bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-insulin B cells are poised for antigen-presentation in pro-inflammatory subsets in type 1 diabetes
Authors: Felton Jamie Lynn , Bonami Rachel , Hulbert Chrys , Thomas James W. 
Published: January 2023

Abstract
Type 1 diabetes (T1D) results from T-cell mediated autoimmune destruction of insulin-producing beta cells. Early breaches in B cell tolerance are central to T1D progression in mouse and man. Conventional transgenic mouse models (VH125.Tg NOD) suggested that B cell specificity is a powerful driver of disease. However, the precise staging of B cell development is limited in the conventional IgM-only model by the inability to class-switch. To investigate the developmental fate and functional status of anti-insulin B cells in NOD mice, we generated a new model (VH125SD.NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus and recombines with endogenous Vk chains to produce fully functional BCRs. This single copy VH transgene generates a small (1–2%) population of class-switch-competent anti-insulin B cells. Tracking their developmental fate reveals that anti-insulin B cells are preferentially skewed into marginal and late transitional zones which are known to have increased sensitivity to innate signals and enhanced capacity for antigen-driven expansion. Functional studies demonstrate that VH125SD.NOD anti-insulin B cells are anergic to antibody production; however, proliferation in response to B cell mitogens remains intact, diabetes is accelerated, and autoaggressive T cell responses to islet epitopes are increased. These findings validate the power of BCR specificity to drive T1D in a new mouse model and highlight the pathogenic potential of coupling a critical beta cell autoepitope to pro-inflammatory B cell subsets. We believe these findings may have implications for the discovery of new therapeutic targets in sources of innate signals that enhance autoreactivity in these B cell subsets, such as gut microbiota.
NZB;NZW chimeras develop strong autoimmunity earlier than NZB/NZW F1
Authors: Hankins Julia , Liu Aijie , Choi Jin , Li Xiaohong , Turer Emre , Beutler Bruce 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease caused by an immune response to many self-antigens, including DNA, histones, and RNA-binding proteins. One of the most physiologically relevant mouse models is the NZB/NZW F1 hybrid mouse, which develops SLE at high penetrance, in contrast to either parental strain. However, the critical genetic contributions of each parent, which must somehow interact to cause SLE, have remained unresolved. We have determined that NZB;NZW embryonic chimeras develop an accelerated form of autoimmunity characterized by the presence of auto-antibodies 6 months earlier, and at titers 10-fold greater, than the NZB/NZW F1 hybrids. The chimeras also developed glomerulonephritis, severe lymphadenopathy, and splenomegaly. Within each chimera, expansion of activated T cells of NZB/BINJ origin and a predominance of B cells of NZW/LacJ origin was observed with respect to the relative proportions of myeloid cells. Furthermore, the expansion of NZB/BINJ T cells correlates with autoantibody production. This SLE phenotype was specific for the NZB/BINJ;NZW/LacJ combination, and occurs despite the fact that neither parental strain develops SLE-like autoimmunity in a non-chimeric environment. Understanding the pathogenesis of SLE in the NZB;NZW embryonic chimeras may elucidate causes of autoimmunity by identifying the intercellular transactions between these two strains that lead to disease.
Comparison of immune cells from germinal centers specific to protein or lipid antigens
Authors: Galicia Viridiana Galicia , Manzano Oscar Arturo Angeles , Castro Ma Natividad Flores , Rostro Elizabeth Martínez , Wong Carlos , Wong-Baeza Carlos , Baeza Isabel , Reséndiz-Mora Albany 
Published: January 2023

