bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recruitment of proteasome catalytic subunit dictates NFkB-mediated transcriptional termination (136.3)
Authors: Cullen Sarah J , Ponnappan Subramaniam , Ponnappan Usha 
Published: January 2023

Abstract
The ubiquitin proteasome pathway plays a vital role in the regulation of transcription. While a biphasic involvement of the proteasome has been demonstrated in the regulation of immune response gene inducer, Nuclear factor Kappa B (NFκB), the precise molecular link between the proteasome and the persistence of NFκB mediated transcription remains to be fully defined.
Using pervanadate, a stimulus that induces nuclear NFκB in the absence of proteasomal proteolysis of IκB-α, akin to reactive oxygen species, ChIP analyses and qPCR, we now present evidence that pervanadate in combination with proteasomal inhibition induces exaggerated expression of NFκB-mediated proinflammatory genes. We also report that both the 19S and 20S components of the proteasome complex appear to play distinct but non-redundant roles in the regulation of NFκB mediated transcription.
Our results provide insight into the role of proteasomal complexes in NFκB transcriptional regulation and uncover a novel role for the proteasome in chronic inflammatory responses and increased inflammation accompanying aging,
This research was supported by grants AG013081 and AG025220 from the NIH.
BCR-induced cell death of B cells from CD22 deficient mice is mediated by a novel ssRNA-directed endonuclease (136.33)
Authors: Poe Jonathan C , Kountikov Evgueni I , Tedder Thomas F 
Published: January 2023

Abstract
B cells from CD22 deficient mice backcrossed onto a C57BL/6 genetic background (B6 CD22-/-) undergo B cell antigen receptor (BCR)-induced apoptosis. By contrast, B cells from parental inbred CD22-/- mice on a mixed B6x129 genetic background (B6/129 CD22-/-) survive and proliferate normally following BCR ligation. Through an extensive reverse genetic screen, a single locus was identified as being responsible for the proliferation defect of B6 CD22-/- B cells. In B6 CD22-/- mice this locus was homozygous for B6 germline DNA (locusB6), and in B6/129 CD22-/- mice this region was homozygous for 129 germline DNA (locus129). In locusB6 CD22-/- B cells, a novel single-stranded RNA (ssRNA)-directed endonuclease was specifically overexpressed compared to locus129 CD22-/- B cells, suggesting a direct role in BCR-induced cell death. Targeted disruption of the endonuclease gene in locusB6 CD22-/- mice restored BCR-mediated B cell survival and proliferation to normal levels. These results identify a novel ssRNA-directed endonuclease as a potent inhibitor of B cell survival when expressed following antigen receptor stimulation. This research was supported by NIH grant R01CA096547.
Mina53, an IL4 repressor controlling TH2-bias (136.42)
Authors: Van Stry Melanie , Okamoto Mariko , Koyanagi Madoka , Chung Linda , Suzuki Yoshie , Ohara Osamu , Kitamura Hiroshi , Hijikata Atsushi , Tamari Mayumi , Kubo Masato , Bix Mark 
Published: January 2023

Abstract
The naïve CD4 T helper (TH) cell can differentiate into several effector TH subsets, depending on the host-pathogen environment. TH1 cells, which express high levels of the cytokine IFNγ, are essential for clearance of intracellular pathogens, while TH2 cells, which express high levels of IL-4, are required for responses to extracellular pathogens. TH2-bias, which occurs when a naïve T cell preferentially differentiates to a TH2 cell, is a genetic trait impacting infectious, autoimmune, and allergic disease susceptibility. Previous studies in our laboratory have identified a quantitative trait locus that regulates TH2 bias in mice (Dice1.2). Here, we have identified Mina53, a JmjC family member, as the genetic determinant of Dice1.2. Mina53 specifically represses transcription from the Il4 promoter in transient reporter assays, while over-expression of Mina53 converts TH2 bias from high to low. Moreover, Mina53 binds to the proximal Il4 promoter, and this binding requires an interaction between Mina53 and nuclear factor of activated T cells (NFAT), a key regulator of cytokine expression. Taken together, these data provide mechanistic insight into the Il4 regulatory pathway controlling effector T cell differentiation and account, in part, for genetic variation in TH2 bias.
The Expression of Inflammatory Mediators and its Association with the Susceptibility to Mucosal Leishmaniasis in Peru (136.6)
Authors: Vargas-Inchaustegui Diego A. , Espinosa Diego , Carlsen Eric D. , Tulliano Gianfranco , Pacheco Rosa , Llanos-Cuentas Alejandro , Arevalo Jorge , Soong Lynn 
Published: January 2023

