bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB inhibition leads to increased synthesis and secretion of MIF in human CD4+T cells (48.2)
Authors: Cho Mi La , Moon Young Mee , Heo Yu Jung , Woo Yun Ju , Ju Ji Hyeon , Park Kyung Su , Kim Sung Il , Park Sung Hwan , Kim Ho Youn , Min Jun Ki , Lee Sang Heon , Jung Young Ok , Yoon Bo Young 
Published: January 2023

Abstract
To examine the effects of NF-κB inhibition on the secretion of macrophage migration inhibitory factor (MIF) in CD4+ T cells. Isolated human CD4+ T cells were cultured with NF-κB inhibitors for 24 hrs. MIF levels were evaluated by intracellular FACs, ELISA, and real time PCR. The levels of intracellular O2-, H2O2, and glutathione were evaluated by intracellular FACs. The amounts of phosphorylated Akt and c-Jun were measured by Western blotting. Treatment of CD4+ T cells with NF-κB inhibitors resulted in a significant increase of MIF concentration in culture supernatants, MIF gene expression and O2- production and decrease of intracellular MIF, H2O2, and GSH. Treatment with LY294002, and SP600125 suppressed NF-κB inhibitors induced MIF mRNA expression and MIF secretion and inhibited parthenolide induced phosphorylation of Akt and c-Jun. Treatment with H2O2 also decreased the amounts of intracellular MIF protein and increased MIF level in the culture supernatant. NAC, an antioxidant precursor of GSH, inhibited parthenolide or H2O2 induced secretion of MIF. These results indicate inhibition of NF-κB leads to release of MIF through de novo synthesis of MIF and secretion of preformed MIF in CD4+ T cells through reactive oxygen species production. .
Decreased immunoregulatory activity of B cells derived from patients with Systemic Lupus Erythematosus (SLE) (48.30)
Authors: Tretter Theresa , Gao Nele , Venigalla Ram K.C. , Eckstein Volker , Lorenz Hanns-Martin 
Published: January 2023

Abstract
Recently B cells with immunoregulatory properties have been found in mice but evidence for a potential role in humans remains elusive. We have identified a population of highly activated human B cells with regulatory properties in vitro which could induce temporary anergy and apoptosis in Th cells. Now we intend to test the role of such "Breg" cells in human autoimmune SLE. Methods: CD19+B and CD4+Th cells were separated from PBMC of healthy (ND) or SLE donors by MACS-sorting. B cells were prestimulated with SAC for 3d and sorted into highly activated FSChiCD25+ (lgB25+) and small resting FSCloCD25- (smB25-) B cells by FACS. Upon 4d coculture with Th cells and αCD3+IL-2, T cell growth was determined by 3H-TdR incorporation. Results: less inhibition of T cell growth by lgB25+SLE-B (60% of proliferation of T cells alone) was observed compared to lgB25+ND-B (35% of proliferation of T cells alone), independent of T-cell origin: ND-T cell proliferation decreased below 50% of controls in 11 of 12 cases with lgB25+ND-B, in contrast to only 5 of 12 cases with lgB25+SLE-B. No significant difference in cell viability or expression of CD80, CD86, B7-H1, GITR or CD27 could be found between both B-cell populations. We conclude that lgB25+B from SLE patients are less effective in control of Th-cells in vitro. Future experiments deal with the mechanisms, potential correlations with treatment or disease stage, and relevance for pathogenesis of autoimmunity.
Prophylactic or therapeutic administration of anti-GM-CSF-M250 inhibits disease in multiple experimental autoimmune models of multiple sclerosis (48.4)
Authors: Hensley Kelly , MacMaster John , Brewer Avery , Kugler David , Kirchner Jacqueline 
Published: January 2023

