreatic endocrine cells in Type 1 Diabetes (T1D)
Authors: Mora Conchi , Sala Ester , Saavedra-Ávila Noemí Alejandra , Sengupta Upasana , Vived Celia , Verdaguer Joan , Stratmann Thomas , Lahti Jill 
Published: January 2023

Abstract
T1D (Type 1 Diabetes) is an autoimmune disorder caused by the immune-mediated destruction of insulin-producing beta cells in the pancreas. There are direct mechanisms that have been demonstrated to cause final beta cell demise, such as the pathways triggered by Fas engagement and Perforin release. However, focus should be placed on other indirect mechanisms, such as pro-inflammatory cytokines present in the beta cell niche early on, that progressively debilitate and alter beta cells from earlier phases of T1D progression, rendering them as helpless targets of the immune system at the end. Though beta cells may resist adverse stimuli in early phases of the autoimmune process, the complicity of both, direct and indirect deleterious mechanisms, leads to beta cell death. In an effort to identify those indirect mechanisms that chronically besiege beta cells from the T1D-prone NOD mouse model, we used the microarray technology. We have identified several candidate genes the expression of which is altered in the NOD islet prior to T1D onset. Several of these genes are related to cell cycle progression and are downregulated due to the insulitic attack to the islet. One of these genes is cyclin D-3, a Dtype cyclin that interacts with either Cdk4 or Cdk6 to promote G1/S cycle progression. We have reported that cyclin D3 protects beta cells against cytokine-induced apoptosis and is required for proper beta cell function in a cell-cycle independent fashion. Cdk11 is also affected by inflammation in islet cells and is a cyclin-dependent kinase which is involved in transcription, mitosis and apoptosis. The natural partners of Cdk11 are L-type cyclins. We have examined whether the immune function is affected in the relative absence of Cdk11.