Abstract
Leishmania braziliensis can cause cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in humans, and the latter is characterized by excessive T- and B-cell responses. We hypothesized that conversion from CL to ML is partially due to an imbalanced production of proinflammatory and regulatory cytokines, leading to uncontrolled host responses to the parasites. To test this hypothesis, we first examined the -2518 SNP of the MCP-1 promoter because its G/G genotype is associated with autoimmune disorders and infectious diseases. We genotyped 142 Peruvian subjects (18 controls, 65 CL and 59 ML patients) using PCR-RFLP on genomic DNA. Our pilot studies suggested that ML patients showed a relatively frequency for the MCP-1 G/G genotype (28/62, 45%) than the A/A (9/22, 41%) or A/G genotypes (2/58, 38%), respectively. Using dot blot analysis, we detected higher levels of MCP-1, IFN-γ, IL-8, IP10, MIP-1β, -1d, and soluble TNF receptors in the sera of CL and ML patients as compared with the healthy controls. Additional quantitative studies confirmed that sera of ML patients contained significantly higher levels of IP-10, MIP-1β and sTNFRII when compared to CL and healthy controls. This study suggests that the over-production of inflammatory cytokines is a contributing factor to the pathogenesis of mucosal lesions. Studies are ongoing to define the sources of these inflammatory mediators.
Dephosphorylation of Ikaros by a specific phosphatase regulates its function in chromatin remodeling (136.9)
Authors: Dovat Sinisa , Gurel Zafer , Payne Kimberly J , Popescu Marcela 
Published: January 2023

Abstract
Ikaros encodes a zinc finger protein essential for lymphoid development. Ikaros localizes to pericentromeric heterochromatin (PC-HC) where it recruits target genes, resulting in their activation or repression via chromatin remodeling. Ikaros' function is controlled by post-translational modification. Our previous studies show that phosphorylation of Ikaros by CK2 kinase controls its PC-HC localization, and its ability to bind the upstream regulatory region (URE) and regulate expression of TdT during thymocyte differentiation. Here, we demonstrate, by co-immunoprecipitation, that Ikaros interacts in vivo with a specific phosphatase for which it is a substrate. Mutational analysis identified specific residues essential for Ikaros-phosphatase interaction. Mutant Ikaros protein with disrupted phosphatase interaction undergoes CK-2-mediated hyperphosphorylation that inhibits its ability to bind the TdT URE, and its PC-HC localization. Alanine mutations at the CK2-phosphorylated residues restore both Ikaros' DNA-binding ability and PC-HC localization, regardless of its ability to interact with the phosphatase. We propose a model whereby the regulation of TdT expression by Ikaros is controlled by CK2 kinase and interaction with a specific phosphatase and that the balance of these two signal transduction pathways is essential for normal T cell differentiation. Supported by NIH K22CA111392 (SD)
Dendritic Cell Molecules Involved in Self Reactive T cell Activation (137.12)
Authors: Cabrera Rosalyn , Radhakrishnan Suresh , Pease Larry R. 
Published: January 2023

Abstract
Dendritic cells (DC) initiate and shape an adaptive immune response. DC can be stimulated with B7-DC XAb, a novel immunomodulatory IgM that crosslinks B7-DC/PDL2 on the DC surface. Previously, we have shown that B7-DC XAb treated DC (DCXAb) reprogram Foxp3+ Tregulatory cells into IFNgamma+, IL-17+ effectors. Adoptive transfer of neoself antigen (OVA)-pulsed DCXAb induces destruction of OVA-bearing pancreatic islets and autoimmune diabetes in RIP-OVA mice. We hypothesized that DC-derived molecules involved in Th1 or Th17 polarization would be important in autoreactive T cell activation by DCXAb. In spite of their ability to induce a CTL response against OVA-bearing targets, we found that DCXAb deficient in either Tbet, IFNgamma (Th1 polarizing) or CD40, IL-6 (Th17 polarizing) fail to cause autoimmunity. In conclusion, both Th1 and Th17 polarizing molecules on DC are needed to stimulate an autoimmune response.
Autoantibody profile against retinal proteins in patients with age-related macular degeneration and possible role in neovascularization (137.13)
Authors: Morohoshi Kei , Patel Nishal , Ohbayashi Masaharu , Chong Victor , Grossniklaus Hans E , Bird Alan C , Ono Santa J 
Published: January 2023

Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the United States and in other developed countries. Recent findings indicate that circulating autoantibodies specific for retinal proteins and macular deposits, drusen, are associated with AMD pathogenesis, yet only a few antibodies have been identified in sera from patients with AMD. In order to reveal an autoantibody profile for AMD, we performed an antigen microarray with constituents of drusen and liquid chromatography and tandem mass spectrometry analysis following two-dimensional immunoblot analysis with retinal proteins using serum samples from patients with AMD and healthy controls. Sera from the AMD group contained high levels of IgG autoantibodies against numerous ocular antigens including lipoproteins and collagen when compared to the normal group. Moreover, IgGs purified from sera of AMD patients induced more tube formation on choroidal-retinal endothelial cells and increased VEGF production on monocytes compared to those of healthy donors. Our data suggest that these IgG autoantibodies may be used as biomarkers for AMD and contribute to progression of this disease.
IL-2 mediated regulation of CD103 Expression on CD4+ T cells and its role in Cutaneous and Mucosal inflammation in Scurfy Mice (137.15)
Authors: Sharma Rahul , Sung Sun Sang , Abaya Christian E , Ju Angela C-Y , Fu Shu Man , Ju Shyr Te 
Published: January 2023

Abstract
Scurfy (Sf) mice lack Foxp3+ regulatory T cells (Tregs) and die of CD4+ T cell mediated multi-organ inflammation. Introducing Il2-/- gene into Sf mice (Sf.Il2-/-) prolonged their lifespan and inhibited inflammation in skin and lung but not liver. We studied, the expression of CD103 (ligand of E-cadherin-a major integrin for cutaneous and mucosal organs), on CD4+ T cells in lymphoid and target organs of Il2-/-, Sf and Sf.Il2-/- mice. CD103+CD4+ T cells were low in normal B6 but were significantly high in Sf mice. Importantly, this population was low in Il2-/- and Sf.Il2-/- mice, indicating that this is a dominant trait of Il2-/- associated with spontaneous T cell activation. Interestingly, Tregs CD103 expression was not reduced in Il2-/- mice. Introducing CD103-/- into Sf mice inhibited inflammation in skin and lung but not liver as compared with age-matched Sf mice. Nevertheless, Sf.CD103-/- mice die at 7 wks of age with inflammation in skin, lungs, colon and liver, demonstrating CD103-independent fatal multi-organ inflammation. The data indicate that IL-2 is required for optimal CD103 expression on CD4+ T cells in Sf mice and this contributes to inflammation in organ-specific manner. IL-2 also plays additional roles because the protection of skin and lung inflammation in Sf.Il2-/- mice is life-long and Sf.Il2-/- mice have longer lifespan than Sf.CD103-/- mice that totally lack CD103-dependent inflammation.
GAD65 p546-554-specific CTL mediate β cell death and loss of insulin production (137.22)
Authors: Rasche Sarah S , Quinn Anthony 
Published: January 2023

Abstract
Autoimmunity to pancreatic β cell proteins such as GAD65 are associated with the destruction of insulin-producing β cells and the progression to autoimmune Type 1 Diabetes (T1D) in both NOD mice and in humans. T cell responses to GAD65 are detectable in the spleens of prediabetic NOD mice and in the peripheral blood of humans prior to the onset of overt hyperglycemia. Previous findings from our lab revealed that p546-554-specific CTL are present in naïve NOD mice and are able to induce islet inflammation in NOD.scid recipients. The GAD65 fragment p546-554 is a naturally displayed dominant epitope on GAD65-expressing APC, and professional APC can generate the p546-554 epitope from a soluble GAD65 fragment, p530-554, as well as from GAD65 released by injured β cells in vivo. Here, we report that p546-554-specific CTL can directly interact with pancreatic β cells to reduce insulin production and induce perforin-mediated cell death. These findings support a role for crosspresentation in the priming and enhancement of dominant GAD65-specific CTL responses in T1D.
This research was supported by funds from NIH-NIAID.
A novel pathogenic mechanism of the ER chaperone BiP/Grp78 response in rheumatoid synoviocytes (137.27)
Authors: Kim Wan-Uk , Yoo Seung-Ah , Kong Jin-Sun , Yoon Hyung-Ju , Park Yoon-Jung , Cho Chul-Soo 
Published: January 2023

