bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-assembly of immune signals to induce and control tolerance
Authors: Jewell Christopher M , Tostanoski Lisa H , Royal Walter 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease in which myelin insulating neurons is attacked. New research in humans shows excess inflammation through toll like receptors (TLR) contribute to disease. In animals, co-administration of self-antigens and regulatory cues leads to more specific tolerance. Polymers and other biomaterials can enable this co-delivery, along with attractive features such as tunable cargo loading, targeting, and cargo protection. However, these materials often exhibit intrinsic properties that can cause inflammation; features that might exacerbate disease. Thus, we designed immune polyelectrolyte multilayers (iPEMs) mimicking attractive features of biomaterial, but constructed entirely from immune signals. iPEMs were built by electrostatic interactions between myelin-derived, cationic peptides with an anionic, regulatory TLR9 antagonist (GpG). We hypothesized iPEMs would reduce TLR-driven inflammation during T cell differentiation, biasing expanding myelin-reactive T cells away from effector cells (TH1, TH17) and toward regulatory T cells (TREG) that control disease specifically. In culture, iPEMs co-deliver each signal to dendritic cells, reduce TLR9 levels, deactivate DCs, and promote myelin-specific TREG. These results depend on the presence of both GpG and myelin. In mice, iPEMs reduce TH17 and TH1 cells, expand TREG, and reverse MS-like disease (EAE). In samples from human MS patients, iPEMs also activate T cells, but polarize cytokine profiles toward tolerance and away from inflammation. This approach represents a simple, modular platform for combatting autoimmunity by programming the combinations and relative concentrations of self-antigens and regulatory TLR ligands.
Mass mining: a crowdsourcing approach for meta-analyzing gene expression signatures of autoimmunity using large-scale public data sets
Authors: Sparks Rachel , Lau William W ,   OMiCC Jamboree Working Group, Tsang John S 
Published: January 2023

Abstract
The volume and diversity of large-scale biological data available in the public domain continues to grow. This data has the potential to be reused to answer questions beyond those envisioned when the data was generated; however, few immunologists have sufficient bioinformatics expertise to do so. We used OMiCC, a free online platform that enables programming-free meta-analysis of public gene expression data and facilitates “crowdsharing” the work of annotating and constructing data compendia. We organized an “OMiCC Jamboree” to evaluate if biologists without bioinformatics training could use OMiCC to identify and annotate public gene expression datasets and design proper disease versus control comparisons for meta-analysis. Twenty-nine volunteer NIH biologists gathered to search and annotate public microarray data of human autoimmune conditions and the corresponding mouse models. Meta-analyses across studies explored 1) gene expression signatures for each disease, 2) pan-disease signatures, and 3) cross-species signatures. A large number of differentially expressed genes and enriched pathways were identified for each disease, with substantial overlap among diseases both within and between species, including pan-disease and pan-species signatures such as those associated with interferon.
Supported by the Intramural Research Programs of NIAID and CIT, NIH.
Identification of novel immune biomarkers in lymphoma
Authors: Derakhshandeh Roshanak , Webb Tonya J 
Published: January 2023

Abstract
The diagnosis and treatment options for lymphoma patients have changed significantly over the past few decades as new immunophenotypic markers and novel biomarkers have emerged. Natural killer T (NKT) cells play a critical role in anti-tumor immunity. However, NKT cells are approximately 50% lower in cancer patients compared to healthy donors of the same age and gender. Thus, prior to initiating immunotherapy, a specific and highly sensitive assessment of NKT cell function should occur; yet, no such assay is currently available. Thus, we have developed a qPCR-based diagnostic assay that can be used to rapidly assess natural killer T (NKT) and total T cell function. In this study we assessed NKT cell number and function in healthy donors (n=30) and lymphoma patients (n=50) by flow cytometry, ELISA, and qPCR. We detected NKT cell function in 82% of healthy donors, compared to 44% of lymphoma patients. To investigate the mechanisms by which NKT cells were functionally impaired in lymphoma patients, we examined circulating levels of cytokines, such as Semaphorin 4D, IL-10, and IL-6. It was found that lymphoma patients have significantly higher levels of both pro- and anti-inflammatory cytokines, compared to healthy donors. These data implicate an immunoregulatory role for NKT cells in lymphoma.
Deficiency of MyD88 signaling in CD4 Tconvs increases Tregs suppression through loss of ST2 signaling
Authors: Griesenauer Brad , Zhang Jilu , Ramadan Abdulraouf M , Paczesny Sophie 
Published: January 2023

