bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of IK cytokine ameliorates the development of murine autoimmune arthritis (P5148)
Authors: Park Hye-Lim , Cho Mi-La , Min Jun-Ki , Nam Jae-Hwan 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a systemic autoinflammatory disorder characterized by synovial hyperplasia and infiltration of inflammatory cells, as well as by the progressive destruction of cartilage and bone. Self-antigen presentation through aberrant major histocompatibility complex (MHC) class II expressing B cells produces autoantibodies, leading to development of more erosive RA. IK cytokine functions as an inhibitor of interferon γ (IFNγ)-induced MHC class II on B cells. Although its cellular and molecular mechanisms have remained unclear, IK cytokine has previously been linked to autoimmune diseases such as lupus nephritis and alopecia areata. Here, we investigated the role of IK cytokine in the pathogenesis of murine autoimmune arthritis. We generated immunodeficient arthritis mice (tIK-Tg-IL-1RaKO) by cross-breeding transgenic mice expressing truncated IK (tIK-Tg) with knockout mice lacking the IL-1 receptor antagonist (IL-1Ra-KO). In this regard, the Type II collagen (CII) immunized tIK-Tg-IL-1RaKO mice showed mild type arthritis and lower incidence than CII immunized IL-1RaKO mice. tIK-Tg-IL-1RaKO mice also showed decreased proinflammatory cytokine expression and immune cell expansion. Taken together, these results suggest that overexpression of IK cytokine may suppress the development of autoimmune arthritis by modulating inflammatory response in the case of autoimmune arthritis. Key words: IK cytokine, MHC class II, Rheumatoid arthritis
Blockade of IL-21 promotes the induction of T regulatory cells in healthy controls and IBD patients (P5158)
Authors: Wu Rebecca , Cox Jennifer , Blumberg Hal , Levin Steven , Lundsgaard Dorthe 
Published: January 2023

Abstract
T regulatory cells (Treg) play a critical role in maintaining immune homeostasis and tolerance to self-antigen. A subset of Treg induced by activation in the presence of TGF-β (induced or iTreg) has been shown to play a role in regulating immune responses and preventing autoimmune disease (AID). IL-21 is a pleiotropic cytokine involved in both innate and adaptive immune responses. Recent data in mouse models has shown that modulation of IL-21 function can influence Treg development and function, but the effect of IL-21 on human Treg is unknown. Therefore, we investigated the role of IL-21 in development of iTreg from T cells from healthy control (HC) and Crohn’s disease (CD) patients. Induced Treg were generated from CD4+CD25- T cells by activation in the presence of IL-2 and TGFβ. Exogenous IL-21 or blocking anti-IL-21 monoclonal antibody was also included on day 0 and cells were stained for intracellular IL-21 and FoxP3 expression on day 7. There was a significant reduction in the number of Foxp3+ T cells (p&lt;0.03) in the presence of exogenous IL-21 and a significant increase when anti-IL-21 antibody was included (p&lt;0.02). These effects on iTreg development were seen in both HC and CD patients. These data suggest targeting IL-21 with neutralizing antibodies can increase iTreg development and hence has promising potential as a novel therapeutic approach for the treatment of AID such as CD.
Redox modulation of the processing and presentation of myelin-associated antigens in experimental autoimmune encephalomyelitis. (P5184)
Authors: Allan Euan , Tailor Pankaj , Yates Robin 
Published: January 2023

Abstract
NOX2 is well known for its microbicidal activity within phagolysosomes of phagocytes. Our research group has recently found that NOX2 activity also impacts two key antigen processing chemistries within the phagosome of macrophages and dendritic cells. NOX2 activation inhibits disulfide reduction and alters proteolysis through the oxidative inactivation of cysteine cathepsins B, S, and L. Both disulfide reduction and proteolysis are vital for antigen and invariant chain processing, and thus are required for efficient antigen processing/presentation. Our objective is to determine if NOX2 influences the progression of EAE, which requires processing of endogenous myelin, by modulating antigen processing and changing the immuno-dominance of MOG peptides. We examined the susceptibility of WT and NOX2-deficient mice to EAE. Varying MOG components were used to induce EAE in WT and NOX2-deficient mice. NOX2-deficient mice were found to be partially clinically protected from MOG35-55 induced EAE, and less so from recombinant MOG induced EAE. Antigen presentation efficiency of MOG35-55 by NOX2-deficient macrophages to 2D2 T cells was reduced compared to WT macrophages when the antigenic source was recombinant MOG, but not when the macrophages were pulsed with MOG35-55. These results suggest that NOX2 may have a role in the modified processing of MOG proteins, which may be partially responsible for the differential susceptibility of NOX2-deficient mice to EAE.
Anti-IFN-gamma autoantibodies in adults with disseminated NTM infection (P4547)
Authors: Lin Chia-Hao , Chi Chih-Yu , Chu Chen-Chung , Liu Jing-Pei , Ku Chung-Lung 
Published: January 2023

