bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peroxisome Proliferator-Activated Receptor Delta (PPARδ) activity is required for normal T cell development
Authors: Zhao Fei , Ahn Jeeyoon Jennifer , Drohomyrecky Paulina , Zuniga-Pflucker Juan Carlos , Dunn Shannon 
Published: January 2023

Abstract
PPARδ is a nuclear receptor that functions as a transcriptional regulator of various processes including metabolic homeostasis, cell proliferation and differentiation; however, whether PPARδ regulates T cell development is not known. We observed that PPARδ-deficient (PPARδ−/−) mice have smaller spleens and thymi compared to wild-type (WT) mice. This reduction in thymus cellularity was apparent across all stages of thymocyte development. To further narrow in on the cellular basis of this effect, radiation bone marrow chimeras were generated where WT or PPARδ−/− mice were reconstituted with WT or PPARδ−/− bone marrow. These experiments clearly revealed that the defects in thymus and spleen mapped to the radio-resistant compartment. This was furthered confirmed by the finding that mice with T cell-restricted deficiency of PPARδ did not exhibit defective thymocyte homeostasis. Given that thymic epithelial cells (TECs) are the major radio-resistant cell population in the thymus, we next generated mice with a TEC-restricted deficiency of PPARδ (PPARδflox/floxFoxN1-Cre+). We observed that PPARδflox/floxFoxN1-Cre+ mice exhibit a trend for reduced thymus and spleen cellularity compared to PPARδflox/flox mice; however, this phenotype was not as striking as seen in PPARδ−/− mice. These results suggest that, in addition to acting within TECs, PPARδ may regulate the production of a circulating factor that in turn regulates thymocyte development. Large-scale serum profiling studies are underway to identify this factor. Altogether, this work highlights a role for PPARδ in T cell development.
Fusion of Early B Cell Factor 1 with Platelet-Derived Growth Factor Receptor Beta in B-ALL disrupts functions necessary for normal B lymphopoiesis
Authors: Hagman James R , Welsh Seth J 
Published: January 2023

Abstract
Human B cell Acute Lymphoblastic Leukemia (B-ALL) cells often lack functional genes encoding Early B cell Factor 1 (EBF1). EBF1 is essential for B lineage specification, where it regulates &gt;500 genes necessary for normal B cell development. Here, we describe molecular mechanisms that contribute to EBF1-associated B-ALL. Intra-chromosomal deletions result in fusion of the nearly complete EBF1 gene with the 3′ half of the Platelet-Derived Growth Factor Receptor Beta gene (EBF1:PDGFRB) in a subset of high risk pediatric B-ALL. The fusion protein, EBF1:PDGFRβ, unifies loss of EBF1 function with a proliferative advantage due to unregulated Receptor Tyrosine Kinase (RTK) activity of PDGFRβ. Our laboratory has utilized biochemical, cell-based, and fluorescence microscopy approaches to study DNA binding, transcriptional activation and repression, oligomerization, and localization of EBF1:PDGFRβ in B cells. EBF1:PDGFRβ transforms B cell progenitors by eliminating their dependence on IL-7. Although the fusion protein includes nearly intact EBF1 and its nuclear localization signal, EBF1:PDGFRβ localizes predominately in the cytosol. Localization of EBF1:PDGFRβ is dependent upon the transmembrane (TM) domain of PDGFRβ; however, rather than docking EBF1:PDGFRβ in the plasma membrane, the TM functions as a nuclear export signal. Treatment with the tyrosine kinase inhibitor (TKI) imatinib reduces RTK activity and partially restores transactivation of EBF1 target genes by EBF1:PDGFRβ. This suggests a potentially undesirable effect of TKI chemotherapy, which could allow evasion of leukemic cells and disease relapse. Our data suggests that the TM domain of PDGFRβ could serve as a therapeutic target to supplement TKI chemotherapy.
BCAP (B-cell adaptor for phosphoinositide 3-kinase) plays a role in development of Marginal Zone B cells in mice
Authors: He Xiao , Dai Hu , Wang Xiaomin , Skidmore David , Kurosaki Tomohiro , Jensen Peter E 
Published: January 2023

