bluuebunny/crossref_metadata_2025_split huggingface dataset:
MHC class II conformers drive differential B cell activation
Authors: Drake James R 
Published: January 2023

Abstract
MHC class II molecules present exogenous antigen-derived peptides to CD4 T cells to elicit T cell-based help/regulation. While these peptides represent a robust source of heterogeneity, the class II molecules themselves are also heterogeneous. MHC class II molecules exist in two distinct conformational states, based on alternative pairing and differential cholesterol binding of the molecule’s α and β chain’s transmembrane domains. What have been termed “M2 paired” class II (M2 class II) represents the majority of cell surface class II, whereas M1 paired class II (M1 class II) is a smaller fraction of surface molecules. However, M1 class II is enriched in “lipid raft” membrane domains, is highly stimulatory for CD4 T cells and is selectively linked to B cell activation signaling pathways. Moreover, in B lymphocytes M1 class II selectively associates with intracellular antigen-B cell receptor (BCR) complexes and is selectively loaded with peptide derived from the processing of BCR-bound cognate antigen. In contrast, peptides from non-cognate antigen internalized by fluid-phase endocytosis (as would happen for self-antigens) is loaded onto both M1 and M2 class II. Here, we show that while selective engagement of M1 class II drives B cell calcium signaling (an activation event), co-engagement of M1 and M2 class II allows an M2 class II-associated inhibitory activity to block M1 class II signaling. These findings provide new insight into the molecular mechanisms of MHC class II signaling by revealing the distinct signaling properties of M1 and M2 class II. The results also suggest a B cell-intrinsic mechanism by which T cell recognition of M1 vs. M2 peptide-class II complexes could regulate B cell activation via differential class II signaling.
Molecular mechanisms underlying the glycation induced-impairment of antigen processing and presentation in diabetic (T2DM) patients and ob/ob mice
Authors: Santambrogio Laura , Clement Cristina , Negroni Maria Pia , Nanaware Padma , Morozova Kateryna , Stern Lawrence 
Published: January 2023

Abstract
Patients with obesity, metabolic syndrome, or type-2 diabetes (T2D) often exhibit hyperglycemia and hyperlipidemia. A consequence of the dysmetabolism is non-enzymatic coupling of reactive sugars and lipids with proteins and DNA inducing glycation and glycoxidation. Biochemically, these modifications disrupt the cellular proteome by changing the protein chemical structure and inducing protein unfolding, cross-linking and aggregation. We investigated protein post-translational modifications (PTM) induced by glycation and glycoxidation in PBMC from non-diabetic, pre-diabetic and diabetic individuals as well as CD11c+ dendritic cells purified from mice fed a high-fat diet, obese (Ob/Ob) mice and relative controls. By employing label-free bottom-up proteomic and bioinformatics analysis we mapped several cellular pathways affected by the oxidative PTMs, including the antigen processing and presentation machinery. Functional assays of endosomal processing, using transthyretin and insulin as model antigens, determined how the oxidative PTMs interfered with antigen processing. Glycation and glycoxidation moieties on MHC II proteins were mapped at sites known to interact with peptides, with the peptide exchange factor DM, and with the TCR. In vitro glycation of human HLA-DR1 resulted in impaired interaction with the peptide exchange factor HLA-DM. In vivo and in vitro impaired immune response to a model antigen (I-Ea protein ) was also observed in Ob/Ob mice. Our results shed light on the biological implications of the role played by glycation and glycoxidation, as observed in T2D and metabolic syndrome, on the antigen processing machinery as well as its functional consequences for MHC II restricted immune responses.
