bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of NK-cell cytokine production via anti-CD48 (98.29)
Authors: Sinha Suwan Kumar , Gao Ning , Yuan Dorothy 
Published: January 2023

Abstract
In addition to the killing of transformed and virally infected cells NK cells also modulate immune responses via secreted cytokines or interaction with other lymphocytes. We have previously reported that B cells can induce IL-2 propagated NK cells to produce IL-13 in culture. The NK cell activation is dependent on B cells surface CD48 and requires CD244 (2B4) expression on NK cells, suggesting that CD48 on B cells can provide a positive signal for activation of NK cells via 2B4. Interestingly, we now show that a similar activation of NK cells can be achieved by interaction with immobilized anti-CD48 in the absence of B cells. CD48 is a glycoprotein found on most lymphocytes, including B and NK cells, but it has no intracellular region to transduce signals on its own. NK cells from 2B4-CD2 double knockout mice do not respond to immobilized anti-CD48 whereas absence of only CD2 does not affect IL-13 production. These results suggest that modulation of CD48 on NK cells can alter the nature of 2B4 signaling in NK cells. To gain some insight into the mechanism, we performed immuno-staining which revealed that immobilized anti-CD48 leads to clustering of CD48 on the surface of NK cells and 2B4 co-localizes with the former. Furthermore, the clustering by anti-CD48 was impaired in NK cells from 2B4-CD2 KO mice. These findings suggest a new relationship between CD48 and 2B4 in NK cells that may impact positive vs. negative signaling via 2B4.
CXCL13 blockade abrogates bone metastasis by impairing beta-3 integrin activation and matrix metalloproteinase expression by prostate cancer cells (98.4)
Authors: El-Haibi Christelle P , Singh Rajesh , Sharma Praveen K , Singh Shailesh , Lillard, Jr. James W 
Published: January 2023

Abstract
Prostate cancer (PCa) is the second leading cause of cancer morbidity and mortality among men in the United States. Mortality is not due to primary tumor growth but rather from complications caused by metastasis to vital organs. It is well known that PCa cells preferentially metastasize to bone; however, the molecular, cellular, and anatomic bases of this spread remain obscure. Chemokines and their receptors are thought to play key roles in this multifactorial process. We have recently shown that CXCR5 expression positively correlates with prostate tumor staging, and that PCa cell lines (LNCaP, C4-2B, and PC3) differentially express CXCR5 unlike their normal counterparts (PrEC and RWPE-1). By virtue of its presence in the bone microenvironment during disease and/or tumor burden, we hypothesized that CXCL13 (the ligand for CXCR5) is critical for bone metastasis and prostate tumor progression. We demonstrate CXCL13 is present in bone marrow of xenograft tumor-bearing mice following intracardiac injection of PC3 cells. Luciferase-expressing PC3 cells established skeletal metastases, but CXCL13 blockade significantly delayed prostate tumor formation and spread to bones, than compared to mice treated with control antibody. Immunohistochemical staining of tumors and viscera excised from experimental versus control groups revealed differential matrix metalloproteinase and integrin expression as well as tumor cell phenotype, which were presumably modulated by CXCL13-CXCR5 interactions. In conclusion, the CXCL13-CXCR5 axis partially supports PCa bone metastasis.
Brain-derived neurotrophic factor BDNF is involved in MP4-induced experimental autoimmune encephalomyelitis (99.11)
Authors: Kuerten Stefanie , Javeri Sita , Rodi Michael , Addicks Klaus , Tary-Lehmann Magdalena , Lehmann Paul V 
Published: January 2023

Abstract
In multiple sclerosis and its animal model EAE, the role of BDNF is still not understood. Results have been ambiguous with some studies pointing to a neuroprotective role while others implied neurodestructive components. The use of gene-modified mice could largely help shed more light on the mechanisms BDNF plays in the disease. Thus far, however, such studies have not been done. Our results show significantly attenuated disease in terms of onset and severity in BDNF-deficient B6.129S4-BdnftmJae/J compared to wild-type mice. Strikingly, while wild-type mice displayed a classical TH1 cytokine profile in response to MP4, levels of antigen-specific T cells secreting IFN-γ and IL-2 were undetectable in the BDNF-deficient mice. In addition, lesion frequencies in the CNS were lower in these mice. Demyelination was also less severe. Analysis of the cellular composition of infiltrates revealed significantly higher numbers of B cells and CD8+ T cells in the wild-type mice. Our results suggest an important role for BDNF in the pathogenesis of MP4-induced EAE, which points to a more disease sustaining than neuroprotective function. Our initial immunological and histological studies suggest the involvement of this factor not only in mediating peripheral T cell responses, but also CNS pathology itself. Further studies are needed to dissect the mechanisms underlying our preliminary data.
Role of Cdk4 in immunological tolerance and in pancreatic beta cell mass homeostasis in T1D (99.14)
Authors: mora conchi , Garcia Ainhoa , Marzo Nuria , Altirriba Jordi , Gomis Ramon , Martín Javier , Ortega Sagrario 
Published: January 2023