Abstract
B-cell adaptor for phosphoinositide 3-kinase (BCAP) connects B cell receptor (BCR) signaling to the phosphoinositide 3-kinase (PI3K)-Akt pathway. Upon BCR engagement, tyrosine kinases Syk and Btk phosphorylate BCAP and phosphorylated BCAP provides the binding site for the regulatory subunit (p85) of PI3K, leading to relocation of PI3K to cytoplasmic membrane and PI3K activation. In response to CD19 engagement, BCAP phosphorylation is also required for p85 binding of BCAP prior to PI3K and Akt activation. It has been shown that disruption of the BCAP gene in the chicken DT40 B cell line inhibits BCR-mediated phosphatidylinositol 3,4,5-trisphosphate generation, leading to an impaired Akt response through a significant reduction in the recruitment of PI3K to glycolipid-enriched microdomains (lipid rafts). Furthermore, using BCAP knock out (KO) mice, BCAP has been shown to be essential for normal Follicular B and B1 B cell development and function. Here we report that the development of another peripheral B cell subpopulation, Marginal Zone B (MZB) cells, is impaired in BCAP KO mice as well. The numbers of MZB (B220+CD23−CD24midCD21high) cells and their surface expression level of CD80 are significantly reduced, compared to the littermate or age-matched B6 controls. The serum IgG3 level of the BCAP KO mice is also significantly lower than that of control mice. This result is further supported by an in vitro co-culture system, using bone marrow (BM) cells with the OP9-DL1 cells, in which the development of MZB cells from BCAP KO BM is also reduced, compared to B6 BM. Moreover, addition of exogenous BAFF could not fully restore the development of MZB cells from BCAP KO BM. Our data ascribes a role of BCAP to MZB cell development in mice.
Anti-FcγRIIB mAb suppresses IgG-dependent anaphylaxis by Fc domain targeting of FcγRIII
Authors: Clay Corey D , Strait Rick T , Mahler Ashley , Khodoun Marat , Finkelman Fred D 
Published: January 2023

Abstract
The inhibitory Fcγ receptor (FcγRIIB) is expressed on human and murine bone marrow-derived cells. FcγRIIB-mediated inhibition of stimulatory Fcγ receptor signaling limits inflammation in autoimmune, infectious and atopic diseases. We evaluated the ability of the anti-mouse FcγRIIB mAb, k9.361, to influence IgG-mediated anaphylaxis.

Methods
Wildtype and Fcγ receptor (FcγR)-deficient mice were used to study IgG-mediated anaphylaxis, which was induced by i.v. injection of 2.4G2 (a mAb that binds both FcγRIIB and the stimulatory receptor, FcγRIII), or by actively immunizing IgE-deficient mice, then challenging them with the immunizing antigen. Pretreatment with k9.361 was assessed for ability to influence anaphylaxis in these models.

Results
Unexpectedly, a single k9.361 injection induced mild anaphylaxis (assessed as hypothermia), which was both FcγRIIB- and FcγRIII-dependent. Injection with k9.361 also prevented the ability of a subsequent 2.4G2 injection to induce anaphylaxis and suppressed myeloid cell expression of stimulatory FcγRs, particularly FcγRIII. Treatment with k9.361 F(ab′)2 did not cause anaphylaxis, deplete FcγRIII, or suppress 2.4G2-induced anaphylaxis, but prevented the ability of intact k9.361 to induce anaphylaxis, without preventing the ability of intact k9.361 to suppress IgG-mediated anaphylaxis.