Abstract
Adult patients with disseminated nontuberculous mycobacterial (dNTM) infections usually have severe immune system defects, such as AIDS or autoimmune diseases. Recently, several reports have shown that anti-IFN-γ autoantibodies may play an important role in the pathogenicity of dNTM infections. However, a considerable proportion of reported anti-IFN-γ autoantibodies cases either have clinical or laboratory evidence of autoimmune disease. In this study, we identified 19 previously healthy adults who suffered from dNTM infections, and 17 received further immunological function assays. High-titer anti-IFN-γ autoantibodies with activity inhibiting IL-12 production were found in the plasma of all of the patients. In addition to dNTM infection, 35% and 71% of our patients also suffered from salmonellosis and herpes zoster, respectively; both types of infections have rarely been reported in previous cases. This observation suggests that IFN-γ may be crucial in controlling salmonella infection and reactivating latent varicella zoster virus infection in humans. Two particular HLA alleles, DRB1*16:02 DQB1*05:02 (odds ratios of 8.68, 95% CI: 3.47-21.90, P=1.1×10-6, Pc=3.08×10-5 and 7.16, 95% CI: 3.02-17.05, P=1×10-7, Pc=1.4×10-6, respectively), were found in 82% (14/17) of our patients. In conclusion, our data suggest that anti-IFN-γ autoantibodies may play a critical role in the pathogenesis of dNTM infections and are associated with HLA-DRB1*16:02 and DQB1*05:02 among healthy adults.
The role of lymphoid micro-architecture in dendritic cell-mediated antigen capture and initiation of cellular adaptive immunity (P5200)
Authors: Gerner Michael , Kastenmuller Wolfgang , Germain Ronald 
Published: January 2023

Abstract
Dendritic cells (DCs) specialize in antigen (Ag) sampling and presentation and are critical for promoting T cell-mediated immune responses. DCs are composed of multiple subsets with divergent functional capabilities, with lymph node (LN)-resident CD8+ vs. CD11b+ DC preferentially processing captured Ags for MHC-I vs. MHC-II presentation, respectively. Utilizing a novel microscopy method, “Histo-Cytometry,” we have recently found that these subsets reside in differential spatial micro-compartments in murine LN, with preferential but not exclusive localization of CD8+ DCs to the central T cell zone and the CD11b+ DCs to the LN periphery. Here, we show that DC spatial positioning has profound functional effects on DC-mediated Ag capture and downstream MHC processing after protein immunization. Specifically, poor Ag penetration deep inside the LN paracortex led to decreased Ag sampling by the centrally localized CD8+ DCs and absence of CD8+ T cell responses at low levels of immunized Ag, as compared to the more effective Ag capture by peripheral CD11b+ DC and CD4+ T cell priming. Moreover, DC subset regionalization directly influenced the location of early CD8+ vs. CD4+ T cell activation, with centrally localized CD8+ T cell vs. predominantly peripheral CD4+ T cell priming. Collectively, these findings indicate that spatial organization by DC subsets creates micro-anatomical domains with specialized functional capacities affecting the development of cell-mediated immunity.
IL-20 receptor signaling inhibits cutaneous IL-1β and IL-17A production to promote methicillin-resistant Staphylococcus aureus infection (P6350)
Authors: Myles Ian , Fontecella Natalia , Valdez Patricia , Vithayathil Paul , Naik Shruti , Belkaid Yasmine , Ouyang Wenjun , Datta Sandip 
Published: January 2023

Abstract
Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. However, host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20 and -24 signal through type I and type II IL-20 receptors and have been associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We hypothesized these cytokines may play a role in S. aureus skin infections. We show here that this family of cytokines promotes cutaneous S. aureus infection in mice by downregulating IL-1β- and IL-17A-dependent inflammatory pathways required for control of infection. Our findings identify an immunosuppressive role for these cytokines during infection, and suggest these pathways may contribute to infectious susceptibility.
The ‘atypical’ chemokine receptor CCRL1 aids dendritic cell migration from inflamed skin. (P6352)
Authors: Bryce Steven , Luster Andrew , Graham Gerry , Nibbs Rob 
Published: January 2023

