bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral administration of antigen mainly induces T helper lineage-negative CD200+ CTLA4+ anergic CD4+ T cells which tend to become regulatory T cells
Authors: Hong Sung-Wook , Jenkins Marc K 
Published: January 2023

Abstract
CD4+ T cells do not normally undergo productive immune responses to orally administered foreign antigens. It has been proposed that this oral tolerance phenomenon is explained by CD4+ T cells with T cell receptors (TCRs) specific for MHCII-bound peptides from ingested antigens becoming unresponsive (anergic) or differentiating into T regulatory (Treg) cells. Not much is known, however, about the phenotype and function of cells undergoing this process within the polyclonal CD4+ T cell repertoire. We addressed this issue by using I-Ab tetramers containing a foreign peptide called 2W to track 2W:I-Ab-specific CD4+ T cells after oral gavage of C57BL/6 mice with 2W peptide. These CD4+ T cells underwent weak clonal expansion when exposed orally to 2W peptide and generated a population consisting of 10% Foxp3+ Treg cells, 10% CXCR5+ follicular helper cells (Tfh), and ~3 % TBET+ Th1 or RORgt+ Th17 cells. The dominant subpopulation, however, did not express any of the known T helper cell lineage markers. Analysis of 80 surface proteins including CD73, FR4, CD200, PD-1, P2X7, and CTLA-4 revealed that these T helper lineage-negative (Thlin−) cells were more similar to anergic cells than to effector or Treg cells. In addition, adoptive transfer of sorted 2W:I-Ab-specific Thlin− cells followed by oral gavage of the peptide showed that these Foxp3− cells can become Foxp3+ Treg cells much more efficiently than naïve T cells. Collectively, our data demonstrate that the majority of CD4+ T cells exposed to oral antigen become Foxp3− anergic cells with a tendency to become Treg cells.
Distinct contributions of CRAMP produced by epithelial cells and macrophages to colon mucosal homeostasis
Authors: Chen Keqiang 
Published: January 2023

Abstract
The cathelicidin-related antimicrobial peptide CRAMP (LL-37 in human) plays an important role in protecting the colon from inflammation, carcinogenesis and dysbiosis as demonstrated in systemic CRAMP-deficient mice. Since understanding the cellular origin of CRAMP in the colon is critical for elucidating its mechanistic basic of action and potential as a therapeutic agent for diseases, we examined the contribution of macrophage- versus epithelial cell-, derived CRAMP in protecting colon by using mice with conditional CRAMP deficiency. Here we report that the colon of mice systemically deficient in CRAMP contained increased bacteria attaching to the mucosa, which was phenocopied by mice with CRAMP deficiency in macrophages, but not epithelial cells. In chemically induced acute colitis, bacteria invading epithelial cells were significantly increased in mice with myeloid CRAMP deficiency, in association with more severe mucosal damage and higher rate of mouse mortality. In addition, macrophages from the bone marrow of myeloid CRAMP deficient, but not wild type, mice failed to eliminate intracellular E. coli. Mechanistically, elimination of intracellular E. coli by macrophages was dependent on a normal autophagy pathway which was disrupted in CRAMP deficient macrophages. In contrast to macrophages in the colon, CRAMP from epithelial cells mainly promoted the development of goblet cells and mucus production, with negligible contribution to bacterial containment. These results demonstrate distinctive roles of CRAMP derived from macrophages and epithelial cells in maintaining the homeostasis of the colon.
Temporal Maternal Influence on the Developing Microbiota
Authors: Greenfield Kara Grace , Floyd Alex , Newberry Rodney D , Knoop Kathryn A 
Published: January 2023

