bluuebunny/crossref_metadata_2025_split huggingface dataset:
VLA4 expression by B cells enables B cell-restricted antigen presentation to support CD4 T cell driven central nervous system autoimmunity
Authors: Parker Harp Chelsea R. , Archambault Angela S. , Sim Julia , Carrero Javier A. , Russell John , Wu Gregory F. 
Published: January 2023

Abstract
Clonal expansion along with immunoglobulin (Ig) class-switching and secretion result from B cell antigen presentation to cognate CD4 T cells. The presence of oligoclonal Ig in the cerebrospinal fluid of most patients with multiple sclerosis raises the important question of where cognate B:T cell interactions occurs during disease. Previously we showed that increasing the frequency of MOG-specific B cells is sufficient to drive EAE in mice expressing MHCII solely by B cells. We have now established a system in which EAE reliably occurs upon expression of MHCII using Tamoxifen-induced temporal regulation in MOG-specific B cells. While B cells express MHCII in the central nervous system (CNS) in these models, whether or not B cells acquire and present antigen in the CNS compartment is unknown. Large clusters of B cells rapidly formed in the subarachnoid space of the spinal cord during EAE in our model, suggesting homing to the CNS is important for antigen presentation. Genetic regulation of B cell MOG-specificity and expression of MHCII and Very Late Antigen-4 (VLA-4) was used to determine the dependence of passive EAE susceptibility on B cell access to the CNS. Mice in which VLA-4 expression was abrogated simultaneously with MHCII expression by MOG-specific B cells were subjected to passive EAE. Disease exclusively mediated by B cell antigen presentation was dependent on VLA-4 expression by B cells. MOG-specific CD4 T cell hybridomas did not detect endogenous MOG presented by B cells harvested from the periphery of mice prior to the onset of disease. Taken together, our findings indicate that B cells require access to CNS myelin targets in order to propagate antigen-specific CD4 T cell-dependent neuro-inflammation.
Adjuvant-induced rheumatoid arthritis in Lewis rats alters dopamine utilization and cytokine concentration in five brain regions
Authors: Yang Han , Stinson Amelia J. , Carcia Carlos A. 
Published: January 2023

Abstract
Word Rheumatoid arthritis (RA) is a chronic autoimmune disease which can cause inflammation in joints, bone damage, as well as disability. A reported symptom of RA includes cognitive dysfunction. This study aimed to measure brain dopamine utilization and inflammatory markers in an adjuvant-induced Lewis Rat model of RA. Arthritic intensity was scored based on physical examination of the four paws. Twenty-eight days after the adjuvant injection, control and RA group were sacrificed and the frontal lobe of the cerebral cortex (Cx), hippocampus (Hip), hypothalamus (Hypo), amygdala (Amg), and cerebellum (Cbl) dissected using the stereotaxic atlas of Paximos and Watson as a guide. High performance liquid chromatography (HPLC) was used to analyze the concentration of dopamine, DOPAC, and homovanillic acid (HVA). Pro-inflammatory cytokines IL-1β, IL-6, and IL-23, and the anti-inflammatory IL-10 were measured by enzyme-linked immunosorbent assays (ELISA) in tissue homogenates. The results indicate RA significantly (p&lt;0.05) decreased the dopamine content in Cbl, Amg, Hip and Cx; DOPAC significantly decreased in Amg and Cbl; HVA significantly decreased in Cbl. RA increased the concentration of pro-inflammatory cytokines and the anti-inflammatory cytokine IL-10 in the Cbl. IL-1β increased in Hyp, and Amg with a concomitant decrease in IL-10. IL-6 and IL-23 increased in Cx, Hip, Hypo, and Amg with a concomitant decrease in IL-10. This data provides evidence that adjuvant-induced RA alters the inflammation status and dopamine utilization of these brain regions. The results are useful in the development of novel drug therapies for the millions of RA patients at risk of developing mood changes, memory loss, and other cognitive deficits.
Autoimmune disease severity is suppressed by type I interferon signaling in radioresistant cells
Authors: Riding Rebecca L. , Richmond Jillian M. , Fukuda Keitaro , Harris John E. 
Published: January 2023

