bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cell-intrinsic expression of the RNA-binding protein HuR is essential for humoral immunity by facilitating B-T communication in the lymphoid follicle. (IRM12P.645)
Authors: DeMicco Amy , Naradikian Martin , Cancro Michael , Bassing Craig 
Published: January 2023

Abstract
Post-transcriptional regulation of gene expression is critical for the survival, differentiation, and function of B lymphocytes. To investigate roles of the RNA-binding protein HuR in B cells, we generated mice with B-cell specific deletion of HuR using Cre recombinase driven by the Mb1 promoter. These mice have modestly reduced numbers of naïve B cells, but show profound loss of serum antibodies of all isotypes and low numbers of germinal center B cells, plasma cells, and switched memory cells. Further, these mice fail to form germinal centers or undergo affinity maturation upon immunization with NP-OVA. In contrast, HuR-deficient B cells survive, proliferate, class switch, and undergo typical gene expression changes upon in vitro stimulation. We find that HuR regulates expression of CD81, CD70, and CD86, which promote the ability of B cells to physically interact with T cells. Biochemically, HuR binds to mRNAs of genes involved in cytoskeletal remodeling upon B cell activation. Because cytoskeletal reorganization is critical for antigen internalization, these data suggest that HuR-deficient B cells may have an antigen presentation defect. Consistent with the notion that B cell-intrinsic functions of HuR promote B-T communication in vivo, mice with HuR-deficient B cells have reduced numbers of T follicular helper cells, whose differentiation and maintenance are dependent on interactions with B cells. In sum, we find that HuR has critical roles in B cell function.
The genetic regulation of the longevity of CD4 memory T cells. (LYM5P.660)
Authors: Song Nianbin , Khoruzhenko Stanislav , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
We have previously reported that CD4 memory T cells enter a stage of quiescence upon resolution of infection and the consequent reduction in antigenic levels. The hyporesponsive memory T cells become responsive again upon challenge with a secondary infection, or antigen and Toll-like receptor agonists. To better understand the genetic mechanisms of the longevity of CD4 memory T cells, we performed cDNA microarray analysis of CD4 memory T cells developed after immunization with vaccinia-OVA virus using DO11.10 transgenic cells in an adoptive transfer experiment. Gene expression levels of CD4 T cells were evaluated at 9 days, 5 weeks, 6 months and 10.5 months post immunization. We repeated the experiment in DR1 transgenic mice immunized with H5N1 influenza vaccine because they have diverse polyclonal TCR repertoire and are better representative of the natural conditions. We used HLA-DR1/H5N1-HA(259-274) tetramers for staining of the antigen specific CD4 memory T cells. We found up-regulation of genes mediating DNA repair and inhibiting apoptosis, and down-regulation of glucose metabolism and up-regulation of lipid metabolism are important in longevity of CD4 memory T cells. Using FACS staining we verified several genes that were detected as significantly up-regulated by microarray experiments. These observations verified our microarray data as well as confirming our findings that long-term CD4 memory T cells are quiescent and switch from glucose to lipid metabolism.
Dysregulated THEMIS results in the escape of pathogenic auto-reactive T cells. (LYM6P.719)
Authors: Baudewijn Magdalena , Spiering Rachel , Lambolez Florence , Cheroutre Hilde 
Published: January 2023

Abstract
THEMIS is required for setting the threshold for conventional selection of thymocytes by dampening TCR signals, resulting in the accumulation of “naïve” T cells in the periphery. In contrast, agonist selection, which is an alternative way to induce self tolerance, requires strong TCR signals and does not involve regulation by THEMIS. Using the OVA-specific monoclonal MHC class II restricted DO11.10 TCR transgenic system, we found that many DO11.10 thymocytes are selected along the agonist selection path and appear as co-receptor double negative (DN) TCRab cells in the intestine. Interesting, some DO11.10 cells also appear as conventional-like CD4 T cells in the spleen, suggesting they escaped agonist selection. Compared to the DN DO11.10 T cells or normal WT conventional selected T cells, these escaped DO11.10 CD4 T cells expressed much higher levels of THEMIS, suggesting that excessive levels of THEMIS might have diverted DO11.10 thymocytes to be selected along the conventional path, resulting in the accumulation of T cells with high affinity for self in the naïve pool. Although these aberrant selected THEMIShigh CD4 T cells remain quiescent at steady state, they caused severe intestinal pathology in RAG-/- recipient mice that were fed an OVA-diet. These data indicate that dysregulated THEMIS can lead to the accumulation of auto-reactive T cells with high potential to induce immune pathology when exposed to their cognate antigen in the periphery.
The molecular signature of T cells undergoing recurrent homeostatic proliferation. (LYM6P.720)
Authors: Fortner Karen , Bond Jeffrey , Austin James , Boss Jeremy , Budd Ralph 
Published: January 2023

