bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Fas in Autoimmune Diabetes (128.30)
Authors: Mora Conchi , Wen Li , Gomis Ramon , Green E. Allison , Chervonsky Alexander V. , Wong F. Susan , García Ainhoa , Flavell Ricahard A. 
Published: January 2023

Abstract
We have studied the role of Fas in the induction of autoimmune diabetes in NOD mice and found that although Fas is required for the development of diabetes, early overexpression of this molecule on pancreatic β cells delays diabetes onset and reduces diabetes incidence in NOD mice. Moreover, Fas overexpression on β cells is not sufficient to restore the diabetic phenotype in Fas-deficient NOD mice. On the other hand we show that induction of β cell death by CD4 T cells is dependent on the expression of Fas on β cells. IL-1β and IFNγ are key cytokines involved in Fas up-regulation on mouse β cells. However, here we demonstrate that IL-1β is not required for either spontaneous t or adoptively transferred diabetes. Interestingly we have also observed that FasL overexpression on β cells seems to confer immune-privilege to islet cells against diabetogenic CD4 T cells.
We hypothesize that early, immune-independent, Fas expression on β cells protects from diabetes by promoting immune tolerance to islet antigens, while late, cytokine-mediated induction of Fas has the opposite effect by promoting massive β cell death and diabetes. There is redundancy regarding the cytokines involved in Fas up-regulation on β cells in vivo.
A critical role of cyclon, a novel cytokine-inducible gene, in the regulation of immune homeostasis (128.31)
Authors: Fleur Shella Saint , Hoshino Akemi , Fujii Hodaka 
Published: January 2023

Abstract
Autoimmunity, which results from hyperreactivity and hypersensitivity of lymphocytes against self antigens, can be caused by various defects in lymphoid cells, including impaired activation induced cell death (AICD) in effector T and B cells. Elimination of activated self-reactive T and B cells may effectively cure autoimmune diseases. We recently identify a novel cytokine-inducible gene, cyclon, by DNA microarray analysis. Cyclon is induced in both CD4+ and CD8+ T cells by T cell receptor ligation. Our data show that transgenic expression of Cyclon has no significant effect on T cell development and functions in wild-type mice. However, transgenic expression of Cyclon normalizes the number of activated T cells and suppresses enlargement of peripheral lymphoid organs in some autoimmune mice such as mice lacking the α subunit or the common γ chain of Interleukin-2 receptor. in vitro assays also suggest that the transgenic expression of Cyclon decreases viability of activated T cells and enhances AICD. Collectively, these results indicate that Cyclon may play an important role in immunosuppression by enhancing AICD.
This work is supported by NIH grant R01 AI059315 to H. F.
A novel approach to generating disease modifying dendritic cells (DCs) (129.13)
Authors: Papenfuss Tracey L. , Kithcart Aaron P. , Powell Nicole D. , McClain Melanie A. , Gienapp Ingrid E. , Shawler Todd M. , Whitacre Caroline C. 
Published: January 2023

Abstract
Dendritic cells (DCs) bridge the innate and adaptive immune responses and DC immunotherapy has shown promise in the treatment of transplantation, allergic and autoimmune diseases. One primary limitation in studying and utilizing DCs is their small numbers in vivo. While the growth factor Flt3-ligand (FL) is used to expand DCs in vivo, GM-CSF is predominantly used to generate DCs in vitro from bone marrow (BM-DC). The purpose of this study was to explore the use of murine FL (mFL), the mouse homologue of human FL, to generate DCs in vitro. In vivo (tumor-based) mFL delivery reliably expanded splenic DCs comparable to hFL In vitro BM-DCs generated with mFL were more similar to hFL than GM-CSF derived BM-DCs and appeared to be immature. Specifically, CD11c, CD11b and maturation markers CD80 and CD86 were lower in mFL and hFL versus GM-CSF BM-DCs. Maturation of mFL BM-DCs with TNF-α±LPS increased CD80, CD86 and CD40 expression. Transfer of matured mFL BM-DCs to mice prior to immunization with myelin oligodendrocyte glycoprotein (MOG35-55) significantly increased cumulative disease (26.79±10.12) and peak disease scores (3.07±1.16) compared to immature mFL BM-DCs (20.21 ±7.64 and 1.86±0.7, respectively). These results suggest that exposure to mFL in vitro is a novel method to generate large numbers of immature BM-DCs which can modulate the course of autoimmune disease.
(Support: NIH AI-43376, K01 R022198 and NMSS RG3272).
Human DcR3 overexpression in mice results in a systemic lupus erythematosus-like syndrome (129.15)
Authors: Wu Jiangping , Han Bing , Moore Paul , Luo Hongyu 
Published: January 2023