Conclusion
Anti-FcγRIIB mAb induces and then suppresses IgG-mediated anaphylaxis by targeting myeloid cell FcγRIII through its Fc domain. Sequential treatment with anti-FcγRIIB F(ab′)2, intact anti-FcγRIIB, and intact anti-FcγRIIB/III mAbs may provide a safe way to prevent IgG-mediated anaphylaxis.
Accumulation of CD23+ CD21-high Bin-like cells in human reactive and rheumatoid arthritis lymph nodes
Authors: Bottaro Andrea , Kuzin Igor , Kates Stephen , Wu Yawen , Rahimi Homaira , Wojciechowski Wojciech , Bernstein Steven , Burack Richard , Schwarz Edward 
Published: January 2023

Abstract
We have previously described a unique population of CD23+ CD21-high B cells in inflamed nodes (Bin) which accumulate in lymph nodes (LN) draining inflamed joints of TNF-transgenic (TNF-tg) mice, and contribute to arthritis flare by distorting node architecture and hampering lymphatic flow. The existence of Bin-like cells in human inflamed LN is yet unknown. Here we report the characterization of resident B cell populations in fresh popliteal lymph nodes (PLN) harvested from discarded tissues from rheumatoid arthritis (RA) patients and patients with other severe lower limb diseases (non-RA), undergoing total knee arthroplasty or lower limb amputation. We also analyzed banked, cryopreserved reactive and normal human LN single cell suspension samples. Bin-phenotype cells were shown to be significantly increased in reactive LN, and strikingly elevated (&gt;30% of total) in RA samples. Histopathology and immunofluorescence analyses were consistent with Bin expansion and histological alterations in RA vs. non-RA PLN. This is the first description of Bin-like cells in human inflamed LN. Consistent with published mouse data, this population appears to be associated with inflammatory arthritis and distortion of LN architecture. Further analysis of this population will be important to assess its role in RA pathogenesis and arthritic flare.
A potential link between immune response to a periodontal bacterium, Aggregatibacter actinomycetemcomintans and Systemic Lupus Erythematosus
Authors: Bagavant Harini , Wolska Nina , Rybakowska Paulina , Kamp Stan , Guthridge Joel , James Judith A , Merrill Joan , Deshmukh Umesh 
Published: January 2023

Abstract
Infections are a significant cause of morbidity in Systemic Lupus Erythematosus (SLE). Although oral health is considerably compromised in SLE patients, the role of oral pathogens in influencing lupus pathogenesis is not known. In the present study, antibody responses to a periodontogenic, facultative anaerobic bacterium, Aggregatibacter actinomycetemcomitans (Aa), (which serve as an indicator of past or ongoing infection with Aa), were measured in SLE patients (n=587) and healthy controls (n=75). The associations between anti-Aa antibody titers and clinical measures of SLE were evaluated. The effect of Aa infection on development of lupus was investigated in the NZM2328 mice. The ability of Aa to induce neutrophil extracellular traps (NETs) was studied in vitro.
Both SLE patients and controls showed the presence of anti-Aa. In SLE patients, the anti-Aa titers correlated strongly with anti-dsDNA, anti-chromatin, anti-RNP, and anti-Sm; but not with anti-Ro52, anti-Ro60, and anti-La antibodies. NZM2328 mice developed a robust immune response to Aa, and the Aa infection caused an accelerated onset of autoantibody and renal disease. In addition, Aa readily induced NETosis in NZM2328 neutrophils.
Our data suggest for the first time that SLE patients are exposed to oral pathogen Aa, and this exposure significantly influences immune responses against a subset of lupus-associated autoantigens, possibly through NETosis. Furthermore, our studies suggest that management of oral health in SLE patients might prove to be beneficial for controlling lupus.
Identification of human effector B lymphocytes that express ARID3a and secrete interferon alpha
Authors: Webb Carol F , Ward Julie M. , Ratliff Michelle L. , Dozmorov Mikhail G. , Wiley Graham , Guthridge Joel M. , Gaffney Patrick M. , James Judith A. 
Published: January 2023