Abstract
T lymphocyte homeostatic proliferation, driven by the engagement of TCR with self-peptide/MHC complexes and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by Fas. However, the functional consequences of sequential rounds of homeostatic expansion are not well defined. We examined the gene expression profiles of wild-type and Fas-deficient lpr CD8+ T cell subsets that have undergone different amounts of homeostatic proliferation as defined by the level of CD44 expression, and the CD4-CD8-TCRαβ+ T cell subset that results from extensive homeostatic expansion of CD8+ T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as PD-1 and Lag3. These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed paradox in clinical immunology of simultaneous autoinflammatory syndromes and immunodeficient states and provide further insight into the regulatory programs that control chronically stimulated T cells.
Regulation of granuloma formation via Myd88 and Nox2 in a model of pulmonary sarcoidosis (MPF5P.741)
Authors: Werner Jessica , Escolero Sylvia , Hewitt Jeff , Mak Tim , Eishi Yoshinobu , Núñez Gabriel 
Published: January 2023

Abstract
Sarcoidosis is characterized by non-caseating granulomas with an unknown etiology that present primarily in the lung. Propionibacterium acnes, an immunogenic commensal skin bacterium involved in acne vulgaris, has been implicated as a causative agent of sarcoidosis because it has been both detected and cultured from granuloma lesions and lymph nodes of sarcoidosis patients. Here we demonstrate that a strain of P.acnes isolated from a sarcoidosis patient and instilled intratracheally into wild type mice can generate pulmonary granulomas. When mice deficient in the innate immunity adapter protein Myd88 are instilled with P.acnes the number and size of granulomas are increased compared to wild type. Additionally there was an increase in granuloma number and size after instillation with P.acnes in mice deficient in Nox2, a critical component of the phagocyte NAPDH that generates reactive oxygen species for microbial killing within the phagosome. Furthermore mice without Myd88 or Nox2 displayed defective killing of P.acnes in the lung, and wild type mice that were given heat-killed P.acnes produce significantly less granulomas then when given viable P.acnes, suggesting that bacterial killing and/or clearance plays a critical role in the development of pulmonary granulomas. In conclusion viable P.acnes can be used to generate a mouse model of pulmonary sarcoidosis, and Myd88 and Nox2 appear to play a key role in the development of these granulomas.
Escherichia coli colonization restores mucosal immune tone during antibiotic treatment (MUC5P.759)
Authors: Caballero Silvia , Samilo Dane , Carter Rebecca , Pamer Eric 
Published: January 2023

Abstract
Molecules derived from gut-colonizing microbes contribute to intestinal homeostasis by stimulating innate immune receptors and maintaining a basal level of activation of host antimicrobial defenses. Depletion of intestinal microbes by treatment with antibiotics severely dampens these responses, increasing the risk for colonization and infection with pathogenic bacteria. A major consequence of antibiotic treatment is downregulation of the antimicrobial protein RegIII-γ. RegIII-γ expression is markedly decreased during antibiotic treatment but can be induced by administration of Toll-like receptor (TLR) ligands derived from Gram-negative bacteria. This observation suggests a role for Gram-negative organisms in stimulating RegIII-γ intestinal levels. In this study, we investigated the ability of several E. coli and K. pneumoniae strains to induce RegIII-γ in the mouse intestine during antibiotic stress. We find that although both bacterial species colonize the gastrointestinal tract of antibiotic-treated mice, only E. coli restores RegIII-γ expression in the ileum. E. coli, but not K. pneumoniae, induces IL-22 expression, a requisite step for RegIII-γ, induction, in the small intestinal lamina propria. Flagellin and TLR5 signaling are not required for E.coli-mediated RegIII-γ induction. Our findings suggest that Gram-negative bacteria colonizing the intestine differ in their ability to mediate IL-22-dependent RegIII-γ.
Campylobacter jejuni induces autoimmune peripheral neuropathy via Siglec-1 and IL-4 axes (MUC5P.746)
Authors: Malik Ankit , Gadsden Barbie , Ethridge Alexander , Dybas Leslie , Mansfield Linda 
Published: January 2023

