bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD25+3G11-CD4+ cells: A highly potent Treg subpopulation (137.16)
Authors: Zhang Guang-Xian , Zhao Zhao , Yu Shuo , Li Hongmei , Ciric Bogoljub , Yang Jingxian , Rostami Abdolmohamad 
Published: January 2023

Abstract
3G11, a sialylated carbohydrate epitope on the disialoganglioside molecule, is expressed predominantly on the surface of mouse CD4+ T cells. Our previous studies suggested that loss of the 3G11 molecule could be a new cell surface marker for regulatory CD4+ T cells. In the present study, we explore the relationship between 3G11- and CD25+ T cells, a well-defined regulatory T cell (Treg) population. We found that large proportion of CD25+CD4+ T cells lack expression of 3G11 and that 3G11-CD4+ T cells express higher levels of Foxp3 compared to the 3G11+CD4+ population. Upon stimulation, 3G11- cells produced a high level of IL-10, but low level of IL-2. Based on 3G11 and CD25 expression we sorted four CD4+ T cell subpopulations and tested their phenotypes. CD25+3G11- T cells expressed the highest levels of Foxp3 and IL-10 and efficiently inhibited mitogenic and antigen-specific immune responses in vitro and clinical EAE in vivo, while CD25-3G11+ T cells exhibited an effector phenotype. Further, upon i.v. antigen, a significant fraction of adoptively transferred 3G11+CD4+ T cells was concerted into 3G11-CD4+ population. Thus, lack of 3G11 expression 3G11-), combined with CD25 expression (CD25+3G11-), defines a cell surface phenotype of a novel, highly potent Treg subpopulation.
Cbl-b-/- T cells are resistant to Treg-expressed TGF-beta: a unifying mechanism for resistance to regulation and autoimmunity (137.18)
Authors: O'Conor Catherine , Housley William J , Clark Robert B 
Published: January 2023

Abstract
Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b deficient (Cbl-b-/-) mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both human lupus and multiple sclerosis. Although the mechanisms underlying the development of autoimmunity in Cbl-b-/- mice are unclear, we have previously reported that Cbl-b-/- CD4+CD25- T cells (Teff) are resistant to regulation mediated by both Tregs and TGF-β in vitro. To characterize the relevance of this resistance in vivo, we now demonstrate that Cbl-b-/- Teff are resistant to Tregs in two models of autoimmunity, colitis and GVHD. To further identify mechanisms underlying this resistance, we asked whether Cbl-b-/- Teff can respond to TGF-β and differentiate into Th17 T cells. In vitro, exogenous TGF-β and IL-6 results in the generation of Th17 cells from Cbl-b-/- Teff; however, unlike WT Teff, Cbl-b-/- Teff are defective in Th17 differentiation when Tregs are the only source of TGF-β. These results suggest that the inability of Cbl-b-/- Teff to respond to TGF-β expressed by Tregs may underlie their resistance to Treg-mediated suppression. Cbl-b-/- T cells may thus offer an important approach for characterizing the functional relationship of Tregs and TGF-β in both suppression and Th17 generation and for identifying related immunoregulatory abnormalities in human autoimmune disease (NIH: 1R56AI072533-01A1).
Hematopoietic TNFR1 signaling mediates protection in a mouse model of arthritis (137.26)
Authors: Scheinman Robert I , Raman Thiagarajan , Williams-Skipp Cheryll , Derry Molly , Helfer Christine 
Published: January 2023

Abstract
TNFα blockade is a common treatment for rheumatoid arthritis (RA). Our hypothesis was that some of the pathological effects of TNFα involved signaling through hematopoietic TNFR1. We tested this using bone marrow transplant. The TNFR1 knockout mouse was backcrossed into the DBA background for 6 generations. DBA mice were irradiated, rescued with bone marrow derived from either DBA mice or from TNFR1-/- mice, and input into the collagen arthritis model. Surprisingly, we found that TNFR1-/-/DBA chimeras developed more intense disease as compared to controls. Increased disease was not caused by an increased immune response to collagen, insufficient backcrossing, or increased TNFα secretion. During intracellular bacterial infections, curiously, TNFα switches function from inflammation to resolution. A central aspect of this switch in function involves inhibition of the secretion of the IL-12/IL-23 cytokine family. We tested this in our system and found that long term culture of DBA/1 macrophages with TNFα resulted in the inhibition of IL-12 p40 subunit secretion and that serum IL-12 p40 subunit levels were elevated in TNFR1-/-/DBA mice at late stages of disease. These data are consistent with the concept that this switch in TNFα function also occurs in chronic inflammatory disease states such as RA. We propose that the genetic strength of this switch may correlate with response to therapy.
Pregnancy-Induced Rheumatoid Arthritis Amelioration in SKG Mice (137.29)
Authors: Dragone Leonard , Shaw Laura A , Rumer Kristen K , Kramer Anita , Sakaguchi Shimon , Winn Virginia D 
Published: January 2023