Abstract
Type I interferons broadly modulate immune responses and can drive both anti-inflammatory and immunostimulatory programs. Vitiligo is an autoimmune disease where melanocytes are destroyed by autoreactive CD8+ T cells. We have previously shown in mice and human patient tissue that IFNγ and the induced downstream chemokines, CXCL9 and CXCL10 drive disease pathogenesis. Since type I interferon signaling can drive expression of multiple overlapping IFNγ target genes, we wanted to determine the role of type I interferon in disease progression. Interestingly, we found that type I interferon-deficient mice developed accelerated and severely enhanced vitiligo compared to WT control mice. These results suggest that in contrast to IFNγ, IFNAR signaling acts to suppress disease. We subsequently found that IFNAR signaling is not required on autoreactive CD8+ T cells or other radiosensitive immune cells but rather it is required on radioresistant cells to suppress vitiligo. In radioresistant IFNAR-deficient mice, autoreactive CD8+ T cells have significantly reduced levels of PD-1 expression which correlates to increased production of the effector cytokines TNFα and IFNγ. Generation of conditional knockout mice showed that epidermal radioresistant Langerhans cells and keratinocytes do not require IFNAR to suppress disease and we are currently investigating the role of IFNAR signaling on epidermal melanocytes. These studies will not only enhance our understanding of the role of IFNAR in promoting tissue specific tolerance, but will have broad insights into the role of IFNAR in other organ–specific autoimmune diseases, such as multiple sclerosis, in which IFNβ is an available treatment.
Metabolic Functions of the Murine Lupus Susceptibility Gene Pbx1
Authors: Roach Tracoyia A. , Titov Anton , Soh Sujung , Robusto Brian , Morel Laurence 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects many organ systems. Poorly characterized genetic factors contribute to SLE, in part through the production of autoreactive or inflammatory T cells. Pre-B cell leukemia homeobox 1 (Pbx1) is a transcription factor whose Pbx1-d dominant negative splice isoform is overexpressed in CD4T cells of lupus patients as well as in the NZM2410 lupus-prone mouse as compared to the normal Pbx1-b isoform. Based on gene expression studies comparing murine CD4 T cells overexpressing Pbx1-d to controls, we hypothesize that Pbx1-d enhances cellular metabolism in T cells through the HIF1α and mTORc1 pathways. CD4 T cells expressing Pbx1-d present a higher cellular metabolism and show a higher mTORc1 activation than normal control T cells. Using mesenchymal stem cells, we showed that transfection of Pbx1-d was sufficient to increase glycolysis, a pathway linked to T cell activation. We found that Ddit4, an mTORc1 inhibitor, shows a lower expression in the Pbx1-d-expressing CD4 T cells than in normal T cells. We also discovered that Pbx1-d preferentially binds to the promoter of Ddit4, as well as Egln1 and Egln3, two HIF1a inhibitors. These results suggest that a mechanism by which the Pbx1-d allele contributes to lupus pathogenesis is to enhance CD4 T cell metabolism. Future work will define how Pbx1 controls the immune system and how the function of this transcription factor is linked to cellular metabolism.
Identification of Btnl2 as a Key Gene in Suppressing Autoimmunity: New Players in SLE pathogenesis
Authors: Khan Shaheen , Hwang Sun-Hee , Belobrajdic Katherine , Viswanathan Kasthuribai , Wakeland Benjamin , Casco Jose , Wakeland Edward K. 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with extensive clinical heterogeneity, affecting mainly females. It is initiated with breach in immune tolerance and as a result one of the main characteristics of SLE is the production of autoantibodies to a wide spectrum of self-antigens. Sle1 is a potent susceptibility locus for spontaneous systemic autoimmunity derived from the NZM2410 mouse strain. The NZW-derived suppressive modifier locus, Sles1, specifically prevents the spontaneous loss in tolerance mediated by the B6.Sle1 congenic. Fine mapping combined with phenotypic characterization of series of recombinant mouse strains have mapped Sles1 to an approximately 638 Kb segment on murine chromosome 17. This revealed extensive epistatic gene interactions within the Sles1 region and suggested Btnl2 and H2 genes as the strongest candidates. We generated BAC transgenic mice by introducing BAC harboring B6 allele of Btnl2 alone or Btnl2 and H2 combined allelic region on to Sle1.Sles1 mice to identify the gene driving the suppressive phenotype. Phenotypic characterization of aging BAC transgenic mice is completed and results strongly indicate Btnl2 as the key gene within the 638 Kb region driving the suppression. Additionally we have performed targeted resequencing on B6 and B6.Sles1 mice and have identified functional polymorphisms within the Btnl2 gene between the two mice strains. We are currently generating and analyzing RNA-seq data on our BAC transgenic mice to gain insight in to the mechanisms on how Btnl2 is suppressing autoimmunity. This study confirms Btnl2 as the key driver gene in suppressing loss of tolerance in SLE pathogenesis.
Dietary Tryptophan Modulates Autoimmunity in a Mouse Model of Lupus
Authors: Brown Josephine Michelle , Choi Seung-Chul , Kanda Nathalie , Morel Laurence 
Published: January 2023