Abstract
Anti-lipid IgG antibodies can participate in the physiopathology of some autoimmune diseases. In our research group, we developed a mouse model of Lupus by the administration of liposomes bearing non-bilayer phospholipid arrangements NPA induced by some drugs like chloropromazine CPZ. The mice of this model produce anti-NPA IgG antibodies; these antibodies are mainly formed via germinal center GC. However, the cells that participate in a GC reaction against lipidic antigens are unknown; therefore, we study these cells in the mouse model of Lupus induced by NPA and compared them with a GC reaction against ovalbumin OVA, because the cells that participate in a GC reaction against protein antigens are well known. We studied germinal center B cells, plasma cells, dendritic cells, follicular dendritic cells FDC, T follicular helper cells TFH, T follicular regulatory cells TFR and macrophages from the groups administered with OVA or NPA and compared them with mice without administration. Then we extracted the spleen and the mesenteric lymph nodes and perform flow cytometry and H&E staining at days 5, 10, 15 and 30 postadministration. Histologically, germinal centers were found in both groups at day 5. The mice administered with NPA, present an increase of germinal center B cells 15 days post-administration and a bigger size of the secondary lymphoid organs, the mice administrated with OVA present an increase of these cells and bigger lymph organs at day 10. The higher percentage of plasma cells was found 30 days after the administration of OVA; while dendritic cells and TFH cells presented similar percentages in both groups at all times. For both antigens, the FDC increase at day 5 and 15, the macrophages from day 10 to 15 and the TFR cells increase at day 15.
The macrophages in the pancreatic islets are activated and sense pathogen associated products in blood
Authors: Zakharov Pavel , Ferris Stephen T. , Wan Xiaoxiao , Unanue Emil R. , Zinselmeyer Bernd , Carrero Javier A. 
Published: January 2023

Abstract
Using RNAseq, we examined the transcriptome of endocrine macrophage in the islets of Langerhans in NOD (non-obese diabetic) and in two non-diabetic controls: NOD.Rag1−/− and B6.g7. The NOD mice spontaneously develop diabetes at 20–24 weeks of age. By gene expression analysis we found that at 3 weeks of age the macrophages from all 3 strains of mice were already activated. They expressed high levels of MHC-II, costimulatory molecules, and the pro-inflammatory cytokines IL-1b, TNF, both at protein and transcript levels. Leveraging the ImmGen database, we found that this activation signature is common for resident macrophages from barrier surfaces of the body, in particular lung and gastrointestinal tract. In addition to the basal level activation found in all islet macrophages at 3 weeks of age, we found an elevated activation signature in NOD when comparing to non-diabetic control. This finding indicates that the diabetic inflammatory process was already underway at as early as 3 weeks of age. These results were confirmed by single cell qRT-PCR that showed a distinct activated population of Cxcl9, Ccl5, Ly6a high (~28%) macrophages in NOD, but not in NOD.Rag1−/−. Additionally, supporting the idea of a barrier phenotype in islet macrophages, we found that they responded to intravenous injection of lipopolysaccharide by rapid upregulation of inflammatory gene expression. In imaging experiments we showed that macrophages were constantly extending filopodias into the blood lumen and capturing microparticles. In conclusion, the islet macrophages are in a highly activated steady state, sense pathogen associated products in blood, and may have a protective barrier function in the endocrine pancreas.
Interleukin-7 receptor pathway controls human T cell homing to the gut and predicts response to anti-TNFα therapy in IBD
Authors: BELARIF LYSSIA , Danger Richard , Kermarrec Laetitia , Daguin Véronique , Boureille Arnaud , Naveilhan Philippe , Vanhove Bernard , Poirier Nicolas 
Published: January 2023

Abstract

Background and aims
Signaling networks perpetuating chronic gastrointestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD), remain unclear in man.

Methods and results
According to an analysis of nearly 500 patients with IBD and 100 controls, we report here that key transcripts of the IL-7 receptor (IL-7R) pathway accumulate in inflamed colon tissues of severe IBD patients not responding to either immunosuppressive/corticosteroids or anti-TNFα therapies. High expression of both IL-7R and IL-7R signaling signature transcripts in the colon before treatment are strongly associated with nonresponsiveness to anti-TNFα therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controls α4/β7 integrin expression and imprints gut-homing specificity on T cells. IL-7 receptor blockade in vivo reduced human T cell homing to the gut and colonic inflammation in humanized mouse models, and decreased production of IFNγ by colon explants from UC patients grown ex vivo.

Conclusion
Our findings suggest that the failure of current treatments for IBD, including anti-TNF, may occur at least in part by dysregulated IL-7R signaling and points to the IL-7R as a relevant novel therapeutic target and biomarker to fill an unmet need in clinical IBD detection and treatment.
Lactoferrin inhibits immune cell adhesion via suppression of cell adhesion molecules expression in hypoxia/reoxygenation animal model
Authors: Lee Tae Hoon 
Published: January 2023

