bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protection of Irf5-deficient mice from pristane-induced lupus involves altered cytokine production and class switching (159.11)
Authors: Barnes Betsy , Feng Di , Yang Lisong , Bi Xiaohui , Stone Rivka , Patel Priya 
Published: January 2023

Abstract
Polymorphisms in the transcription factor interferon (IFN) regulatory factor 5 (IRF5) have been identified that show strong association with increased risk of developing the autoimmune disease systemic lupus erythematosus (SLE). A potential pathologic role for IRF5 in SLE development is supported by the fact that increased IRF5 mRNA and protein abundance are observed in primary blood cells of SLE patients that correlate with increased risk of developing the disease. Here, we demonstrate in clean littermates that IRF5 is required for pristane-induced lupus via its ability to control multiple facets of autoimmunity. We show that IRF5 has a distinct influence on pathological hypergammaglobulinemia and provide evidence for its role in regulating IgG1 class switching and antigen specificity. Examination of in vivo cytokine expression (and autoantibody production) identified an imbalance in Irf5-/- mice favoring Th2 polarization. In addition, we provide clear evidence that loss of Irf5 significantly weakens the in vivo type I IFN signature that is critical for disease pathogenesis in this model of murine lupus. Together, these findings demonstrate the global effect that IRF5 has on autoimmunity and provides significant new insight into how overexpression of IRF5 in blood cells of SLE patients may contribute to disease pathogenesis.
The immunodominant CD4+ T cell epitope of myeloperoxidase induces cell mediated injury in murine anti-myeloperoxidase glomerulonephritis (159.14)
Authors: Kitching A Richard , Ooi Joshua , Chang Janet , Holdsworth Stephen 
Published: January 2023

Abstract
Microscopic polyangiitis, characterized by pathogenic autoantibodies to neutrophil cytoplasmic proteins (ANCA), including myeloperoxidase (MPO), frequently targets the glomerulus. Although the pathogenicity of ANCA has been established, the role of CD4+ cells, cell mediated effector responses and MPO T cell epitopes are not known. By screening overlapping peptides of 20aa spanning the entire MPO molecule, we identified an immunodominant MPO CD4+ cell epitope (MPO409-428). Immunization with MPO409-428 induced disease similar to that seen with whole MPO when disease was triggered with anti-glomerular basement membrane antibodies. A CD4+ MPO409-428 specific clone transferred into Rag1-/- mice induced necrotizing glomerulonephritis with renal impairment when MPO409-428 was planted in glomeruli, or when whole MPO was deposited in glomeruli after neutrophil recruitment induced by transfer of anti-MPO antibodies with LPS. MPO409-428 also induced biologically active anti-MPO antibodies in mice. The MPO409-428 T cell epitope has a minimum immunogenic core region of 11 aa, MPO415-426, with several critical residues. These studies identify an immunodominant MPO T cell epitope and redefine how effector responses induce injury in MPO-ANCA associated microscopic polyangiitis. ANCA activate neutrophils not only induce injury, but also lodge the autoantigen MPO in glomeruli, where autoreactive CD4+ cells act to induce delayed-type hypersensitivity like necrotizing glomerular lesions.
IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation (159.27)
Authors: Yang Min , Lu Liwei 
Published: January 2023

