bluuebunny/crossref_metadata_2025_split huggingface dataset:
SLP-76 Adaptor Binding to SUMO-RANGAP1 of the Nuclear Pore Complex Regulates Multiple Aspects of T-cell Immunity
Authors: Rudd Christopher E , Jules Felix 
Published: January 2023

Abstract
While immune cell adaptors regulate various proximal events in T cell signaling, the direct regulation of the nuclear pore complex (NPC) has not been reported. On the cytoplasmic side of the NPC, there are cytoplasmic filaments composed of two fundamental proteins RanGAP1 and RanBP2. We previously showed that the immune cell adaptor SLP-76 binds directly to SUMO-RanGAP1 of cytoplasmic fibrils of the NPC, and that this interaction is needed for optimal NFATc1 and NF-κB p65 nuclear entry in T cells (Liu et al., 2015 Mol Cell 59, 840–9). The use of a mutant form of SLP-76 that is unable to bind to RanGAP1 (i.e. K56E) reduced nuclear entry and T-cell cytokine production by &gt;60%. It represents the second step in NFATc1 entry into the nucleus of T-cells following classic NFATc de-phosphorylation by calcineurin. We now show that K56E mutant reduced toll-like receptor induction of NF-κB nuclear entry (innate signaling) and that T-cells from K56E mutant mice show major defects in T-cell proliferation and immunity. Our findings further underscore the importance of this direct regulation of NPC function in T cell function.
NAADP mediated calcium signaling in memory CD4+ T cells
Authors: Chakraborty Anish , Giovannucci David R. , Slama James T. , Wall Katherine Ann 
Published: January 2023

Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a metabolite of NADP that serves as a Ca2+ mobilizing second messenger in a variety of different eukaryotic cells including lymphocytes. Although the sources of Ca+2 mobilized by NAADP in lymphocytes are still under study and controversial, NAADP-responsive stores in other cells are often acidic, lysosome-related organelles. NAADP-mediated calcium signaling and its downstream physiological responses have been studied in our lab in naïve, effector, and natural regulatory T cells; however, these have not been studied in memory T cells. Since calcium responses vary in different T cell subsets, it is important to examine this pathway in memory cells as well. Memory T cells are important in terms of maintaining a pool in a quiescent state and activating more rapidly than do naïve cells during exposure to cognate antigen. Using a pharmacological approach with the NAADP antagonist Ned-19, we are studying the involvement of NAADP in memory CD4+ T cells during TCR activation and its downstream physiological events, such as proliferation and cytokine production. This study will gain insight into the possible sources of Ca2+ released in response to NAADP-mediated TCR activation of memory CD4+ T cells.
Human germinal center B cells are intrinsically distinct from naive B cells
Authors: Quizon Nicolas , Kwak Kihyuck , Sohn Haewon , Pierce Susan K. 
Published: January 2023

Abstract
In germinal centers (GCs) B cells undergo cycles of proliferation and somatic hyper mutation followed by affinity discrimination. Selection of GC B cells expressing high affinity B cell receptors (BCRs) is driven by the ability of B cells to signal through the BCR and extract antigen to present to follicular helper T cells. Here we provide evidence that human tonsillar GC B cells, as compared to naïve tonsillar B cells, may have a higher threshold for affinity selection but be better able to interact with T cells and, once triggered through the BCR, may form more stable signaling complexes. A comprehensive quantitative analysis of surface proteins showed distinct profiles for naïve and GC B cells. In particular, GC B cells express less of the integrin VLA-4 and as a consequence were less able to engage beads coated with its ligand, VCAM-1. Given that VLA-4 tethers B cells to VCAM-expressing cell surfaces and facilitates BCR-dependent activation, a reduction in VLA-4 expression would be predicted to raise the threshold for affinity selection in GC B cells. GC B cells also tended to have increased surface expression of proteins that mediate T-B-cell interactions, such as CD80 and CD86, suggesting that once antigen is captured and presented GC B cells would be better equipped to engage helper T cells. To explore BCR signaling we imaged synapses formed between B cells with anti-Ig-containing planar lipid bilayers via total internal reflection fluorescence microscopy. GC B cells tended to form more stable signaling complexes showing greater co-localization between their BCRs and components of their signaling pathway. Taken together these data point toward intrinsic differences between GC and naïve B cells that may contribute to the outcome of GC responses.
Regulatory effects of Interleukin (IL)-15 on allergen-induced airway obstruction
Authors: Venkateshaiah Sathisha Upparahalli , Manohar Murli , Verma Alok Kumar , Mishra Anil 
Published: January 2023