Abstract
Cdk4 plays a central role in perinatal pancreatic β cell replication and is also highly expressed in healthy, adult human pancreatic beta cells. We have previously reported that, when the hyperactive mutant form of Cdk4, Cdk4R24C replaces the wild type gene, it causes β cell hyperplasia without promoting hypoglycemia in a non-autoimmune-prone mouse strain. We found out that when the mutant Cdk4R24C knockin model is backcrossed onto the NOD genetic background, diabetes is exacerbated due to the expression of the mutated Cdk4R24C form in the NOD immune system too, as in the absence of NODCdk4R24C lymphocytes (NOD/SCID model), βcells become resistant to adoptively transferred autoimmune attack.
Since the knockin model does not allow discriminating between the role of Cdk4 in either β cells or in the immune system, we have designed a model where overexpression of Cdk4 is restricted specifically to NOD β cells. We have obtained transgenic lines in the NOD genetic background in which the Rat Insulin Promoter (RIP) drives the expression of either Wild Type (WT) Cdk4 (Cdk4wt) or its mutant, hyperactive form, (Cdk4R24C), leaving the lymphocytic compartment presumably intact.
This experimental approach will allow us to determine whether β cell hyperproliferation induced by Cdk4 overexpression specifically on pancreatic β cells, balances the autoimmune attack against β cells inherent to the NOD mice, and leads to an steady-state of long-lasting imunological tolerance.
Enhanced activation of Notch signaling in peripheral blood T helper cells of patients with rheumatoid arthritis (99.21)
Authors: jiao Zhijun , Wang Wenhong 
Published: January 2023

Abstract
Expression of Notch homologues in local inflammation issue of rheumatoid arthritis (RA) and cultured synoviocytes has been reported, but the expression profile of Notch-related molecules in peripheral lymphocyte in RA remains unclear. Here, the expression of Notch receptors in peripheral lymphocytes of RA patients was assessed by both flow cytometry and real-time polymerase chain reaction (PCR). The expression of Notch target gene HES-1, regulatory gene NUMB and Notch-ICD was determined by PCR and immunoblot. There was an increased expression of Notch 2, Notch 3 and Notch 4 in T helper cells from active RA patients among which increased Notch 3 was mainly expressed by activated T cells. Notably, Notch 3-expressing T cells decreased in inactive RA patients and the level was similar to that of healthy controls (HC). T helper cells from RA patients exhibited increased expression of target gene HES-1 but decreased expression of negative modulation gene NUMB of Notch signaling. There was also an increased nuclear translocation of Notch-ICD in active RA disease. The present study demonstrate that T helper cells from RA patients display significantly altered expression profile of Notch receptors and enhanced activation of Notch signaling compared with those from HC.
This study was supported by grants from the Natural Science Foundation of China (30872335) and Society Development Foundation of Zhenjiang (SH2008035).
Absence of sphingosine kinase 1 alters progression of TNF-alpha induced arthritis (99.25)
Authors: Baker DeAnna , Obeid Lina , Gilkeson Gary 
Published: January 2023