Abstract
Previously, we observed increased numbers of B lymphocytes expressing the transcription factor ARID3a in patients with systemic lupus erythematosus (SLE).* Although numbers of ARID3a+ B cells in individual patients varied over time, enhanced disease activity was associated with increased numbers of circulating ARID3a+ B cells. Because increased disease activity has also been correlated with interferon alpha (IFNa) responses in many SLE patients, we hypothesized that ARID3a expression might be associated with IFNa in SLE. Our new data show increased levels of IFNa in plasma from patients with increased numbers of circulating ARID3a+ B cells. Surprisingly, we found that ARID3a+ SLE B cells secrete IFNa. In vitro stimulation of healthy control B cells with the TLR 9 agonist, CpG, resulted in expression of both ARID3a and IFNa. Furthermore, co-cultures of healthy ARID3a+ B cells with autologous plasmacytoid dendritic cells increased IFNa production in the dendritic cells by up to 9-fold. These data identify ARID3a+ B cells as a novel type of effector B cell, and link ARID3a expression in B lymphocytes to IFN-associated inflammatory responses in SLE.
Choroid Plexus Infiltrates in MRL/lpr Lupus-Prone Mice Represent Tertiary Lymphoid Structures
Authors: Stock Ariel D , Laban Sivan , Ben-Zvi Ayal , Putterman Chaim 
Published: January 2023

Abstract
In addition to an overt neuropsychiatric phenotype (depression and cognitive dysfunction), MRL/lpr mice display robust infiltration of lymphocytes through the brain choroid plexus (CP). However, the functional features of these cells, or their potential contribution to neuropsychiatric disease, have not been explored in detail.
Localized tertiary lymphoid structures have been described in the kidney and peritoneum in spontaneous and inducible lupus models. Given the immunoprivileged nature of the brain and recent studies describing the critical role of the CP in immune surveillance, we evaluated 3D reconstructions of B-cell and T-cell infiltrates. We hypothesized that these CP infiltrates consist of tertiary lymphoid structures (ectopic germinal centers), induced in response to local and/or systemic inflammation.
We found dramatically increased lymphotoxin-β and CXCL13, key molecules in lymphoid follicle organization, in the CP of MRL/lpr mice. Lymphotoxin-β and CXCL13 were upregulated by 8 weeks of age, well before any cellular infiltration was present. Organizational and phenotypic features of lymphoid follicles, including clusters of proliferating (PCNA+) T and B cells, organized according to local chemokine gradients, were present. Furthermore, we identified phenotypically distinct groups of B-cells (e.g. IgM+, GL7+, BCL6+) and T-cells (e.g. FoxP3+, BCL6+, GL7+), as well as follicular dendritic cells and extracellular reticular networks, consistent with lymphoid follicles. We therefore conclude that the CP of MRL/lpr mice contain germinal-center like structures. The contribution of these structures to the pathogenesis, including local production of neuropathic autoantibodies, remains to be determined.
The α2,3 sialyltransferase ST3Gal1 regulates galectin-3 binding to human B cells
Authors: Giovannone Nicholas , Sweeney Jenna Geddes , Liang Jennifer , Antonopoulos Aristotelis , Pochebit Stephen M , Bhattacharyya Neil , Barthel Steven R. , Haslam Stuart M. , Dimitroff Charles J 
Published: January 2023