Abstract
The microbiota present on every mucosal surface of the body is imperative for the development and maintenance of the immune system. Disruption of the microbiota from environmental factors can affect immune components in both the mucosal and the systemic immune compartments. Following birth in mammals including humans and mice, the microbiota rapidly develops and matures into a composition generally seen in adults when infants are weaned. Gut microbiota composition is directly affected by feeding type, breast-fed vs formula-feeding, in humans, and the microbiota associated with breastfeeding has been shown to promote intestinal health. As the composition of breastmilk changes throughout lactation, we hypothesize maternal provided factors within breastmilk support the development of the microbiota in a temporally sensitive manner. To address this question we asynchronously cross-fostered (ACF) litters born on day 1 to dams who had delivered 2 weeks earlier. Gut microbiota composition was assessed by 16S analysis of stool samples at the time of weaning, and while the microbiota of synchronous cross-fostered pups resembled the microbiota of their foster dam, the microbiota of ASF mice was different from both their foster dam and the healthy microbiota seen in weanling mice. ACF mice had a significant reduction in bacteroides and firmicute species, species that generally represent the majority of the bacteria within a healthy microbiota, and expansion in prevotella species, which include clinically important opportunistic pathogens, suggesting ACF mice contain a dysbiotic microbiota. Future work will explore and identify what temporally dependent components in breast milk support the development of a healthy microbiota.
Genetic regulation of immune homeostatic lung leukocyte populations
Authors: Hampton Brea K , Jensen Kara , Whitmore Alan C. , Morrison Clayton R. , Plante Kenneth S. , Leist Sarah R. , Gralinski Lisa E. , Menachery Vineet D. , Schäfer Alexander , de Villena Fernando Pardo-Manuel , Baric Ralph S. , Heise Mark T. , Ferris Martin T. 
Published: January 2023

Abstract
Immune homeostasis is the state where the immune system maintains stability in the absence of insult. Much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. There is evidence that homeostatic immunity can affect subsequent responses to infection or vaccination. Since the lungs are a major site of infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at the steady state. We found that all immune cell populations measured showed strong genetic (i.e. strain-specific) variation in cell type abundances. We identified 12 quantitative trait loci (QTL) associated with variation in 12 immune cell populations or the relationships between cell populations. Given the role of various immune cells in the lungs during respiratory virus pathogenesis, we asked whether any of the mapped QTL correlated with influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease following infection in the same strains of mice. Notably, a locus we mapped for baseline abundance of CD8+ T cells in the lungs was associated with peak weight loss following IAV infection. Additionally, a locus mapped for variation in Ly6C+ monocyte/macrophage abundance was associated with SARS-CoV titer at days 2 and 4 post-infection. These data suggest that abundance of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.
Quantifying the durability, expansibility, and tissue-autonomous nature of the immune system uncovers a resident reservoir for circulating immunity
Authors: Wijeyesinghe Sathi , Beura Lalit K. , Pierson Mark J. , Stolley J. Michael , Rosato Pamela C. , Masopust David 
Published: January 2023

Abstract
Immune cells develop in specialized lymphoid organs, but the mature immune system is integrated throughout the body and regulates tissue homeostasis and defense. This study examines how immunity persists within adult murine tissues while addressing issues of tissue autonomy, resistance to perturbations, and numerical contribution to the cellularity of visceral organs. Using quantitative immunofluorescent microscopy, we report that the immune system is expansible in nonlymphoid tissues following microbial experience, and hematopoietic cells comprise up to 30% of cells in visceral organs of laboratory mice housed in non-SPF conditions. Most hematopoietic cells in nonlymphoid tissues were autonomously maintained for &gt;30 days, without contribution from circulation or primary lymphoid organs. Focusing on antiviral T cell immunity, we demonstrate tissue-autonomous maintenance of resident memory T cells for &gt;200 days. Resident T cell memory was largely durable following significant environmental perturbations and de novo immune responses. Once established, resident T cells did not require the T cell receptor for survival, longevity, or retention of a poised effector-like phenotype. Ultimately, T cell memory did decay in some organs, not others, and gradually increased in circulation. Surgical separation of parabiotic mice unexpectedly revealed a tissue-resident provenance for memory T cells in peripheral blood. We propose a model whereby circulating memory T cells do not replenish resident populations, but instead a tissue-resident reservoir supports long-term maintenance of the bloodborne pool. Collectively, these data demonstrate the durability and autonomous nature of the tissue-integrated immune system.
Verdinexor, a selective inhibitor of nuclear export, decreases plasma cell survival in human lupus
Authors: Nandedkar Neha D , Meednu Nida , Albrecht Jennifer , Rangel-Moreno Javier , Barnas Jennifer L , Widman Douglas G , Anolik Jennifer H 
Published: January 2023