Abstract
OBJECTIVE: DcR3, a TNFR family member, is a secreted protein, and can enhance cell survival by interfering with multiply apoptosis pathways. The objective of this study was to understand the role of DcR3 in pathogenesis of autoimmune diseases.
METHODS: We generated transgenic (Tg) mice with actin promoter-driven expression of human DcR3, and investigated the development of autoimmune diseases in these mice.
RESULTS: Beyond 5–6 months of age, DcR3 Tg mice developed a systemic lupus erythematosus (SLE)-like syndrome. They produced autoantibodies against various organs, and against dsDNA and Smith Ag. The kidneys of these Tg mice showed pathological changes indicative of glomerular nephritis and IgG and C3 deposition; kidney dysfunctions, such as proteuria, leukocyturia, and hemuresis, were obvious. Aged Tg mice also developed skin lesions and lymphocyte infiltration in the liver, and suffered from leukopenia, anemia and thrombocytopenia. The SLE-like symdrome penetrance in DcR3 Tg mice was gender-dependent, with about 60% in females versus 20% in males. Mechanistically, exogenous recombinant DcR3 or endogenous DcR3 produced by Tg T cells effectively protected CD4 cells from activation-induced apoptosis in vitro. Probably as a consequence, in the peripheral blood of Tg mice beyond 6 months of age, CD4 cells with a phenotype of previous activation were increased.
CONCLUSION: DcR3 overexpression could lead to a SLE-like syndrome in mice.
Expression of transgenic FLIP on thyroid epithelial cells in CBA/J mice inhibits induction and promotes resolution of granulomatous experimental autoimmune thyroiditis (G-EAT) (129.17)
Authors: fang yujiang , Braley-Mullen helen 
Published: January 2023

Abstract
G-EAT is induced by transfer of thyroglobulin-primed in vitro activated splenocytes. In EAT susceptible DBA/1 and CBA/J mice, inflammation either resolves or progresses to fibrosis by day 60 depending on the extent of damage at day 20. Depletion of CD8+ T cells inhibits G-EAT resolution. We previously showed that FLIP transgene (Tg) expressed on thyroid epithelial cells (TEC) of DBA/1 mice had no effect on induction, but promoted earlier resolution of G-EAT. However, when Tg+ CBA/J mice expressing FLIP on TEC were used as recipients of WT donor splenocytes, they developed less severe G-EAT than FLIP Tg− littermates (average severity score of 1.3 vs. 4.5 at day 20), although both strains had similar levels of FLIP transgene. Following transient depletion of CD8+ T cells, FLIP Tg+ and Tg− CBA/J recipients both developed severe G-EAT (severity score of 4.4) at day 20. Lesions in CD8-depleted Tg+ recipients were resolving by day 60, whereas lesions in Tg− littermates did not resolve and most were fibrotic. FLIP and FasL were mainly expressed by TEC in FLIP Tg+ recipients and by inflammatory cells in Tg− recipients. mRNA expression of IL-10 and IL-13 was higher, and IFN-γ and TNF-α were lower, in FLIP Tg+ compared to Tg− recipients. The results support the hypothesis that transgenic FLIP expressed on TEC in CBA/J mice promotes G-EAT resolution, but induction of G-EAT is inhibited unless CD8+ T cells are depleted (NIH Grant DK35527).
IFN-gamma inhibits inflammatory arthritis via suppression of mast cell activation. (129.23)
Authors: Miyake Sachiko , Kaieda Shinjiro , Oki Shinji , Yamamura Takashi 
Published: January 2023