Abstract
Background: During pregnancy 75% of women with Rheumatoid Arthritis (RA) have amelioration of their disease. The mechanism of pregnancy-induced amelioration of RA is poorly understood. A mouse model of RA has been characterized (SKG). SKG mice have a spontaneous mutation in ZAP-70 and a single dose of zymosan induces arthritis. To determine if the SKG model is valid for studying the effects of the immune system on RA amelioration, we looked at whether remitted arthritis in SKG mice.
Methods: Cohorts of SKG mice were treated with zymosan (Z, n=17), zymosan plus pregnancy (Z+P, n=6), pregnancy (P, n=2) or no treatment (CTL, n=2). A subset of mice was sacrificed on day E14.5 (Z=5, Z+P=3, P=2, CTL=2) to harvest lymphoid and joint tissues.
Results: Pregnancy remitted arthritis in 4 of the 6 Z+P mice with an overall decrease in arthritis progression (Z+P=0.48+0.4 vs Z=1.91+0.2, p=0.01). The Z+P group flared postpartum. Histological analysis showed decreased joint inflammation in the Z+P compared to the Z mice. Flow analysis showed an increased percentage of Th17 cells, known to drive arthritis in SKG mice, in the Z (2.07+0.4) and in the P group (2.72+0.4) vs CTL (0.99+0.005, p&lt;0.04). Interestingly, the Th17 cell increase was additive for the Z+P group (4.37+0.15) despite arthritis improvement.
Conclusions: Pregnancy-induced amelioration of RA can be achieved in SKG mice and is accompanied by an increase in Th17 cells.
MicroRNAs mediate autoimmune disease pathology (137.3)
Authors: Smith Kristen M. , Liu Chang-gong , Taccioli Cristian , Williams Jessica , Kithcart Aaron , Mavrikis Gina , Shawler Todd , Whitacre Caroline C. 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE), studied as a model for multiple sclerosis (MS), is mediated by autoreactive CD4+ T cells. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression posttranscriptionally. Aberrant expression of miRNAs has been implicated in various disease processes. Recent evidence indicates that miRNAs are central to immune function and play a role in T cell responsiveness to antigen stimulation. We hypothesized that certain miRNAs would be differentially expressed in mice with EAE, and that these miRNAs represent critical mediators of autoimmune disease pathology. We utilized microarray technology, followed by PCR verification, to evaluate miRNA expression level at varying times during the EAE disease course. RNA was obtained from the lymph nodes and spleen during the acute and effector phases of EAE, and compared to animals receiving adjuvant alone. We found that several miRNAs are up- or downregulated during EAE and expression is temporally distinct. These data indicate that miRNAs represent a critical component of EAE pathology, and may be useful therapeutic targets or biomarkers in MS and other autoimmune diseases. Supported by NIH grants T32 GM068412, NS 48316 and AI 064320.
Quantitative and functional gender-biased differences in regulatory and CD8+ suppressor T cells in SLE patients (137.35)
Authors: Singh Ram P , Christina Charles , Grossman Jannifer , Taylor Mihaela , Mccurdy Deborah , Furst Daniel , Dinesh Ravi , Ranganath Veena , Louie James , Gupta Smita Rani , Grewal Iqbal , McEarchern Julie , La cava Antonio , Bevra Hahn 
Published: January 2023