Abstract
Airway obstruction is a highly specific term that represents physiologic abnormalities of the airways and induced levels is observed in steroid treated asthmatic patients. We tested the hypothesis that regulation of IL-15 is critical for the preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance and compliance in response to methacholine. Airway inflammation, AHR, resistance and compliance were assessed in IL-15-deficient mice and IL-15 overexpressed mice in allergen-induced murine model of asthma. Lung histological analysis for eosinophils by anti-MBP immunostaining, Goblet cells hyperplasia by PAS staining, cytokines and chemokine levels by qPCR and ELISA analyses. Herein, we made a novel observation that IL-15 deficiency promotes baseline airway resistance in naïve mice. Moreover, rIL-15 delivery to the lung downregulates expression of inflammatory cytokines, and improves allergen-induced AHR, resistance and compliance. These observations were further validated in DOX-inducible CC-10-IL-15 transgenic mice. DOX exposed Aspergillus extract challenged CC-10-IL-15 bitransgenic mice exhibited significantly reduced levels of inflammatory cytokines (IL-4, IL-5, IL-13) and goblet cell hyperplasia. Airway obstruction, including AHR and resistance was diminished in allergen challenged DOX exposed compare to no-DOX exposed CC-10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-induced protection of airway obstruction is associated with the induced IL-10-producing regulatory CD4+CD25+Foxp3+ T cells. We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens/pollutants.
IL-15-deficient mice develop enhanced airway allergic responses in a mouse model of allergic airway disease
Authors: Mathias Clinton B , Schramm Craig M , Guernsey Linda , Polukort Stephanie , Rovatti Jeffrey , Ser-Dolansky Jennifer , Secor Eric , Schneider Sallie S , Thrall Roger S , Aguila Hector L 
Published: January 2023

Abstract
Interleukin-15 is a pleiotropic cytokine critical for the development of multiple hematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+T cells. We therefore hypothesized that IL-15−/− mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). Here we report that IL-15−/− mice developed enhanced allergic responses in an OVA-induced model of AAD. C57BL/6 wild-type (WT) and IL-15−/− mice were sensitized and challenged with ovalbumin (OVA) and the development of AAD was ascertained. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+T and B cells in the spleens and broncholaveolar lavage were also observed. Examination of OVA-challenged IL-15R−/− animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15−/− animals to levels observed in WT mice, but had no further effects. These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK and NKT cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice.
Toll-like receptor-7-mediated activation of pDCs suppresses the ILC2-mediated airway hyperreactivity and inflammation through type-I interferon
Authors: Maazi Hadi , Banie Homayon , Aleman German , Lewis Gavin , Patel Nisheel , Wang Bowen , Soroosh Pejman , Akbari Omid 
Published: January 2023

Abstract
Type 2 innate lymphoid cells (ILC2s) are newly identified subset of immune cells that play important roles in the pathogenesis of allergic diseases and asthma. The regulatory mechanisms that control the function and homeostasis of ILC2s are incompletely understood. Plasmacytoid dendritic cells (pDCs) have been previously associated with maintaining respiratory tolerance. To identify a novel mechanism for alleviating ILC2-mediated asthma we investigated impact of pDCs on ILC2s and ILC2-mediated airway hyperreactivity and inflammation.
We investigated human and murine ILC2s and used clinically relevant allergen, Alternaria Alternata, as well as IL-33, to activate ILC2s in several mouse models including BDCA-2-DTR transgenic and Interferon alpha receptor-1 deficient mice.
We found that activation of pDCS by a Toll-like receptor-7 agonist, R848, suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. Moreover, we found that pDCs suppress cytokine production and proliferation of ILC2s through the production of interferon alpha. Transcriptome analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by interferon alpha.
In addition, activation of pDCs alleviates airway hyperreactivity and inflammation by suppressing ILC2’s function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications.
Role for dysregulated iron in the pathogenesis of murine models of lung disease
Authors: Horvat Jay C , Ali Md Khadem , Johnstone Daniel , Kim Richard Y , Mayall Jemma R , Karim Rafia , Pinkerton James W , Heidari Moones , Martin Kristy L , Donovam Chantal , Liu Gang , Milward Elizabeth A , Hansbro Philip M 
Published: January 2023