Optimizing steroid administration in murine models of Citrobacter rodentium-induced acute phase colitis
Authors: Clarke Sandra T , Shelton Tara , Boras Valerie , Brumer Harry , Wang Chang Qing , Abbott D. Wade , Xing Xiaohui , Uwiera Richard R.E. , Inglis G. Douglas 
Published: January 2023

Abstract
This study used Citrobacter rodentium-infected C57BL/6 mice as a model of acute colitis to assess treatment with steroids prednisolone (pred) and dexamethasone (dex). Both germ-free (GF) and normal flora (NF) adult mice were used to determine an optimal steroid dosing strategy to mitigate intestinal inflammation caused by C. rodentium attachment/effacement lesions. Male and female mice (6-weeks of age) were orally inoculated with C. rodentium (1.0 × 108 CFU/100 μL) for two consecutive days. Five days post-infection, mice were gavaged with pred (1 mg/kg/d or 3 mg/kg/d), dex (0.6 mg/kg/d or 1.5 mg/kg/d) or controls for five days (GF n = 3 and NF n = 4 for each treatment). GF mice had longer colons (base of cecum to anus) than NF mice (7.1 ± 0.1 cm vs. 6.2 ± 0.2 cm; P &lt; 0.001) and lighter total liver weight than NF mice (1.0 ± 0 g vs. 1.1 ± 0.2 g; P = 0.03). Colonic cytokines were quantified by ELISA. Steroid treatment decreased concentrations of colonic KC (CXCL1; P &lt; 0.001) in NF mice; and high-dose dex decreased KC more effectively than low-dose dex (3207.5 ± 583.5 pg/g vs. 9217.6 ± 1375.4 pg/g; P = 0.019). Although C. rodentium increased colonic concentrations of KC (P &lt; 0.001), MIP-2 (CXCL2; P = 0.19), TNF-α (P = 0.031), IL-22 (P = 0.018) and myeloperoxidase (P &lt; 0.001) in NF mice, no differences were attributable to steroids or sex in GF and NF mice. Colonic MIP-2 (P &lt; 0.001), IL-10 (P = 0.032), TNF-α (P &lt; 0.001), IL-17 (P &lt; 0.001) and IL-22 (P = 0.005) were higher in NF than GF mice, likely due to underdeveloped gut-associated lymphoid tissue in GF mice. In summary, high-dose dex (1.5 mg/kg/d) but not high-dose pred (3 mg/kg/d) mitigated production of the potent neutrophil chemoattractant KC in a C. rodentium induced model of acute-phase colitis.
Enhancement of gut barrier function by microbial metabolite, urolithin A via AhR-Nrf2 dependent pathways in IBD
Authors: Jala Venkatakrishna R , Singh Rajbir , Chandrashekarappa Sandeep , Bodduluri Sobha Rani , Becca Baby V , Hegde Bindu , Kotla Niranjan , Hiwale Ankita A , Saiyed Taslimarif , Patel Paresh , Vijay-Kumar Matam , Langille Morgan , Douglas Gavin M , Dryden Gerald , Cheng Xi , Rouchka Eric , Waigel Sabine J , Alatassi Houda , Zhang Huang-Ge , Haribabu Bodduluri , Vemula Praveen K 
Published: January 2023

Abstract
Inflammatory bowel diseases (IBD) consisting of Crohn’s and ulcerative colitis are resultant of dysregulation of the immune system leading to intestinal inflammation and microbial dysbiosis. Numerous studies in recent years highlighted the pivotal role of gut microbiota and their metabolites in host physiological processes including in IBD. Urolithin A (UroA) is a microbial metabolite derived from polyphenolics (e.g., ellagitannins/ellagic acid) of pomegranate and berries. We also synthesized a potent structural analogue of UroA (UAS03) and tested their efficacies in preventing and treating colitis in pre-clinical models. Our studies showed that UroA/UAS03 significantly enhance gut barrier function in addition to blocking unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. In addition, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction and blocking increased inflammatory mediators such as IL-6, TNF-α and IL-1β. UroA/UAS03 failed to induce tight junction proteins and protect against 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis in AhR−/− and Nrf2−/− mice suggesting an obligatory requirement of AhR and Nrf2 pathways for UroA/UAS03 mediated beneficial activities. Overall, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing systemic and local inflammation to protect from colonic diseases.