Abstract
Chemokine-directed leukocyte migration is essential for immune and inflammatory responses. The chemokine receptor CCR7, by responding to chemokines CCL19 and CCL21, is critical in regulating the recruitment of dendritic cells (DC), from peripheral tissues to draining lymph nodes (LNs). CCR7 is required for DC entry into lymphatic vessels, and for the passage of these cells across subcapsular sinus of the lymph node. Here, they initiate adaptive immune responses by priming antigen-specific T cells. CCRL1, an unexpected second receptor for CCL19 and CCL21, belongs to the family of atypical chemokine receptors and is able to bind and sequester extracellular chemokine without exhibiting any form of classical chemokine signaling. CCRL1 function in vivo is still unclear. We have generated CCRL1 deficient mice but find no perturbations in DC numbers in the LNs at rest, and DC trafficking from the skin is normal after painting with hapten (FITC). However, if FITC is applied after the induction of cutaneous inflammation, FITC+ DCs fail to reach draining LNs. Using a combination of microscopy and flow cytometry, we show that DCs are unable to enter lymphatic vessels and remain trapped in the skin. These data will be presented in the context of new insights into the identity of CCRL1-expressing cells in the skin and lymph node. Collectively, our data indicate that CCRL1-mediated regulation of CCL19 and/or CCL21 is required to maintain DC departure from the skin during inflammation.
Divergent roles for AdipoR1 and AdipoR2 in mediating revascularization and metabolic dysfunction (P6358)
Authors: Duffen Jennifer , Nakamura Kazuto , Silver Marcy , Zuriaga María , Aprahamian Tamar , Walsh Kenneth 
Published: January 2023

Abstract
Adiponectin is a well-described anti-inflammatory adipokine with a collectin-like structure. Previous reports have found that its deficiency leads to cardiovascular and metabolic dysfunction whereas its overexpression is protective. Two adiponectin receptors, AdipoR1 and AdipoR2, are poorly characterized and their metabolic functions remain controversial. Here, we subjected AdipoR1- and AdipoR2-deficient mice to hind limb ischemia surgery, a mouse model of peripheral artery disease. Blood flow recovery in AdipoR1-deficient mice was similar to wild-type; however, revascularization in AdipoR2-deficient mice was severely attenuated. Treatment with adiponectin enhanced the recovery of wild-type mice but failed to rescue the impairment observed in AdipoR2-deficient mice. These data show for the first time that AdipoR2 is functionally important in an in vivo model of vascular disease and that its expression is essential for the revascularization actions of adiponectin. Given the connection between cardiovascular and metabolic disease, AdipoR1- and AdipoR2-deficient mice were also evaluated in a model of diet-induced obesity. Strikingly, AdipoR1-deficient mice developed severe metabolic dysfunction compared to wild-type littermates. In contrast, AdipoR2-deficient mice were protected from diet-induced weight gain and metabolic perturbations. Taken together, AdipoR1 and AdipoR2 have divergent roles in mouse models of vascular and metabolic disease.
The contribution of individual TCR signaling components to thymic selection (P4540)
Authors: Brockmeyer Claudia , Herzmark Paul , Robey Ellen 
Published: January 2023

Abstract
In the thymus, T cell progenitors undergo an extensive selection program that shapes the repertoire of T cell receptors to ensure that mature T cells released into the periphery are tolerant to peptides derived from self proteins but able to recognize foreign peptide antigens. The engagement of the T cell receptor on a developing thymocyte triggers the formation of a proximal signaling complex at the plasma membrane and initiates a calcium signal, which together activate multiple downstream signaling cascades crucial for the thymocyte’s survival and maturation. One of the major signaling pathways initiated is the Ras/MAP kinase cascade, which plays an essential role during the positive selection of thymocytes. As thymic positive selection does not occur efficiently in 2-dimensional co-cultures, we are using a thymic slice preparation that provides the 3-dimensional stromal architecture of the thymus. We aim to study the signaling properties of MHC class I-restricted T cell receptor transgenic CD4+CD8+ thymocytes during positive selection either by flow cytometry or by two-photon laser scanning microscopy. We are using pharmacological inhibitors to understand the contribution of individual T cell receptor signaling components to positive selection. We hope to dissect both their longer-term effect on the thymocytes’ development, as well as their interconnection and potential compensatory mechanisms.
Innate and adaptive immunity against oxidative damage cooperate in the pathogenesis of age-related macular degeneration (P3367)
Authors: Cruz-Guilloty Fernando , Saeed Ali , Duffort Stephanie , Ballmick Asha , Tan Yaohong , Salomon Robert , Perez Victor 
Published: January 2023

