bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFNβ promotes the conversion of pro-inflammatory M1-like into anti-inflammatory M2-like microglia (171.14)
Authors: Yen Jui-Hung , Ganea Doina 
Published: January 2023

Abstract
IFNβ is an approved therapeutic option for the treatment of certain autoimmune diseases such as MS/EAE. However, the molecular mechanisms underlying the effects of IFNβ in MS/EAE are not fully understood. In this study, we identified a novel mechanism for the beneficial effect of IFNβ in MS/EAE through the conversion of microglia (MG) from pro-inflammatory M1-like (MG1) to anti-inflammatory M2-like (MG2). Our results show that IFNβ inhibits expression and production of proinflammatory M1-type cytokines, such as IL-12p40, IL-23 and TNFα and promotes the anti-inflammatory M2 cytokine IL-10 in LPS-stimulated primary MG. In addition, IFNβ treatment also enhanced the expression of specific M2 makers, such as arginase and YM-1. Through this phenotype switch, IFNβ-treated MG suppressed Th1 and Th17 activation leading to the downregulation of IFNγ and IL-17. In vivo, IFNβ-treated EAE mice exhibit lower clinical scores, reduced Iba-1, IFNγ and IL-17 expression, and increased expression of the M2 markers, arginase, YM-1 and IL-10 in the CNS. Taken altogether, our results demonstrate that IFNβ favors the generation of MG2 leading to the secretion of the anti-inflammatory cytokine IL-10 and reduced expression of the pro-inflammatory cytokines, IL-12, IL-23, IFNγ and IL-17 in vitro and in vivo.
Kinetics of knee synovial lavage inflammation in rodent models of collagen induced arthritis. (171.15)
Authors: Goess Christian , McCarthy Richard , Rundell Lian , Mathieu Suzanne , Wu Fei , Cuff Carolyn , Long Andrew 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation, swelling, and destruction of joints. In this study we used intra-articular lavage of the knee joint to easily and rapidly assess the kinetics of cellular infiltration and cytokine production within the local joint synovial environment during disease in rodent models of arthritis. In collagen induced arthritis in rats, knees of arthritic animals had increased cellularity composed of neutrophils, monocytes and T cells as well as marked increases in pro-inflammatory cytokines and chemokines including IL-1b, IL-6, and KC. The kinetics of infiltration showed an initial infiltration of monocytes shortly followed by a significant increase in neutrophil infiltration that strongly correlated with paw swelling. CD4+ T cells increased as well, but were not found in high numbers in the joint until after maximal paw swelling had been reached. We also found that the influx of monocytes into the knee joint space correlated with increased levels of KC, IL-1b, and IL-6, with KC levels preceding the subsequent neutrophil influx. Mouse models show similar disease course in regards to both inflammation and cytokine production in the synovial knee lavage. Understanding the kinetics of disease in the local joint presents new opportunities for biomarker development, target identification, and improvement of mechanistic understanding of disease processes in rodent models of arthritis.
Natural killer cells suppress cardiac eosinophilia in autoimmune myocarditis (171.21)
Authors: Ong SuFey , Ligons Davinna , Baldeviano Christian , Barin Jobert , Talor Monica , Wu Lei , Legault Jillian , Rose Noel , Cihakova Daniela 
Published: January 2023

Abstract
Eosinophilic myocarditis is a likely fatal form of myocarditis characterized by high mortality, compromised cardiac function, and severe cardiac infiltration dominated by eosinophils. We have demonstrated that eosinophils are present in the heart and contribute to disease severity during a murine model of experimental autoimmune myocarditis (EAM). We now show that natural killer (NK) cells exert control of cardiac eosinophilic inflammation and recruitment. Animals were depleted in vivo of DX5+CD3- NK cells by i.p. injection of anti-asialo GM1 antibody throughout EAM, resulting in significantly more severe disease (pathology score of 3.7 versus 1.5) and cardiac fibrosis. Depleted animals demonstrated greater numbers of SiglecF+Ly6Gmid cardiac eosinophils (6.9% versus 0.56%, p&lt;0.001) during the peak of disease at day 21. The observed increase in number of eosinophils after NK cell depletion was not seen for Ly6GhiSiglecF- neutrophils. Analysis of cardiac supernatants revealed increased levels of eotaxin (CCL11) and IL5, while flow cytometry demonstrated an expansion of CD4+ T cells producing either IL13 or IL17A in the heart. From these data, we propose a mechanism by which NK cells impact CD4+ cell polarization and downstream production of eosinophil growth factors and chemokines, thereby suppressing the development of eosinophilic myocarditis. Therefore, we provide the first direct in vivo evidence of NK cells regulating eosinophilic inflammation.
Antigen-targeting to dendritic cells is required for engraftment of antigen-encoding bone marrow and long-term tolerance under non-myeloablative conditions (171.27)
Authors: Coleman Miranda , Thomas Ranjeny , Steptoe Ray 
Published: January 2023