Abstract
GM-CSF (granulocyte-macrophage colony stimulating factor) has been implicated in MS by virtue of its elevated expression in resident cells of the target tissue and invading pathogenic T cells, as well as the presence of cell types which require GM-CSF for differentiation and activation. Using a neutralizing antibody to GM-CSF (M250) we evaluated its role in three different EAE models of MS: C57Bl/6/MOG35-55, SJL/PLP139-151 and Adoptive Transfer-EAE (AT-EAE). A single dose of M250 on day of immunization in both the C57Bl/6/ MOG35-55 and SJL/PLP139-151 models prevented disease. Therapeutic administration of a single dose of M250 on day of disease onset reversed disease and reduced relapse in the SJL/PLP139-151 model. In the AT-EAE model, a single dose of M250 on day of cell transfer or disease onset significantly reduced mean clinical score. Histological evaluation of spinal cord tissue in the SJL/PLP139-151 model showed that therapeutic treatment with M250 resulted in a substantial reduction of the inflammatory infiltrate by 24 hours. These data indicate a role for GM-CSF in both the priming and effector phases of EAE, and suggest it may be an important target in MS.
New Roles for LTA4 Hydrolase, LTB4 and BLT1 in Multiple Sclerosis and Experimental Allergic Encephalomyelitis (48.9)
Authors: Parkinson John F , Guilford William J , Mendoza Lisa M , Rosser Mary , Post Joseph , Schaefer Caralee , Halks-Miller Meredith , Kirkland Tom , Cleve Arwed , Lassmann Hans , Reder Anthony T 
Published: January 2023

Abstract
5-lipoxygenase (5-LO), leukotriene A4 hydrolase (LTA4h), leukotriene B4 (LTB4) and its high affinity receptor BLT1 are known drivers of allergy, adaptive immunity and vascular inflammation, but have unknown roles in human multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We show that LTA4h and BLT1 are markers of inflammatory perivascular cuffs and actively demyelinating plaques in relapsing-remitting and progressive human MS, as well as spinal cord inflammatory foci in rodent EAE. Encephalitogenic murine CD3+ T cells experienced with proteolipid protein peptide antigen (PLP139-151) migrate to LTB4 and express functional BLT1. Peripheral blood immune cell LTB4 synthetic capacity is markedly primed prior to/during onset of rat and mouse EAE and mouse spleen 5-LO/LTA4h/BLT1 mRNAs are dynamically regulated during the immune response after T cell adoptive transfer. Potent, selective LTA4h inhibitors decrease clinical score and cumulative disease burden in rat antigen-induced and murine adoptive T cell transfer EAE. LTA4h inhibitors are also synergistic in suppressing rat EAE when combined with agents having an orthogonal mode of immunomodulatory action, such as the PDE-IV inhibitor mesopram. The results define new roles for the 5-LO / LTA4h / LTB4 / BLT1 pathway in autoimmunity and disease progression in EAE. Human MS may be a therapeutic target for inhibitors of LTB4 synthesis.
Diminished IL-2 responsiveness and FOXP3 expression in T1D subjects is revealed by a disease-associated variant of PTPN2 (49.1)
Authors: Long Sarah Alice , Bollyky Paul , Cerosaletti Karen , Shilling Heather , Pihoker Catherine , Sanda Srinath , Greenbaum Carla , Buckner Jane 
Published: January 2023