Abstract
Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT). We found that plasma soluble suppression of tumorigenicity 2 (sST2) predicted GVHD-related mortality in allo-HCT patients. ST2 signals through the adapter protein MyD88. Lack of MyD88 in CD4 Tconvs has been shown to decrease ovalbumin or a peptide to the haplotype H2b stimulated Th1/Th17 cells via the IL-1R. Thus, we hypothesized that absence of MyD88 signaling would protect against aGVHD through IL-1R, ST2, or both.
We found that knocking out MyD88 in the donor T cells protected against aGVHD while recipients of IL-1R−/− donor T cells showed no difference. We found that the aGVHD protection was entirely driven by MyD88−/− CD4 T cells. There were no differences in proliferation, apoptosis, or migration in WT or MyD88−/− CD4 T cells. We next explored the cell-intrinsic role of MyD88−/− Tconvs and Tregs. We did not find a difference in survival in aGVHD models with MyD88−/− Tconvs or MyD88−/− Tregs. However, use of MyD88−/− Tconvs with WT or MyD88−/− Tregs ameliorated aGVHD. We hypothesized that this was mediated by lack of ST2 on donor Tconvs. Recipients of ST2−/− Tconvs with WT or ST2−/− Tregs lowered aGVHD mortality, mirroring MyD88−/− Tconvs. Transcriptome analysis comparing 10 days post-HCT CD4 T cells from MyD88−/− versus WT recipients showed lower levels of Irak1, Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, and Jak2 as well as decreased systemic plasma sST2 and IFN-γ levels. Our data suggests that Tregs suppression from lack of MyD88 signaling in Tconvs during alloreactivity uses the ST2 but not the IL-1R pathway, possibly by different antigen stimulation. MyD88 represents an aGVHD therapeutic target sparing Treg function.
TIM-1 blockade of the donor graft provides protection against lethal GVHD
Authors: Iliopoulou Bettina , Hsu Katie , Pierini Antonio , Freeman Gordon J. , Dekruyff Rosemarie H , Meyer Everett 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) continues to be a common cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The T cell immunoglobulin and mucin (TIM) proteins represent a family of molecules that act in concert with T–cell receptor and costimulatory signals to regulate expansion, differentiation and effector function of T and NKT cells. TIM-1 binds to phosphytidylserine, exposed on the surface of apoptotic cells. Given the immunoregulatory role of TIM-1, we explored how TIM-1 influences GVHD in a murine model of allogeneic HSCT which causes massive apoptosis. Here we show that mice treated with an antagonistic anti-TIM-1 mAb that blocks phosphatidylserine recognition are protected from lethal GVHD. Protection against GVHD appears to be mediated by TIM-1 expression on the donor graft as TIM-1 knockout mice showed minimal survival advantage after allogeneic HSCT. Mice treated with anti-TIM-1 mAb cleared the A20 tumor cells suggesting that GVL effects are preserved. By bioluminescent imaging, it was determined that TIM-1 blockade does not alter the homing and expansion of donor T cells in vivo, nor does it affect T or NKT cells proliferation in vitro. Moreover, using microarray analysis, we found that anti-TIM-1 treatment protects from lethal GVHD by promoting an anti-inflammatory environment in the gut tissue. Antagonistic anti-TIM-1 mAb also protects from lethal GVHD in a xenogeneic model of GVHD. Overall, these findings can form the basis for the development of novel therapeutic strategies to prevent GVHD and improve HSCT.
Maximizing the potential of Treg-based therapies for transplant rejection via computational immune-modeling: effect of dose, timing, and distribution
Authors: Raimondi Giorgio , Arun Anirudh , Dorabiala Olga , Arciero Julia 
Published: January 2023