Abstract
Systemic lupus erythematous (SLE) is a complex autoimmune disease affecting multiple organs. Anti-nuclear antibody (Ab) producing plasma cells (PCs) play a critical role in the disease pathogenesis and are an important target for developing therapies against SLE. Karyopharm Therapeutics (KPTI) is an oncology-focused pharmaceutical company dedicated to the discovery, development, and commercialization of novel first-in-class drugs for the treatment of cancer and other major diseases. KPTI’s lead compound, XPOVIO™ (selinexor), received accelerated approval from the FDA in combination with dexamethasone as a treatment for patients with heavily pretreated multiple myeloma. KPTI’s selective inhibitors of nuclear export (SINE, verdinexor) are effective in reducing nephritis in the NZBW/F1 mouse model, and dramatically reduced autoreactive PCs. To further define whether SINEs directly decrease PC survival and/or generation, we studied PCs in human lupus ex vivo. Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from healthy (n=3) and SLE donors (n=3) were treated with verdinexor and PC survival was determined by IgG ELISPOT and apoptosis assay. Verdinexor treatment significantly reduced the number of Ab secreting cells from healthy and SLE donor PBMCs as well as BMMCs (IC50 =0.1uM). Upon ex vivo verdinexor treatment (0.5uM), the levels of live blood plasmablasts and bone marrow CD19+ PCs were reduced by 30% with increased level of apoptotic cells. In contrast, ex vivo verdinexor treatment had no effect on naïve B cells and T cells from healthy and SLE PBMCs and BMMCs. These results support the hypothesis that SINEs have a direct effect on PC survival and represent a novel treatment approach for SLE.
Retinoic acid exerts disease stage-dependent and tissue-specific effects on pristane-induced lupus
Authors: Abdelhamid Leila , Cabana-Puig Xavier , Swartwout Brianna , Lee Jiyoung , Li Song , Sun Sha , Li Yaqi , Ross A. Catharine , Cecere Thomas E. , LeRoith Tanya , Wang Haifeng , Reilly Christopher M. , Luo Xin M. 
Published: January 2023

Abstract
We previously showed that all-trans-retinoic acid (tRA) exacerbated pre-existing autoimmunity in lupus; however, its effects before disease onset are unknown. Here, using a pristane-induced model, we show that tRA exerts tissue-specific effects when given at the initiation vs. continuation phase of lupus. Pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow CD11b- conventional dendritic cells, increasing the splenic CD4:CD8 ratio, and upregulating the interaction of ICAM-1 and LFA-1 that led to the infiltration of inflammatory cells to the spleen. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated genes associated with cell differentiation, activation, and migration. Moreover, compared to pristane alone, tRA pre-treatment potentiated, whereas tRA post-treatment significantly suppressed, the renal expression of proinflammatory TNF-α, IL-1β, CCL2, and CCL3. While it may benefit the kidney, post-pristane treatment with tRA worsened the onset and severity of pristane-induced arthritis through promoting neutrophil and mononuclear cell infiltration into the joints. Together, these findings suggest that tRA supplementation regardless of the time of administration promotes chemokine-driven migration and tissue-specific infiltration of inflammatory cells, thereby exacerbating lupus-associated kidney or joint inflammation. Interestingly, both pre- and post-treatments with tRA modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.
Hydroxychloroquine enhances efferocytosis and inhibits IL-6 and TNF-α productions through upregulating both Gas6/Axl and MFG-E8/TG2 Signaling pathways in Pristine-induced lupus mice
Authors: Tsay Gregory J , Hsieh Fei-Hung , Xue Ting-Yin , Peng Hsin-Yi , Tsao Yan-Chi , Yin Mei-Chin , Chen Jiunn-Horng , Huang Chung-Ming , Chen Der-Yuan , Lan Joung-Liang 
Published: January 2023

Abstract

Objectives
Impaired clearance of apoptotic cells (efferocytosis) plays an important role in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE). Hydroxychloroquine (HCQ) has been widely used to treat autoimmune diseases. We aimed to investigate the underlying mechanism of efferocytosis in the action of HCQ.