Abstract
While our knowledge of acute immune responses is extensive, the cooperation of innate and adaptive immunity in chronic inflammatory diseases remains poorly defined. Age-related macular degeneration (AMD) is the leading cause of legal blindness in the developed world. Recently, the immune system has been shown to play a role in AMD. However, the specific roles of the adaptive immune system and different types of macrophages have not been studied in detail. Oxidative stress is a major contributing factor in the development of pathological inflammatory conditions, including atherosclerosis and AMD. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD and mice immunized with CEP-adducted self proteins develop AMD-like pathology. Here, we show CEP-specific T cell activation, pro-inflammatory cytokine production (IFN- γ, IL-17) and infiltration of M1 macrophages in the subretinal space, linking both the adaptive and innate immune systems in the onset of AMD. In vitro, CEP-specific T cells specifically promote M1 macrophage differentiation, while CEP directly induces TLR-2-independent M1 polarization. Moreover, CEP-immunized Ccr2-deficient mice lack macrophage infiltration and retinal lesions, suggesting a deleterious role for macrophages in this model. Our data provide new insights into the pathogenesis and possible treatment of AMD, while providing a more general view of chronic inflammation applicable to other settings.
Successful immunotherapy with interleukin 2 for hypoxia-induced pulmonary hypertension (P3371)
Authors: Bauer Eileen , Zheng Han , Bauer Philip , Lotze Michael 
Published: January 2023

Abstract
The development of therapies to treat pulmonary hypertension (PH) has primarily focused on targeting intrinsic endothelial dysfunction and vasoreactivity. Recent meta-analysis of controlled trials utilizing these therapies, however, shows only modest decreases in mortality. Despite evidence that inflammatory mechanisms complicate/possibly initiate events in PH, no strategies have been developed to target specific endothelial-extrinsic abnormalities of the inflammatory cells involved. We previously reported on the contributory role of the inflammatory damage associated pattern molecule HMGB1 in patients with PH and in a well-established murine model of hypoxia-induced PH. With reports on the dysfunctional behavior of natural killers (NK) cells in PH patients and on its prevention by adoptive transfer of CD4+CD25bright Tregs in a rat model, we decided to target PH using immunotherapy. Treatment with low-dose Interleukin 2 (IL-2,6x104 IU BID) not only attenuated the development of hypoxia-induced PH in mice but more importantly reversed established PH. IL-2 treated mice demonstrated decreased: 1) pulmonary vascular remodeling 2) right ventricular systolic pressures indicative of pulmonary pressures and 3) right heart hypertrophy, all of which are standard assessments of PH, but increased NK and CD4 T-cell number. These findings demonstrate for the first time that PH is an immune-responsive disorder and suggest IL-2 administration as a viable and novel therapeutic strategy.
A single peptide-MHC triggers digital cytokine secretion in both naive and activated CD4+ T cells (P1368)
Authors: Huang Jun , Davis Mark 
Published: January 2023

Abstract
We have developed a single molecule imaging technique that uses quantum dot labeled pMHCs to study CD4+ T cell functional sensitivity. We find that both naive and activated T cells can be triggered by a single pMHC to secrete cytokines with a rate of ~1,000 and ~10,000 molecule/min respectively and that additional pMHCs do not increase secretion, thus these cells display a digital response pattern. We also find that a single pMHC induces the formation of a long-lasting TCR microcluster, consistent with a serial engagement mechanism. These data show that scaling up T cell cytokine responses must involve efficient T cell recruitment rather than increasing individual cell cytokine production.
Guardian angels in the graveyard: B1 B cells promote thymic Treg survival (P1386)
Authors: Zhong Xuemei , Alaimo Danielle , Hall Matthew , Lovell John , Vo Hung , Bai Chunyan , Lau Stanley 
Published: January 2023