Abstract
KBxN mice spontaneously develop arthritis similar to RA in humans, and transfer of serum from arthritic K/BxN mice into healthy animals provokes arthritis within days independently on T and B cells. K/BxN serum-induced arthritis is mediated by anti-glucose-6-phsophate-isomerase IgGs. Here we demonstrate that synthetic glycolipid ligand, a-galactocylceramide (alpha-GalCer) or its analogue with an elongated sphingosine chain strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cellular infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by these glycolipd ligands was abolished by neutralization of IFN-gamma and systemic administration of IFN-gamma prevented the development of inflammatory arthritis. Furthermore, we demonstrate that histamine release involved in the induction of arthritis was suppressed by administration of glycolipid ligands or IFN-gamma. In addition, degranulation of mast cells in synomium was significantly suppressed in glycolipid ligands-treated mice, suggesting that the suppression of mast cell activation contributes to the inhibition of arthritis.
Th17 Cells Alone are not Sufficient to Induce CNS Autoimmunity, but can Synergize with Th1 Cells to Induce EAE (129.24)
Authors: Shriver Leah , Mann Monica , Dittel Bonnie N 
Published: January 2023

Abstract
During a primary immune response, CD4 T cells can polarize into two subsets, Th1 or Th2 depending on the cytokine environment. These subsets have been differentially implicated in the pathogenesis of autoimmune (Th1) or allergic (Th2) disorders. Recently a new lineage of T helper cells has been described, Th17 cells, which produce the cytokine IL-17, and evidence has pointed to these cells as key mediators of autoimmune disorders such as the inflammatory demyelinating disease multiple sclerosis (MS). A novel in vitro skewing paradigm shows that the cytokines IL-6, IL-1, TGF-β, and IL-23 are responsible for the development of this lineage. However, to date, no study has examined whether these cells are solely responsible for induction of CNS autoimmunity. We examined this question using an adoptive transfer model of MS in B10.PL mice termed experimental autoimmune encephalomyelitis (EAE). We found that 1 x 106 MBP-specific Th1 cells induced a monophasic disease course, while the same number of Th17 cells did not induce EAE. These data suggest that Th17 cells alone are not sufficient to initiate EAE disease. The adoptive transfer of 0.125 x 106 Th1 T cells did not result in EAE, but when mixed with 1 x 106 Th17 cells the mice exhibited full blown EAE. In a coculture model of immune cell-neuron interaction that mimics neuronal dysfunction during EAE, we found that Th1 cells induced neuronal dysfunction, while Th17 cells did not. These cumulative data suggest that the two T cell subtypes play differential roles that are synergistic during CNS inflammation and that therapeutic targeting of Th17 cells alone may not prevent pathology in diseases such as MS.
Signal via IL-12Rβ2 plays an essential role in the development of CD4+CD25+ regulatory T cells (129.27)
Authors: Zhao Zhao , Zhang Guang-Xian , Yu Shuo , Ciric Bogoljub , Fitzgerald Denise , Rostami A.M. 
Published: January 2023

Abstract
It has been recently found that mice lacking IL-12 specific receptor subunit, namely IL-12Rβ2, developed more severe clinical and pathological signs of in experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. However, whether this phenomenon is also true in other autoimmune disorders and the mechanism underlying this phenomenon is not known. We in the present study have shown that IL-12Rβ2-deficient mice also develop earlier and more severe disease in the streptozotocin-induced model of diabetes, indicating a universal susceptibility to autoimmune diseases in IL-12Rβ2-deficient mice. IL-12Rβ2-deficient mice exhibited significantly higher effector T cell proliferative responses not only to autoantigens, but also to non-specific stimuli. Compared to wild type mice, IL-12Rβ2-deficient mice exhibited significantly reduced capacity to develop regulatory T cells (Treg) in vivo in the thymus and in vitro upon stimulation with TGF-β. Further, naturally-occurring Treg cells from these mice were less functional in suppressing effector T cells. These findings indicated that signal via IL-12Rβ2 plays an essential in developing high quantity and quality of Treg cells, which confers a novel mechanism underlying the regulation of autoimmune diseases by the IL-12 pathway.
Monoclonal B Cell Expansion and Antigen-driven Somatic Hypermutation of Ig VH Genes in Synovial Membrane of Patients with Crystal-Induced Arthritis (129.3)
Authors: Kolln Johanna , Da Reng-Rong , Qin Yufen , Baeten Dominique , Zhang Yiping 
Published: January 2023