Abstract
Changes in sphingolipid levels can alter cellular functions. Sphingosine 1 phosphate (S1P) and hTNF stimulates COX-2 and PGE2 in fibroblast-like synoviocytes (FLS). In vitro, hTNF and S1P both produce more COX-2 and PGE2 than either separately. Blocking sphingosine kinase 1(SphK1) decreases COX-2 and PGE2 after hTNF stimulation. Our hypothesis is mice overexpressing hTNF without functional SphK1 (hTNF/SphK1-/-) will have less synovial inflammation than mice that overexpress hTNF with functional SphK1 (hTNF/SphK1+/+). Transgenic hTNF mice were crossed with SphK1-/- mice, genotyped and observed, while histological sections were collected to evaluate disease activity. FLS were isolated from the knee joints of WT and SphK1-/- mice, cultured, and stimulated with hTNF. hTNF/SphK1-/- mice had significantly lower arthritis scores, less inflammatory infiltrates and preserved joint spaces compared to hTNF/SphK1+/+ mice. hTNF-stimulated FLS from SphK1-/- mice produced less PGE2 than WT mice. Deletion of SphK1 significantly delays progression and severity of hTNF induced arthritis, synovial proliferation and inflammatory infiltrates. SphK1-/- FLS produced less PGE2 in response to hTNF. Therefore, inhibiting SphK1 is a potential novel therapeutic agent. The project described was supported by Grant Number R01GM062887 from the National Institute of General Medical Sciences and a grant from the ACR REF.
Anti-Inflammatory Properties of IL-35 Promote Induction of Regulatory CD4+T Cells To Suppress Collagen II-Induced Arthritis (CIA) (99.27)
Authors: Kochetkova Irina , Golden Sarah , Callis Gayle , Pascual David W. 
Published: January 2023

Abstract
IL-35, a novel heterodimeric cytokine (IL-12p35 subunit plus Epstein-Barr virus-induced gene 3 [EBI3]), had been reported to expand regulatory CD4+CD25+ T cells and ameliorate CIA in mice. IL-35 was expressed as a single chain polypeptide, and the recombinant cytokine was detected by Western blot using anti-EBI3 or anti-IL-12 mAbs. To assess its activity, BALB/c mice were adoptively transferred with DO11.10 CD4+ T cells, challenged s.c. with OVA in IFA, and treated every day for 5 days with IL-35, resulting in diminished IgG2a and IgG2b anti-OVA Abs, as well as suppressed DTH responses. To exploit IL-35's therapeutic potential, B6 mice were induced with CIA, and upon the onset of disease (day 21), mice received 2.0 μg/mouse every 2 days until day 39. All mice in the control group developed arthritis by day 28 post-induction, whereas none of IL-35-treated mice had any clinical symptoms. Restimulated sorted CD4+ T cells from LNs of protected mice showed decreased IFN-γ and IL-17 production. FACS analysis revealed enhancement of regulatory CD4+ CD25+ T cells, of which, half co-expressed CD39, an ectonucleoside triphosphate diphosphohydrolase. Cell-sorted CD39+ CD4+ T cells from IL-35-treated mice could suppress CII-specific proliferation by CD39- CD4+ T cells via enhanced IL-10 production. These findings suggest the stimulation by IL-35 for the induction of regulatory CD4+ T cells. Supported by NIH R01 AI78938.
Oral administration of the tolerogenic peptide pCons induces CD4+CD25+Foxp3+ regulatory T cells in mesenteric lymph nodes (99.28)
Authors: Skaggs Brian J , Connolly Jay , LaCava Antonio , Hahn Bevra H 
Published: January 2023

Abstract
Purpose: We wanted to examine whether pCons, a 15 amino acid peptide based on the VH regions of murine anti-DNA antibodies that delays nephritis and anti-DNA antibodies in NZB/NZW F1 (BWF1) mice when administered i.v. or subcutaneously, is also efficacious when given orally.
Methods: Ten-week old lupus-prone BWF1 mice were fed different concentrations of pCons (25μg/100μg/250μg) by gavage for 5 days every four weeks. Control animals were fed saline. Both the L- and D- amino acid forms of pCons were given. After twelve weeks, four mice in each group were killed to examine the regulatory T cell populations in the spleen and mesenteric lymph nodes (MLN) by flow cytometry. Progression of lupus is monitored by proteinuria and the presence of anti-DNA antibodies in peripheral blood.
Results: MLN Treg were increased 2-fold in the 250μg D-pCons group. No increase in CD4+ Treg and CD8+ Ts was observed in splenocytes, and no increase in Treg or Ts populations were observed in the lower doses of each peptide. Interestingly, anti-DNA antibody titers and proteinuria were lower in L-pConsed mice vs. D-pCons and saline fed mice.
Conclusions: Oral administration of D-pCons increases MLN Treg populations in preclinical BWF1 mice. However, oral L-pCons appears to delay SLE disease onset better than D-pCons. These studies could shed light on oral tolerance in SLE, as well as the development of a potential orally-based lupus therapy.
Migration of marginal zone precursor B cells into the T-cell zone promoted by interferon-alpha induces a T-dependent germinal center response (99.33)
Authors: Hsu Hui-Chen , Wang John , Wu Qi , Li Jun , Yang PingAr , Li Hao , Mountz John D 
Published: January 2023