Neuroantigen-specific regulatory CD8+ T cell responses as a therapy for relapsing autoimmune demyelinating disease
Authors: Brate Ashley A , Itani Farah R. , Pewe Lecia L. , Harty John T , Karandikar Nitin J. 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). We have shown that CNS-specific CD8+ T cells possess a disease suppressive function in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In humans, this suppressive function of CD8+ T cells is deficient during MS relapses. We thus evaluated the role of CD8+ T cells in the context of the relapsing-remitting model (RR-EAE), using SJL mice. We demonstrate here that PLP178–191- and MBP84–104-specific CD8+ T cells ameliorated disease severity in an antigen-specific manner. Moreover, PLP178–191 CD8+ T cells reduced the number of relapses in PLP178–191-induced disease, even when transferred during ongoing disease. We were further able to ascertain that the suppressor population of CD8+ T cells express CD25, and show that a very low number of CD25+ CD8+ T cells are sufficient to suppress RR-EAE. We also probed the role of endogenously generated CNS-specific CD8+ T cell responses by using Listeria monocytogenes (LM) encoding CNS antigens to preferentially prime suppressive CD8+ T cells in vivo. Using this system, we show infection with LM expressing PLP175–194 endogenously induced disease suppressive CD8+ T cells that protected and treated PLP178–191 disease. Importantly, a combination of CD8+ T cell transfer boosted by LM infection also successfully treated ongoing disease induced by a non-cognate peptide (PLP139–151), indicating that this approach could be effective even in the context of epitope spreading. These studies support a potential immunotherapeutic strategy using LM vaccination to prime disease regulatory CD8+ T cells.
The Aryl Hydrocarbon Receptor as a regulator of CNS autoimmunity
Authors: Kenison-White Jessica , Jhaveri Aditi , Tezza Sara , Nowakowska Dominika , Sherr David , Quintana Francisco Javier 
Published: January 2023

Abstract
Therapeutic approaches aimed at controlling the balance between effector T cells and regulatory T cells in an antigen-specific manner are of high clinical significance in the field of autoimmunity. The aryl hydrocarbon receptor (AhR) has been identified as a key regulator of the adaptive immune system and thus represents a strong targetable candidate for the induction of immune tolerance. Here, we report the generation of a novel liposomal platform to co-administer a tolerogenic AhR ligand, ITE, and an autoimmune disease-specific T cell antigen. Liposomes containing ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 are taken up by dendritic cells and induce a tolerogenic transcriptional program which promotes the differentiation and expansion of long-lasting antigen-specific regulatory T cells. Treatment with these liposomes almost completely prevented the development of experimental autoimmune encephalomyelitis (EAE), an experimental model of relapsing-remitting multiple sclerosis (MS), and reversed symptoms in mice with ongoing EAE. This disease suppression was associated with the expansion of antigen-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells) as well as the suppression of CNS-infiltrating effector T cells. Furthermore, treatment with liposomes containing ITE and MOG reversed symptoms of disease in chronic progressive EAE in nonobese diabetic mice, an experimental model resembling several aspects of secondary progressive MS. Taken together, these results suggest that our liposomes represent a novel therapeutic platform to induce antigen-specific tolerance for the treatment of autoimmune diseases.
Myelin basic protein specific TCR-engineered regulatory T cells from multiple sclerosis patients are suppressive to MBP-specific T effector cells
Authors: de Paula Alves Sousa Alessandra , Kim Yong Chan , Jacobson Steven , Scott David W 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal injury. Expanded T regulatory cells have been used in clinical trials for autoimmune diseases, but CNS-specific cells are rare in polyclonal populations and have the potential to be non-specifically immunosuppressive. Previously, we developed MS-specific Tregs by transducing a MBP-specific T-cell receptor (Ob2F3 TCR) into expanded human Tregs. Ob2F3 TCR-transduced Tregs successfully suppressed MBP-specific Ob2F3 T effector cells in vitro as well as MOG-induced EAE in vivo (Kim et al., J. Autoimm. 92: 77–86, 2018). However, Tregs in MS patients have been reported to be impaired in their suppressive function. Herein, we transduced Tregs from MS patients and healthy controls and tested them for suppression of effector T-cells to determine whether this activity is significantly different with patient Tregs. Treg (CD4+CD25hiCD127low) and naïve T-cells (CD4+CD25lowCD127hi) were isolated from peripheral mononuclear cells and retrovirally transduced with specific the Ob2F3 MBP-specific TCR, expanded and tested for suppression in vitro. We found that MBP-specific Tregs isolated from MS patients maintain Treg markers and are able to inhibit autologous MBP-specific T effector cells as well as MBP-specific Tregs from healthy controls. Our data suggest that Tregs obtained from MS patients can retain their suppressive function upon expansion and transduction with the MBP-specific TCR, and could be used therapeutically to restore a tolerance in patients. (Supported by NMSS RG1612-26484 and NIH Intramural funds)
Photobiomodulation therapy (PBMT) regulates the production of IL-10 and IFN-Ɣ by peripheral blood mononuclear cells (PBMC) and CD4+ T cells isolated from subjects with Multiple Sclerosis (MS)
Authors: Tolentino Miguel , Cho Chi C. , Lyons Jeri-Anne 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a CD4+ Th1/Th17 mediated autoimmune disease characterized by myelin destruction, neurodegeneration and mitochondrial dysfunction. Current therapies suppress inflammation during early stages but are not effective in chronic stages characterized by oxidative damage. New therapies to slow progression, offer neuroprotection, and ameliorate the symptoms at any stage are urgently needed. Photobiomodulation therapy (PBMT) with light at 600–1100 nm is demonstrated to improve inflammatory and neurodegenerative disorders by down-regulating pro-inflammatory mediators and up-regulating anti-inflammatory mediators.