Abstract
IL-10-producing CD1dhiCD5+ B cells, namely B10 cells, have been shown to possess a regulatory function in inhibiting immune responses, but whether and how B10 cells suppress the development of autoimmune arthritis remains largely unclear. In this study, we detected significantly decreased IL-10-producing B cells but increased Th17 cells in both spleen and draining lymph nodes of mice at the acute stage of collagen-induced arthritis (CIA) when compared with adjuvant-treated control mice. Upon adoptive transfer of in vitro-expanded B10 cells, collagen-immunized mice exhibited a marked delay of arthritis onset with reduced severity of clinical symptoms and joint damage, accompanied by a substantial reduction of Th17 cells. To determine whether B10 cells directly inhibit Th17 cell generation in culture, CFSE-labeled naïve CD4+ T cells were cocultured with B10 cells. It was found that B10 cells suppressed Th17 cell differentiation via reducing STAT3 phosphorylation and RORγt expression. Moreover, Th17 cells exhibited significantly decreased proliferation when cocultured with B10 cells. Although adoptive transfer of Th17 cells triggered the development of CIA in IL-17-/- DBA mice, co-transfer of B10 cells with Th17 cells profoundly delayed the onset of arthritis. Thus, our findings have demonstrated a novel regulatory role of B10 cells in arthritic progression via suppressing Th17 cell generation.
Cellular and molecular mechanisms for lupus nephritis in a mouse model of systemic lupus erythematosus (159.4)
Authors: Hai Si-Han , Lam Viola , Cook Brian , Hermiston Michelle 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder with a range of presentations. Lupus nephritis is a particularly severe feature of SLE that predicts a poor outcome. Currently, it is unclear why some patients develop severe end organ disease while others have a relatively benign course. The CD45E613R mouse is a tractable model of SLE to study the transition from autoreactivity to autoimmunity. These mice express a single amino acid substitution (E613R) in the juxtamembrane wedge of CD45 that results in dysregulated phosphatase activity in all hematopoietic cells. Mirroring the variable presentation of human SLE, the phenotype of CD45E613R mice varies with genetic background. CD45E613R mice backcrossed to C57BL/6 (B6) or 129/Sv backgrounds fail to develop autoantibodies or end organ damage while F1 B6-129 CD45E613R mice develop high titer auto-antibodies and severe nephritis. Interestingly, BALB/c CD45E613R mice develop auto-antibodies but no nephritis. Using cytokine arrays and flow cytometry, we identified dysregulated cytokines and immune cell subsets in F1 B6-129 CD45E613R mice relative to the parental strains and wild-type controls. Classical inflammatory cytokines IL-1a and TNF-a were elevated in B6-129 F1 wedge mice. In contrast, MIP-1a and GM-CSF were most elevated in BALB/c wedge mice, implicating a protective effect. Uncovering new biomarkers and understanding disease pathogenesis should provide new insights into therapies for lupus nephritis.
Epigenetic contribution to between-animal variation in their fibroblast response to lipopolysaccharide (160.11)
Authors: Green Benjamin , Kerr David 
Published: January 2023

Abstract
Considerable variation exists between cows in the ability of their fibroblasts to produce IL-8 in response to LPS in vitro, and there is some evidence in support of an association with in vivo responsiveness to LPS or E. coli infection. Dermal fibroblast cultures were established from 43 cows and challenged with LPS for 24 h. A 4.5 fold difference (P&lt;0.05) in the production of IL-8 was found between the 4 highest (HR) and 4 lowest (LR) ranked cultures. Preconditioning the cultures with DNA demethylating (5-aza-2'-deoxycytidine) and hyper-acetylating (trichostatin A) agents (AZA-TSA) potentiated the IL-8 response to LPS and eliminated the difference between HR and LR cultures. Subsequent gene expression studies on cultures with or with out AZA-TSA, and with or without 3 h LPS treatment indicated that IL-8, but not TNF, IL-6, SAA3, CCL20, or TLR4 was increased following AZA-TSA in the absence of LPS. After LPS treatment all genes studied except for TLR4 were up-regulated in response to LPS exposure under control conditions, with HR cultures displaying higher expression than LR cultures of IL-8, IL-6, and TNF (4.1, 2.8 and 6.8 fold, respectively). Preconditioning with AZA-TSA prior to LPS increased expression, more so in LR cultures, resulting in lower HR to LR differences of 1.1, 1.7 and 2.6 fold, respectively. The reduction in differential response to LPS due to AZA-TSA suggests a role for epigenetic modification in contributing to between-animal variation in immune response.
The identification and expression of a new light chain isotype, Igλ, in rainbow trout, Oncorhynchus mykiss (160.17)
Authors: Bromage Erin , Rego Kate , Ramirez-Gomez Francisco , Hansen John 
Published: January 2023