Abstract
Regulatory T cells (Treg) are a promising target to treat transplant rejection but the optimal conditions for their effective clinical use still remain to be identified. Exploring all possible Treg conditions is unrealistic using conventional in vivo experimentation. Computational modeling provides an efficient and inexpensive solution to guide experimentation and the design of therapeutic protocols. Here, strategies for the adoptive transfer of Tregs are theorized using an experimentally-based mathematical model of the immune response to murine heart transplants. The model tracks populations of innate and adaptive immunity and proxies for pro- and anti-inflammatory factors within the graft and a representative lymph node. The model is used to predict the impact of different Treg adoptive transfer strategies on graft survival. In particular: timing of dosing, dosing rate, activation status of Tregs, and site of accumulation post-injection. Model results show that activated Tregs accumulating directly to the graft are most protective. The administration day of a single dose of Tregs has an unexpected impact on graft survival: delaying administration to POD2 or POD3 is more effective than peri-transplant transfer. The model also suggests that distributing a total dose over multiple days exerts a more protective effect than administering the same dose amount on a single day. Finally, the model predicts that a delayed dose at a lower rate can have a greater impact on graft survival than multiple doses at the same rate, suggesting that the timing of doses is most important. Thus, theoretical simulations are an invaluable tool that reveals unexpected treatment strategies for transplant patients that can be validated experimentally.
Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome.
Authors: Varelias Antiopi , Ormerod Kate L , Bunting Mark D , Koyama Motoko , Gartlan Kate H , Kuns Rachel D , Lachner Nancy , Locke Kelly R , Lim Chun Y , Henden Andrea S , Zhang Ping , Clouston Andrew D , Hasnain Sumaira Z , McGuckin Michael A , Blazar Bruce R , MacDonald Kelli PA , Hugenholtz Philip , Hill Geoff R 
Published: January 2023

Abstract
Donor T cell-derived IL-17A can mediate late immunopathology in graft-versus-host disease (GVHD), however protective roles remain unclear. Using multiple cytokine and cytokine receptor subunit knockout mice we demonstrate that stem cell transplant (SCT) recipients lacking the ability to generate or signal IL-17 develop intestinal hyper-acute GVHD. This protective effect is restricted to the molecular interaction of IL-17A and/or IL-17F with the IL-17RA/C receptor. The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and non-hematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we hypothesized a microbiome contribution. Cohousing of WT with IL-17RA and IL-17RC deficient mice, dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted towards that of the IL-17RA/C mice during cohousing prior to transplant, confirming that IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A deletion peri-transplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis. Importantly, this implies that blocking IL-17 in a clinical trial could have adverse effects via dysbiosis, particularly in the early post-transplant setting and raises caution about their potential effects if used long term.
On Hyperleucocytosis and Its Bearing on Specific Therapy
Authors: Zinsser Hans , Tsen Edgar 
Published: January 2023

Abstract
The literature of the last ten years contains a great many reports of the successful treatment of various acute infectious diseases with suspensions of the dead bacteria causing the disease, i.e., homologous “vaccines.” However, although this method has attained universal acceptance as a prophylactic measure in typhoid fever, cholera and paratyphoid infections, and promises similar prospects in some other conditions, it can hardly be said that it has been more than hopefully suggestive as a therapeutic procedure used during the course of actual disease. Indeed there has been an increasing suspicion among bacteriologists that the effects produced, when bacterial protein was injected into patients, were not in any sense specific, and depended rather upon the general character of the injected substances as bacterial proteins, than upon their specifically immunizing properties.
The Selection of Horses for the Production of Diphtheria Antitoxin by an Intra-Palpebral Toxin Test
Authors: Hitchens A. Parker , Tingley E. K. 
Published: January 2023

Abstract
An interesting result of the work of Park and Zingher1 upon the immunization of persons with mixtures of diphtheria toxin and antitoxin has been with regard to the production of antitoxin by various individuals. It has been shown that those persons who already possess immunity to diphtheria toxin more readily react to the injections with the production of antitoxin than do those individuals who possess little or no natural immunity to diphtheria toxin. This being the case, it occurred to us that if the same thing held true with horses, we might have, in a modification of the Schick test, some indication of the productive possibilities of horses with regard to diphtheria antitoxin. The experiments that we are about to report indicate that, to a considerable degree, the antitoxin productiveness of horses can be anticipated with the use of the Schick test.
Studies in Anaphylaxis
Authors: Weil Richard , Eggleston Cary 
Published: January 2023

