bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced inflammation and increased endothelial activation in children with asymptomatic Plasmodium falciparum parasitemia in a low transmission area
Authors: Okafor Elizabeth Chioma , Shabani Estela , Park Gregory S. , Opoka Robert O. , John Chandy C. 
Published: January 2023

Abstract
Few studies investigate asymptomatic parasitemia (AP) and researching the mechanism by which these children remain healthy can provide novel information to understand the pathogenesis of Plasmodium falciparum malaria. We hypothesized children with AP to have higher levels of pro-inflammatory cytokines, angiogenic growth factors, and markers of endothelial activation compared to children without parasitemia. Healthy children were recruited from the community as part of a study on cognitive and neurological deficits in children with central nervous system malaria in Kampala, Uganda. Plasma was prepared from blood samples acquired at enrollment and tested using magnetic bead assay. Nested PCR was performed to detect P. falciparum DNA. Of the 211 community children (CC) samples tested, 73 CC had AP and 138 CC without parasitemia. CC with AP had lower levels of pro-inflammatory cytokines and chemokines IFN-γ (p&lt;0.0001), IL-1β (p=0.0001), IL-8 (p=0.0015), MIP-1α (p=0.01), IL-12p70 (p=0.0002), and RANTES (p=0.0001), and higher levels of TNF-α (p=0.05), MIP-1β (p=0.04), and IP-10 (p=0.01) when compared to CC without parasitemia. CC with AP had lower levels of angiogenic growth factors G-CSF (p&lt;0.0001) and FGF-basic (p&lt;0.0001), and higher levels of markers of endothelial activation ICAM-1 (p=0.0007), VCAM-1 (p&lt;0.0001), and VWF (p=0.0006). In this area of low malaria transmission, children with parasitemia have suppression of these pro-inflammatory cytokines, chemokines and angiogenic factors, but an increase in endothelial activation. Endothelial activation may be an early uniform response to P. falciparum, but symptoms may be controlled by ability to suppress the inflammatory response.
Innate immunity does not contribute to the resistance of mice from different vendors to P. yoelii infection
Authors: Ganusov Vitaly V , Bejnood Aram 
Published: January 2023

Abstract
Nearly 500,000 individuals die annually from Plasmodium infections. Factors contributing to susceptibility to Plasmodium infections remain poorly understood. It was recently observed that C57BL/6 mice from different vendors (NCI, Harlem, Taconic, Jackson) have different susceptibility to Plasmodium yoelii infection: Jackson/Taconic mice generally have lower peak parasitemia in the blood and better survival than NIC/Harlem mice (Villarino et al. PNAS 2016). Bioinformatic analysis suggested that high mortality of susceptible mice could arise due to a higher expression of basigin, a protein required by Plasmodium falciparum to invade red blood cells in humans (Stough et al. Front Microbiol 2017). We applied a series of mathematical models of different levels of complexity to experimental data on P. yoelii dynamics in mice from these 4 vendors. Our analysis suggests that there are no statistically significant differences in the P. yoelii dynamics during the first 10–14 days post infection, and that the estimated rates of parasite replication were independent of the vendor type. In contrast, we found large differences in parameters for Plasmodium-specific adaptive immune response suggesting that resistant mice mounted a faster and a more efficient response. Our results thus suggest that higher expression of basigin is unlikely to explain higher susceptibility of NCI/Harlem mice to P. yoelii infection and that innate immunity controlling parasite replication during the first 2 weeks of infection unlikely to be different between susceptible and resistant mice. In contrast, a faster generation of the adaptive immunity in resistant mice was likely to be responsible for better parasite control.
Evaluation of the pathogenesis of Chlamydia induced reactive arthritis
Authors: Volin Michael V , Ahmed Farah , Zanotti Brian , Manam Srikanth , Murthy Ashlesh K 
Published: January 2023

Abstract
We hypothesized that reactive arthritis can be induced in the knees and ankles of wild-type C57BL/6 mice following infection with Chlamydia muridarum through the involvement of inflammatory mediators. Reactive arthritis is a chronic form of arthritis, which can also result in conjunctivitis and inflammation of the genital, urinary, or gastrointestinal systems. C. muridarum is a gram-negative obligate intracellular pathogen which can infect the epithelium of the cervix, urethra, and rectum. The exact pathological mechanism of reactive arthritis is unknown. It is understood to result from CD4+ and CD8+ T cells, and factors including TNF-alpha and perforin. Five groups of C57BL/6J mice were used including a positive control group, CD4+ T cells knockout mice, TNF-alpha knockout mice, perforin knockout mice and TNFRSF knockout mice. Mice from each group were intra-vaginally infected with 5×104 inclusion forming units of C. muridarum, marked as day 0. The mice were swabbed a few days after infection to confirm C. muridarum. The mice from each group were euthanized on day 7 and day 14, and sera was collected and analyzed for cytokine expression using an antibody array. Ankles collected from C57BL/6J positive control mice were histologically processed and graded to determine pathology. C57BL/6J positive control mice showed increased synovial lining thickening 14 days following infection. Cytokine expression from TNF-alpha knockout mice, CD4+ T cells knockout mice, perforin knockout mice, and TNFRSF knockout mice was generally reduced. The results show that chlamydial induced reactive arthritis can be detected in the ankles of C57BL/6J mice and suggest that TNF-alpha and CD4+ T cells may be involved in this inflammatory process.
Role for skin-associated microbiota in development of endogenous anti-melanocyte immunity in vitiligo
Authors: Vujkovic-Cvijin Ivan , Wei Maria , Restifo Nicholas P , Belkaid Yasmine 
Published: January 2023

