bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis (HUM1P.316)
Authors: Zhu Lin , Nan Liu 
Published: January 2023

Abstract
Dysfunction of the immunologic mechanism is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), which is a classical experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid, has been used for hepatitis B in clinical. Previous reports have suggested that MAT could ameliorate the clinical symptoms of EAE rats, but haven’t clarified the mechanism of action until now. Our present study showed that MAT reduced the neurological scores of EAE rats, suppressed infiltration of inflammatory cells and demyelination in the CNS significantly. Furthermore, we studied the possible immunologic mechanism underlying the treatment of MAT for EAE by measuring the expression of system and molecules related with immunoregulation mechanism. In our study, an administration of MAT significantly increased the expression and production in the CNS of Nrf2 and HO-1, the correlation factors of oxidative stress that confront inflammatory cells into the CNS. Furthermore, the expressions of Interleukin-4, Interleukin-5, Interleukin-10, transforming growth factor-1 and Foxp3, which play an important role in the balance between Th1 and Th2 cells in EAE, were also significantly increased. Our findings reveal that MAT could promote the expressions of factors for inhibiting the inflammation. In conclusion, our study clarifies the possible mechanisms underlying the treatment of MAT for EAE, implies that MAT may be a novel therapeutic option for MS.
Treatment of MS patients with BG-12 results in a decline in circulating memory T and B lymphocytes (HUM1P.317)
Authors: Lundy Steven , Wu Qi , Le Lisa , Mao-Draayer Yang 
Published: January 2023

Abstract
BG-12 (Tecfidera®) is a recently approved oral treatment for multiple sclerosis that has shown remarkable efficacy. The mechanisms by which BG-12 acts on the human immune system are poorly defined. In the current study, we analyzed the effects of BG-12 treatment on subsets of circulating human T and B lymphocytes using multicolor flow cytometry. Patients treated for four months with BG-12 had decreased total numbers of lymphocytes in their blood that did not reach significance, and no changes in their overall percentages of CD4+ T cells, CD8+ T cells, or CD19+ B cells compared to pretreatment levels. Significant differences were observed when subsets of T and B cells were evaluated. BG-12 treatment resulted in a decrease in percentages of circulating CD4+CD45RO+CD45RAneg memory TH cells and CD8+CD45RO+CD45RAneg memory CTL. Treatment with BG-12 also resulted in significant decreases in circulating CD27+CD19+ memory B cells, and a relative increase in the levels of CD24highCD38highCD19+ regulatory B cells. A CD27+CD24lowCD19+ B cell subset was present in the circulation of some MS patients prior to treatment, but returned to the very low levels found in healthy controls following four months of BG-12 treatment. The data suggest that BG-12 has in vivo down regulatory effects on some lymphocyte subsets, particularly memory T and B cells. Ongoing experiments are focused on measuring functional differences in T and B cell cytokine production in BG-12 treated patients.
The effects of microRNAs on regulatory T cells in multiple sclerosis (HUM1P.319)
Authors: Severin Mary , Lovett-Racke Amy 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. The pathophysiology that propagates MS is hypothesized to be an autoimmune reaction mediated by pro-inflammatory T cells activated against myelin. Regulatory T cells (Tregs), protectors against such autoimmune responses, are dysfunctional in MS patients. We investigated which microRNAs, modulators of cellular and disease processes, are regulators of MS pathogenesis and the extent to which these miRNAs regulate genes critical for Treg development. To this end, miRNA profiling studies performed on naïve CD4+ T cells have identified 85 differentially expressed miRNAs in MS patients compared to healthy donors. Of the miRNAs, 23 were predicted to target genes of the transforming growth factor beta (TGFβ) signaling pathway. Given the importance of TGFβ in regards to Treg development and function, we hypothesized that dysregulated miRNAs in the naïve CD4+ T cells of MS patients target the TGFβ-signaling pathway, resulting in defective Tregs and enhanced susceptibility to developing MS. Our data indicate that 1) expression of TGFβ-associated genes is decreased in MS patients, 2) several of the identified miRNAs directly target genes of the TGFβ-signaling pathway, and 3) overexpression of TGFβ-targeting miRNAs causes a decrease in Treg development. Taken together, our data have allowed us to highlight specific miRNAs as being potentially highly relevant in the development of defective Tregs in MS.
Exacerbation of neurodegeneration by an α-synuclein specific CD4+ effector T cell line in a mouse model of Parkinson’s disease (HUM1P.326)
Authors: Wilshusen Rebecca , Anderson Kristi , Szlachetka Adam , Mosley R. 
Published: January 2023