Abstract
Altered iron levels and/or dysregulated iron homeostasis have been associated with a number of lung diseases, however, the mechanisms that underpin these associations, and whether iron plays a role in the pathogenesis of disease, are yet to be fully elucidated. In this study, systemic and pulmonary iron and lung structure and function were assessed in transferrin receptor (TFR)2 mutant and wild-type (WT) BALB/c mice fed a high-iron diet (containing 2% carbonyl iron) compared to normal diet controls, respectively. The effects of increased iron loading on murine models of ovalbumin- and house dust mite-induced allergic airways disease (AAD) were also assessed. Excess iron accumulation was observed in the lungs in both the genetic and diet-induced models of iron overloading. Increased iron levels in the lung were associated with emphysema-like alveolar enlargement, small airways collagen deposition, alterations in baseline lung function and increased airways hyper-responsiveness (AHR). Increased iron loading also resulted in altered type 1, 2 and 17 cytokine production, increased eosinophilic inflammation and severe, steroid-resistant AHR in AAD. Interestingly, AAD also results in altered systemic and pulmonary iron levels and iron regulatory molecule expression. These data show that increased iron levels in the lung results in emphysema and airways fibrosis that corresponds with reduced lung function. We also show that lung disease may be closely associated with changes in iron homeostasis. These models will be used to characterize the interplay between iron and immunity in the pathogenesis of lung disease and determine the therapeutic effectiveness of correcting dysregulated iron homeostasis for the treatment of lung disease.
Systemic and unconventional antigen presentation generates insulin autoantibodies targeting the islet of Langerhans
Authors: Wan Xiaoxiao , Thomas James W , Unanue Emil R 
Published: January 2023

Abstract
The presence of class-switched insulin autoantibodies (IAAs) is a prominent feature of patients with type 1 diabetes (T1D) and the non-obese diabetic (NOD) mice. Although IAAs are commonly used as a biomarker for T1D prognosis, their genesis and whether they play a pathogenic role is largely unknown. In this study, we developed a novel anti-insulin T cell and B cell receptor transgenic mouse model to investigate cognate interactions between insulin-reactive T and B lymphocytes, a process necessary for IAA production. Strikingly, dynamic anti-insulin T-B cell interactions, spontaneous germinal center formation, and active class-switch recombination occurred in multiple lymphoid organs, leading to remarkable IAA production. Naïve anti-insulin T cells differentiated into competent T follicular helper cells that produced critical factors for reversing B cell tolerance, promoting GC selection, and broadening the repertoire of insulin epitope presentation. Furthermore, the IAAs produced in the peripheral sites relocated into the islets of Langerhans, formed deposits on β-cells, and enhanced presentation of diabetogenic antigens by the resident islet macrophages. Overall, these results indicate that insulin presentation is disseminated throughout secondary lymphoid tissues, and is sufficient for generation of autoantibodies that precipitate previously unrecognized pathogenic outcomes in the target organ.
IL-10 producing B cells regulate sex bias in male mice with experimental immune-mediated drug-induced hepatitis
Authors: Njoku Dolores B , Cottagiri Merylin , Nyandjo Maeva 
Published: January 2023