Abstract
Despite major advances in immunotherapeutic approaches designed to bolster endogenous immune responses against tumors, metastatic melanoma remains associated with high mortality and rapid progression. Development of novel approaches toward enhancing endogenous immune responses against melanoma constitutes a critical step toward the management of disease. Of note, initiating immune responses against non-mutated melanocyte-specific protein antigens has shown efficacy in augmenting immunotherapies. Vitiligo is an autoimmune disease characterized by immune-mediated destruction of melanocytes, though the etiology of this disease remains poorly understood. Microbes have been recently found to have a profound effect on immune processes of the skin, including those that are associated with vitiligo progression. Identifying skin-resident microbes that initiate or exacerbate anti-melanocyte immunity, as well as the precise pathways that mediate these processes, may provide a novel framework for the development of immunotherapies to augment anti-tumor immune responses and efficacy of existing therapies. Thus, we have recruited a cohort of individuals with vitiligo and profiled their skin microbiomes at various body sites. We have found that vitiligo subjects harbor a skin microbiota that is unique from healthy subjects, and have isolated numerous vitiligo-associated bacteria. Furthermore, we have adapted a mouse model of vitiligo to understand mechanisms of host-microbiome interactions in this setting. Interrogation of this host-microbiome relationship may lead to the identification of novel targets and pathways by which to treat vitiligo and augment melanoma immunotherapies.
Gut dysbiosis contributes to autoimmune pathogenesis in lupus-prone mice
Authors: Choi Seung-Chul , Mohmadzadeh Mansour , Morel Laurence 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by a combination of genetic and environmental factors. We have used a congenic model of the disease, the B6.Sle1.Sle2.Sle3 (TC) mice, which share 95% of their genome with B6 controls. TC and B6 mice have a different distribution of gut bacteria based on 16S rDNA sequencing. Fecal transfers into germ free (GF) B6 mice showed that microbiota from aged TC mice was sufficient to induce the production of anti-dsDNA IgG. TC microbiota expanded germinal center (GC)-like organization in Peyer’s patches and TFH cells in the mesenteric lymph node. Co-housing TC and B6 mice for 6 months starting at weaning revealed significant interactions between disease status and the microbiota compared with independently housed mice from both strains. Remarkably, the frequency of TFH cells was decreased in co-housed TC mice, corresponding to a drastic reduction of autoantibodies and amelioration of renal disease. Co-housed TC and B6 mice showed a similar fecal metabolome profile, which was significantly different from those of independently housed mice. Studies to characterize the role of specific metabolites related to disease pathogenesis are ongoing. Finally, treatment of TC mice with a combination of antibiotics significantly delayed anti-dsDNA IgG induction and expanded Treg and TFR cells. Overall, our results suggest that the dysregulated gut microbiota in lupus contributes to disease pathogenesis either directly or indirectly, through the production of critical metabolites.
Inherited CD55 Deficiency in Patients with Early Onset Protein-Losing Enteropathy and Thrombosis
Authors: Comrie William A , Ozen Ahmet , Ardy Rico Chandra , Su Helen , Boztug Kaan , Lenardo Michael 
Published: January 2023