Abstract
Activated leukocytes commonly remodel cell surface carbohydrates (glycans) in order to modulate lectin-glycoprotein interactions involved in trafficking, adhesion, antigen receptor signaling, and cell fate. Because germinal center (GC) B cells upregulate glycan ligands for peanut lectin (PNA), we hypothesized that B cells remodel cell surface glycans upon GC differentiation in order to alter interactions with endogenous lectins. To test this, we studied cell surface glycosylation of ex vivo tonsillar naive, GC, memory, and plasmablast (PB) B cells using a panel of lectin probes. We found that in addition to PNA ligands, polylactosamine chains (polyLNs) are &gt;4-fold enriched on GC B cells compared to naive, memory, and PB subsets, and that polyLNs are predominantly present as O-glycans on CD45. Moreover, qRT-PCR analysis and overexpression studies in tonsil and Ramos B cells, respectively, revealed polyLNs are inversely correlated with expression of ST3Gal1, an α2,3 sialyltransferase that competes for polyLN precursors. Given that polyLNs are preferred ligands of galectin-3 (Gal-3), a known regulator of apoptosis enriched in GCs, we assessed whether ST3Gal1 regulates Gal-3 binding to B cells. Unexpectedly, B cells with the lowest ST3Gal1 expression and most polyLNs (GC, ST3Gal1loRamos B cells) showed poor Gal3 binding, whereas B cells with natively high or enforced ST3Gal1 expression (Naive, Memory, ST3Gal1hi Ramos B cells) exhibited robust Gal-3 binding. Thus, our data implicate ST3Gal1 as a novel regulator of Gal-3 binding in B cells by a non-canonical mechanism. We propose GC B cells reduce Gal-3 ligand expression by repressing ST3Gal1 transcription, and as a result tune CD45-related signaling and susceptibility to apoptosis.
Complement mannan-binding lectin associated serine proteases 1 and 3 generated by allo-liver transplantation cleave in vivo pro-Factor D generated by the adipose tissue into active Factor D
Authors: Banda Nirmal K , Acharya Sumitra , Scheinman Robert I. , Mehta Gaurav , Takahashi Minoru , Thiel Steffen , Sekine Hideharu , Fujita Teizo , Holers V Michael 
Published: January 2023

Abstract
The alternative pathway (AP) of the complement system plays an important role in human diseases such as rheumatoid arthritis. MBL-associated serine proteases 1 & 3 (MASP-1/3)of the lectin pathway (LP) cleave pro-Factor D (proDf) (inactive) into Df(active), a necessary step to allow the AP to be activated. However, the site(s) of this cleaving activity are unknown; MASP-1/3 are predominantly liver-derived and proDf is produced by adipocytes. We hypothesized that the cleavage event can take place in the circulation, and may be facilitated by a complement activating surface. Liver from fD−/− but MASP-1/3sufficient (donor) was transplanted under the kidney capsule of MASP-1/3−/− (recipient)mice. H & E staining showed the presence of healthy hepatocytes under the kidney capsule of recipient mice. After five weeks of transplantation, the transplanted liver was found to generate MASP-1/3 proteases in the circulation, and concurrently proDf was cleaved into Df. Following liver transplantation, adherent anti-collagen antibodies in vitro also now activated C3 and generated C5a in the serum from transplanted MASP-1/3−/− mouse through the AP. This result illustrates one point of control of the AP by the LP. Furthermore, in vitro mixing and incubation of the sera from mice lacking MASP-1/3 or fD in the absence of anti-collagen antibodies did not cleave proDf. These results show that MASP-1/3 cleaves circulating proDf in a process facilitated by a complement activating target surface. Because the AP of complement is necessary for the development of collagen antibody-induced arthritis (CAIA), MASP-1 and/or MASP-3 inhibition, either at the mRNA or protein activity level, may be used as a new therapeutic approach for CAIA and its deleterious effects.
Role of retinoic acid in diet induced obesity
Authors: Gundra Uma Mahesh , Poles Jordan , Loke Png 
Published: January 2023