Abstract
Impairment in the IL-2/IL-2R pathway results in a loss of regulatory T cells (Treg) and the development of autoimmunity in animal models. Recent genome-wide association studies (GWAS) have identified several genes associated with Type 1 Diabetes (T1D) which may influence IL-2R signaling including the protein tyrosine phosphatase, PTPN2. We demonstrate that CD4+ T cells of healthy subjects that carry the T1D associated variant of PTPN2rs1893217 exhibit impaired signaling in response to IL-2. This is characterized by decreased phosphorylation of STAT5 and diminished FOXP3 expression in response to IL-2. In T1D subjects, a similar defect in IL-2R signaling is seen, however, in T1D subjects this phenotype is present irrespective of PTPN2 genotype. In comparison to controls, the CD4+ T cells of T1D subjects displayed decreased STAT5 phosphorylation upon exposure to IL-2 and IL-15, decreased FOXP3 expression upon activation in the presence of IL-2 and a loss of FOXP3 persistence in nTreg cultured in IL-2. Together these findings indicate that the PTPN2rs1893217 genotype reveals a phenotype common to T1D subjects. This impairment of IL-2 responsiveness may contribute to the development of T1D through diminished number and function of Treg in the inflamed islet.
Evidence for linkage of Type 1 Diabetes (T1D) resistance and upregulation of eotaxin (CCL11) in pancreatic beta cells to a chromosome 12 locus in the Biobreeding rat (49.2)
Authors: Chao Gary Y.C. , Wallis Robert H , Marandi Leili , Poussier Philippe 
Published: January 2023

Abstract
The Biobreeding (BB) rat spontaneously develops autoimmune Type 1 Diabetes (T1D). We tested the hypothesis that the recently reported upregulation of CCL11 in BB rat βcells prior to insulitis is genetically determined and linked to T1D. This time-dependent upregulation of CCL11 transcription was not observed in T1D resistant ACI rats. Therefore linkage analysis for T1D and pancreatic CCL11 was performed in a conditioned cross/intercross between BB and ACI rats where all animals (n=574) carried T1D susceptibility alleles at the two known BB rat T1D genes. Eight T1D loci (chr 1, 2, 3, 2 in 6, 12, 14 and 17) were mapped establishing the polygenic nature of T1D in the BB rat and at three of these (chr 1, 3 and 12) the BB allele confers T1D resistance. Strikingly, upregulation of pancreatic CCL11 transcription mapped to the T1D locus on chromosome 12 (LOD=3.65) and the peak of linkage (D12rat51) was the same for the two traits. At D12rat51, homozygosity for the BB allele confers high levels of pancreatic eotaxin expression and T1D resistance, raising the possibility that upregulation of the Th2 chemokine CCL11 in the target tissue of the anti-pancreatic autoimmune process is protective. Research supported by Genome Canada and Banting and Best Diabetes Centre.
Copy number variation (CNV) of human FCGRIIIB is concurrent with FCGRIIC and HSP70B: low copy number is a risk factor for and high copy number is a protective factor against systemic lupus erythematosus (SLE) (49.24)
Authors: Wu Yee Ling , Yang Yan , Zhou Bi , Chung Erwin K. , Birmingham Dan J. , Nagaraja Haikady N. , Hebert Lee A. , Rovin Brad H. , Yu Chack-Yung 
Published: January 2023

Abstract
Immunoglobulin Fcγ-receptors FcγRIIA, IIB and FcγRIIIA, IIIB are important effectors of immune response. Fanciulli and colleagues first reported low copy number (0 or 1 copy) of FCGRIIIB-related 5' sequences in 40-45% of SLE patients and ~25% of controls, but their assays did not faithfully reflect the actual CNV of FCGRIIIB. Thus, we investigated the genomic diversity of human FCGR region at chromosome 1q23.3. Through Southern blot analyses of PmeI-digested genomic DNA resolved by pulsed-field gel electrophoresis, we established the concurrent duplications of three contiguous genes FCGRII, heat shock protein HSP70B, and FCGRIII (FRH). We further defined gene specificities of the FRH complex by TaqI-genomic RFLPs in 281 SLE patients and 485 matched controls of European ancestry. One to four FRH modules are frequently detectable in haplotypes with different combinations of FCGRIIIA and FCGRIIIB, polymorphic variants of FCGRIIC, and HSP70B' and HSP70B. Homozygous and heterozygous deficiencies of FCGRIIIB had a combined frequency of 0.125 in SLE and 0.062 in controls. By contrast, high copy numbers of FCGRIIIB (3 or 4 copies) had a lower frequency in SLE (0.082) than in healthy controls (0.120) (p=0.0016). In conclusion, significant increase in low copy number and decrease in high copy number of FCGRIIIB were present in human SLE.
Increased breast cancer-associated metastasis in PyV MT mice induced to develop arthritis (49.3)
Authors: Das Roy Lopamudra , Pathangey Latha , Tinder Teresa , Schettini Jorge , Mukherjee Pinku 
Published: January 2023