Abstract
We have previously shown in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model that T cell-mediated immunity regulates innate immunity to exacerbate neuroinflammation. Effector T cells that recognize nitrated α-synuclein (N-α-syn) as non-self, increase reactive myeloid microglia and inflammatory mediators with prolonged progression and increased dopaminergic neurodegeneration within the substantia nigra (SN) of MPTP treated mice. This study focuses on the generation of an N-α-syn specific CD4+ T cell line with the ability to increase release of reactive nitrogen species (RNS) from myeloid lineage cells and also intensify the loss of tyrosine hydroxylase (TH) expressing dopaminergic neurons within the SN of MPTP intoxicated mice. Flow cytometric analysis showed the T cell line exhibited very distinct expression of CD3, CD4 and IL-17a, moderate staining for CD146, yet very little expression of CD8 and FoxP3. Co-culture of the T cells with N-α-syn and BV-2 cells increased RNS production of BV-2 cells by 150% compared to controls. Lastly, adoptive transfer of the T cell line to MPTP intoxicated mice exacerbated the loss of TH+ dopaminergic neurons by 63% compared to controls. Together, these results support the notion that effector T cells specific for N-α-syn increase oxidative stress as measured by RNS release from reactive myeloid microglia, increase the loss of TH+ neurons, and thus may play a pivotal role in the tempo and progression of Parkinson’s disease.
The autoimmunity-associated gene CLEC16A controls HLA-II expression by participating in the molecular machinery of late endosomal maturation (HUM2P.337)
Authors: Laman Jon , van Luijn Marvin , Kreft Karim , Jongsma Marlieke , Mes Steven , Wierenga-Wolf Annet , van Meurs Marjan , Melief Marie-Jose , van der Kant Rik , Janssen Lennert , Janssen Hans , Priatel John , Tan Rusung , Neefjes Jacques , Hintzen Rogier 
Published: January 2023

Abstract
In GWA studies, CLEC16A has been identified as a risk gene for several major autoimmune diseases, including multiple sclerosis (MS). We show that CLEC16A is increased in MS and functionally links to HLA-II, and uncovered the molecular mechanism of CLEC16A as key regulator of HLA-II antigen presentation. We used the human melanoma cell line MelJuSo and primary moDC as APC models to silence CLEC16A with different siRNA and lentiviral shRNA. CLEC16A knockdown in MelJuSo cells and moDC resulted in cytoplasmic dispersion and strong accumulation of HLA-II+ late endosomes, suggesting impaired formation of multivesicular late endosomal compartments, i.e. MIIC. Indeed, in CLEC16A shRNA transductants, MIIC contained no or a few abnormally enlarged internal vesicles and showed an increased number of HLA-II molecules as compared to scrambled shRNA transductants of MelJuSo cells. CLEC16A associated with Rab7-interacting lysosomal protein (RILP) and the homotypic fusion and protein sorting (HOPS) complex, two members of the dynein motor complex regulating late endosomal trafficking and maturation. In addition, CLEC16A silencing disrupted RILP-mediated recruitment of HLA-II+ late endosomes to perinuclear regions. We reveal direct involvement of CLEC16A in the machinery regulating late endosomal processing of HLA-II. This novel C-type lectin function supports a pathogenic role of CLEC16A in autoimmune disease by promoting HLA-II antigen presentation via the formation of MIIC.
Alcohol consumption increases ultraviolet radiation induced immune dysfunction. (HUM2P.341)
Authors: Brand Rhonda , Stottlemyer J. Mark , Paglia Melissa , Falo Louis 
Published: January 2023