Abstract
The mechanisms underlie the inflammation in crystal-induced arthropathies (CyA) is not fully understood. Inflammatory mediators, like crystal-specific antibodies and macrophages have been explored as possible factors in the generation or progression of CyA. To examine whether B cells are involved in the pathogenesis of CyA, we analyzed immunoglobulin (Ig) heavy chain variable region (VH) genes of B cells from synovial membrane of five CyA patients. Using a RT-PCR technique, we could detect rearrangements of Ig VH genes in all five cases. Sequence analysis of CDR3 region of rearranged VDJ genes revealed a monoclonal B cell expansion in four out of five CyA patients. The nucleotide sequences of VH genes from clonally expanded B cells demonstrated the heterogeneous usage of the Ig VH gene family. All expanded B cell clones showed somatic mutations in the CDRs with a high replacement-to-silent ratio (&gt; 2.9) and were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. The intraclonal variations is also common, indicate that consistent antigen stimulation is close related to CyA development. These data demonstrate that there are antigen-driven clonal accumulations of B cells in CyA synovial membrane. Whether these antibodies are specific to crystal epitopes is currently under investigation.
This study was supported by the NIH Grant RO1 AI 54911.
IL-4 promotes experimental drug-induced hepatitis by reducing immune responses to haptenated proteins and inhibiting regulatory responses to native CYP2E1 (129.38)
Authors: Njoku Dolores B. , Li Zhaoxia , Talor Monica V , Rose Noel R. 
Published: January 2023

Abstract
Susceptible persons develop drug-induced hepatitis (DIH) following administration of halogenated anesthetics or similar drugs. IL-4 worsens autoimmune hepatitis by promoting Th2 responses while other possible mechanisms for this observation have not been fully investigated. Using our experimental model of anesthetic DIH created by immunizing mice with hepatic proteins covalently linked to the TFA hapten (TFA-S100) formed from CYP2E1 metabolism of anesthetics, we found that IL-4 deficient (KO) mice developed significantly less hepatitis than BALB/c (WT) mice. Moreover, ex vivo, antigen specific T cells to CYP2E1 and TFA from IL-4 KO mice proliferated significantly less than those from WT mice. To uncover additional IL-4-dependent mechanisms for the development of anesthetic DIH we measured supernatant cytokines from splenocytes stimulated in vitro with TFA or CYP2E1 and obtained from WT and KO mice following TFA-S100 immunization. KO mice had less IL-1β (p &lt; 0.01), IL-2, IFN-γ, TNF-α, (p &lt; 0.05), IL-13 (p &lt; 0.05) and IL-6 (p &lt; 0.05) in response to TFA when compared to WT mice, suggesting that IL-4 had a critical role in the development of immune responses to TFA-haptenated proteins. Ex vivo, antigen specific T cells to CYP2E1 had higher levels of IL-10 (p &lt; 0.01) suggesting that IL-4 promotes anesthetic DIH by diminishing regulatory responses to CYP2E1.
Supported by R21DK075828.
Characterization of immune response in â-tubulin induced murine experimental autoimmune hearing loss (129.44)
Authors: Zhou Bin , Glickstein Jonathan , Zhou Yixuan , Kermany Mohammad Habiby , Cai Chun , Cai Qing , Kim Jun Woo , Kim Patrick , Liu Wenxia , Yoo Tai June 
Published: January 2023