Abstract
We determined if inflammation caused by collagen induced arthritis in the PyV MT mice that develop spontaneous mammary gland tumor increases secondary metastasis. The PyV MT mice were injected with 2mgs/ml Type II collagen to induce arthritis at two time points, at 9 and 18 weeks of age for pre-metastatic and metastatic conditions respectively. At both time points, data demonstrated a significantly higher primary tumor burden and a 2-fold increase in lung metastasis in the arthritic versus non-arthritic PyV MT mice. Increased COX2 and CD31 staining in the bones of arthritic PyV MT mice correlated with increase in epithelial metastatic cells in the bone marrow (BM) of these mice compared to non-arthritic PyV MT. We noted increased levels of myeloid suppressor cells in the BM and decreased levels of natural killer cells in the tumor microenvironment of the arthritic versus non-arthritic PyV MT mice. Subsequent increase in circulating levels of proinflammatory cytokines, in particular prostaglandin E2, IL-6, IL-17, vascular endothelial growth factor and tumor necrosis factor-α were found to be the underlying factors contributing to the increased metastasis. The data clearly shows that breast cancer associated metastasis is increased in arthritic conditions and the data have important clinical implications especially in the prevention of secondary metastasis. Supported by DOD BCO63396
Genetic dissection of the effect of Fcgr2b polymorphism on systemic lupus erythematosus (49.30)
Authors: Hirose Sachiko , Lin Qingshun , Ohtsuji Mareki , Tsurui Hiromichi , Nishimura Hiroyuki , Shirai Toshikazu 
Published: January 2023

Abstract
Telomeric chromosome 1 contains a cluster of potent polymorphic autoimmune-susceptibility genes including Fcgr2b. SLE-prone strains, including BXSB, share deletion polymorphism in Fcgr2b promoter region. Here we established congenic BXSB.IIBB6 that carry normal C57BL/6-type Fcgr2b. While BXSB females do not develop severe disease, BXSB males develop much severe disease because of Y chromosome-linked autoimmune acceleration (Yaa) mutation. Compared with BXSB females, (NZW x BXSB) F1 females develop severe SLE even in absence of Yaa because of the contribution of susceptibility alleles from the NZW strain. The present study addressed the question of whether wild-type Fcgr2b could prevent SLE in mice prone to develop SLE. As compared to BXSB males and (NZW x BXSB) F1 females, all SLE features were markedly suppressed in BXSB.IIBB6 males and (NZW x BXSB.IIBB6) F1 females, respectively. Importantly, activation and proliferation of not only B cells, but also T cells and monocytes/macrophages, were all inhibited in the latter two strains. Thus, the wild-type Fcgr2b appears to have a strong suppressive effect on the susceptibility of both Yaa-dependent and Yaa-independent murine lupus through the mechanisms that inhibit the activation of a wide variety of immune cells. Conversely, due to the loss of such inhibitory effects, autoimmune-type Fcgr2b probably plays a crucial role in SLE susceptibility.
Src-like adaptor protein (SLAP)-deficiency prevents chronic arthritis in SKG mice (49.7)
Authors: Dragone Leonard , Shaw Laura A , Sakaguchi Shimon , Peterson Lisa K 
Published: January 2023