Abstract
Both kynurenine and serotonin are synthesized from dietary tryptophan via indolamine-2,3-dioxygenase (IDO) and tryptophan hydroxylase (tph1) respectively. SLE patients have altered serum and PBMC tryptophan metabolites relative to healthy controls such that there is a depletion of both tryptophan and serotonin and an accumulation of kynurenine. Mass spectrometry analyses showed that SLE B6.Sle1.Sle2.Sle3 congenic (TC) mice on a standard diet that were positive for serum autoantibodies have the same serum tryptophan metabolite alterations reported in SLE patients as compared to B6 controls. Additionally, TC mice have an altered fecal tryptophan metabolite profile relative to B6 controls, and antibiotic treatment restores this profile, suggesting a microbial involvement. Based on these findings, we sought to understand how altering dietary tryptophan would impact autoimmunity in lupus-prone TC mice. Congenic mice consuming low (0.1%) or no (0%) tryptophan for 6 months were protected from autoimmunity whereas those consuming supplemented tryptophan (1%) had exacerbated autoimmunity, including anti-dsDNA IgG production that was correlated with serum kynurenine levels. Furthermore, enzyme expression within the tryptophan catabolic pathway was altered in total CD4+ T cells from SLE congenic mice relative to B6 controls. These data show an altered tryptophan metabolism in lupus prone mice associated with the gut microbiome and with changes in enzyme expression within the tryptophan catabolic pathway in immune cells. Further we showed that manipulation of tryptophan metabolites through diet modulates autoimmunity in these lupus-prone mice.
Noc4L dictates Treg activation in vivo
Authors: Zhou Xuyu 
Published: January 2023

Abstract
Regulatory T cells (Treg) are a specialized CD4+ T cell lineage that plays a central role in controlling self-immune tolerance. It is well documented that antigen triggered Tregs activation is crucial for their suppressive function; however, the underlying molecular mechanism is poorly understood.
The ribosome plays a universally conserved role in catalyzing the translation of all mRNAs in every cell across all kingdoms of life. It is therefore not surprising that the ribosome is one of the most complex and elaborately formed “molecular machines” in the cell, whose biogenesis is extraordinarily orchestrated. Although ribosome biogenesis is considered as a conserved housekeeping process, emerging of evidence support a new hypothesis that different cell types might actually have various of the repertoire of ribosome biogenesis factors (RBFs), which are required to generate specialized ribosome and confer the translation of selected mRNAs.
Here, we focused on the conserved ribosome protein Noc4L based on the observations that Noc4L was highly expressed in activated CD4+CD25+ T cells compared with the resting Treg cells in vitro. Treg specific knockout Noc4L mice developed a lethal autoimmune phenotype, resembling Treg-deficient “scurfy” mice. Interestingly, Noc4L defection did not globally affect the overall protein translation in Tregs, but a rather select detriment of the expression of the genes related to Treg activation. Together, these results demonstrated a central role for the ribosome biogenesis factor Noc4L in controlling Tregs activation. The specialized ribosome is a new layer in the regulation of gene expression of Tregs.
Generation of a mouse model of extrathymically-derived regulatory T cells in type 1 diabetes
Authors: Holohan Daniel R. , Dong Shen , Porter Caroline , Rozenblatt-Rosen Orit , Regev Aviv , Van Gool Frederic , Bluestone Jeffrey A. 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are an immunosuppressive population that were initially identified as uniformly and stably expressing the transcription factor Foxp3. Tregs have now been further distinguished based on whether they developed in the thymus (thymically-derived Tregs, or tTregs) or in the periphery (peripherally-derived Tregs, or pTregs). Previous studies have shown that deletion of CNS1, a conserved non-coding DNA response element in the Foxp3 locus, leads to selective impairment of pTreg generation without disrupting tTreg generation in the B6 background. However, the role of pTregs versus tTregs in autoimmunity is unclear. Using CRISPR-Cas9, we removed the CNS1 region in the NOD mouse model of spontaneous type 1 diabetes. Based on in vitro Treg generation assays, removal of the CNS1 region impairs Foxp3 induction in naïve NOD CD4+ T cells. However, it did not lead to statistically significant differences in the percent of Tregs found in various tissues, including the spleen, thymus, gut, lymph nodes, and pancreatic islets of non-diabetic mice aged 8–13 weeks. Single-cell RNA seq comparing a 12-week old NOD mouse to a CNS1 KO NOD mouse also did not reveal strong differences in gene expression in the pancreatic islet, gut, or pancreatic lymph node, although flow cytometry analysis does reveal a small but significant decrease in RORyt+ Tregs and an increase in Helios+ Tregs in the gut of CNS1 KO NOD mice. CNS1 KO NOD mice are also being compared to normal NOD mice for type 1 diabetes onset and incidence. These preliminary data suggest that extrathymically-derived Tregs do not play a large role in this mouse model of type 1 diabetes.
Migration Kinetics and Migratory Morphology of Mycobacterium-Infected CD11c-eYFP Murine Bone Marrow Derived Cells
Authors: Gilpin Trey E. 
Published: January 2023