Abstract
The immunopathogenic mechanisms by which IFNα triggers and promotes autoimmune B-cell responses have not been well characterized. In the spleens of autoimmune BXD2 mice, we found very high numbers of plasmacytoid dendritic cells (pDCs) in the marginal zone (MZ) that produce high levels IFNα. There is a larger population of MZ precursor (MZP) B cells, defined as being IgMhighCD21high and CD23high in BXD2 mice as compared to normal B6 mice. MZP B cells express high levels of ICOS ligand, CD80 and CD86, but low levels of ICOS. MZP B cells are extremely efficient antigen presenting cells (APCs) to induce Ag specific CD4 T cell activation more effectively compared to follicular (FO) and conventional CD23low MZ B cells in the spleens of BXD2 mice. IFNα induced higher levels of CD69 expression by MZP B cells and lead to greater suppression of the S1P induced chemotactic response by MZP B cells as compared to conventional MZ and FO B cells. Knockout of IFNαR in BXD2 mice abrogated the development of the spontaneous autoreactive GCs, and this is associated with significant reduction of IFNα-induced CD69 upregulation in MZP B cells and dramatic suppression of MZP migration into the T-cell zone following toll-like receptor 9 stimulation in vivo. Our results indicate that IFNα− producing pDCs that are localized primarily in the MZ of the spleen can promote a T dependent humoral response through their regulation of the migration of high APC function MZP B cells in the spleens of autoimmune BXD2 mice.
Impact of clinical and demographic features in influenza vaccination responses in human systemic lupus erythematosus (99.38)
Authors: Crowe Sherry R , Air Gillian M , Thompson Linda F , James Judith A 
Published: January 2023

Abstract
The goal of this study is to understand intrinsic and extrinsic defects in influenza vaccination responses in systemic lupus erythematosus (SLE) patients. SLE is a prototypic autoimmune disease characterized by high titers of autoantibodies. We enrolled 72 patients to evaluate anti-influenza antibody responses, autoantibody titers and disease activity after vaccination. In addition, detailed clinical and demographic information was collected. Individuals received the current influenza vaccine and sera were collected at baseline, 2, 6, and 12 weeks post vaccination. Based upon post-vaccination antibody responses, relative antibody affinities and hemaglutination inhibition levels, patients were grouped into "high" and "low" responders. Surprisingly, the high responder group was enriched in older subjects and African Americans. Patients with high anti-influenza antibodies had an increased frequency of discoid rash and anti-nRNP autoantibodies, while patients with low antibody responses had an increase in hematological criteria and anti-aPL autoantibodies. Interestingly, several patients had increased autoantibody titers following vaccination, but there were no significant associated increases in disease flare. In summary, specific demographic, clinical, and autoantibody features were associated with poor antibody responses to influenza vaccination in SLE patients. NIH: NO1-AI-50026
Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment (99.40)
Authors: Jeganathan Venkatesh , Kawabata Daisuke , Ramanujam Meera , Davidson Anne , Grimaldi Christine M , Diamond Betty 
Published: January 2023

Abstract
A major goal for the treatment of SLE patients with cytotoxic therapies is the induction of long term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects cyclophosphamide (CY) on the selection of the re-emerging B cell repertoire in transgenic mice that express the H chain of an anti-DNA antibody (R4A-Tg).
The reconstituting B cell repertoire contained an increased frequency of mature, high affinity DNA-reactive B cells as determined by single cell PCR analysis, and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in levels of BAFF, a B cell survival factor. Treatment with BAFF-R-Ig, a BAFF blocking agent or with DNase, to reduce exposure to autoantigen, limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, negative selection of high affinity DNA-reactive B cells is impaired by increased BAFF. B cells escaping negative selection are positively selected by autoantigen. BAFF blockade following treatment with B cell depleting agents may be useful for the successful long-term remission of SLE.
Increased Expression of BCMA on Systemic Lupus Erythematosus B Cells is Associated with Enhanced Response to CpG (99.43)
Authors: Kim Jinoh , Gross Jane A , Dillon Stacey R , Elkon Keith B 
Published: January 2023