Abstract
Background: Intrinsic defects in lymphocyte signaling have been implicated in the pathogenesis of rheumatoid arthritis (RA) by a mouse model of inflammatory arthritis (SKG). SKG mice have a spontaneous mutation in ZAP-70 that leads to impaired thymocyte development, reduced positive selection and impaired negative selection of thymocytes. These defects result in autoreactive peripheral T cells that cause RA. SLAP is known to influence TCR levels and signaling in developing thymocytes. We hypothesize that SLAP-deficiency can alter TCR avidity and influence the negative selection of SKG autoreactive T cells.
Methods: To test this hypothesis we generated SLAP-deficient SKG expressing mice (DSSKO).
Results: Thymocytes from DSSKO mice have increased TCR complex mediated signaling as evidenced by increased surface expression of CD5 and ERK phosphorylation. DSSKO mice have a 3-fold increase in thymic and peripheral FOXP3+ Tregs compared to SKG controls. Upon zymosan challenge, none of the DSSKO mice develop chronic arthritis. TH17 cells develop normally in DSSKO and SKG mice treated with zymosan suggesting that arthritis protection was not due to lack of their development.
Conclusions: These data support the hypothesis that SLAP deficiency alters thymocyte development possibly by both enhancing the negative selection of autoreactive T cells and converting them to Tregs to prevent the development of arthritis.
Abrogation of established inflammatory arthritis by the GABAA agonist Honokiol. (50.18)
Authors: Munroe Melissa E. , Bishop Gail A. 
Published: January 2023

Abstract
Rheumatoid arthritis is a chronic, systemic autoimmune disease characterized by debilitating stiffness and erosive joint destruction. Honokiol (HNK), a phenolic compound isolated and purified from magnolia, has been found to have anti-inflammatory properties without the toxicity found with current treatments. Whether given i.p. or orally, HNK abrogated established collagen induced arthritis in a dose dependent manner. Treatment with HNK in vivo resulted in decreased antigen-specific pro-inflammatory responses as well as altered T- and B-cell activation and antibody responses. The anti-inflammatory effects of HNK could be reversed using inhibitors of the neurotransmitter GABA(A), a previously reported target for HNK interaction. Preliminary evidence indicates that HNK influences transcriptional regulators of T- and B-cell activation. Thus, the anti-inflammatory properties of HNK show significant promise for blocking the autoimmune response, effectively and without toxicity. These findings also suggest that other agonists of neurotransmitter receptors should be investigated as anti-inflammatory agents. This research was supported by NIH grant 1 R21 AT003998-01.
Diet and DNA methylation in lupus (50.29)
Authors: Ray Donna , Richardson Bruce C 
Published: January 2023

Abstract
T cell DNA demethylation contributes to human lupus. The mechanisms causing demethylation are incompletely understood. DNA methylation depends on DNA methyltransferase activity and S-adenosylmethionine (SAM), and is inhibited by S-adenosylhomocysteine (SAH). SAM levels are determined by Zn, B2, B6, B12, folate, Met and choline, and SAH by homocysteine (Hcy). We hypothesized that decreasing nutrients required for SAM or increasing Hcy increases expression of methylation sensitive T cell genes, and that levels of these nutrients are abnormal in lupus patients. PHA stimulated T cells were cultured in custom media with variable concentrations of each nutrient, and effects on methylation sensitive gene expression (CD70, KIR and perforin) compared by flow cytometry. T cells cultured in media adjusted to median serum levels of each nutrient overexpressed all methylation sensitive genes relative to complete media. Increasing Hcy caused further increases in CD70 while increasing folate or B6 concentrations suppressed perforin overexpression. Lupus patients had lower B6 and Zn levels, and higher Hcy levels than controls. These results suggest that a poor diet may contribute to abnormal T cell gene expression in lupus, and that dietary supplementation may have a beneficial effect.
Probiotics control lupus progression via induction of regulatory cells and IL-10 production (50.30)
Authors: Alard Pascale , Parnell Sarah , Manirarora Jean , Kosiewicz Michele , Atay Safinur 
Published: January 2023