Abstract
The goal of the present study was to study the quantity and function of regulatory and suppressor T cells, and the effect of sex hormones on T reg functions in healthy individuals and in SLE patients of both genders. Immunophenotyping of PBMC from SLE patients (n =27) indicated significantly reduced numbers of CD4+CD25hi Foxp3+ T cells (p&lt;0.0002) and CD8+Foxp3+ suppressor T cells (p&lt;0.005) as compared to healthy matched controls (n =15) and autoimmune disease controls RA patients (n=25). Moreover, both CD4+CD25hi and CD8+CD25hi subsets of males had 3-4-fold higher Foxp3 mRNA compared to females. The in vitro proliferative potential of CD4+T regulatory cells and CD8+T suppressor cells were defective in CFSE staining experiments in SLE patients as compared to the healthy controls (p&lt;0.001). Foxp3 expression was higher in males than in female PBMC with and without stimulation of with recombinant TGFb (p&lt;0.06). In regard to the role of sex hormones, stimulation of PBMCs with b estradiol (30pg/ml) decreases Foxp3 expression in healthy female but not in age matched healthy male. At higher doses (60, 150pg/ml) estrogen has little effect in both the sexes. Estrogen decreases Foxp3 mRNA expression in both female and male SLE patients (p&lt;0.05). Estrogen decreases Foxp3 protein expression in CD4+CD25- T cells from SLE patients.
An Inhibitor of bestradiol (ERa) increased apoptosis in male SLE patients only. These data suggest that estrogen affect the T regulatory compartment in healthy females and and further decreases Foxp3 mRNA in SLE patients of both genders.
Immunophenotypic Characterization of Th17 Cells in Human Peripheral Blood (137.38)
Authors: Li Linda , Yang Xifeng , Chen Benjamin Pin-Wen , Struss Peter E. , Perna Avi , Wei Bing-Yuan , Jiang Nan , Kraft Brad , Lay Gene 
Published: January 2023

Abstract
IL-17-secreting T cells represent a distinct lineage of CD4+ T effector cells (Th17) that is essential in the pathogenesis of numerous inflammatory and autoimmune diseases. Although the functionality of Th17 cells has been extensively studied, the phenotypic characteristics are still not well understood. In this study, we investigated the surface marker expression patterns of the Th17 cells. Human peripheral blood mononuclear cells (from healthy donors) were stimulated with PMA/Ionomycin (in the presence of monensin). The cells were then harvested and multi-color immunofluorescent staining was performed with a combination of fluorochrome-conjugated monoclonal antibodies to CD4, IL-17, and a panel of cell surface markers and analyzed by flow cytometry. Our results show that about 0.2% to 0.6% of CD4+ cells in healthy individuals produce IL-17. The CD4+ IL-17+ cells express high levels of integrin αL, α4, α6, β1 and β2, but not αM, αX and α2. All of the Th17 cells have high expression of CD45RO, CD50, CD58, CD95, CD150, CD229 and negative expression of CD25 and CD45RA. In addition, the Th17 cells do not express CD38 and its counter receptor CD31. We then further analyzed chemokine receptors expression on Th17 cells, and found that the Th17 cells express CCR6 (which is the same as reported by others), CCR7 and CXCR4, but not CCR1, CCR4, CXCR3 and CXCR6. More interestingly, IL-17+ cells can be divided into two subpopulations by CD27 (CD27+ Th17 and CD27- Th17). The functional differences of these Th17 subsets remain to be elucidated.
Oxazolone-Induced Delayed Type Hypersensitivity (DTH) Reaction in Adult Yucatan pigs: Validation of the Model with Cyclosporine A (CsA) (137.39)
Authors: nuhaily Samer , Yei Soonpin , Lopez Carlos , Incardona Francesca , Esber Henry J , Damaj Bassam B 
Published: January 2023

Abstract
DTH reactions are an important arm of the immune system and their deregulation results in several auto-immune and inflammatory diseases. Although rodents are widely used for the validation of novel anti-inflammatory drugs, it represents a challenge since their immune system is much less diverse and complex then the human immune system. We describe here and validate the first DTH swine model induced by Oxazolone using CsA. The results show a dramatic decrease in the ear inflammation in CsA treated pigs. In particular, this drug reduced the redness, inhibited the accumulation of ear fluid and inflammatory cells, as well as the accumulation and/or the release of the inflammatory mediators, CRP, IL-2 and IL-8 in the inflamed ears. Additionally, dosing with CsA significantly inhibited the levels of CRP, IL-2 and IL-8 in the sera of sensitized pigs, and also inhibited the in vitro proliferation of T cells collected from their spleens or PBMCs, particularly when these cells were stimulated in vitro with PMA plus ionomycin. Furthermore, CsA also inhibited the in vitro IL-2 released from PBMCs or splenocytes with or without stimulation with PMA plus ionomycin. Although CsA tended to reduce the ear thickness developed in mice and rats, this reduction did not reach significance, suggesting that pigs represent a better and more suitable model for screening the anti-inflammatory activity of compounds.
Anti-CD3 antibody ameliorates experimental autoimmune uveitis (EAU) by increase in IL-10 and TGF-1-secreting regulatory T cells and down-regulation of both Th1 and Th17 T cells (137.41)
Authors: KE YAN , Jiang Guomin , Bian Yang , Wang Yali , Kaplan Henry J. , Shao Hui 
Published: January 2023