Abstract
Transplantation of hematopoietic stem cells (HSC) or bone marrow (BM) engineered to encode antigens is a means of inducing antigen-specific tolerance that might be suitable for ‘turning off’ pathogenic effector and memory T-cell responses. However, transplantation into primed hosts under non-myeloablative conditions could lead to rejection of engineered HSC or BM. We hypothesized targeting antigen expression to mature APC would alleviate rejection of engineered HSC while still permitting expression in the ‘tolerogenic’ cells that arise after transplantation. Using non-myeloablative conditions, we compared engraftment and ‘tolerogenicity’ in naïve or immune hosts of BM encoding an antigen that was ubiquitously expressed, targeted to diverse APC, or targeted to DC. When antigen was expressed ubiquitously, engraftment failed (&lt;1%) but targeting antigen to DC, permitted high levels of BM engraftment (≈40%). Unexpectedly, BM failed to engraft (&lt;1%) when antigen was targeted using a MHC class II promoter. This was due low level MHC class II expression by HSC leading to antigen expression and subsequent immune rejection of engrafting HSC. Long-term tolerance of antigen-specific memory T cells occurred only when engraftment was facilitated by targeting antigen to DC. For clinical translation, careful selection for a promoter that optimally targets DC will be imperative to ensure engraftment of antigen-encoding cells and long-term tolerance.
Steroid Resistant Autoimmune Inner Ear Disease: An Autoinflammatory Disease Instead? (171.28)
Authors: Pathak Shresh , Hatam Lynda , Bonagura Vincent , Vambutas Andrea 
Published: January 2023

Abstract
Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss that has periods of exacerbation triggered by unknown stimuli. We have previously shown that IL-1β is aberrantly expressed in steroid unresponsive AIED patients. These patients exhibit low titer antibodies to mixed molds, at dilutions 1:256 (p&lt;0.005) and 1:512 (p &lt; 0.05) and the inner ear protein, cochlin at dilution 1:256 (p &lt; 0.05), compared to control subjects. PBMC exposure to mold induces an up-regulation of IL-1β mRNA expression, enhanced IL-1β secretion and the generation of IL-17 expressing cells. Mold enriched T-cell cultures from AIED patients showed a five-fold induction of IL-17 producing cells in response to cochlin, suggesting that AIED patients share cross-reactive epitope(s). These results suggest that AIED may, in fact, be better characterized as an auto-inflammatory disease rather than autoimmune, as dysregulation of IL-1β and low-titer autoantibodies are observed in these patients. To further investigate the hypothesis that these patients have autoinflammatory disease, we asked whether LPS alone would be sufficient to induce IL-1β or whether the second stimulus of ATP was necessary. Monocytes from AIED patients secrete higher levels of IL-1β in response to LPS alone than healthy controls, and that the addition of ATP fails to augment IL-1β secretion. Further studies are underway to characterize the inflammasome defect in these patients.
BCR/TLR7 coligation uniquely drives plasma cell differentiation of autoreactive B cells (171.34)
Authors: Kiefer Kerstin , Green Nathaniel , Oropallo Michael , Cancro Michael , Marshak-Rothstein Ann 
Published: January 2023

Abstract
Endosomal Toll-like receptors (TLRs) play an important role in the manifestation of systemic autoimmune diseases such as SLE. In vitro, DNA-/RNA-associated autoantigens have been reported to activate B cells, pDCs, and other APCs, through TLR9/TLR7-dependent pathways. However, in vivo, TLR9 appears to negatively regulate TLR7-dependent responses. Hence, TLR9-/- autoimmune prone mice develop more severe disease and increased autoantibody titers against RNA associated proteins, while TLR7-/- and TLR7/9-/- autoimmune-prone mice develop less severe disease. AM14 BCR side-directed transgenic B cells recognize IgG2a-bound immune complexes (ICs) and initially proliferate in response to both DNA and RNA autoantigens. However, the TLR9-dependent DNA responses eventually promote a form of programmed cell death that can only be rescued by B cell survival factors such as BLyS. By contrast, the TLR7-dependent RNA responses promote differentiation to the plasma cell lineage. The RNA-driven phenotype is characterized by increased levels of plasma cell associated proteins such as IRF-4 and CD138 and antibody secretion. Even in the presence of BLyS, DNA containing ICs did not promote plasma cell development. Our results identify B cell intrinsic mechanisms whereby TLR9 activation restrains B cell responses and TLR7 activation induces a unique signal for plasma cell development.
The unique properties of neonatal NK cells predispose newborns to autoimmune ovarian disease (nAOD) induced by maternal autoantibody (171.37)
Authors: Rival Claudia , Samy Eileen , Setiady Yulius , Sun Yuefang , Sparks Joshua , Yagita Hideo , Tung Kenneth 
Published: January 2023