Methods
Eighteen 6-week-old female BALB/c mice were treated Intraperitoneally with pristine in Pristine-induced lupus mice (PIL). Efferocytosis was performed using mouse cell lines EL4 as apoptotic cells and co-cultured with RAW 264.7 and peritoneal macrophages of PIL to investigate the effect of HCQ on efferocytosis which was analyzed with fluorescent microscopy and flow cytometry. Real time PCR was performed to investigate molecular mRNA expressions of signalling pathways. Protein level was measured by ELISA.

Results
HCQ could enhance efferocytosis with dose-dependent manner in both RAW264.7 cell lines and peritoneal macrophages of PIL with increased expression of GAS6 and MFG-E8 signallings. Both Gas6/Axl and MFG-E8/TG2 Signalling pathways play important roles in HCQ-enhanced efferocytosis. In HCQ-treated mice of PIL, HCQ reduced of IL-6 (p&lt;0.0036) and TNF-α (p&lt;0.06) protein levels in their ascites.

Conclusions
Our study shows that HCQ can enhance efferocytosis through both Gas6/Axl and MFG-E8/TG2 Signalling pathways and suppress the production of IL-6 and TNF-α. Our findings provide novel insights into understanding the mechanisms of HCQ, which could have the long-term beneficial effects on the therapy of SLE.
Amelioration of skin and kidney disease in a spontaneous murine lupus model via CD6 modulation
Authors: Chalmers Samantha A. , Garcia Sayra J , Ramachandran Rajalakshmy Ayilam , Mohan Chandra , Herlitz Leal , Ampudia Jeanette , Ng Cherie , Connelly Stephen , Putterman Chaim 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that can affect multiple organ systems, including the kidneys, skin, and brain. T cells are an important mediator in this end organ damage. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, which binds with activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and various epithelial and endothelial tissues. This signaling pathway is vital for T cell activation, proliferation, differentiation and trafficking. We found increased expression of both CD6 and ALCAM in the kidneys of MRL/lpr mice (a spontaneous model of SLE) versus healthy control B6 mice. In a separate experiment, female MRL/lpr mice were aged to 9–10 weeks of age, at which point we began treating with either anti-CD6 antibody (60 ug/dose, intraperitoneally twice per week), isotype control (60 ug/dose, twice per week), or cyclophosphamide (25 mg/kg, once per week). We also included a no treatment group and a group of MRL/MpJ mice, a congenic healthy control strain. Mice treated with anti-CD6 show lower levels of proteinuria and BUN (p&lt;0.05), improved survival rates, and decreased renal pathology compared to isotype control mice. Flow cytometry revealed decreased numbers of activated and effector T cells within the kidneys of anti-CD6 treated mice compared to isotype control mice. While there was no difference in anti-DNA levels, anti-CD6 treatment significant improved the spontaneous skin lesions associated with disease progression. Overall, these results indicate that targeting CD6-ALCAM interactions may have promising therapeutic potential within the context of different end organ pathologies within lupus.
Tumor necrosis factor like weak inducer of apoptosis (TWEAK) Promotes Inflammatory Activity in Keratinocytes with IL-17 and TNF to Drive Psoriasis
Authors: Gupta Rinkesh Kumar , Gracias Donald Tom , Burkly Linda C , Croft Michael 
Published: January 2023