Abstract
The thymus is the primary site for T cell development. Within the medulla of the thymus, negative selection of immature T cells causes a large number of cells to undergo apoptosis, appropriately deeming this thymic region a “grave yard.” In observing the thymus medulla of BXSB mice, we noted a significant increase of B cells in lupus-symptomatic males as compared to female controls or lupus- asymptomatic males. Composition analysis of these thymic B cells revealed that both B1 and B2 cells are present. Immunohistochemistry analysis suggests possible chemo-attraction for B cells in the medullar of the thymus due to the expression of CXCL13 in lupus male mice, but not control females. In vivo tracking of peritoneal B cells over a two-week time period indicated that some of the thymic B cells originated from the peritoneal cavity. To test the possible influence of B cells on thymic T cell development, we co-cultured peritoneal and spleen B cells with thymocytes in a 3D hanging drop plate. Our results suggest a “guardian angel” effect by B1 B cells, depicting an enhanced central tolerance by thymic-migration and promoting regulatory T cell survival.
Ultra-violet irradiation and riboflavin treatment blocks capping of cellular adhesion molecules and abrogates immunogenicity of antigen presenting cells (P1388)
Authors: Carrillo Ralf , Norris Philip , Jackman Rachael , Marschner Susanne , Goodrich Raymond 
Published: January 2023

Abstract
UV light has known immunomodulatory activity and is used in clinical situations such as for psoriasis. Mirasol treatment, a pathogen reduction technology based on ultra-violet light irradiation in the presence of riboflavin (UV+R), suppresses the ability of treated WBCs to stimulate proliferation of allogeneic T cells in vitro. Prior work showed that surface expression of adhesion molecules was down-regulated after UV+R treatment. We now show that, UV+ R treatment also decreased capping of the intercellular adhesion molecules (ICAMs)-1, -2, -3 and lymphocyte function-associated antigen (LFA)-3. UV+R treated U937 antigen presenting cells (APCs) induce decreased cell-cell conjugation with PBMCs 25% (p = 0.003) and show a 66% (p = 0.0005) reduction in stimulating T cell proliferation in a mixed lymphocyte reaction compared to untreated or gamma-irradiated U937 APCs. Additionally, UV+R treated U937 APCs failed to induce expression of the early T cell activation marker CD69 and also have decreased membrane viscosity when compared to untreated APCs. Diminished surface expression and perturbation of adhesion receptors within the U937 APCs plasma membrane down-regulates T cell stimulation and proliferation in vitro by lowering the surface expression of adhesion receptors needed for cell-cell conjugation and by perturbation of the ability to mobilize and aggregate adhesion receptors to form a cap, a critical component needed for T cell activation.
Transition from heterotypic to homotypic PDK1 homodimerization is essential for TCR-mediated NF-κB activation (P1370)
Authors: Kang Jung-Ah , Jeong Sang Phil , Park Daeho , Hayden Matthew S , Ghosh Sankar , Park Sung-Gyoo 
Published: January 2023

Abstract
Strong NF-κB activation requires ligation of both the CD28 co-receptor and TCR. PDK1 acts as a scaffold by binding both PKCθ and CARMA1 and is therefore essential for signaling to NF-κB . Here, we demonstrate the importance of PDK1 threonine (Thr)-513 phosphorylation in regulating the intermolecular organization of PDK1 homodimers. Thr-513 is directly involved in heterotypic PDK1 homodimer formation, in which binding is mediated through the pleckstrin homology (PH) and kinase domains. Upon activation, phosphorylated Thr-513 instead mediates homotypic intermolecular binding through the PH domains. Consequently, cell permeable peptides with a Thr-513 to Ile derivative (PTD-PDK1-Thr-513-Ile) bound the kinase domain and while a Thr-513 to Asp peptide (PTD-PDK1-Thr-513-Asp) bound the PH domain. PTD-PDK1-Thr-513-Ile blocked binding between PDK1 and PKCθ, phosphorylation of PKCθ Thr-538, and activation of both NF-κB and AKT. In contrast, PTD-PDK1-Thr-513-Asp selectively inhibited binding between PDK1 and CARMA1 and blocked TCR/CD28 induced NF-κB activation. Therefore, Thr-513 phosphorylation regulates a critical intermolecular switch governing PDK1 homodimer structure and the capacity to interact with downstream signaling pathway components. Given the pleiotropic functions of PDK1, these data may open the door to the development of immunosuppressive therapies that selectively target the PDK1 to NF-κB pathway in T cell activation.