Abstract
The accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we investigated the role of the ER chaperone BiP/Grp78 in abnormal proliferation of rheumatoid arthritis (RA) synoviocytes, which is the pathologic hallmark of RA. The results showed that BiP protein was highly expressed in RA synovium and synoviocytes. The proinflammatory cytokines, such as TNF-alpha and IL-1beta, and hypoxic stimuli, but not IL-10, increased the BiP expression in RA synoviocytes. RA synoviocytes were more resistant to ER-stress-induced apoptosis as compared to OA synoviocytes. ER stress inducers, thapsigargin and tunicamycin, increased BiP and Bcl-2 expressions in synoviocytes, which were much greater in RA synoviocytes than in OA synoviocytes. A BiP-inducer, BIX, blocked the ER-stress induced synoviocyte apoptosis, possibly by increasing Bcl-2 and BiP expression. In contrast, BiP knockdown in RA synoviocytes, using siRNA, abolished the TNF-alpha- and TGF-beta-induced synoviocyte proliferation and cyclin D1 upregulation. BiP with a higher molecular size than intracellular BiP was found in all (6/6) RA synovial fluids tested. Exogenous BiP strongly increased IL-17 and TNF-alpha production from RA mononuclear cells, but not from mononuclear cells of healthy controls. In summary, we demonstrated first that BiP is crucial to the resistance to apoptosis of RA synoviocytes and synoviocyte proliferation, and it involves the production of IL-17 and TNF-alpha from mononuclear cells, suggesting that ER chaperone BiP response contributes to RA pathogenesis by inducing synovial hyperplasia and Th17 cell generation.
The role of MR-1 restricted MAIT cells in murine models of arthritis (137.28)
Authors: Miyake Sachiko , Tajima Ryosuke , Miyazaki Yusei , Ichikawa Daiju , Chiba Asako , Yamamura Takashi 
Published: January 2023

Abstract
Mucosal associated invariant T (MAIT) cells express an invariant Vα19-Jα33 TCR and are restricted by MR1, a class Ib MHC molecule. Here we investigated the role of MAIT cells in arthritis models. The severity of clinical scores of K/BxN serum transfer arthritis and anti-CII antibody-induced arthritis were reduced in MR1-/- mice compared to control B6 mice. Histological examination revealed that cell infiltration and cartilage and bone destruction were significantly less apparent in MR1-/- mice. The number of infiltrated cells in the synovia was one third lower in MR1-/- mice compared to B6 mice. The levels of transcript of IL-1, TNF-α and IL-6 were reduced in infiltrated cells in the joints of MR1-/- mice. The transfer of NK1.1+CD3+ cells from Vα19Tg mice into MR-1-/- mice exacerbated the severity of arthritis to the similar level of arthritis in wild type B6 mice. Taken together, MR-1 restricted MAIT cells contribute to the pathogenesis of inflammatory arthritis.
Increased Th17 cell activity in patients with early rheumatoid and psoriatic arthritis (137.30)
Authors: Leipe Jan , Thuemmler Katja , Schulze-Koops Hendrik , Skapenko Alla 
Published: January 2023

Abstract
To gain insights into the role of Th17 cells in human autoimmune diseases, we analyzed Th17 cell biology in patients with ongoing inflammatory autoimmune arthritis (e.g., rheumatoid (RA) and psoriatic arthritis (PsA)), and for control in patients with osteoarthritis and healthy individuals. Frequencies of Th17 cells were significantly elevated in the blood of patients with early, treatment-naive RA and PsA. Moreover, upon activation in vitro, CD4 T cells from the patients yielded enhanced Th17 frequencies and elevated levels of IL-17. In contrast, Th1 frequencies and IFNγ production were not different between patients and controls. As the frequencies of Th17 cells and IL-17 production, but not of Th1 cells or IFNγ production correlated with disease activity, early inflammation in RA and PsA is characterized by both, selectively enhanced Th17 cell generation and increased Th17 cell activity. Of interest for the pathogenesis of autoimmune arthritis, CD4 T cells from early RA and PsA patients were partially resistant to the inhibitory capacity of IL-4 and IFNγ on Th17 generation, suggesting a potential mechanism underlying the breakdown of peripheral tolerance at disease onset. However, as effective immunosuppressive treatment was associated with normalization of Th17 cell activity in the patients, the data further suggest that Th17 cells might also contribute to sustained autoimmune inflammation in RA and PsA.
A role for lymphotoxin in primary Sjögren's Disease (137.34)
Authors: Shen Long , Suresh Lakshmanan , Kumar Vijay , Pankewycz Oleh , Ambrus Jr. Julian L. 
Published: January 2023