Abstract
The transfer of maternal autoantibody (autoAb) to the progeny can cause neonatal autoimmune diseases. An example is the fatal congenital heart block elicited by maternal SSA/SSB antibodies in Sjogren’s patients. Disease mechanism is unknown but can now be investigated in a nAOD model developed in our laboratory. Ovarian inflammation and atrophy occurs in C57BL/6 Rag ko pups after the exposure to maternal autoAb against ovarian zona pellucida 3 within 1-5 days of life. Resistance to nAOD induction in both NK cell-depleted Rag ko pups, and Rag/common gamma chain (Rag/γc) double ko pups demonstrates the critical role of NK cells. Notably, neonatal but not adult NK cells restore nAOD in Rag/γc ko pups. Compared to adult NK cells, neonatal NK cells have lower expression of Ly49 receptors and higher frequency of the CD27+ subset. We now show that the expression of CD27, CXCR3 and IFNγ by neonatal NK cells are crucial for nAOD. Furthermore, Ly49C/I-depleted adult NK cells acquire the ability to induce nAOD. This suggests that the low expression of Ly49 reduces the activation threshold and enhances the pathogenic capacity of neonatal NK cells. Lastly, FcgRIII expression on both neonatal NK cells and ovarian resident macrophages and dendritic cells (APC) is obligatory for nAOD induction. However, ovarian APC requirement is not ontogenetically regulated. We conclude that the unique properties of neonatal NK cell predispose newborns to autoimmune disease by maternal autoAb.
CD40 as a T cell biomarker in multiple sclerosis (171.38)
Authors: Wagner David , Waid Dan , Corboy John 
Published: January 2023

Abstract
Multiple sclerosis is a neurodegenerative disease with strong evidence for autoimmune components. Auto-aggressive T cells are implicated in the pathogenesis and maintenance of the disease in both mouse models and human disease. We described a T cell subset, CD4 cells expressing CD40, which prove highly pathogenic in autoimmunity. Using the McDonald criteria, diagnosed relapsing/remitting (RR) MS subjects have a significantly increased percentage of CD4CD40 cells in PBL compared to controls. Comparing to type 1 diabetes (T1D), MS subjects (78 total) had CD4CD40 cell levels equal to or greater than T1D (238 total) subjects. CD4CD40 cells from MS subjects recognize MS associated antigens and produce Th1 cytokines and IL-17, suggesting that CD4CD40 cells bridge Th1 and Th17. CD4CD40 cells produce high levels of IL-6 that shunts regulatory T cells into a Th17, pro-inflammatory, pathway. During RRMS CD4CD40 cell expansions occur regardless of age or gender or disease duration. In many MS subjects a clonal expansion of TRAV 8.1.3+ cells within the CD4CD40 population was evident. During pregnancy CD4CD40 cell levels dropped dramatically corresponding with the remission phase of disease, and returned to pathogenic levels post partum. In the mouse EAE model of MS CD4CD40 cells are expanded in percentage and adoptively transfer EAE to non-sick hosts; thus demonstrating pathogenicity. This suggests that controlling CD40 relative to T cells will prove therapeutic in MS.
A case for microbial involvement in the activation of lupus-antigen reactive T cells (171.39)
Authors: Szymula Agnieszka , Szczerba Barbara , Bagavant Harini , Fu Shu Man , Deshmukh Umesh 
Published: January 2023