Abstract
The pathological mechanism(s) of autoimmune sensorineural hearing loss (ASNHL) is still unknown. An autoimmune reaction to inner ear structures could be one of several possible pathogenic factors involved in ASNHL. In the current study we show that the inner ear–specific proteins b-tubulin are capable of targeting experimental autoimmune hearing loss (EAHL) in mice. Two weeks after immunization of BALB/c mice with b-tubulin, auditory brainstem responses (ABR) showed significant hearing loss, and the hearing loss can lasted at least six weeks. The antibodies activity to â-tubulin increased in dose dependent compared with controls. In addition, sera of these mice contained high levels of anti-â-tubulin antibodies could transferred EAHL to naive mice. Flow cytometry analysis showed that b-tubulin activated CD4+ T cells with a proinflammatory Th1-like phenotype. T cell mediation of EAHL was determined by showing significantly increased ABR thresholds 6 weeks after adoptive transfer of b-tubulin-activated CD4+ T cells into naive BALB/c recipients. Immunocytochemical analysis showed that leukocytic infiltration of inner ear tissues, and histological analysis showed that the loss of inner and outer hair cells in â-tubulin-immunized mice. Moreover, the percentage of CD4+CD25+ regulatory T cells and the level of FoxP3 were significantly decreased in EAHL. Our study provides an experimental confirmation that ASNHL may be a humoral and cellular immune reactivity against b-tubulin, which may be sufficient for mediating the hearing loss observed in ASNHL.
Increased Amyloid β Protein Levels in Children with Down Syndrome (129.47)
Authors: Mehta Pankaj D , Mehta Sangita P , Capone George 
Published: January 2023

Abstract
Objective: To quantitate plasma amyloid β protein (Aβ)40, Aβ42, and neopterin levels in Down Syndrome (DS) children and controls.
Background: DS persons (&gt;40 years) have neuropathological changes characteristic of Alzheimer disease (AD). Soluble forms of Aβ generated from amyloid precursor protein (APP) end at C-terminal residues 40 and 42. Neopterin is an immune activation marker for the cell-mediated immune response.
Design/Methods: Blood was collected from DS (N = 35; 7 ± 3.8 years old) and their siblings (N = 34; 10 ± 4.5). Plasma Aβ40, Aβ42, and neopterin levels were quantitated by ELISA.
Results: Aβ40 (Mean ± SD; 277 ± 70 pg/ml) and Aβ42 (31 ± 8 pg/ml) levels were higher in DS children than controls (Aβ40 155 ± 35 pg/ml, Aβ42 22 ± 5 pg/ml) (p&lt;.0001). There were significant negative correlations between age and Aβ40 in DS (r=.47, p&lt;.004) or controls (r=.38, p&lt;.026) and Aβ42 levels in DS (r=.61, p&lt;.001) but not in controls. Neopterin levels were higher in DS (3.01 ± 1.37 ng/ml) than controls (1.57 ± 0.65 ng/ml) (p&lt;.0001). There was no correlation between neopterin levels and age, and Aβ40 or Aβ42 levels in DS or controls.
Conclusion: The overexpression of APP gene in DS leads to increases in plasma Aβ40 and Aβ42 levels before plaque formation in DS brain. A lack of correlation between neopterin and Aβ levels suggests that higher neopterin concentrations in DS reflect inflammatory cell activation rather than AD neuropathology.
Cloning and characterization of nucleolar-specific autoantibodies from a murine model of lupus/scleroderma (129.6)
Authors: Kole Hemanta K , Bolland Silvia 
Published: January 2023