Abstract
Lactoferrin (Lf), an 80 kDa iron binding protein, belongs to transferrin family found in secretions such as milk and in plasma secreted from neutrophils granules upon inflammatory stimulation. Lf is a multifunctional protein mainly involved in both the innate and adaptive immune defenses. In this study, we investigated the anti-adherent activity of Lf in hypoxia/reoxygenation (H/R)-stimulated human endothelial cells (HUVECs). Lf dramatically reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by hypoxia-situation HUVECs. Our results also demonstrated that Lf was reduced the expression of cell adhesion molecules on H/R-induced vascular inflammation mouse model. Lf significantly reduced the gene expression of pro-inflammatory cytokine such as IL-6, IL-1β and TNF-α in hypoxia-induced HUVECs. These results demonstrate that Lf inhibits the expression of cell adhesion molecules including ICAM-1, VCAM-1 and pro-inflammatory cytokines. It also suggests that Lf may play an important role in the development of drug for anti-vascular inflammation by inhibiting the expression of cell adhesion molecules.
Evaluating the Effects of Systemic, Exercise-Induced Skeletal Muscle Injury using Whole Transcriptome Sequencing
Authors: Tanner Elizabeth A. , Kim Tracy A. , Gary Melody A. , Stelly Steven , Davis Asheal , Bowman Erin M. , McFarlin Brian Keith 
Published: January 2023

Abstract
Recent advances in next generation sequencing have dramatically reduced the cost of whole transcriptome sequencing to measure differential gene expression. Extreme physical performances represent a unique model for investigating the combined effects of oxidative stress and eccentric muscle contraction on systemic skeletal muscle injury outcomes. Studying changes in whole transcriptome RNA expression may allow identification of specific potential treatment targets for a variety of disease states associated with chronic inflammation and oxidative stress. The purpose of this study was to investigate changes in whole transcriptome RNA expression in response to prolonged endurance running. The protocols were approved by the University IRB committee (in accordance with the latest Declaration of Helsinki) and subjects gave written informed consent to participate. Blood samples were collected in PAXgene RNA tubes at baseline, 4-h, and 24-h after performing a half-marathon race. After collection, tubes were frozen and total RNA was extracted and verified using accepted methods. RNAseq analysis was conducted using an Illumina NextSeq 500 sequencing platform. RNAseq analysis revealed distinct changes in injury, inflammation, anti-oxidant defense, and stress-associated RNA expression with responses appearing more pronounced at 24-h compared to 4-h post-race. These results confirm the systemic changes that occur following whole-body exercise-induced muscle injury in a human model. The next step in this research is to test potential therapeutic strategies to determine their effectiveness on altering the changes in the transcriptome.
TREML4 affects lesion composition but not calcification in the Apolipoprotein E deficient model of experimental Atherosclerosis
Authors: Cotto Marieli Gonzalez , Guo Liang , Karwan Megan , Palmieri Erika M. , Boelte Kimberly , Quigley Laura , Sen Shurjo K. , Biesecker Leslie G. , McVicar Daniel W. 
Published: January 2023

Abstract
The Triggering Receptor Expressed on Myeloid cells-like 4 (Treml4) is a member of the TREM receptor family which are recognized fine-tuners of the inflammatory response. We have previously found that Treml4 expression correlates to increased risk of Human Coronary Arterial Calcification and Acute Coronary Syndrome. Moreover, we show that carriage of either one of the eQTL SNPs previously identified to permit Treml4 expression, confers the highest treml4 expression in human inflammatory macrophages when compared to alternative activated macrophages. However, the exact role of Treml4 in the pathogenesis of coronary diseases remains incompletely defined. To elucidate the role of Treml4 in atherosclerosis, we investigated whether treml4 deficiency affected pathogenesis in the Apolipoprotein E knockout mouse (apoe−/−). We found that aortas from apoe−/− mice had increased treml4 expression when compared to wild type and that treatment with either LDL or oxLDL upregulated macrophage treml4 expression in vitro. After a western diet, overall plaque burden and calcification in the aortic sinus of apoe−/−/treml4−/− mice remained unchanged compared to controls. However, we found that treml4 deficiency resulted in less complex lesions as indicated by decreased foam cell content, plaque necrosis and collagen deposition as well as dysregulation of matrix metalloproteinases expression within the plaques. Moreover, less collagenous metaplasia was observed in the brachiocephalic artery of apoe−/−/treml4−/− mice. Taken together, our results suggest that Treml4 contributes to the inflammatory mechanisms and extracellular matrix regulation associated with lesion complexity without affecting lesion burden or calcification.
PLAG ameliorates LPS-induced ALI by attenuation of neutrophil infiltration into alveolar via a prompt resolution of TLR4 signaling.
Authors: Shin Su-Hyun , Lee Ha-Reum , Jeong Jinseon , Kim Joo Heon , Lee Do Young , Moon Byoung-Gon , Sohn Ki-Young , Yoon Sun Young , Kim Jae Wha 
Published: January 2023