Abstract
One of the major goals for the immunotherapy of autoimmune diseases is the induction of regulatory T cells that mediate immunologic tolerance. In this study, we wanted to determine whether treatment of anti-CD3 mAb could suppress EAU by up-regulating regulatory T cells. EAU was induced in B10RIII by immunization with IRBP161-180 and anti-CD3 mAb was injected at various doses before immunization or at the disease onset. We have found that anti-CD3 Abs significantly suppressed the severity of the disease when administered both prior to disease induction and at disease onset. Ab treatment selectively suppressed the activation and expansion of pathogenic T cells, but enhanced division and functions of regulatory T cells in vivo, since the frequency of regulatory cells of both CD1d-restricted natural killer T (iNKT) cells and CD4+Foxp3+ T cells was increased in CD3mAb treated mice. The inhibition of pathogenic T effector cells might be mediated directly by anti-CD3 mAb and indirectly by regulatory T cells. By releasing TGF-¦ Â and IL-10, regulatory T cells inhibited differentiation of Th17 and Th1 cells by antagonizing ROR¦Ã T and T-bet function. Moreover, Disease suppression also occurred following adoptive transfer of T cells from anti-CD3-treated animals to naïve mice immunized with IRBP161-180. Our results demonstrate that anti-CD3 Ab is potent inhibitor for established autoimmune uveitis.
Autoantibody-mediated regulation on B cell responses by functional anti-CD22 autoantibodies in patients with systemic sclerosis (137.42)
Authors: Fujimoto Manabu , Odaka Maki , Hasegawa Minoru , Takehara Kazuhiko 
Published: January 2023

Abstract
Objectives. Studies have demonstrated that B cells play important roles in systemic sclerosis (SSc), especially through the gCD19/CD22 autoimmune loop h. In this study, we examined the presence and functional property of circulating autoantibodies reacting with CD22.
Methods. Serum samples from 10 tight skin (TSK/+) mice and 50 SSc patients were assessed for anti-CD22 autoantibodies by enzyme-linked immunosorbent assays using recombinant mouse or human CD22. The association between anti-CD22 antibodies and clinical features was also investigated in SSc patients. Furthermore, the influence of SSc serum including anti-CD22 autoantibodies for CD22 tyrosine phosphorylation was examined by western blotting using phospho-tyrosine specific antibodies reacting with four major tyrosine motifs of CD22 cytoplasmic domain.
Results. Anti-CD22 autoantibodies were positive in 80% of TSK/+ mice and in 22% of SSc patients. Patients positive for anti-CD22 antibodies showed significantly higher modified Rodnan skin thickness score compared with patients negative for anti-CD22 antibodies. Furthermore, anti-CD22 antibodies from patients' sera were capable of reducing phosphorylation of all four CD22 tyrosine motifs, while sera negative for anti-CD22 antibodies did not affect CD22 phosphorylation.
Conclusions. A subset of SSc patients possessed autoantibodies reacting with a major inhibitory B cell response regulator, CD22. Since these antibodies can interfere CD22-mediated suppression onto B cell activation in vitro, SSc B cells produce functional autoantibodies that can enhance their own activation. This unique regulation may contribute to the autoimmune aspect of SSc.
Frequency of acetylcholine receptor specific B cells correlates with experimental myasthenia gravis severity (137.5)
Authors: Allman Windy R. , Saini Shamsher S. , Christadoss Premkumar 
Published: January 2023

Abstract
Myasthenia gravis (MG) is a condition in which neuromuscular transmission is impaired by antibodies (Abs) specific for muscle acetylcholine receptor (AChR). Anti-AChR Abs can be detected in the serum of patients with MG, but serum anti-AChR Abs level do not correlate to disease severity. In this study, we developed a flow cytometric assay for the detection of peripheral blood AChR-specific B cells to characterize B cell phenotypes associated with experimental autoimmune myasthenia gravis (EAMG). Alexa-conjugated AChR was used as a probe for AChR-specific B cells. B cells were characterized as B220+MHCII+. Female mice had significantly more B cells than males. However, there were no differences in the frequencies of antigen-specific AChR+ B cells between male and female mice with EAMG. Mice with EAMG have significantly elevated frequencies of AChR+IgG2+ B cells but not AChR+IgM+ B cells compared to healthy controls. AChR+IgG2+ B cells have significant correlations to clinical grade of disease and loss of limb muscle strength. Now we can identify the frequency of AChR specific B cells in MG which could be used as a marker for disease severity. This research has been supported by AFM and MGFA.
Novel mouse NK progenitors in lymph node: developmental origin and functional contributions. (138.1)
Authors: Luther Claudia , Senger Laura , Takei Fumio 
Published: January 2023