Abstract
Central nervous system tuberculosis (CNSTB) is the most serious manifestation of extrapulmonary tuberculosis infections that represent 5–10% of all cases. Although migration of mycobacterium infected cells from the lung to the CNS is critical in bacterial dissemination into the CNS, very little is known about the migratory phenotypic changes of mycobacterium infected cells and overall the mechanism of dissemination into the brain is poorly understood. Mycobacterium tuberculosis is an obligate pathogenic bacterial species with it’s only mode of transportation being within innate immune cells. Dendritic cells (DCs) are potent antigen presenting cells that migrate long distances and through interactions with T-cells, initiate the adaptive immune response. Our lab has previously shown DCs are able to leave Mycobacterial granulomatous lesions from the lung with bacteria intact. Here we used live cell imaging of an under-agarose migration assay and cell tracking to define the kinetics of CD11c-eYFP DC migration during Mycobacterial infection. We found that migration of mycobacterium infected cells was impaired towards CCL19 chemokine and infected cells portrayed a migratory morphology distinct from uninfected DCs. With the use of CD11c-eYFP-LifeAct-RFP reporter mice, we characterized actin polymerization dynamics within infected CD11c cells. As actin polymerization plays a central role in cell migration, morphology, and pathogen internalization, to understand this process during mycobacterial infection will lead to novel therapeutic therapies to modulate dissemination into the CNS.
CD8 T cells are recruited to the central nervous system after peripheral infections and adopt a tissue resident memory phenotype
Authors: Urban Stina Lisa , Pewe Lecia L. , Harty John T. 
Published: January 2023

Abstract
The central nervous system (CNS) is classically viewed as an immune privileged site; however recent advances in the field highlight the importance between the interaction of the peripheral immune system and the CNS in maintaining tissue homeostasis. Tissue resident memory (Trm) CD8 T cells have been described in almost every organ and are shown to provide a first line of defense against secondary invading pathogens. Trm cell generation generally involves active infection at the site of tissue residence. Using multicolor flow cytometry and 2-photon microscopy, we describe a population of CD8 T cells isolated from the CNS after peripheral systemic infections. At an effector time point, intravascular (IV) stain negative antigen-specific cells isolated from the CNS express high levels of chemokine receptors CXCR6 and CXCR3, adhesion molecules CD11a and CD49a and the Trm marker CD69. This CD8 population acquires CD103 expression and persists long term. Peripherally-induced CNS CD8 T cells are highly dynamic both inside and outside the blood vessels. Within the blood vessels, CD8 T cells can be seen flowing free, sticking to the walls of the vessels and crawling along the blood vessels with and against the flow of blood. Outside the vessels, CD8 T cells are seen surveying the tissue with multiple mechanisms including moving along the blood vessels, traveling long distances in apparently random fashion or remaining stationary. The purpose of systemically-induced Trm-like CD8 T cell populations remains to be determined; however, it is possible that that these cells are similar to conventionally-derived Trm populations and may provide the first line of defense should an invading pathogen reach the CNS.
Trafficking of lung-migratory cDC2s into the spleen following influenza virus infection
Authors: Jenkins Meagan M. , Bachus Holly , Leon-Ruiz Beatriz , Ballesteros-Tato Andre 
Published: January 2023