Our lab showed that PBMT with 670nm light reduced clinical severity in the C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of MS by down-regulation of oxidative stress, apoptosis and pro-inflammatory cytokines, and up-regulation of anti-inflammatory cytokines. Data presented here evaluate the effect of PBMT on cytokine production by immune cells isolated from MS patients and healthy donors. PBMC and CD4+ T cells activated with Phytohaemagglutinin (PHA) or CD3/CD28 activator, respectively, received PBMT in vitro and cytokines were measured in cell culture supernatants by ELISA. Light at 670nm and 830nm increased IL-10 and reduced IFN-Ɣ produced by PBMC from MS patients. Light at 670nm, 735nm and 830nm increased IL-10, whereas 670nm and 830nm, but not 735nm, light reduced IFN-Ɣ produced by CD4+ T cells. Light at 670nm and 830nm reduced IFN-Ɣ produced by PBMC, while 830nm light increased IL-10 production by CD4+ T cells isolated from healthy donors. Our results demonstrate that PBMT differentially regulates the immune response in persons with MS and healthy donors.
Alcohol consumption leads to sex-specific amelioration of disability in a mouse model of multiple sclerosis
Authors: Caslin Blaine , Karmakar Aditi , Maguire Cole , Helmsdoerfer Kristen , Mohler Kailey , Kirwin Stefanie , Wylie Dennis , Melamed Esther 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disorder and the leading cause of neurological disability in young people. Alcohol consumption is known to have both neuroinflammatory and immunosuppressive effects, yet despite high rates of alcohol abuse among MS patients, its effects on MS disease progression have not been well studied. The few studies on alcohol consumption during MS have produced conflicting results and suggest opposing clinical outcomes at different alcohol doses. In this study, we hypothesized that low-dose daily alcohol consumption could ameliorate the clinical course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male and female C57BL/6 mice were fed a 2.6% ABV Lieber-deCarli diet or isocaloric control prior to MOG35–55-mediated EAE induction and monitored for 40 days. Male alcohol consumers (AC) experienced significantly greater remission compared to controls or AC females. Histological analysis revealed significantly fewer Iba1+ cells in the dorsal horns and lateral columns of AC male cervical and thoracic spinal cords compared to the other groups. 16S rRNA gut microbiome sequencing revealed distinct flora patterns during EAE onset and remission, and showed increased abundance of immunoregulatory species A. muciniphila and A. equolifaciens in AC males. These results demonstrate that moderate alcohol consumption can ameliorate EAE by modulating male microglial activation while simultaneously promoting an anti-inflammatory gut microbiome.
Increased activated platelet binding to T cells in lung cancer patients is correlated with history of thrombosis
Authors: Meikle Claire K , Meisler Adam , Garg Priyanka , Kelly Clare A. , Jeffries Joseph A. , Gao Tess , Bird Cara M. , Willey James C. , Worth Randall G. 
Published: January 2023

Abstract
This study aimed to characterize the role of platelet-leukocyte aggregation in lung cancer patients in context of history of thrombosis. Whole blood from lung cancer patients and healthy volunteers was labeled with fluorescently-conjugated antibodies, then fixed prior to flow cytometry. Platelet-leukocyte aggregates were quantified by detecting the number of platelets within all leukocyte-positive events.