Abstract
The discovery of a trout EST bearing similarity to Igλ prompted an investigation of this previously uncharacterized isotype. Cloning and sequencing of gene-specific mRNA allowed the identification of two products. While the smaller product represented a fully spliced form, containing a variable segment (V), the joining segment (J), the constant region (C), and the 3’ UTR, the larger product was not fully spliced and contained a V segment, a 194bp intron, and a spliced J-C segment followed by the 3’ UTR. Phylogenetic analysis of the constant region confirmed that this new antibody isotype clustered with Igλ sequences of other species. Analysis of the recombination signaling sequences revealed that like Igλ in other species, the V and J segments are in the same transcriptional orientation with the V segment is followed by a heptamer-23bp spacer-nonamer while the J segment is preceded by a nonamer-12bp spacer-heptamer. In contrast to the Igκ and Igσ isotypes in trout that possess multiple VJC clusters, genomic analysis suggest that only a single Igλ VJC segment exists. Igλ accounts for only 1% to 3% of the total light chain expressions (IgκLC1 ~70%; IgσLC2 ~20%; IgκLC3~3%; IgλLC4~2%). Our identification of Igλ in rainbow trout shows that it is conserved throughout the teleost lineage. However, the role of the various Igλ splicing forms and whether the three Ig Heavy isotypes (IgM, IgD, IgT) demonstrate preferential light chain utilization still requires investigation.
Ontogenic analysis of Xenopus γδ T cells: expressed T cell receptor (TCR) γ and δ chains and IL-17 family members (160.8)
Authors: Jackson Shawn , Undieh Ada , Steiner Harold , Parra Zuly , Miller Robert , Ohta Yuko , Flajnik Martin 
Published: January 2023

Abstract
γδ TCR that have structural differences from conventional γδ TCR in mammals have been observed in non-eutherian vertebrates. Three different types of Vδ regions are present in Xenopus tropicalis, similar to Vδ, Vα, and VHδ (derived from the V regions of Ig H chains). Semi-quantitative PCR analyses in adult and larval Xenopus laevis show that expression levels of TCRδC and TCRγC, as well as of TCRδV and TCRγV repertoires, vary between tissues. Comparative analyses of adult and larval CDR3 sequences suggest ontogenic-, tissue- and perhaps V family-specific expression. We have detected changes at the VDJ junctions including N-nucleotide addition, nucleotide trimming, and homologous recombination events. γδ T cell populations in mammals differentially express either IL-17 or IFNγ. In mammals, six IL-17 forms have been described (A-E), the least well characterized of which is IL-17D. Most non-mammalian IL-17 homologs, including those in chicken, fish, lamprey, nematode, oyster, sea urchin, and tunicate, and especially, Xenopus, are the IL-17D form. We have cloned two types of IL-17A/F, IL-17B, and IL-17D from X. laevis. Semi-quantitative PCR analyses in adult and larval Xenopus show that the expression of these IL-17 family members vary during ontogeny and between tissues. Study of γδ TCR and IL-17 family expression in Xenopus will illuminate evolutionary and developmental changes in γδ T cell antigen recognition and effector strategies.
Analysis of the mechanism underlying contact hypersensitivity-induced hair growth (161.13)
Authors: Kitoh Akihiko , Nakamizo Satoshi , Natsuaki Yohei , Miyachi Yoshiki , Kabashima Kenji 
Published: January 2023

Abstract
Alopecia areata (AA) is believed to be a tissue-specific autoimmune disease mediated by T cells. Topical immunotherapy using contact sensitizer such as squaric acid dibutylester (SADBE) is one of the most effective treatments for intractable AA. However, the precise mechanism under which topical immunotherapy, i.e., contact hypersensitivity (CHS) reaction, induces hair regrowth in AA remains to be elucidated. It has been reported that CHS in the skin lesion of human and murine AA modulates the composition of the peribulbar mononuclear cell infiltrate, which may abrogate autoimmune reaction and promote hair regrowth. In fact, we have revealed that CHS induces predominant accumulation of CD4+Foxp3+ regulatory T cells and elevated expression of Il10 in the skin, which might contribute to tolerance induction in the AA lesion after topical immunotherapy. In addition, interestingly, CHS induces hair growth not only in bald skin of AA mouse but also in telogen skin of non-alopetic mice, implying the possibility that some mechanism other than abrogating autoimmunity may underlie the effect of topical immunotherapy in AA. In this study, we have disclosed the underlying mechanism of CHS-induced hair growth in alopetic and non-alopetic skin, which may provide a fundamental finding for the development of a better topical immunotherapy for AA.
Expression and histopathological correlation of CXCR5 and its natural ligand CXCL13 in ovarian cancer (161.14)
Authors: Singh Rajesh , Grizzle William , Singh Shailesh , Lillard, Jr. James 
Published: January 2023