Abstract
Trafficking of antigen-bearing, migratory conventional dendritic cells type 1 (cDC1) and type 2 (cDC2) from the lung into the lung-draining mediastinal LN (mLN) is essential for priming T cell responses to influenza virus. In the absence of cDC1s and cDC2s, or when these are unable to traffic from the lung into the mLN, T cell responses are compromised, which highlights the importance of these DC subsets in the generation of T-cell-dependent immunity to influenza. Importantly, it is generally considered that cDCs shortly die after reaching the mLN and therefore do not recirculate back to the blood. Nevertheless, DCs purified from the spleen of intransally influenza-infected mice efficiently prime CD8+ T cell responses. Paradoxically, the two locations are not connected by the lymphatic vasculature and the intransally-administered antigens do not freely reach the blood circulation. Thus, is not clear how DCs in the spleen acquire influenza antigens following intranasal infection. Here we show that a fraction of the lung-migratory cDC2s that reach the mLN following influenza virus infection egress from the mLN, reenter the blood circulation and subsequently migrate into the spleen to prime CD8+ T cell Responses. Collectively, our results demonstrate a new paradigm of DC migration, offer new insights into how systemic T cell responses to influenza are initiated, and will ultimately reveal new strategies to elicit systemic responses to vaccination.
Mono-(2-ethylhexyl) phthalate (MEHP)-induced neutrophil and macrophage infiltration into the testicular interstitium of peripubertal rats does not exacerbate MEHP-induced germ cell apoptosis.
Authors: Voss Jorine J. L. P. , Stermer Angela R. , Ghaffari Rashin , Tiwary Richa , Richburg John H. 
Published: January 2023

Abstract
The testis is an immune-privileged organ that maintains an immune suppressive environment. We have previously shown that exposure of postnatal day (PND) 28 Fischer rats to an acute dose of the Sertoli cell toxicant MEHP leads to an accumulation of CD11b+ cells in the testicular interstitium that correlates with a robust incidence of germ cell (GC) apoptosis. Here we hypothesize that the infiltrating immune cells contribute to GC apoptosis. PND 28 Fischer rats that received an oral dose of 700 mg/kg MEHP showed a significant infiltration of both CD11bc+/CD68+/CD163− macrophages and neutrophils, which peaked at 12 hours but had reduced by 48 hours. Testicular macrophages from MEHP-treated cells showed significantly upregulated expression of Tnfa and Il6, and the Arg1/Nos2 ratio was reduced. However, small increases in anti-inflammatory genes Il10 and Tgfb1 were also observed. Depletion of circulating monocytes with clodronate liposomes prior to MEHP-treatment reduced the macrophage influx, but did not lower GC apoptosis. Additionally, depletion of neutrophils using an anti-polymorphonuclear cell antibody prevented both macrophage and neutrophil infiltration, but also did not affect germ cell apoptosis. Together, these results show that exposure to MEHP leads to a rapid and temporary influx of pro-inflammatory monocytes and neutrophils in the interstitium of the testis. However, with this dosing paradigm, these infiltrating leukocytes do not exacerbate MEHP-induced testicular GC apoptosis. Current experiments are targeted to further investigate the functional significance of these infiltrating cells in the pathogenesis of MEHP-induced testicular injury, considering both a destructive and resolving/protective role.
Anti-sulfated-glycan monoclonal antibody S2 inhibits lymphocyte recruitment to nasal-associated lymphoid tissues and attenuates allergic rhinitis
Authors: Hirakawa Jotaro , Kawashima Hiroto 
Published: January 2023

Abstract
Nasal-associated lymphoid tissue (NALT) is a mucosal lymphoid tissue that functions as a border of defense against inhaled antigens. Lymphocyte recruitment to NALT is mediated by the interaction between L-selectin on lymphocytes and sulfated-glycans on high endothelial venules (HEV) in NALT. HEV are specialized post capillary venules regulating lymphocyte entry form blood into parenchyma of lymphoid organs. It has been previously reported that lymphocyte recruitment to NALT was markedly blocked in HEV-expressed N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) −1 and −2 double-deficient (DKO) mice. In the DKO mice, immune responses against nasally administered ovalbumin (OVA) including OVA-specific IgE, sneezes and nose scratches were significantly diminished.
We previously generated an anti-sulfated-glycan monoclonal antibody S2 which recognizes 6-sulfo sialyl Lewis X (sLeX) and 6-sulfo sialyl N-acetyllactosamine expressed on HEV in NALT by immunizing GlcNAc6ST-1/2 DKO mice with CHO-K1 cells stably expressing 6-sulfo sLeX. S2 administration inhibited lymphocyte recruitment to NALT and allergic rhinitis induced by intranasal administration of OVA. S2 administration to OVA-immunized mice resulted in the reduction of OVA-specific serum IgE, and counts of sneezes and nose scratches after nasal immunization. Total cell numbers in NALT and expression of Th2-related cytokines such as IL-5 and IL-13 were also diminished after S2 administration. Taken together, these results suggest that S2 would serve as a novel therapeutic agent useful for the treatment of allergic rhinitis.