Abstract
Sex modulates severity in autoimmune diseases. In susceptible individuals, drug metabolites induce hepatitis, autoimmunity and liver injury. This drug–induced hepatitis is a leading cause of liver failure and is the most common reason an approved medication is removed from the consumer market. We modeled this hepatitis in BALB/c mice and showed that estrogen and IL-6 increase severity and down-regulate IL-10 and Foxp3+ regulatory T cells; however, additional regulatory cells have not been identified. We induced experimental hepatitis in female and male CD1d−/− mice (NKT and CD1d+B cell-deficient), JH−/− (mature B cell and IgG deficient) and BALB/c (WT) mice by immunizing them with a cytochrome P4502E1 (CYP2E1) epitope (JHDN5) modified by a drug metabolite. Mice were evaluated for CFSE proliferation to drug metabolites as well as CYP2E1 and JHDN5, hepatitis and cytokines by ELISA. CD1d and B cell deficiency abolished sex bias. Male CD1d −/− mice developed more hepatitis than male WT mice (p&lt;0.05); however these mice were also deficient in NKT cells as well as B cells expressing CD1d. Even though CFSE proliferation was 50% of male WT, male JH−/− mice developed more severe hepatitis (p&lt;0.05) and higher TGF-β (p&lt;0.01) levels than male WT. In contrast, IL-10 and IL-17 levels were up-regulated in male WT mice (p&lt;0.05). Prior studies show that IL-17 promotes B cell help in immune responses, while IL-10 supports regulatory T and B cells. Our studies suggest regulatory roles for B cells in male mice and preliminarily suggest regulatory roles for CD1d expression on B cells in the development of sex bias in drug-induced hepatitis. We are currently characterizing B cells to determine their therapeutic potential in drug-induced hepatitis.
Isotype-switch competent anti-insulin B cells promote autoimmune diabetes despite functional silencing
Authors: Felton Jamie Lynn , Bonami Rachel , Hulbert Chrys , Thomas James W 
Published: January 2023

Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin producing beta cells, leading to chronic hyperglycemia and a lifelong need for exogenous inulin. In humans, T1D can be predicted by the emergence of multiple, islet autoantibodies years before the onset of clinical symptoms, highlighting an early breach in B cell tolerance that is central to disease development. Studies using a transgenic mouse model with increased frequencies of insulin-specific B cells (VH125SD/B6) have demonstrated that these pathogenic B cells are functionally silenced in the B6 mouse. However, mechanisms of tolerance induced by transgenes are often reversed when introduced onto autoimmune backgrounds. To determine whether an autoimmune background alone is necessary to reverse tolerance in T1D, the VH125SD transgene was introduced into the NOD mouse (VH125SD/NOD). Unexpectedly, despite their ability to accelerate disease progression and clear capacity to promote pathogenic inflammatory responses, insulin-specific B cells remained functionally silent (unable to mount antibody or proliferative responses) in the NOD mouse. Together, these results suggest that it is a degree of functional impairment, and not an overt breach in tolerance, that drives autoimmunity in the NOD mouse.
Multiple extrinsic signals are required for the enrichment of dual-reactive B cells in autoimmune mice
Authors: Sang Allison L , Fournier Emilie , Torres Raul M , Pelanda Roberta 
Published: January 2023

Abstract
Dual-reactive B cells expressing two different immunoglobulin heavy or light chains are present in both healthy humans and mice. However, a subset of systemic lupus erythematosus patients are enriched for dual-reactive B cells. To study dual-reactive B cells in an autoimmune background we used congenic mice bearing a gene targeted human Cκ allele which allowed for the identification and tracking of dual-κ B cells within a polyclonal B cell repertoire. We previously showed that dual-κ B cells positively correlated with disease progression and were enriched in the plasmablast and memory B cell compartments of lupus-prone MRL/lpr mice. Recent studies showed that T cells play a major role in the enrichment of dual-κ B cells, as MRL/lpr mice deficient in the IL-21 receptor had a significant reduction in total dual-κ B cells. In addition, IL-21 signaling was required for the maximal differentiation of dual-κ B cells into plasmablasts and was essential for the development of dual-κ memory B cells. Dual-κ B cells were shown to significantly upregulate antigen presenting molecules such as MHCII, CD80, and CD86. While dual-κ B cells are enriched for polyreactive B cells, immunization with a T-dependent antigen elicited a similar response between single and dual-κ B cells. However, the addition of TLR9 stimulation amplified the antigen-specific response exclusively in dual-k B cells. Furthermore, in vivo EdU incorporation studies showed that dual-k B cells have a higher proliferation rate than single-κ B cells in the absence of exogenous stimuli. Overall, elucidating the diverse molecular pathways promoting the enrichment of dual-reactive B cells in autoimmunity will allow for the selective targeting of these cells in autoimmune patients.
Anti-myelin oligodendrocyte glycoprotein (anti MOG) antibodies in Neuromyelitis optica patients
Authors: Zarkesh-Esfahani Sayyed Hamid , Mirmosayyeb Omid , Manouchehri Navid , Shaygannejad Vahid 
Published: January 2023