Abstract
Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment into the bronchoalveolar space and results in severe mortality. To evaluate 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, PLAG was administered orally to mice intranasally challenged with lipopolysaccharide (LPS). The excessive neutrophil infiltration in the bronchoalveolar lavage fluid (BALF) was detected in LPS-treated mice. Intranasally introduced LPS especially stimulates tissue-resident macrophages in the pulmonary tissue and induces neutrophil-attracting chemokine production such as MIP-2. Co-administrated PLAG dramatically ameliorated neutrophil infiltration into the bronchoalveolar region via modification of TLR4 signaling. We found that PLAG effectively accelerated endocytosis of LPS-TLR4 complex and promoted the NADPH oxidase activity through the formation of Rac, p47phox assembly into membrane for ROS production which results in elimination of exotoxin in Raw264.7 cells. PLAG also triggered a prompt TLR4 signals occurred in endosome mediated by TRIF and terminated signaling including MIP-2 expression when endocytosed exotoxin is cleared. Moreover, immunofluorescence microscopes of RAW264.7 cells showed that PLAG accelerated the endocytosis of the LPS-TLR4 complex and the clearance of the internalized LPS. Our results suggest that PLAG promotes the clearance of invaded exotoxin and eventually triggers an earlier termination of MIP-2 secretion in the exotoxin-cleared macrophages, and might be used as a potential therapeutic agent to prevent ALI through speedy resolution of exotoxin.
Elevated adipose tissue expression of CCL19 in obese individuals with or without type-2 diabetes: Its association with metabolic inflammation
Authors: Alrashed Fatema , Kochumon Shihab , Tuomilehto Jaakko , Sindhu Sardar , Ahmad Rasheed 
Published: January 2023

Abstract
Adipose tissue produces inflammatory molecules considered to be involved in the development of chronic low-grade inflammation in obesity and type 2 diabetes (T2D). The adipose tissue expression of CCL19 or macrophage inflammatory protein (MIP)-3β in obesity is poorly understood. We, therefore, determined CCL19 gene expression in the adipose tissue samples from lean, overweight, and obese individuals with or without T2D. Subcutaneous adipose samples were collected from 58 non-diabetic (ND) (27-obese, 21-overweight, and 10-lean) and 49 T2D (34-obese, 11-overweight, and 4-lean) individuals. Gene expression of CCL19 and other inflammatory markers was determined using real-time RT-PCR. Plasma CRP and adiponectin were measured by ELISA. CCL19 expression was significantly higher in obese compared with lean individuals (ND: P&lt;0.04; T2D: P&lt;0.02). Notably, CCL19 expression was relatively higher in T2D than ND individuals regarding each body mass index (BMI) group. CCL19 expression correlated with BMI (ND: r=026, p=0.04; T2D: r=0.45, P=0.001). In relation to immune markers, CCL19 expression had association with CXCL10, IL-12A, and TLR2 in ND individuals, and with IL-6, IL-1β, TGF-β, TNF-α, TLR9, CCL11 and IRAK-1 in T2D individuals, while it associated with MyD88, CCL5, CCR2, and CRP in both populations. However, CCL19 gene expression associated negatively with adiponectin in ND individuals. With regard to clinical markers, in both populations, CCL19 expression correlated positively with triglycerides, fasting blood glucose, and HbA1C, whereas it had negative association with HDL cholesterol. These data support that increased adipose tissue expression of CCL19 may represent an immune signature of metabolic inflammation.
The damage signal IL-33 facilitates focal immune responses to Toxoplasma gondii in the brain
Authors: Still Katherine M. , Thompson Jeremy , Batista Samantha , Hayes Nikolas , Harris Tajie H. 
Published: January 2023