Abstract
The etiology of salivary gland injury in primary Sjögren's disease is poorly understood. Increased expression of lymphotoxin (LT) has been demonstrated in patients with Sjögren's disease. The current studies were designed to determine whether LT contributes to early salivary gland injury in a murine model of Sjogren's disease, IL-14alpha transgenic mice (IL-14α TG).
Lymphotoxin mRNA and protein is found in the salivary glands of IL-14αTG mice as early as 3 months of age. IL-14αTG.LT-/- mice retained normal salivary gland secretions and failed to develop lymphocytic infiltration of their salivary glands. However, deposition of IgM antibodies in the salivary glands and infiltration of the lungs still occurred in IL-14αTG.LTA-/- mice. B cell subpopulations and responses to T-dependent and T-independent antigens were similar in IL-14αTG and IL-14αTG.LTA-/- mice.
These studies suggest that locally produced LT may cause direct injury to the salivary glands in IL-14α TG mice. There can be discordance between antibody deposition in the salivary glands and salivary gland dysfunction. The mechanisms of salivary gland and lung injury in Sjogren's disease may differ. Further studies are needed to determine the roles of LT in early injury to the salivary glands in IL-14α TG mice and patients with Sjögren's disease.
Effects of DDE on development and progression of autoimmunity (137.36)
Authors: Viselli Susan M. , Lerner Daniel M. , Miaoulis Anthony G. , Rahmani Kaveh , Torski Brian A. 
Published: January 2023

Abstract
DDE, a metabolic breakdown product of the pesticide DDT, persists in the environment and acts as an androgen receptor antagonist. Androgen deprivation by castration of male mice causes changes in immune function and the lupus-like disease of NZB/W F1 hybrid mice is treated by androgens. Therefore, we hypothesized that the anti-androgenic effects of DDE may alter immune function, with consequences for autoimmunity. We treated both normal C57Bl/6 female mice and lupus-prone NZB/W F1 female mice with oil control or DDE, at 200 mg/kg for 3 days at the study's beginning. NZB/W mice were studied over 6 months and C57Bl/6 mice for 18 months. DDE did not alter organ or body weights. Proteinurea was increased in DDE-treated mice compared to age-matched oil-treated controls, as early as one month after treatment with DDE. By histopathology we observed glomerulonephritis sooner in kidneys of NZB/W mice treated with DDE than control. Kidneys of DDE-treated C57Bl/6 mice showed increased glomerular mesangium compared to kidneys of age-matched controls. By immunohistochemistry we saw increased glomerular expression of monocyte chemoattractant protein-1 and increased tubulointerstitial expression of osteopontin in response to DDE; upregulation of both chemokines occurs in murine lupus nephritis. We conclude that DDE impacts development and progression of autoimmune disease and continue to explore the mechanism of action.
Exosomes are associated with pregnancy-induced suppression of experimental autoimmune encephalomyelitis (137.4)
Authors: Williams Jessica L , Song Fei , Smith Kristen , Kithcart Aaron , Mavrikis Gina , Shawler Todd , Whitacre Caroline C 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, myelin damage, and axonal degeneration. MS disease relapses are markedly decreased during pregnancy with the greatest reduction in disease observed during the third trimester. We have studied pregnancy in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). Disease severity is significantly reduced when pregnancy is induced during established EAE. We also observed a post-partum flare in disease scores, with EAE suppression only occurring during the gestation period. A serum factor has been implicated as the primary mediator of disease suppression. Exosomes found in peripheral blood are able to modulate the immune response by relaying molecular signals from their cell of origin to target cells bearing specific adhesion molecules. We have shown that pregnancy-associated exosomes are able to suppress antigen-specific T cell proliferation. Exosomes are hypothesized to dampen immune responses during pregnancy; thus, we examined exosomal proteins that are known to influence T cell activity such as Fas ligand, MHC II, TGF-β, IL-17, and IFN-γ. Harnessing the mechanism by which exosomes suppress immunity, and consequently EAE, can have remarkable implications for therapy development in MS. (Supported by NIH grants AI 064320 and T32 AI055411, and National MS Society grant RG3272)