Abstract
Campylobacter jejuni is the most common bacterial cause of gastroenteritis worldwide. C. jejuni infection has also been causally linked with development of the peripheral neuropathy called Guillain Barré Syndrome (GBS). We have previously shown that C. jejuni isolates from human enteritis patients induce a Type1/17 cytokine dependent colitis response in IL-10-/- mice. In contrast, isolates from human GBS patients colonize the IL-10-/- mice without inducing colitis but instead induce autoantibody elicitation targeted against peripheral nerve antigens. We show here that the autoantibody response is dependent upon blunted Type1/17 but enhanced Type2 cytokine production by T helper cells. Autoantibody elicitation also correlated with enhanced macrophage infiltration in the sciatic nerve and its dorsal root ganglia. Autoantibodies and these histological changes were significantly decreased in mice depleted of IL-4, without leading to colitis induction. Histological damage in the sciatic nerve was associated with abnormal gait and hind limb movements in the IL-10-/- mice, consistent with this syndrome’s manifestation in humans. Furthermore, we show here that Siglec1 is a central antigen presenting cell receptor that mediates GBS but not colitogenic isolate uptake, T cell differentiation and autoantibody elicitation. Therefore, this is the first mouse model of an autoimmune disease induced directly by a bacterium and it is dependent upon Siglec1 and IL-4 axes.
Relapse of lupus after B cell depletion therapy is associated with loss of apoptotic debris clearing marginal zone macrophages in BXD2 mice (THER5P.911)
Authors: Hsu Hui-Chen , Yang Zhaoqi , Li Hao , Yang PingAr , Wu Qi , Li Jun , Luo Bao , Harrington Laurie , Mountz John 
Published: January 2023

Abstract
B-cell depletion therapy (BCDT) is used to treat autoimmune diseases but development of autoreactive B cells can occur during repopulation. Marginal zone macrophages (MZMs) are essential for tolerogenic clearance of apoptotic debris. Maintenance of MZMs requires MZ B cells. To determine if BCDT using anti-CD20 depletes MZ B cells and promote the loss of MZMs, lupus prone BXD2 mice were administered α-CD20 or isotype control (250 µg/single dose i.v.). This resulted in depletion of &gt;80% B cells in the spleen at week 2 in BCDT group. This was associated with increased uncleared apoptotic debris in the spleen MZ and a dramatic decline in MZMs. By 5 weeks of BCDT, the B-cell repopulation rate was &gt;50%. However, there was a significantly elevated expression of type I IFN signature genes Usp18 and Oasl in repopulated MZ precursor B cells in anti-CD20 group. There was a 2.8-fold increase in PNA+Fas+ CD19+ germinal center B cells in the spleens of anti-CD20-treated BXD2 mice, compared to isotype-treated mice. At week 9, the serum titers of IgG autoantibodies against DNA, histone, and malondialdehyde, a lipid peroxidation product associated with apoptotic blebs, were markedly increased in the α-CD20-treated BXD2 mice than control group. These results indicate that BCDT in BXD2 mice promotes an environment with excessive uncleared apoptotic debris which enhanced the effects of type I IFNs on repopulating B cells, leading to the return of autoreactive B cells.
Male microbiota protects female BWF1 mice from lupus and death by restoring CD103DC function possibly via metabolite(s) production (THER5P.914)
Authors: Kosiewicz Michele , Alard Pascale , Zhang Xiang , Fausnaught Thomas , Chhabra Anita 
Published: January 2023

Abstract
Alterations in microbiota composition are associated with autoimmune diseases. Little is known about the effect of microbial metabolite production on disease development. CD103 dendritic cells (CD103DC) induce regulatory T cells (iTregs) in the periphery. We have found that lupus-resistant male BWF1 mice exhibit increased disease incidence/mortality when treated with anti-CD103 antibody. Female CD103DC exhibit lower tolerogenic function than male cells in vitro and in vivo (i.e., oral tolerance) possibly due to a defect in the retinoic acid synthesis pathway. We also found that microbiota composition differed significantly between female and male BWF1 mice, and transfer of male microbiota decreased autoantibody production in female BWF1 mice. Here we report that transfer of male microbiota prevents kidney disease and dramatically increases survival of female BWF1 mice which correlates with enhanced female CD103DC function in both in vitro and in vivo assays, and increased iTregs. Furthermore, our preliminary study suggests that treatment with anti-CD103 antibody prevents male microbiota-mediated protection. Finally, metabolomic analysis of feces from female and male BWF1 mice revealed significant quantitative differences in 17 metabolites, including one that exhibits retinoid X receptor agonist activity. Taken together, these data suggest that male microbiota may protect against lupus through the production of metabolite(s) that enhance the retinoic acid synthesis pathway.
Repository corticotropin injection (H.P. Acthar® Gel) attenuates established collagen-induced arthritis when used alone or as adjuvant therapy with etanercept (Enbrel®) (THER5P.902)
Authors: Decker Dima , Higgins Paul , Bendele Alison , Becker Patrice 
Published: January 2023