Abstract
Alcohol ingestion and sun exposure often occur simultaneously. Excessive ultraviolet radiation (UVR) is associated with increased incidence of nonmelanoma skin cancers (NMSCs). More recently, epidemiologic studies have revealed an independent correlation between alcohol use and increased incidence of NMSC. Although multiple factors have been proposed to explain these interactions, the underlying mechanisms responsible for this association have not been determined. Impaired tumor surveillance contributes to the development of skin cancer, and UVR can suppress immune function. Furthermore, the metabolism of alcohol can also suppress immune function. We therefore sought to determine whether UVR mediated immune dysfunction is affected by alcohol consumption. Specifically, we evaluated UVR induced immune suppression in the presence or absence of alcohol ingestion by combining standard mouse models of alcohol consumption and UVR induced immune suppression. In this controlled system, our results demonstrate that mice exposed to both ETOH and UV suffer greater immune suppression than those exposed to either alone. These results suggest that combining alcohol and UV exposure increases immune suppression, and support additional efforts to investigate the interactions between UVR and alcohol relevant to immunosuppression and the development of NMSC.
Activating mutations in p110δ cause human immunodeficiency and reveal important roles of PI3K in T cell senescence and homeostatic cell death (HUM2P.334)
Authors: Lucas Carrie , Lenardo Michael 
Published: January 2023

Abstract
The p110δ subunit of phosphatidylinositol-3-kinase (PI3K) is selectively expressed in leukocytes and plays critical roles in lymphocyte biology. We have identified 14 patients from 7 families who were heterozygous for one of three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ) and suffered from sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia, and viremia due to cytomegalovirus and/or Epstein-Barr virus. Strikingly, hyperactivation of PI3K signaling caused significant skewing of peripheral blood CD8 T cells toward an effector phenotype with exaggerated effector characteristics in vitro. Mechanistically, T cell blasts harboring gain-of-function mutations in p110δ exhibited constitutively hyperactive Akt and mTORC1 signaling with enhanced glucose uptake. These changes promoted marked terminal effector cell differentiation and senescence of CD8 T cells. Notably, treatment of patients with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely ‘rescued’ the in vitro T cell defects, and greatly improved clinical course. In addition to enhanced effector characteristics, in vitro analyses of patient T cell blasts also revealed a greater susceptibility to TCR restimulation-induced cell death. Indeed, in an independent chemical genetics screen, PI3K stood out as a critical pro-death kinase whose downstream signaling connected with caspase activation upon TCR restimulation.
Fluvastatin suppresses IgE-mediated mast cell activation in vitro and in vivo (HYP3P.411)
Authors: Kolawole Elizabeth , Ndaw Victor , Ryan John 
Published: January 2023

Abstract
Fluvastatin, the HMG-CoA reductase inhibitor known for its role in the treatment of hypercholesterolemia and cardiovascular disease, has more recently been shown to play a role in the immune response. Given the critical role that mast cells play in allergy and inflammatory diseases such as asthma, which effects one third of America’s population, we assessed the effect of Fluvastatin on mast cell function. We demonstrate that Fluvastatin downregulated IgE-mediated cytokine production and mast cell migration. Additionally, in vivo studies showed that Fluvastatin suppressed IgE-mediated anaphylaxis. Interestingly, the effect of Fluvastatin may be restricted to mast cells cultured from mice with a Th1-prone background. Characterizing the role of Fluvastatin on mast cells may prove to be therapeutically important.
Suppression of IgE-mediated disease by rapid desensitization with anti-FcεRIα mAb (HYP3P.345)
Authors: Khodoun Marat , Kiselev Artem , Mulloy James , Wunderlich Mark , Morris Suzanne , Strait Richard , Finkelman Fred 
Published: January 2023