Abstract
Obesity is a complex disease associated with chronic, low-grade inflammation of the adipose tissue, which promotes insulin resistance and type-2 diabetes. Adipose tissue macrophages (ATMs) with an inflammatory M1 profile are involved in the development and progression of obesity associated metabolic diseases. In contrast, alternatively activated M2 macrophages (AAMs) may promote anti-inflammatory responses and polarization of CD4+Foxp3+ regulatory T cells (Tregs), attenuating adipose tissue inflammation. We now show that AAMs in the adipose tissue promote the polarization and maintenance of Tregs, through expression of the enzyme retinal dehydrogenase 2 (Raldh2). Diet induced obesity reduces expression of Raldh2 by adipose tissue AAMs and disrupts the polarization of Tregs. Treatment of lean mice with a pan-retinoic acid receptor inverse agonist BMS493 disrupts polarization of Tregs in the adipose tissue. In contrast, retinoic acid (RA) treatment of obese mice reverses defects in Tregs. Induction of AAMs and Tregs in adipose tissue occurs through a Stat6 dependent mechanism. Conditional deletion of Raldh2 with LysM-Cre or CD11c-Cre resulted in the disruption of Treg polarization. These findings suggest that RA may be important for maintaining adipose tissue Tregs by AAMs under steady state non-obese conditions and could perhaps be used as a novel therapeutic agent for diet induced metabolic diseases.
A cancer-associated gene signature bifurcates healthy subjects into cancer-associated and cancer-distinct phenotypes
Authors: Scheid Adam , Van Keulen Virginia , Felts Sara , Zhang Yuji , Neier Steven C , Block Matthew , Markovic Svetomir , Mansfield Aaron , Pease Larry R 
Published: January 2023

Abstract
In the context of immunity, genomic sequence, epigenetic, and environmental factor diversity combine to propagate variable gene expression and immune function among individuals. We hypothesize that we can harness gene expression variability across people to study molecular immune phenotypes and predict individual responses to immune stimuli. To test this we used RNA-Seq to derive a set of genes whose expression is stable over time and differential among healthy people in peripheral blood CD4+ cells. This gene set, which we term the molecular immune response signature (MIRS), identifies transcriptomic “fingerprints” in each healthy person. The same gene set also identifies unique signatures in independent stage IV melanoma patients, and, intriguingly, groups the cancer patients with a particular subset of healthy people. We further clarified the subset by selecting MIRS genes that differentiate it from the other healthy subset. To test if a larger population of melanoma patients grouped with the same healthy subset we clustered additional independent patients with the healthy subsets using these genes. Each of the patient samples grouped with the cancer-associated healthy subset (p=0.00195). We also tested if the gene set would segregate an additional independent cohort of healthy donors into two subsets and found that it did. This, and the fact that no known demographics differentiate the healthy subsets, suggests the observed healthy phenotype may relate to a cancer-like phenotype. Pathway analysis implicates Th1-skewing in the cancer-associated healthy subset. Future directions include further understanding the biological impacts of the phenotype and using the MIRS to predict individual responses to immunotherapeutics.
The Role of Cbl-b in CD4+ T Cell Resistance to Regulatory T Cell Suppression
Authors: Han SeongJun , Chapatte Laurence , Ohashi Pamela S 
Published: January 2023

Abstract
Cancer immunotherapy has demonstrated enormous potential as a novel therapeutic modality in the management of multiple malignancies, including melanoma and leukemia. While cancer immunotherapy is designed to enhance effector T cell function and promote tumor destruction, one of its limitations is the negative influence of tumour-resident CD4+ FoxP3+ regulatory T (Treg) cells on T cell anti-tumour activity. Previous attempts to overcome this challenge have largely focused on the depletion of Treg cells, but this has proven to be a challenging and largely ineffectual process. An alternative approach to overcoming this problem involves generating effector T cell resistance against Treg cell-mediated suppression. Work in this area to date has shown that deficiency in the E3 ubiquitin ligase, Cbl-b, in mice results in the development of hyper-proliferative and pro-inflammatory effector T cells, even in the presence of Treg cells. This study investigates the cellular mechanisms behind this Treg resistance using Cbl-b deficient CD4+ FoxP3− and CD8+ T cells. We demonstrate that Cbl-b −/− CD4+ FoxP3− T cells exhibit both hyper-secretion of and hyper-sensitivity to IL-2, and that this serves as an important mechanism to escape suppression by Treg cells. Accordingly, we show that the blockade of IL-2Rα is sufficient to reverse the Treg cell-mediated suppression and excess IL-2 alone is sufficient to override suppressive signals by Treg cells. Overall, this study provides further insight into the potential development of Treg resistant effector T cells able to generate a more robust anti-tumor immune response.