Abstract
BLyS and APRIL are members of the TNF superfamily that regulate B cell survival and autoreactivity, and can exist as homotrimers or BLyS/APRIL heterotrimers (HT). To further understand BLyS and APRIL function in SLE, we examined the expression profiles of their receptors (BAFF-R, TACI and BCMA) and their functional effects on B cell subsets. Whereas BAFF-R expression on SLE B cells was significantly lower compared to its levels on healthy control B cells (MFI of control vs SLE, naïve=1387 vs 929, p=0.002; memory=1290 vs 840, p=0.003), BCMA expression was substantially higher on SLE B cells (MFI of control vs SLE: 18 vs 28, p=0.038). This was most pronounced in the memory B cell subset (MFI of control vs SLE=19 vs 29, p=0.008) but was also evident on certain subsets of CD27- B cells. BCMA+ cells were mostly IgD+ and tended to be larger than BCMA-negative cells, and had higher CD19 and CD86 expression, indicating a greater degree of activation. FACS sorted BCMA+ B cells proliferated and differentiated much more potently than BCMA- B cells following CpG stimulation. CpG mainly induced the proliferation of BCMA+ B cells and increased BCMA expression on total B cells. These findings may help to explain the observed expansion of DNA-reactive SLE B cells in the presence of BLyS, APRIL or HT.
An inducible antigen system to investigate CD8 T cell tolerance (99.46)
Authors: Jellison Evan R , Turner Michael J , Lefrançois Leo 
Published: January 2023

Abstract
The induction of peripheral tolerance is critical for deterrence of autoimmunity. Most self-reactive T cells are deleted during development in the thymus. However, this deletion process is not absolute and self-reactive T cells can escape to the periphery. These self-reactive cells must either be deleted or regulated in the periphery to prevent autoimmunity. To study these processes, we generated mice in which antigen expression (the ovalbumin-derived peptide SIINFEKL) can be tightly controlled in small intestinal epithelial cells or dendritic cells by administration of doxycycline. Our system provides the unique ability to examine endogenous T cell responses to tissue-specific and developmentally regulated self antigen. Importantly, the transgenic mice are ignorant of antigen prior to induction. This result indicated that AIRE-mediated tolerance was not operating in our system. Antigen induction in either the small intestine or dendritic cells caused tissue-specific activation of transferred TCR transgenic OT-I T cells. Antigen induction also resulted in activation and expansion of endogenous SIINFEKL-specific CD8 T cells. Following antigen induction, an impairment of the SIINFEKL-specific response to infection with vesicular stomatitis virus expressing ovalbumin was observed, suggesting an antigen-specific regulation of the immune response. Characterization of immune responses in these antigen-inducible mice will provide key insights into mechanisms controlling tolerance versus autoimmunity in the intestinal mucosa. Supported by NIH grant DK57932
Kainate receptor activation may serve as a novel mechanism of B cell activation in autoimmunity (99.47)
Authors: Sturgill Jamie Lynn , Conrad Daniel H 
Published: January 2023

Abstract
Glutamate, the major excitatory neurotransmitter in the CNS, has recently been implicated in a variety of diseases. For example, it has been shown that patients with HIV, certain cancers, epilepsy, and autoimmune illnesses such as SLE all have elevated levels of glutamate in the periphery. While glutamate receptor signaling has been examined in T cells, there are currently no published observations on the effects of glutaminergic stimuli on B cells. Therefore, we performed a novel study to examine the effects of glutamate on B cells and thus humoral immunity. Both human B cell lines as well as primary B cells were first examined for the presence of glutamate receptors via RT-PCR and Western Blot. We identified the presence of the kainate receptor (KAR), a specific subtype of ionotropic glutamate receptor thought to be exclusively resident in the CNS. We found that KAR activation increased ADAM10 mRNA which is in agreement with receptor activity in the CNS. We also observed a significant corresponding increase in CD23 released into the supernatant as ADAM10 has been identified as the protease responsible for CD23's ectodomain shedding. Remarkably, we also detect a significant increase in cellular proliferation and Ig synthesis. Thus, we report for the first time the unique presence of a neurotransmitter receptor and that activation of this receptor could serve as a novel mechanism for B cell activation in autoimmunity.