Abstract
Neuromyelitis Optica (NMO) is an autoimmune disease of the central nervous system. It is associated with optic neuritis and concomitant acute myelitis. As the anti Aquaporine-4 antibodies (NMO-IgG) is routinely used for disease evaluation, other markers are being proposed for a better understanding of the disease. The aim of this study was to assess the status of anti-myelin oligodendrocyte glycoprotein (anti MOG) antibodies in NMO patients and controls.
41 previously diagnosed NMO patients and 30 healthy controls were enrolled. Baseline demographic data, imaging features and disease characteristics were recorded from all patients. Disease characteristics were compared between different patient groups based on their NMO-IgG and anti MOG results.
For anti MOG antibodies, 39 % of the patients and 13.3 % of the controls showed positive results (P = 0.01). There was no significant correlation between the disease longevity and anti MOG levels in patients (r= 0.29, P = 0.08). Also no significant difference was observed between the anti MOG results and EDSS status among patients (P = 0.58). Among the patients, 22% had positive results for NMO-IgG while 29.2% of them tested positive for anti MOG but negative for NMO-IgG. Regarding the MRI results, NMO-IgG positive patients had normal brain appearance and higher rates of longitudinally extended transverse myelitis along with less disease severity while positive anti MOG group included more patients with severe disease and less normal brain appearances; however these findings were not statistically significant.
Anti MOG antibody levels are helpful for better categorization of NMO patients. Presence of anti-MOG in NMO patients may suggests a particular pattern of disease progression.
The association of monocytes and Tregs with disease activity in rheumatoid arthritis
Authors: Eakin Amanda Jayne , Ahmed T , McGeough C M , Alexander H D , Wright G D , Gardiner P V , Bjourson A J , Gibson D S 
Published: January 2023

Abstract

Background
Rheumatoid arthritis (RA) is an autoimmune condition characterised by inflamed joints. Disease-modifying anti-rheumatic drugs (DMARD) are ineffective in 30–40% of patients. CD169 (Siglec-1) is expressed by monocytes and correlates with disease activity in RA. It drives pro-inflammatory processes including the suppression of Tregs through its cognate ligand, CD169L. This study aims to define the relationship between CD169, CD169L and disease activity, as a potential early biomarker of treatment response.

Methods
Peripheral blood mononuclear cells were isolated from healthy controls and RA patients who failed DMARD treatment. FACS was used to: (i) immunophenotype CD169+ monocytes and CD169L+ Tregs, and (ii) assess levels of FoxP3 within Tregs.

Results
RA patients had a significantly higher percentage of CD169+ monocytes (28.47 ± 7.17, (mean ± SEM), n=19) compared to healthy controls (8.03 ± 1.48, n=19, p=&lt;0.01). A negative correlation was also observed between the percentage of CD169+ monocytes and CD169L+ Tregs in RA patients (r=−0.72, n=19, p=&lt;0.01). Furthermore, the ratio of CD169:CD169L percentages has a positive association with DAS28-ESR (r=0.77, n=9, p=0.02). FoxP3 is expressed at lower levels in RA patients (24.14 ± 1.87, n=25) compared with healthy controls (46.65 ± 6.16, n=13, p=&lt;0.01).

Conclusion
These results provide preliminary evidence of a relationship between CD169 and CD169L, and further define how their balance is associated with disease activity. Low levels of FoxP3 in RA patients indicates reduced Treg activation, which may cause increased disease activity. We postulate that this balance of cells is key in the immune response and could be used as a surrogate measure of disease activity.