Abstract
Although events responsible for the activation of lupus-antigen reactive T cells are not known, the strong environmental influence on SLE is suggestive of microbial involvement. Microbes can influence T cell activation through molecular mimicry. To test this hypothesis, we selected Ro60 as the candidate antigen and HLA-DR3 transgenic mice as the experimental mouse model system. Autoantibodies against Ro60 are present in lupus patients and HLA-DR3 has the strongest genetic linkage to lupus. Using a panel of T cell hybridomas, 3 T cell epitopes on Ro60 were characterized. Amino acids critical for T cell activation were identified and pattern search analysis was carried out. This strategy identified hundreds of mimicry peptides. Several mimicry peptides originated from microbes residing in the human oral cavity, gut and skin, and were able to activate the Ro60 reactive T cell hybridomas. In addition, immunization of HLA-DR3 transgenic mice with some of the mimicry peptides induced autoantibody responses. Our data suggests that T cells reactive against Ro60 can be activated by exposure to multiple peptides originating from different microbes that are present in the human microbiome. Thus, we would like to suggest that repeated exposure to different microbes shapes the self-reactive T cell repertoire in SLE and a dysregulated immune response against normal microbiota can initiate autoimmune responses in lupus.
Alteration of the germinal center checkpoint by the lupus associated NZM2410/NZW SLAM family genes in the Sle1b sub-locus (171.40)
Authors: Wong Eric , Khan Tahsin , Rahman Ziaur 
Published: January 2023

Abstract
C57BL/6 (B6) mice carrying the Sle1b sub-locus that harbors the lupus-associated NZM2410/NZW SLAM family genes produce anti-nuclear antibodies (ANA). However, the role and mechanisms of alteration in the germinal center (GC) checkpoint in the development of autoantibodies in these mice (named B6.Sle1b mice) is not clear. Here we show significantly higher spontaneously formed GC (Spt-GC) response in aged B6.Sle1b mice compared to B6 controls. The increased Spt-GC response in B6.Sle1b mice did not result from a generalized defect in the response of B cells expressing Sle1b as no difference was observed between two groups of mice in the anti-sheep red blood cell (sRBC) GC responses. We found a significant increase in CD4+CXCR5hiPD-1hi follicular helper T cells (TFH) within Spt-GC and anti-sRBC GCs in B6.Sle1b mice. The increase in Spt-GC and TFH cell responses in B6.Sle1b mice was not due to reduced CD4+CD25+Foxp3+ T effector (iTreg) and TFH regulatory (TFR) cells in GCs. Sle1b GCs compared to controls had significantly higher proliferating B cells. This elevated Spt-GC response in B6.Sle1b mice was associated with increased DNA and nucleosome-specific plasma cells (PCs), memory B cells and ANAs. These data indicate that the mechanisms that control the formation of Spt-GCs and generation of autoreactive B and TFH cells in GCs are altered by the NZM2410/NZW SLAM family genes located in Sle1b.
Altered CD4+ T cell differentiation with preferential expansion of Th1 cells in TLR7-driven autoimmunity (171.45)
Authors: Horton Christopher , Pan Zijian , Lawrence Christina , Bolland Silvia , Farris Darise 
Published: January 2023

Abstract
TLR7 is a single-stranded RNA-recognizing innate immune receptor with roles in anti-viral immunity and systemic lupus erythematosus (SLE) in humans and SLE-like autoimmunity in mice. TLR7 gene duplication drives inflammation and autoimmunity in the BXSB mouse model and other Y autoimmune accelerator (Yaa)-derived models of murine lupus. Additionally, TLR7 SNPs associate with SLE in Eastern Asian populations. In this study, we investigated effects of TLR7 overexpression on CD4+ T cell subsets. In unmanipulated, 5-6 month old TLR7 BAC transgenic mice, we observed amplified activated:naïve T cell ratios and preferential expansion of the Th1 subset compared to wild type controls. We also evaluated the phenotype of TCR transgenic T cells specific for the RNA-binding autoantigen, human La, following adoptive transfer into TLR7 BAC transgenic mice. These human La-specific T cells demonstrated enhanced differentiation to Th1 and PSGL1lowCXCR4+ extrafollicular helper phenotypes after recovery from TLR7-overexpressing human La transgenic mice compared to wild type human La transgenic controls seven days after transfer. Moreover, TLR7 overexpression in recipient mice resulted in significantly reduced expansion of the CD4+ Foxp3+ phenotype among transferred, human La-specific cells. These data indicate that TLR7 overexpression alters CD4+ T cell populations in a manner that potentially contributes to autoinflammatory disease in these animals.
Role of RIG-1 signaling in the Pathogenesis of Alzheimer’s Disease (172.1)
Authors: de Rivero Vaccari Juan Pablo , Brand III Frank , Sedaghat Christina , Mash Deborah , Dietrich W. Dalton , Keane Robert 
Published: January 2023