Abstract
Melanocortins have anti-inflammatory and immunomodulatory properties mediated by receptors expressed on cells relevant to the pathophysiology of immune-mediated arthritis. Repository corticotropin, a melanocortin preparation, is approved as adjunctive therapy for rheumatoid arthritis (RA), but its mechanism of action in RA has not been determined. We therefore explored the efficacy of corticotropin when used alone or as adjunct therapy with etanercept in a rat collagen-induced arthritis (CIA) model. Corticotropin (160 or 400 U/kg) administered after disease onset significantly attenuated CIA-related changes in ankle diameter and paw weight compared to vehicle treatment (p ≤ 0.05). Corticotropin (400 U/kg) also significantly reduced clinical (4.15 ± 0.38 vs 5.65 ± 0.21, p ≤ 0.01) and summed ankle histopathology (9.90 ± 0.88 vs 15.20 ± 0.85, p ≤ 0.0001) scores below those in vehicle treated rats. Overall efficacy of corticotropin and etanercept used alone in established CIA were comparable, however corticotropin in combination with etanercept synergistically attenuated anti-collagen antibodies and both clinical and histopathologic measures of CIA vs etanercept alone (p ≤ 0.05). In addition, corticotropin administered with etanercept significantly attenuated CIA-induced decreased average bone density, whereas neither drug alone was efficacious (p ≤ 0.05). These data support the potential clinical efficacy of repository corticotropin as an adjunctive therapy for patients with RA.
Efficacy in collagen induced arthritis models with a selective, reversible covalent Bruton’s tyrosine kinase inhibitor PRN473 is driven by durable target occupancy rather than extended plasma exposure (THER5P.904)
Authors: Bisconte Angelina , Hill Ronald , Bradshaw Michael , Verner Erik , Finkle David , Brameld Ken , Funk Jens , Goldstein David , Nunn Phil 
Published: January 2023