Platelet-CD4 T cell and platelet-CD8 T cell aggregates were both significantly increased in lung cancer patients (both p &lt; 0.0001). Lung cancer patients had significantly more CD4 and CD8 T cells aggregated with activated platelets compared to healthy volunteers (p &lt; 0.01 and p &lt; 0.001, respectively). Lung cancer patients were then separated into groups based on history of thrombosis: No previous thrombosis, arterial thrombotic event (ATE), and venous thromboembolism (VTE). ATE patients had significantly more CD8 T cells aggregated with platelets than patients with no history of thrombosis (p &lt; 0.05). VTE patients had significantly higher expression of platelet activation markers in CD4 and CD8 T cell aggregates than patients with no history of thrombosis (p &lt; 0.01 and p &lt; 0.001, respectively) and ATE patients (p &lt; 0.05 and p &lt; 0.001, respectively).
Platelet-T cell aggregates were significantly increased in lung cancer patients compared to healthy volunteers, and platelet activation within aggregates was significantly correlated with history of VTE in patients with lung cancer. These findings indicate that interactions between platelets and T cells in cancer patients may contribute to a procoagulant phenotype.
Preclinical development of natural compound emodin as an agent to halt breast cancer metastasis
Authors: Fan Daping , Liu Qing , Hodge Johnie 
Published: January 2023

Abstract
Our previous studies demonstrated that a natural compound, emodin, suppresses breast cancer growth and metastasis by modulating tumor-associated macrophages (TAMs), we aim in this study to further develop emodin as an agent to diminish breast cancer post-surgery metastatic recurrence. Using various mouse and human breast cancer cell lines, we demonstrated that emodin not only directly reversed TGF-β1-induced epithelial to mesenchymal transition (EMT), migration and invasion, but also indirectly attenuated EMT by suppressing TAM polarization and TGF-β1 production. Emodin also suppressed the stemness and progenitor properties of tumor-initiating cells (TICs). The EMT process and TIC populations in primary breast tumors were diminished by emodin in vivo, and pretreating tumor cells with emodin suppressed breast cancer lung metastasis in a stem cell-like circulating tumor cell-seeding model. In orthotopic metastasis mouse models, administration of emodin before surgery suppressed the metastatic recurrence of breast cancer and improved the overall survival. Mechanistic study revealed that emodin inhibited both canonical and non-canonical pathways of TGF-β1 signaling in breast cancer cells. Taken together, our study demonstrated that emodin can be developed as a therapeutic agent to prevent post-surgery metastatic recurrence of breast cancer by suppressing TGF-β1-mediated crosstalk between breast cancer cells and TAMs.
RELT stains prominently in B cell lymphomas and binds proteins associated with leukemia
Authors: Cusick John K , Alhomsy Yasmeen , Talbott George , Sumida Cara , Aghaians Dino , Hejazi Nazila , Jacobs Aaron 
Published: January 2023

Abstract
Receptor Expressed in Lymphoid Tissues (RELT) is a human TNFR that is expressed prominently in the hematopoietic system and negatively regulates T-cell activation in mice. RELT has two identified homologous binding partners, RELL1 and RELL2. This study sought to further elucidate the function of RELT by identifying novel protein interactions with RELT family members and to study the localization of RELT in both normal and diseased tissues. A yeast two-hybrid screen identifed Phospholipid Scramblase 1 (PLSCR1) and MyoD family inhibitor domain-containing protein (MDFIC) as potential RELT-family member binding proteins that were confirmed by in vitro co-immunoprecipitations. PLSCR1 has been demonstrated to possess anti-leukemic properties, and RELT expression results in an altered cellular localization of PLSCR1 as determined by immunofluorescence (IF). The MDFIC gene encodes for a transcription factor and is located proximally to regions of chromosome 7 (7q31.1) frequently lost in AML patients. MDFIC was observed to co-localize with RELL1 at the plasma membrane and co-localize with RELT in intracellular compartments as determined by IF. Since RELT, PLSCR1 and MDFIC are prominently expressed in the hematopoietic system, we sought to characterize the expression of RELT in both normal lymph nodes and B cell lymphomas. Immunohistochemistry revealed a higher intensity of RELT staining in germinal centers in comparison to surrounding lymph node regions. Interestingly, the level of RELT staining increased progressively in low and high-grade B cell lymphomas versus normal lymph nodes. Collectively, these results further our understanding of proteins that interact with RELT and identify an association of RELT with B cell lymphomas.