Abstract
An intact immune system is critical for survival of hosts chronically infected with T. gondii. We observe clusters of immune cells surrounding regions of free parasite within brain tissue. Many of these cells are monocyte-derived and have parasite-limiting capacity, but the initial cues which instruct their proximity to parasite are not well understood. One potential mechanism of broad relevance is the incitement of damage. We explored the importance of IL-33, a protein released upon cell damage, in the recruitment of monocytes in our model. We found IL-33 to be expressed by oligodendrocytes during T. gondii infection, and observed regions of oligodendrocyte loss in infected mouse and human brain tissue, implying ample opportunity for IL-33 release. Upon infection, induction of the monocyte chemoattractant, CCL2, was dependent on IL-33 signaling, as visualized using CCL2-mcherry reporter mice. CCL2 signal was focal and expressed by astrocytes surrounding immune cell foci. The concept that IL-33 could be acting on astrocytes directly was supported by bone marrow chimeras which implicated a radio-resistant responder to IL-33. In alignment with CCL2 induction, IL-33 was required for infiltration of monocyte-derived myeloid cells, and expansion of focal myeloid cell-derived iNOS, an anti-parasitic mechanism crucial for survival during chronic infection. Consequently, intact IL-33 signaling was necessary for control of brain parasite burden. These results expand our knowledge of alarmin signaling in the brain, an environment which is likely unique to the periphery in immune response initiation due to the structural challenge of the BBB, and demonstrate the importance of one damage signal in focal control of T. gondii infection.
T cell restricted TGF-βR3 (betaglycan) null mice develop exacerbated experimental autoimmune encephalomyelitis (EAE) associated with expanded generation of Th1 cells
Authors: Duesman Samuel J. , Ren Clark , Chellappan Rajeshwari , Sestero Christine , Kesterson Robert A. , De Sarno Patrizia , Soldevila Gloria , Raman Chander 
Published: January 2023

Abstract
TGF-β receptor 3 (TGFβ-R3), also known as betaglycan, promotes high-affinity binding of TGF-β (1, 2 and 3) to TGFβ-R1 and TGFβ-R2 and is also a receptor for bone morphogenetic proteins (BMP) and inhibins. The embryonic lethality of TGFβ-R3 knock-outs hindered the understanding of its mechanistic function in immune response. To interrogate the function of TGFβ-R3 in mature T cells (T-Tgfbr3KO), we generated a conditional Tgfbr3f/f mouse and bred it with the dLckCre mouse. We found EAE in mice with T-Tgfbr3KO developed with greater severity and mortality than WT littermate mice in both males and females. The onset of disease was similar. The greater severity in T cell T-Tgfbr3KO mice was associated with increased proportion of Th1 cells in the CNS with no difference in numbers of Th17 cells. OT2 T-Tgfbr3KO CD4 T cells also polarized more efficiently to Th1 cells than T-Tgfbr3WT CD4 T cells. The lack of TGF-βR3 had no significant effect on differentiation of Th17 cells. Since our results indicates that TGF-βR3 regulates differentiation to IFN-γ expressing T cells, we interrogated if T-dependent B cells responses to IFN-γ switching will be altered in mice immunized with TNP-KLH. We found that IFN-γ switch dependent anti-TNP IgG2c and IgG3 was greatly enhanced in T-Tgfbr3KO mice compared to WT littermates. All other isotypes were similar in both groups. Our data reveal a novel role for TGFβ-R3 in regulating differentiation of naïve CD4 T cells to IFN-γ expressing cells.
IL-7 promotes naïve T cell motility and regulates T cell-dendritic cell contacts in the lymph node via JAK/STAT signaling.
Authors: Byrum Janie Rae , Torres David J. , Mrass Paulus , Oruganti Sreenivasa Rao , Cannon Judy L. 
Published: January 2023

Abstract
Naïve T cells contact dendritic cells (DCs) presenting antigen in lymph nodes to become activated. T cell motility is a key step to enabling T-DC interactions by bringing T cells into close proximity with DCs. We find a novel role for interleukin 7 (IL-7) in regulating T cell motility in lymph nodes. We show using 2 photon microscopy that IL-7 promotes T cell speed and increases the search area for individual T cells. Downstream of IL-7R, IL-7-mediated T cell motion required JAK/STAT activation, but IL-7R-mediated T cell motility occurred independently of mTOR signaling. Inhibition of IL-7-IL-7R signaling resulted in reduced contact with DCs in the T cell zone of the lymph node. Using computational modeling, we show IL-7-IL-7R is specifically important for T cell contacts with unique DCs. Our results show a new role for IL-7-IL-7R in regulating T cell function by controlling T cell motility in the lymph node. Thus, IL-7-IL-7R axis promotes not only T cell development, survival, and proliferation, but also T cell motion, leading to enhanced T cell interaction with DCs.