Abstract
FcγRIIB knock-out mice in B6 background develop a lupus like autoimmune disease. With the addition of the yaa (Y-chromosome autoimmune accelerator) gene, pathogenecity in these male mice is significantly enhanced and autoantibodies switch from nuclear to nucleolar specificity. To characterize the autoantibodies produced by RIIB−/−yaa mice and the nucleolar antigens that react with these antibodies, we have produced hybridomas by fusing RIIB−/−yaa mouse splenocytes with myeloma cells. Hybridoma H526 produced anti-nucleolar and hybridoma H333 produced anti-nuclear antibodies. H526 antibody binds RNA in an anti-RNA ELISA. Antibodies from H333 are IgG2a-κ whereas H526 are IgG2a-λ. For sequence analysis, variable regions of heavy chain (VH) and light chain (VL) of H526 and H333 antibodies were amplified by PCR from respective cDNAs, cloned, and sequenced. The VH and VL region sequences of both the antibodies showed high homology with anti-nuclear antibodies, chromosome 12 of C57BL/6 mouse genome, and the J558 immunoglobulin variable regions. There were only a few amino acid changes in the variable regions. The functional roles of the amino acid changes and the pathogenecity of the antibodies are under investigation. H526 nucleolar antibodies pull down five proteins from a nuclear extract as detected by Coomassie blue staining. Characterization of these nucleolar antigenic proteins is in progress.
Aged B6.SB-Yaa/J Mice develop an SLE-like Disease (130.11)
Authors: Bubier Jason A , Brown Aaron C. , Foreman Oded , Sproule Thomas J. , Roopenian Derry C. 
Published: January 2023

Abstract
Mouse models of SLE are considered pivotal in understanding the genetics of SLE along with identifying targets for therapy. Male mice of the BXSB/MpJ recombinant inbred strain, first described by Murphy and Roths in 1978, develop a spontaneous and severe SLE-like syndrome resulting in death averaging ~6 months of age, while females show only a very chronic syndrome. A mutant locus found on the Y chromosome is, therefore, appropriately named the Y-linked autoimmune accelerator (Yaa). Previous analysis have suggested that Yaa fails to induce an SLE-like disease in B6 mice, the caveat to this being that the SLE criteria analyzed were limited to serological analysis, histopathology, and mortality on mice up to 8–12 months of age. We report here that when mice of a significantly older age, 15–24 months, are compared to age-matched B6 controls, the B6.SB-Yaa/J mice clearly developed an SLE-like disease. This is characterized by significant splenomegaly, monocytosis, immune cells with an activation phenotype, the presence of homogeneous anti-nuclear antibody staining, glomerulonephritis, decreased weight and survival as well as a gene expression signature similar to BXSB/MpJ mice. These results suggest that Yaa alone is sufficient to induce an SLE-like syndrome in aged B6 mice.
Funded by NIH R21DK074463 and DK56597 to DCR, Arthritis Foundation to JAB.
CNS lupus in MRL/Faslpr mice (130.15)
Authors: Choi Jinyoung , Chahboune Halima , Hyder Fahmeed , Craft Joe 
Published: January 2023

Abstract
Neuropsychiatric involvement is common in patients with SLE; however, its etiology is incompletely understood. Fas-deficient MRL/Faslpr (MRL/Faslpr) mice develop a spontaneous autoimmune disease that is similar to human SLE, including cognitive and neurological deficits. We hypothesized that autoantibodies in MRL/Faslpr mice may promote central nervous system (CNS) injury. Antibody (Ig) deposition in the CNS and structural abnormalities were assessed by immunofluorescent microscopy and diffusion tensor imaging (DTI) using a 11.7T system. At 20 weeks of age, MRL/Faslpr mice exhibited dense deposits of IgG in the choroid plexus, whereas several other control mice, including Fas-intact MRL mice, Fas-deficient C57BL6/Faslpr mice, and membrane only IgM-transgenic MRL/Faslpr mice (B cell-intact, but incapable of Ig secretion) did not reveal IgG staining, suggesting spontaneous Ig entry into the CNS in this lupus-prone mouse. DTI analysis demonstrated that MRL/Faslpr mice exhibited significantly increase in dorsal-ventral directional anisotropy in the hippocampus, compared to other control mice, suggesting these mice may have a structural abnormality in the hippocampus. Future work will focus on the role of Toll-like receptors in the Ig deposition and subsequent DTI alteration at distal regions of hippocampus in the MRL/Faslpr mice.
Funding sources: Arthritis Investigator Award and Arthritis Innovative Grant, Arthritis Foundation