Abstract
Natural killer (NK) cells are widely distributed in various tissues. Among them, lymph node (LN) NK cells have been shown to differ from spleen NK cells in their phenotype and function. About ~20% of LN NK cells have rearranged TCRγ genes, express CD127+ (IL-7Rα), and they are thought to derive from the thymus. However, LN NK cells from nude mice are normal in number and phenotype, suggesting that the majority of LN NK cells are thymus-independent. We have recently found a novel cell population in the LN of C57/BL6 mice that is lineage (LIN)-negative but expresses the pan NK cell marker CD49b (DX5). LIN-CD49b+ cells are also found in the bone marrow (BM), but they differ from the LN counterparts. BM LIN-CD49b+ cells are Sca-1locKithiCD127- and include common lymphoid progenitors and other immature hematopoietic progenitors whereas LN LIN-CD49b+ cells are Sca-1+cKit-CD127+. When cultured on OP9 stroma cells, LN LIN-CD49b+ cells acquire the NK cells markers NK1.1, CD122 and Ly49 as well as cytotoxic function and IFN-γ production. They also retain CD127 expression. The precursor frequency of NK progenitors among LIN- CD49b+ cells in LN and BM are 1/40 and 1/13, respectively. Thus, LN LIN- CD49b+ cells seem to represent a novel NK progenitor that migrates from the BM to the LN for final differentiation into unique subsets of mature NK cells.
This work is supported by a grant from the German Research Council (DFG) and the National Cancer Institute of Canada.
Identification of the branchpoint between B and T cell development through MiDReG (138.17)
Authors: Inlay Matthew A. , Bhattacharya Deepta , Sahoo Debashis , Seita Jun , Karsunky Holger , Serwold Tom , Plevritis Sylvia , Dill David , Weissman Irving L. 
Published: January 2023

Abstract
Early hematopoietic development proceeds in a stepwise manner through progenitor intermediates. One such intermediate, the common lymphoid progenitor (CLP), can give rise to all lymphoid but not myeloid lineages in vivo, but has been suggested to preferentially give rise to B cells. Thus it remains unclear whether CLPs represent a node where lymphoid fate decisions are made, an intermediate en route to B cell commitment, or a mixture of the two. To determine if the CLP population contains both B-committed and uncommitted lymphoid progenitors, we used a novel algorithm called MiDReG (Mining Developmentally Regulated Genes) on over 2000 publicly-available mouse expression arrays to predict surface proteins with differential expression during the transition from fully multipotent progenitors to committed B cells. One of these markers bisects CLPs into two distinct populations, which we call CLPa and CLPb. Upon adoptive transfer, CLPa have robust B, T, NK, and DC output, while CLPb produce almost exclusively B cells. Thus, this surface protein marks the earliest identified step at which B cell commitment is established in vivo, with CLPa residing at the branchpoint where the B cell lineage separates from the other lymphoid fates. These results highlight the utility of MiDReG to identify novel stages of hematopoietic development. M.I. is funded by a fellowship from CIRM.
Role of stem cell factor and bone marrow derived fibroblasts in airway remodeling. (140.1)
Authors: Dolgachev Vladislav , Ullenbruch Matthew R , Lukacs Nicholas W , Phan Sem H 
Published: January 2023

Abstract
Recent evidence suggests involvement of bone marrow derived fibroblasts in airway remodeling in asthma, but their role and the mechanism of recruitment remain unclear. Stem cell factor (SCF), a key factor in the propagation of hematopoietic stem cells, is important in airway remodeling. To test the hypothesis that SCF is involved in the recruitment and differentiation of these bone marrow derived progenitor cells, GFP bone marrow chimera mice were created. These mice were then sensitized and chronically challenged with cockroach antigen (CRA) to induce chronic airway disease. Fluorescence microscopy revealed the influx of significant numbers of GFP expressing fibroblasts in these airways, which was confirmed by flow cytometric analysis for cells co-expressing GFP and collagen I. These cells preferentially expressed c-kit, IL-31 receptor and telomerase reverse transcriptase when compared to lung-derived fibroblasts. Interestingly, SCF stimulated IL-31 receptor expression in bone marrow cells, while IL-31 strongly induced telomerase reverse transcriptase expression in fibroblasts. Treatment with neutralizing antibodies to SCF significantly reduced airway remodeling and suppressed recruitment of these bone marrow-derived cells to the lung. Thus SCF in conjunction with IL-31 may play a significant role in airway remodeling by promoting the recruitment of bone marrow-derived fibroblast precursors into the lung with the capacity to promote lung myofibroblast differentiation.