Abstract
Psoriasis is an autoimmune skin disease caused by hyper-proliferation of keratinocytes driven by distinct inflammatory cells making cytokines such as IL-17 and TNF. Our previous studies with knockout animals revealed that the TNF-related cytokine TWEAK (TNFSF12) was also a critical contributor to skin inflammation and could be a potential therapeutic target in psoriasis. As Fn14, the receptor for TWEAK, is expressed by keratinocytes, we examined the inflammatory effects of TWEAK alone and with IL-17A and TNF in modulating psoriatic genes in human keratinocytes using RNA-seq. We found that TWEAK upregulated the expression of multiple chemokines and cytokines, such as IL-36G, IL-23A, IL-19, CCL5, CCL20, and other inflammation-associated genes, that have previously been found highly expressed in the skin of patients with psoriasis. TWEAK’s action was partially overlapping with IL-17 and TNF, but interestingly, in combination with IL-17 or TNF, TWEAK had strong synergistic effects in enhancing the expression of a number of these inflammatory genes. We then tested the impact of TWEAK neutralization on already existing skin inflammation in an imiquimod-induced psoriasis model. Mice treated therapeutically with anti-TWEAK showed significantly decreased numbers of immune cell infiltrates in the skin, with fewer γδ T cells, neutrophils and macrophages. These mice also exhibited a marked reduction in epidermal thickening, similar to mice treated with anti-IL-17 alone. Furthermore, co-neutralization of TWEAK and IL-17 demonstrated a greater effect in terms of reducing clinical symptoms. These data suggest that blocking TWEAK could be considered as a potential therapeutic avenue in humans to overcome the pathophysiology of psoriasis.
The VR23 anticancer proteasome inhibitor also exhibits anti-inflammatory activity through the downregulation of the IL-6-JAK-STAT pathway
Authors: Durkin Amanda , Lee Hoyun 
Published: January 2023

Abstract
We previously demonstrated that the novel proteasome inhibitor, VR23, possesses anti-tumor activity without causing any ill-effects to animals. We have now shown that the compound VR23 also possesses potent anti-inflammatory activity. Our data from a monocyte cell model shows that VR23 down-regulates pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 at similar efficacy as dexamethasone, a steroid widely used for the control of inflammatory conditions. Studies from a rheumatoid arthritis (RA) cell model show that VR23 can not only down-regulate IL-6 but also inhibit the cell migration. Importantly, the down-regulation of pro-inflammatory cytokines by VR23 is more pronounced in the primary synovial cells from RA patients than those from healthy donors. Since VR23 down-regulates not only STAT3 phosphorylation but also the expression of its downstream pathways, our data is consistent with the notion that VR23 exhibits its anti-inflammatory properties through the downregulation of the IL-6-JAK-STAT signaling pathway. The latter down-regulation is at the level of transcription of several important members of the IL-6-JAK-STAT family. Finally, VR23 effectively reduces neutrophil migration, TNF-α secretion, and tissue inflammation in mice with an LPS-induced acute lung injury. Our data thus suggest that VR23 is an agent with significant potential of controlling cancer as well as acute and chronic inflammatory conditions.
Tolerogenic nanoliposomes for the treatment of Rheumatoid Arthritis
Authors: Kenison-White Jessica , Nowakowska Dominika J , Jhaveri Aditi , Khase Nikita , Tezza Sara , Sherr David , Quintana Francisco Javier 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a T-cell mediated chronic inflammatory disease characterized by inflammation of the synovial joints, and cartilage and bone tissue destruction. Therapeutic approaches for the induction of immune tolerance are of high clinical significance, and approaches aimed at controlling the balance of effector and regulatory T cells in an antigen-specific manner remain an unmet medical need. Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) represents a strong candidate target for the development of novel immunotherapies. Here, we report the development of nanoliposomes (NLPs) which co-deliver a tolerogenic AhR ligand, ITE, and collagen type IIa. These NLPs ameliorated disease symptoms in the collagen-induced arthritis (CIA) model of RA in preventive and therapeutic treatment paradigms. CIA amelioration was associated with reduced levels of pro-inflammatory cytokines in the joints and decreased collagen type II specific IgG antibodies in serum. In addition, treatment with tolerogenic NLPs induced the expansion of FoxP3+ and IL10+ regulatory T cells and suppressed collagen-specific IFNγ+ effector T cells. Taken together, these results suggest that NLPs suppressed both T-cell and B-cell pathogenic responses and represent a novel therapeutic platform to induce antigen-specific tolerance for the treatment of autoimmune diseases.