Abstract
Bruton’s Tyrosine Kinase (BTK) is an essential signaling element downstream of the B-cell receptor (BCR). Inhibition of BTK activity in B cells produces phenotypic changes consistent with blockade of the BCR, including inhibition of cell proliferation, differentiation, maturation, and survival. A selective BTK inhibitor has the potential to treat diseases involving inflammation and autoimmunity. Using Principia Biopharma’s proprietary Tailored Covalency™ technology, we discovered PRN473, a reversible covalent BTK inhibitor that selectively binds BTK with a slow off-rate as assessed in biochemical and cell based assays. A slow off-rate molecule with rapid systemic clearance may lead to a long duration of action and high efficacy, while reducing the potential for off target toxicities. The duration of binding of PRN473 was measured in vivo, with prolonged BTK occupancy confirmed after drug was cleared from plasma. In mouse and rat collagen-induced arthritis (CIA) models, PRN473 when dosed therapeutically demonstrated dose-dependent inhibition, reversal of arthritis, with almost complete abrogation of clinical scores and preservation of joint integrity and histology. BTK occupancy in splenocytes was found to be a robust measure of BTK inhibition and correlated with efficacy in the CIA models. These data in combination with GLP toxicology studies, where no organ specific toxicities were observed, validate using a reversible covalent BTK inhibitor to treat autoimmune diseases.
Control of lupus by novel tryptophan metabolite 5-methoxytryptophan. (THER5P.907)
Authors: Wu Hsu-Feng , Wang YiFu , Kuo Cheng-Chin 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of pathogenic autoantibodies which potentially drive immune-complex related inflammation in various tissues and organs. We previously identified that 5-methoxytryptophan (5-MTP), a soluble factor released by fibroblasts, provides endogenous control of proinflammatory cytokine-induced cyclooxgenase-2 expression. However, its effect on controlling systemic inflammation and systemic inflammatory disorders such as SLE remains unclear. Clinical studies by measuring serum 5-MTP concentrations found that a considerable amount of 5-MTP was detected in healthy subjects and was significantly reduced in SLE patients. Mouse models of experimental lupus-like disease induced by pristine shown that exogenous supplementation of 5-MTP not only prevented serum anti-dsDNA IgG production but also rescued the loss of body weight. Notably, 5-MTP administrations rescued kidney by reducing the accumulation of IgG. The beneficial effect of 5-MTP was correlated with inhibition of IL-6 production in bone-marrow derived dendritic cells treated with TLR7 ligand, which is a stimulator of lupus progression. Additionally, 5-MTP also suppressed Th1 cell while increased regulatory T cells which play an essential role in preventing autoimmunity. These results that 5-MTP is a novel circulating anti-inflammatory molecule which protects against excessive systemic inflammatory responses in animal models.
Recipient IL-33 stimulates donor T cells to promote Type 1 alloimmunity and lethal acute GVHD (TRAN1P.931)
Authors: Matta Benjamin , Reichenbach Dawn , Schwarze Vincent , Tkachev Victor , Mathews Lisa , Liu Quan , Warncke Max , Ferrara James , Zeiser Robert , Blazar Bruce , Turnquist Heth 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) is a severe and often fatal complication of allogeneic (allo) hematopoietic cell transplantation (HCT). Total body irradiation (TBI) conditioning of the recipient and subsequent GVHD-associated alloimmune responses cause significant gut epithelial cell damage. As IL-33 is an epithelial cell-derived cytokine with pleiotropic functions, we investigated the impact of IL-33 on GVHD pathogenesis. Mice received TBI and alloHCT (allogeneic bone marrow (BM) +/- T cells). Where indicated, recipient mice, donor BM or T cells were deficient for IL-33 or its receptor, ST2. Survival, weight, and clinical score were monitored. Tissues and serum were harvested for IL-33 quantitation and analysis of alloimmune responses. We find that IL-33 expression is increased rapidly in CD45- cells of the gut after TBI, and sustained at least through day 14 in alloHCT recipients. Recipient, but not donor, IL-33 acting on ST2-expressing donor T cells fueled Type 1 responses and GVHD. The IL-33 antagonist ST2-Fc prevented GVHD and reduced Type 1 alloimmune responses, whereas IL-33 administration post-alloHCT (d+3 to d+7) accelerated GVHD lethality and Type 1 alloimmunity. These potent responses overcome regulatory functions of IL-33 to promote GVHD. In summary, our findings are the first to reveal a detrimental role for IL-33 underlying GVHD pathogenesis and establish the IL-33/ST2 axis as a targetable pathway to lessen the risk of GVHD following alloHCT.
An increase in the level of anti-Gal IgM is associated with an early graft failure in intraportal porcine islet xenotransplantation (TRAN1P.935)
Authors: Kang Hee Jung 
Published: January 2023

Abstract
In order to develop laboratory tests to predict graft outcome in porcine islet transplantation (ITx), we investigated the association between anti-Gal antibody responses and the graft failure in NHP recipients after porcine ITx. Total 35 naïve diabetic NHP recipients were intraportally administered with adult porcine islets and then graft function was monitored. Early graft failure (EGF) was defined as returning to diabetic state within a month after ITx. Among the recipients, 7 and 28 received induction immunosuppression (IS) without and with CD40 pathway blockade, respectively: 19, anti-CD154 and 9, anti-CD40. The levels of anti-Gal IgG and IgM in the recipients on the day 0 (0 d) and on the day 7 (7 d) of ITx were quantitatively measured by in-house ELISA. Whereas an increase in the level of anti-Gal IgG after ITx was suppressed by the use of either anti-CD154 or anti-CD40, a response of anti-Gal IgM was suppressed by anti-CD154, not by anti-CD40. The anti-Gal antibody ratio of 7 d/0 d was significantly higher in the recipients with EGF than in those without EGF (IgG ratio, 1.54 vs 0.75, P=0.0025; and IgM ratio, 1.48 vs 0.87 P=0.0035). An increase in the level of anti-Gal IgM on the day 7 of ITx is significantly associated with EGF in the recipients with porcine ITx regardless of use of CD40 pathway blockade, suggesting that an early response of anti-Gal IgM may reflect the innate immune responses which account for killing of porcine islets in early period of porcine ITx.