Abstract
IgE-mediated mast cell and basophils activation is critical for the pathogenesis of anaphylaxis, drug allergy, food allergy and allergic skin disorders and contributes to the pathogenesis of asthma and allergic rhinitis. We recently demonstrated that IgE-mediated anaphylaxis in mice can be safely blocked by rapid desensitization with ascending doses of an anti-mouse FcεR1α Abs, starting with a dose too small to induce detectable disease and ending with a dose that induces anaphylaxis if injected into previously untreated mice (JACI, 131:1555-64, 2013). We have now modified this approach, which removes IgE from mast cells, to make it human-applicable, faster and safer. To do this, we: (1) generated a chimeric anti-human FcεR1α mAb that has V regions from a mouse anti-human FcεR1α mAb (15.1) and C regions from human IgG1; (2) substituted a mAb that binds FcεR1 regardless of whether it is associated with IgE for a mAb that only binds FcεR1 that is not IgE-associated; and (3) mutated the γ1 chain C region to increase its affinity for the inhibitory receptor, FcγRIIB. The potential usefulness of this approach has been demonstrated in IgE-mediated anaphylaxis models in mice that express human, instead of mouse FcεRIα and in human cord blood-reconstituted NSGS mice, which generate human mast cells, basophils and IgE-secreting B cells. These observations suggest that full development of this approach should provide a way to safely and rapidly suppress IgE-mediated human allergy.
Signaling via neurokinin 1 and 2 receptors exerts opposing effects on mast cell pro-inflammatory and Th2-biasing functions. (HYP3P.347)
Authors: Sumpter Tina , Tkacheva Olga , Shufesky William , Morelli Adrian , Larregina Adriana 
Published: January 2023

Abstract
Following activation via FcεRI, peripheral tissue mast cells (MCs) initiate and sustain atopic diseases, by secreting proinflammatory and Th2 biasing cytokines. MC express neuropeptide receptors and are exposed to neuroinflammatory mediators. However, the role of neuropeptides in FcεRI-activated MCs remains mainly unknown. Two of the most potent pro-inflammatory neuropeptides, substance-P (SP) and hemokinin-1 (HK-1), bind with high affinity to the neurokinin 1 receptor (NK1R) and with lower affinity to the NK2R. We addressed in vitro and in vivo the role of the NK1R and NK2R in MC responses initiated via FcεRI. In vitro, FcεRI activation of bone marrow derived (BM)MCs from wild type (WT) mice increased NK1R and NK2R expression and HK-1 release, but not release of SP. Utilizing NK1R-/- BMMCs, we determined that the NK1R was necessary for Akt-NFκB signaling and for the secretion of the pro-inflammatory TNF-α, IL-6 and Th2 biasing IL-4 and IL-13. Conversely, inhibition of NK2R signaling in WT BMMCs with GR159897 decreased the release of proinflammatory and Th2 cytokines. In vivo, NK1R signaling was necessary for amplifying IgE-Ag mediated cutaneous and systemic anaphylaxis and chronic asthma. We conclude that NK1R and the NK2R display opposing effects on the inflammatory function of FcεRI-activated MCs relevant for the control of MC derived atopic disorders.
Tetraspanin CD151 specifically regulates ERK1/2 signaling to limit FcεRI-mediated production of cytokines by mast cells (HYP3P.349)
Authors: Abdala-Valencia Hiam , Bryce Paul , Wechsler Joshua , Cook-Mills Joan , Hsu Chia-Lin , Berdnikovs Sergejs 
Published: January 2023

Abstract
Mast cells and basophils are granulocytes critical in the pathogenesis of allergic disease due to the release of preformed and newly synthesized mediators. Tetraspanins are emerging as novel modulators of signals for cellular activation, however, mechanistic understanding of their function is currently lacking. We found tetraspanin CD151 to be specifically induced in human and mouse mast cells upon IgE stimulation, suggesting a functional role in activation of these cells. Here, we show that CD151 modulates IgE-induced mast cell activation by exerting selective control over downstream pathways regulating de novo synthesis of cytokines IL-4, IL-13 and TNF-α. Mechanistically, CD151 selectively targets IgE-induced activation of ERK1/2, associated with cytokine production, but has no regulatory effect on PLCγ1 or calcium release necessary for degranulation. Inhibition of ERK1/2 blocks the exaggerated induction of cytokines by CD151 deficient mast cells. In vivo, CD151 deficiency significantly exacerbates IgE-mediated late phase response in a murine model of passive cutaneous anaphylaxis. Collectively, our data indicate that CD151 functions in the late phase of IgE-induced mast cell activation by limiting cytokine synthesis.
Leukotriene enhanced allergic lung inflammation through induction of chemokine production (HYP4P.414)
Authors: Kwon Bo-In , Shin Kihyuk , Lee Seung-Hyo 
Published: January 2023