Abstract
Chemokines and their corresponding receptors play an important role in metastasis and organ specific homing of cancer cells including ovarian cancer (OvCa). CXCL13 is a homeostatic chemokine that acts through its only known receptor, CXCR5. In this study, we provide the first evidence that in OvCa CXCR5 and CXCL13 are highly elevated in OvCa cell lines and clinical samples. Flow cytometry analysis of OvCa cell lines (OVCAR3 and SKOV3) show significantly higher expression of CXCR5 in comparison to normal adult ovarian epithelial cells. To determine the clinical significance of CXCR5 expressed by OvCa cell lines, ovarian cancer tissue microarrays were stained for CXCR5 and CXCL13. Aperio ScanScope scanning system was used to quantify the immunohistochemical staining of CXCR5 and CXCL13. Our results show significantly higher expression of CXCR5 and CXCL13 (p &lt; 0.001) in cancerous tissue than compared to non-neoplastic ovarian tissue. Among cancerous tissues, CXCR5 and CXCL13 expression was highest in serous adenocarcinoma followed by serous papillary cystadenoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, cystadenoma, mucinous boderline adenocarcinoma, clear cell carcinoma, granulosa cell tumor, dysgerminoma, transitional cell carcinoma, brenner tumor, yolk sac tumor, adenocarcinoma and fibroma. These data demonstrate biological and clinical significance of CXCR5 and CXCL13 as an OvCa biomarker.
Co-expression of IL-15 and IL-15Rα on pancreatic β islet cells induced insulin dependent diabetes mellitus in mice (161.2)
Authors: Chen Jing , Feigenbaum Lionel , Awasthi Parirokh , Butcher Donna , Anver Miriam , Bamford Richard , Thomas Craig , Waldmann Thomas 
Published: January 2023

Abstract
Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates T and natural killer (NK) cells. Increased serum levels of IL-15 are found in type 1 diabetes (T1D). Here we showed increased serum levels of soluble IL-15Rα in T1D. Moreover, co-expression of IL-15 and IL-15Rα on pancreatic beta islet cells induced insulin dependent diabetes mellitus in mice. Inhibiting IL-15 signaling by blocking IL-15 trans-presentation with TMβ1 (anti-CD122) or by Jak3 inhibitor Tasocitinib completely reversed diabetes in the mice. Islets purified from the double transgenic mice demonstrated increased expression of pro-inflammatory cytokines/chemokines and increased surface expression of MHC class I/II and ICAM-1. Depletion of CD4 cell at the diabetes onset reversed hyperglycemia while CD8 and NK cell depletion had no effect. Furthermore, CD4 cells purified from the double transgenic mice proliferated in response to wild type islets in vitro. Moreover, in non-obese diabetic (NOD) mice, inhibiting IL-15 signaling delayed diabetes development at pre-diabetic stage. Taken together, our data suggested that disordered IL-15 and IL-15Rα may be involved in the pathogenesis of type 1 diabetes and IL-15/IL15Rα pathway may be a rational therapeutic target for type 1 diabetes.
Development of IGF-1R signaling antibody arrays for the identification of hepatocellular carcinoma biomarkers (161.9)
Authors: Mao Ying-Qing , Zhou Qi , Jiang Wei-Dong , Chen Yun-Ru , Zhou Xiang-Bing , Wang Ya-Feng , Shi Zhi , Liu Yan-Li , Huang Ruo-Pan 
Published: January 2023

Abstract
A novel IGF-1R signaling antibody array was created through immobilizing the antibodies against ten IGF family proteins (IGF-1, IGF-1R, IGF-2, IGF-2R, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, and Insulin) on the surface of glass slide in array format. Tissue lysates prepared from patient’s liver cancer tissues and adjacent tissues were then applied to the arrays. The proteins captured by antibodies on the arrays were then incubated with a cocktail of biotinylated detection antibodies and visualized through fluorescence detection system. By comparison with standard protein amount, the exact protein concentrations in the samples can be determined. Using this novel antibody array technology, the expression levels of the ten IGF family proteins in 25 pairs of hepatocellular carcinoma (HCC) and adjacent tissues were quantitatively measured. The different expressions between cancer tissues and adjacent tissues were then statistically analyzed. Using this approach, we found that the levels of IGF-2R and IGFBP-2 in HCC tissues were higher than those in adjacent tissues.
IRF8-dependent regulation of MMP3 influences tumor progression (162.1)
Authors: Banik Debarati , Abrams Scott 
Published: January 2023