Abstract
Recent evidence has accumulated that Alzheimer’s disease (AD) is associated with a central nervous system (CNS) inflammatory response. Neuroinflammation is a complex response against harmful effects of diverse stimuli and plays a critical role in the pathogenesis of AD. An important arm of the inflammatory response is the innate immune response. The innate immune response is regulated by pattern recognition receptors (PRRs) and their signaling pathways. Here we report that the expression of the innate immune response proteins, retinoic acid-inducible gene-I (RIG-1), virus-induced signaling adaptor (VISA), and the NACHT leucine-rich domain and pyrin-containing protein, NLRP12 are significantly elevated in neurons of the temporal cortex, the cerebrospinal fluid and plasma in presymptomatic AD patients, post-mortem diagnosis. Increased expression of RIG-1 and VISA were not found in pathologically confirmed cases of amyotrophic lateral sclerosis, Diffuse Lewy Body disease or Huntington’s disease, suggesting that activation of RIG-1 signaling may be a specific marker for early AD pathogenesis. Moreover, in vitro results show that stimulation of RIG-1 signaling induces expression of amyloid precursor protein and β-amyloid, supporting the idea that activation of the RIG-1 signaling system occurs in presymptomatic AD.
Modulation of the unfolded protein response via XBP1 splicing: a novel mechanism that regulates Natural Killer cell effector function. (172.10)
Authors: Mujaj Sally , Gandhi Maher , Vari Frank , Nourse Jamie 
Published: January 2023

Abstract
The transcriptional factor X-box-binding protein 1 (XBP1), a critical gene in the unfolded protein response (UPR), has recently been demonstrated to be essential for the development, survival and function of B cells, T cells and Dendritic Cells. However, the involvement of the UPR in Natural Killer (NK) cell function has yet to be investigated. To address this we examined XBP1 during NK cell killing. Following activation of the UPR, XBP1 mRNA is converted to its active form (XBP1s) through splicing mediated by inositol-requiring enzyme-1 (IRE1). Splicing of XBP1 mRNA was observed within 1 hour following initiation of NK cell direct-cytotoxicity or antibody-dependent cell-mediated cytotoxicity (ADCC) towards leukaemia or lymphoma target cells. This indicates that the IRE1/XBP1 arm of the UPR is rapidly induced during killing of target cells. To determine the impact of induction of the IRE1/XBP1 pathway on NK cell cytotoxicity, IRE1 mediated splicing of XBP1 was pharmacologically inhibited. This significantly impaired both NK cell mediated direct-cytotoxicity and ADCC. Together these results indicate that induction of the UPR and splicing of XBP1s is essential for optimal NK cell cytotoxicity and demonstrates a novel mechanism to modulate NK cell effector function.
Identification of hemopexin as an anti-inflammatory factor that inhibits hemoglobin synergy with HMGB1 in sterile and infectious inflammation (172.11)
Authors: Lin Tian , Sammy Fatima , Yang Huan , Thundivalappil Sujatha , Tracey Kevin J. , Warren H. Shaw 
Published: January 2023

Abstract
In many clinical settings such as trauma, infections and other hemorrhagic diseases, multiple endogenous substances are released into the extracellular space, including hemoglobin (Hb) from degrading RBC and HMGB1, an intracellular DNA-binding protein that has been shown to be pro-inflammatory, from injured or immune cells. We studied the effects of Hb and HMGB1 on the activation of macrophages. In the supernatant of cultured bone marrow-derived macrophages from C57BL/6 or C3H/HeN mice, significantly increased levels of pro-inflammatory cytokines (TNF and IL-6) were detected when Hb was added with HMGB1 compared to the culture with HMGB1 alone ( P &lt; 0.01), while Hb itself did not induce detectable TNF and IL-6. This synergistic effect was also present in the culture of TLR2 knockout and TLR4 deficient (C3H/HeJ) macrophages. Addition of hemopexin (Hx), an endogenous heme-binding plasma protein, significantly decreased TNF and IL-6 induced by Hb and HMGB1 (P &lt; 0.01). Co-incubation of microbial ligands LPS or Pam3Cys with Hb and HMGB1 in the culture resulted in further dramatic increases of TNF and IL-6 that were also significantly decreased by Hx (P &lt; 0.01). These findings suggest that Hb may play an important role in amplifying sterile as well as infectious inflammation, and that endogenous Hx may play a role in controlling it. Administration of Hx could be a beneficial strategy in clinical settings where extracellular Hb and HMGB1 are both present.