Abstract
Microorganisms can evade the immune response via induction of regulatory cells, and can prevent the development of various autoimmune diseases. Probiotics, including Lactobacilli, are beneficial bacteria that play an important role in the immune system development. The goal of this study was to test whether gavaging (NZBxNZW)F1 (BWF1) lupus-prone mice with Lactobacilli weekly could control lupus development and identify the mechanisms mediating protection. BWF1 mice fed with Lactobacilli starting before disease onset exhibited a delay in lupus onset indicated by decreased severity and increased survival. This protection was associated with an increase in the percentage of CD4+Foxp3+ regulatory cells and IL-10 production. Moreover, T cells from Lactobacilli-fed BWF1 mice transferred some protection when injected into young BWF1 mice. More importantly, mice that were fed after disease onset remained stable for several months and exhibited a delay in disease progression and an increase in survival. Regular feeding of Lactobacilli appears, therefore, to delay lupus progression via regulatory cell induction and possibly IL-10 production.
Altogether, these data indicate that the use of probiotics may be a viable strategy for controlling disease development and progression in patients with lupus, i.e., extending the length of remission and reducing flare frequency. Funded by the Lupus Research Institute.
Immunotherapy of experimental autoimmune encephalomyelitis by adoptive transfer of B cells stimulated with MOG (50.4)
Authors: Do Jeong-Su , Song Eun-Jung , Seo Hyo-Jung , Hwang Jin-Ki , Kim Jun-Hee , Shin Sung-Hye , Hwang Pyung Han , Yi Ho Keun , Nam Sang-Yun 
Published: January 2023

Abstract
The efficacy of adoptive transfer of activated B cells in an experimental autoimmune encephalomyelitis (EAE) model was investigated. B cells were prepared from C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG 323-339) in CFA. Primary (1o) or secondary (2 o) stimulation of purified B cells was performed with MOG, LPS, and anti-CD40. EAE was induced by immunization with MOG plus M. tuberculosis and pertussis toxin. Adoptive transfer of 2 o B cells on day-1(D-1) of MOG immunization significantly prevented EAE development in a dose-dependent manner, but not 1o B cells. Adoptive transfer on D13 of immunization also suppressed EAE progress. At day 50, controls and treated mice were reimmunized with MOG and the results showed that adoptive transfer of activated 2o B cells induced long-term resistance to disease. 2o B cell treatment enhanced MOG-specific IgG1 but suppressed IgG2a antibody secretion. Cytokine profiles of splenic CD4+ T cells obtained on D21 of immunization clearly indicated that adoptively transferred 2o B cells drive Ag-specific TH2 responses. The fail of transfer of EAE with T cells from treated mice, but not control mice, supported that T cells polarized toward TH2 are responsible for the efficacy of 2o B cells. Neither regulatory T cells nor TH17 were likely to be involved in 2o B-mediated suppression of EAE. In conclusion, adoptive transfer of 2o B cells may be a promising strategy for immunotherapy of TH1-dominant autoimmune disorders.
A novel flow cytometric based in vivo ADCC assay for screening lytic murine antibodies (50.42)
Authors: Evans Lawrence S , Butz Eric A 
Published: January 2023

Abstract
CD70 is a TNF superfamily member that is not normally expressed on resting cells, but is induced on lymphocytes and dendritic cells upon activation. Aberrant upregulation of CD70 is observed in several human autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and graft versus host disease (GVHD). Therefore, depletion of CD70+ cells could have a significant impact in these diseases and in animal models where CD70+ cells play a prominent role. Though in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays perform well with human cells they are difficult to do using mouse effectors and targets. We have developed an in vivo ADCC assay using carboxyfluorescein succinimidyl ester (CFSE) labeled target cells that allows us to measure in vivo target depletion in the presence of anti-CD70 antibodies. The antibodies tested displayed differential lytic capacities in vivo that were not evident from in vitro ADCC assays. The relative roles of NK cells, FcγIII/II Receptor (CD16/CD32), and complement on in vivo depletion have also been examined. We believe that this assay is a useful tool in examining the lytic activities of mouse Ab that have been difficult to determine using in vitro assays.