Abstract
Matrix metalloproteinases (MMP) are involved in tissue remodeling under physiologic or pathologic conditions, including neoplasia. Although the stromelysin member, MMP3, has been implicated in early stages of tumorigenesis, its role during later stages of tumor progression are poorly understood. Thus, we tested the hypothesis that tumor-derived MMP3 influences the neoplastic process beyond the level of tumor initiation. We employed two mouse tumor models, CMS4 sarcoma and 4T1 mammary carcinoma, in which endogenous MMP3 levels could be experimentally altered. Using loss-of-function approaches, we showed that MMP3 downregulation reduced CMS4 or 4T1 tumor growth rate in vivo, but not in vitro. Moreover, MMP3 downregulation attenuated CMS4 experimental lung metastasis. Conversely using gain-of-function approaches, we found that MMP3 overexpression enhanced CMS4 tumor growth. MMP3 levels also directly correlated with invasion capacity in vitro, consistent with MMP mode of action. Lastly, we examined potential mechanisms of MMP3 regulation in our CMS4 model. Interestingly, we identified interferon regulatory factor-8 (IRF8), previously portrayed as a leukemic suppressor, as a negative regulator of MMP3 expression. Altogether, our data show that tumor-derived MMP3 impacts the neoplastic process at stages beyond initiation and may do so via novel IRF8-dependent mechanisms. Thus, these data unveil new factors of tumor progression, which may have implications for cancer therapy.
Distinct transcriptome of regulatory T cells in prostate cancer (162.18)
Authors: Arredouani M. Simo , Kissick Haydn , Dunn Laura , Sanda Martin 
Published: January 2023

Abstract
The inhibitory role of regulatory T-cells (Tregs) in cancer is now well established. Furthermore, inhibition of Treg function has been shown both experimentally and clinically to improve the immune response towards a variety of cancers. Developing new and more effective strategies interfering with the function of Tregs in cancer requires a deep understanding of Treg suppressor machinery, and a thorough dissection of the molecular elements that orchestrate their differentiation from T cells. With this in mind, we sorted Tregs and non-Treg CD4 cells from the prostate-draining LN or spleens of prostate tumor-bearing male mice and their control age-matched controls. Gene expression profiling was performed and data were analyzed to identify differential gene expression and major dysregulations in biological pathways, functions and networks. These changes encompassed key pathways such as T cell differentiation, TREM1, IL-17 and IL-10 signaling, as well as many important biologic functions that include inflammation, cellular movement, immune cell trafficking and cell-to-cell interaction. In addition, the most affected network is centered on TGF-β. Interestingly, prostate cancer Tregs exhibit many markers that are distinctive of macrophage and B cell lineages. This work paves the way for a better understanding of Treg biology in the context of prostate cancer and offers new avenues for Treg manipulation toward improving the outcome of immunotherapy.
Evidence for a BCR-ABL-induced anergic state of iNTK cells in chronic myeloid leukemia patients at diagnosis (162.32)
Authors: Levescot Anais , Rossignol Alexis , Jacomet Florence , Robin Aurélie , Basbous Sara , Giraud Christine , Roy Lydia , Guilhot François , Turhan Ali , Barra Anne , Herbelin André , Gombert Jean-Marc 
Published: January 2023

Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disorder, caused by the presence of the Philadelphia chromosome and the consecutive chimerical BCR-ABL oncoprotein, with deregulated tyrosine kinase (TK) activity. Whether invariant NKT (iNKT) cells, which are documented for their anti-tumoral activity, are affected during the disease remains unknown. Here, we addressed this issue by showing that proliferation rate of blood iNKT cells in response to their cognate ligand α-galactosylceramide is altered in CML patients at diagnosis, as compared to healthy subjects. This anergic state of iNKT cells was associated with both intrinsic and APC-dependent alterations. Furthermore, expression of perforin and CD95-L as well as that of PLZF, a transcription factor that is requisite for maintenance of functions of iNKT cells, were also decreased in patients at diagnosis. Importantly, all these functional impairments were corrected in patients who achieved a complete cytogenetic remission with the TK inhibitor imatinib mesylate (IM) or IFN-γ therapy. Together, these data demonstrate that chronic phase CML is associated with an acquired but potentially reversible defect in iNKT cells. Given the critical role of iNKT cells in tumor surveillance, it is tempting to propose that iNKT cell dysfunctions associated with CML thus could be one way used by tumors to escape from the anti-CML immune response while IM and IFN-γ exert their anti-leukemic effects in part in targeting iNKT cells.