Abstract
Leukotrienes, which are mainly expressed by mast cells, macrophages and eosinophils, have been shown to act as important mediators in allergic asthma. In addition to leukotrienes, IL-13, a Th2 specific cytokine, has also been considered as the most important effector cytokine to induce allergic asthma, by increasing airway hyper-responsiveness, airway inflammation, eosinophilia and mucus hyper-production. But, the exact mechanisms how leukotrienes elicit allergic lung responses at initial stage and the effect of leukotrienes on allergic asthma through IL-13 remain unclear. To reveal this, we adopted two distinct models of allergic inflammation: intranasal Aspergillus protease allergen and recombinant IL-13 induced Th2 mediated inflammation. Here we measured AHR, bronchoalveolar lavage cytology, glycoprotein secretion, as well as IL-13 related chemokines such as CCL7, CCL11 and CCL17, which directly regulate homing of Th2 cells to lung with 5-lipoxygenase deficient and wild type mice. 5-lipoxygenase that convert arachidonic acid into leukotriene A4 null mice showed attenuated airway inflammation, AHR and bronchoalveolar lavage eosinophilia, as well as diminished chemokines including CCL7 and CCL17. Finally, addition of LTB4 and LTC4 to the airways of 5-lipoxygenase deficient mice restored rIL-13 induced asthma. Thus, our results indicate that LTs augment the effect of IL-13 in allergic asthma, are required for Th2 specific chemokine production.
Allergen-specific lung resident CD4+ Th2 cells in asthma (HYP4P.417)
Authors: Pepper Marion , Hondowicz Brian , Moon James 
Published: January 2023

Abstract
Asthma is an inflammatory disease of the airways that affects more than 300 million people worldwide. Clinically, asthma is characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. Allergen-specific CD4 T cells contribute to this process by producing cytokines and inducing B lineage production of IgE. Allergen-specific CD4 memory T cells are also thought to persist after resolution of inflammation to rapidly drive asthma-induced pathology. Due to the challenge of tracking small populations of CD4 T cells that express allergen pMHCII-specific TCRs, little is known about what regulates Th2 memory cell differentiation, migration and maintenance. We have therefore produced a MHCII tetramer containing a peptide from the Derp1 protein of the house dust mite (HDM), the most common cause of atopic asthma, to elucidate the underlying mechanisms of Th2 memory cell differentiation during atopic asthma. Tetramer-based enrichment strategies used to isolate Derp1:I-Ab+ cells from the secondary lymphoid organs and lungs have revealed that heterogenous Th2 memory populations form, including a CD69+ Derp1:I-Ab+ population in the lung thats persists post-contraction. Intravascular staining techniques demonstrate that these cells reside in the lung parenchyma and are driven to the lung by early cytokine exposure. These findings have important implications for novel immunotherapeutics in both asthma and allergy.
Peroxiredoxin released in inflammasome condition activates the classical complement pathway (INM2P.427)
Authors: Lee Hyun Sook , Kim Sook Young , Shin Jeon soo 
Published: January 2023

Abstract
Peroxiredoxin (Prx) family proteins are expressed in diverse cellular components and play roles as antioxidant proteins that control ROS level. Recently, it has been reported that Prx was released in ischemic brain. We, therefore, focused on investigating how Prx is released and the role of released Prx. In this study, we show that Prx could be released by LPS stimulation in immune cells. Moreover, the release of Prx was dramatically increased in inflammasome condition through priming LPS followed by ATP treatment. To examine the interaction between released Prx and complement, we performed in vitro binding assay. Recombinant Prx protein binds recombinant C1q protein. Also, we observed membrane attack complex (MAC) in normal human sera, which is a result of activation of the complement pathway. To clarify whether these complement activation by Prx is a C1q-dependent response; we confirmed the formation of MAC using C1q-depleted human sera. The effect of Prx in formation of MAC was significantly reduced in C1q-depleted human sera. Through this, we found that complement activation by Prx is a C1q-dependent response. In conclusion, our results reveal that Prx was released by inflammasome-dependent and -independent pathways in immune cells. Released Prx, then, binds to C1q and activates the classical complement pathway. These findings suggest that released Prx may have synergistic effect with complement in inflammation, which can be a target in septic inflammation therapy.