Abstract
This study, which was being conducted in connection with the work described in the preceding paper, has been interrupted by the war. In view of the indefinite postponement of its complete publication, it seems advisable at the present time to give a brief preliminary statement of the results, in so far as they have been clearly established. The following protocol of one of the experiments is illustrative of the essential findings.
The liver was removed from a dog actively sensitized to horse serum, and placed in a warm perfusion chamber. By means of a cannula tied in the portal vein the liver was washed out with a liter of salt solution. The defibrinated blood of the same animal was divided into equal portions of 200 cc. each. The organ was then perfused with one of these portions, the blood being passed through a number of times successively.
Studies on Pollen and Pollen Extracts
Authors: Cromwell Hobart W. , Moore Marjorie B. 
Published: January 2023

Summary
Skin sensitivity to pollen extracts has been demonstrated in actively immunized rabbits using trypan blue as an aid, after the method of Ramsdell. The reaction is specific, and is more delicate than the precipitin test as indication of an immune response of the animal. The localization of the trypan blue also occurs in the abdominal fluid of the immune animal following intraperitoneal injection of the pollen antigen. Passive transfer of the skin sensitivity from immune to normal rabbit has been accomplished by the use of large quantities of immune serum.
The Production of Group Specific Human Hemagglutinins with a Note on the Separation of the Isoagglutinogens from the Red Corpuscles
Authors: Davidsohn I. 
Published: January 2023

Summary
From the foregoing there is evidence to the effect: That it was possible in a relatively small percentage of cases to remove partly or completely the group agglutinogens from the human red corpuscles by the mechanical procedure of repeated washing and shaking with physiological saline, thus confirming the results of Schuetz and Wohlisch, and of Hallauer.That it is possible to produce group specific anti-A and anti-B immune sera by adsorbing the heterologous agglutinins in rabbit immune sera with the corpuscles A or B, respectively.That by using unwashed human red bloo corpuscles a relatively high percentage of group specific agglutinating sera is obtained.
Exposure to silver nanoparticles primes mast cells for enhanced IgE/FcɛR1-mediated activation
Authors: Alsaleh Nasser B. , Brown Jared M. 
Published: January 2023

Abstract
Nanotechnology has been greatly expanding over the past few years and engineered nanomaterials (ENM) are being employed into many consumer products; yet, a basic understanding about their potential associated adverse responses is largely lacking. Silver nanoparticles (AgNP) are one of the most utilized ENMs primarily for their antimicrobial properties. We recently demonstrated a non-IgE activation of signal transduction pathways including PI3K, PLCγ, PKC and calcium signaling leading to robust mast cell degranulation (early-phase response) following AgNP exposure. Here, we examined late-phase activation, reactive oxygen species (ROS) formation, stress response and IgE-induced activation following exposure to AgNPs. Our data revealed that, unlike IgE, exposure to 20 nm AgNP resulted in a delayed (24 hours) activation of the MAPK pathway without release of inflammatory cytokines. Although AgNPs induced transient ROS formation (within the first hour), long-term exposure (6, 24 hours) was neither associated with cellular stress response (e.g. glutathione levels) nor it involved apoptotic or necrotic cell death. Importantly, despite the lack of major AgNP toxicity, our results demonstrated that exposure to AgNPs primed mast cells for exacerbated IgE/FcɛR1 activation. Specifically, exposure to AgNPs for 24–72 hours resulted in enhanced IgE-mediated phosphorylation of FcɛR1-linked protein tyrosine kinases, degranulation, and cytokine release. Together, albeit exposure to AgNPs appeared non-toxic to mast cells, our findings suggest that AgNPs might prime mast cell for exacerbated allergic type responses and further investigation is warranted to understand the underlying mechanism.
Lipoxin A4 restrains mast cell function and inhibits type 2 mediated cutaneous inflammation
Authors: Baxendell Haylee , Haduch Alexandra , Alwine Jeremy , Naumov Nicholas , Falo Louis D. , Sumpter Tina L. 
Published: January 2023

Abstract
Atopic dermatitis (AD) is a frequently occurring allergic inflammatory disease. In AD, IgE-activated dermal mast cells amplify type 2 immune responses. Current MC-therapies have limited success, necessitating exploration of MC-targeting agents for AD treatment. Lipoxin A4 (LXA4) is an immunoresolvin family member derived from arachadonic acid that signals primarily through the formyl peptide receptor 2 (FPR2). Limited reports investigate the relationship between LXA4, MCs and cutaneous inflammation. Here, we tested the hypotheses that LXA4 downregulates MC function and cutaneous inflammation utilizing bone marrow derived (BM)MCs and the murine type 2 skewed, MC-dependent, FITC-contact hypersensitivity model (CHS), respectively. In resting BMMCs, antagonism of FPR2 and pharmacological inhibition of LXA4 synthesis increased IL-6 and IL-13 release, suggesting that resting BMMCs generate LXA4. Exogenous LXA4 inhibited IgE-initiated MC activation, blocking degranulation and IL-13, TNF, and IL-6 release. Mechanistically, exogenous LXA4 blocked STAT5B and NFkB nuclear translocation and reduced mRNA for STAT5 and NFkB transcribed genes. FPR2 antagonists failed to reverse the effects of exogenous LXA4, suggesting that a second inhibitory receptor may be activated by LXA4 in BMMCs. In vivo, LXA4 reduced ear swelling in the MC-dependent FITC-CHS model. Collectively, these data suggest that LXA4 restrains MC function and may be therapeutically beneficial in AD.
Mast cell-driven clearance in N. brasiliensis is masked by IL-25-dependent B1 cell IgE.
Authors: Martin Rebecca , Valentine Yolander , Davis Elijah , Lownik Joseph Cornelius , Luker Andrea , Zellner Matthew , Urban Joseph F. , Finkelman Fred D. , Conrad Daniel 
Published: January 2023

Abstract
A large amount of poly-specific IgE is generated during helminth infection. We have previously shown that innate-like B1 cells are responsible for this IgE production during infection with the nematode parasite Nippostrongylus brasiliensis. In vitro analysis demonstrated a novel role for IL-25-enhancement of IgE in B1 cells from helminth infected mice. In T cell-reconstituted RAG1−/− mice, N. brasiliensis clearance was enhanced with the addition of B2 cells in an IgE-dependent manner. This enhanced clearance was impeded by reconstitution with IgE sufficient B1 cells. IL-25 receptor-deficient B1 cells did not impede this clearance. Mucosal mast cells mediated the B2 cell-enhancement of clearance only in the absence of B1 cells. This was shown using mast cell depletion with anti-ckit (ACK.2) in a helminth-infected RAG1−/− reconstitution model. Additionally, gene expression analysis of the jejunum on day 7 post-inoculation found increased mast cell protease genes and mucus related genes in RAG1−/− mice reconstituted with B2 cells over T cells alone. This revealed a potential mechanism for B2 cell-enhanced clearance. Finally, R1E4, an antibody that prevents IgE from binding to FcɛRI, was administered in a model of RAG1−/− reconstitution infected with helminth and results confirmed that the B2 cell IgE/mast cell clearance enhancement was mediated through FcɛRI. Overall, these data shine new light on B2 cell derived IgE and mast cells and their role in helminth clearance that is impeded by IL-25-driven B1 cell IgE.
Selective Serotonin Reuptake Inhibitors Suppress Mast Cell Function
Authors: Haque Tamara , Ryan John J. 
Published: January 2023

Abstract
There is considerable evidence of links between depression and inflammation. Selective serotonin reuptake inhibitors (SSRIs) are effective anti-depressants with well documented off-target effects. Because SSRI also has anti-inflammatory effects, we tested the hypothesis that SSRIs can attenuate mast cell function. We show that SSRIs reduce IgE-mediated degranulation and cytokine production in mouse bone marrow derived and peritoneal mast cells in vitro, and suppress IgE-mediated anaphylaxis in vivo. Since exogenous serotonin had no effect on IgE-induced mast cell activation, we suspected an SSRI mechanism independent of serotonin inhibition. We show that inhibiting the purinergic receptors P2X3 and P2X7 mimic SSRI effects, and combining these inhibitors and SSRIs has no additive effects. SSRIs blocked ATP-induced activation and ATP uptake in mouse mast cells, further suggesting SSRIs are targeting P2X signaling. Because IgE induces ATP release, we postulate that SSRIs suppress an IgE-ATP positive feedback response by limiting P2X signaling. These data indicate that SSRIs may be effective therapeutics for mast cell-associated diseases.