Abstract
Studies of monogenic gastrointestinal diseases have revealed molecular pathways crucial for gut homeostasis and enabled the development of targeted therapies. We studied 11 patients with abdominal pain and diarrhea caused by protein-losing enteropathy with primary intestinal lymphangiectasia, hypoproteinemia, malabsorption, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease. DNA sequencing identified autosomal recessive mutations in the gene encoding CD55/Decay accelerating factor, leading to loss of protein expression. CD55 regulatory function including complement deposition, costimulation, and anaphylatoxin responses were assessed by shRNA and CRISPR-mediated gene suppression and rescue of CD55 expression using lentiviruses. In all patients, Patient T lymphocytes and CD55-deficient cell lines displayed uncontrolled complement activation causing C3d deposition and generation of C5a. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody normalized complement activation. Patient T lymphocytes produced increased tumor necrosis factor, which was associated with a decreased ratio of the anti-coagulatory protein thrombomodulin to the pro-coagulatory protein tissue factor on endothelial cells. Additionally, CD55 costimulation by CD97 and contingent production of interleukin-10 were defective in patient T lymphocytes. Altogether, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (CHAPLE) disease is caused by abnormal complement activation due to autosomal recessive loss-of-function mutations in CD55, and may be effectively treated with complement-inhibitory therapeutics.
Dominant-activating Gαi2 mutations cause human immunodeficiency and autoimmunity by causing defective leukocyte migration and altered T cell activation
Authors: Ham Hyoungjun , Lamborn Ian , Zhang Yu , Berchiche Yamina , Koval Alexey , Jing Huie , Mandl Judith N. , Happel Corinne , murdock Heardley M , Masutani Evan , McElwee Joshua J , Matthews Helen F , Druey Kirk M , Mustillo Peter J , Germain Ronald N , Sakmar Thomas , Katanaev Vladimir , Su Helen 
Published: January 2023

Abstract
Heterotrimeric Ga subunits are the essential molecular switches that activate intracellular signaling in response to G-protein coupled receptor (GPCR) ligation. Gai2, one of 16 human Ga subunits serving nearly 800 GPCRs, plays critical roles in leukocyte biology; however, how Gai2 modulates human immunity in vivo is unknown. We found a dominant missense mutation in GNAI2, the gene encoding the heterotrimeric G-protein Gai2, in a patient with life-threatening, multisystem autoimmunity and susceptibility to mucocutaneous bacteria and virus infections. The mutant proteins impaired immunity by uncoupling chemokine receptor signaling and thereby interfering with leukocyte chemotaxis in vitro and to sites of inflammation in vivo. They also augmented T cell effector responses and diminished the requirement of co-stimulation for T cell activation by constitutively signaling downstream co-stimulatory pathways. These results identify essential roles of Gai2 in maintaining immune-competence and self-tolerance in humans and highlight Gai2-responsive pathways as potential candidates for new therapeutics for autoimmune diseases.
B cell-Intrinsic Defects of Wiskott-Aldrich Syndrome Protein-Deficiency in generating humoral memory responses
Authors: Dai Rongxin , Li Wenyan , Zhao Hongyi , Zhao Qin , Shu Zhou , Sohn Hae-Won , Pierce Susan K. , Zhao Xiaodong , Song Wenxia 
Published: January 2023

Abstract
Patients with Wiskott-Aldrich syndrome protein (WASP)-deficiency exhibit severe immunodeficiency, including a lack of long-lasting humoral protection. Our published data reveal that T follicular helper cells in both WAS patients and WASP-deficient mice are impaired. This study demonstrates a B cell-intrinsic role of WASP in generating antigen-specific memory B cells and humoral recall responses. While the serum IgG levels in patients with WAS are equivalent to those in age-matched healthy controls, the number and percentage of isotype-switched CD27+ memory B cells and the serum level of tetanus toxin-specific IgG post immunization in the patients are significantly lower than those in controls. Furthermore, the peripheral blood of the patients exhibits a substantial increase in atypical memory B cells that resemble B cells expanded in persistent viral and parasite infections. In immunized WASP knockout mice, the percentages of antigen-specific germinal center, isotype-switched memory B cells, and plasmablasts in the spleen all are decreased, while the percentages of total germinal center B cells and plasmablasts are unchanged, compared to wild-type mice. In bone marrow chimera mice, where only B cells lack WASP expression, WASP-deficient B cells show reductions in the antigen-specific germinal center and memory subsets similar to those seen in WASP knockout mice. However, the percentages of total germinal center and isotype-switched B cells in the WASP knockout chimera mice are equivalent to or higher than those in the wild-type chimera. These results indicate that WASP-deficient B cells play a critical and cell-intrinsic role in developing the humoral immune deficiency in WAS.
Immunodeficiency, centromeric instability and facial dysmorphism Syndrome in a Saudi boy with an unusual presentation diagnosed by whole exome sequencing
Authors: Alonazi Noufa Afri 
Published: January 2023

Abstract
Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disorder. It is characterized by variable reduction in serum immunoglobulin, sometimes combined with defective cellular immunity.
We present 18 month old boy, a product of emergency C-section due to fetal distress at term with good APGAR score and low birth weight. He presented at the age of one year with history of fever, vomiting and abdominal distention complicated by colonic perforation required Laparotomy and Ileostomy. He was born to a consanguineous healthy parent (first degree cousins). Clinical examination showed failing to thrive infant dysmorphic, with low-set ears, hypertelorism, micrognathia and flat nasal bridge. No lymphadenopathy or hepatosplenomegaly. Normal muscle tone and reflexes with delayed gross motor activities. Investigations showed normal full blood count and differential, with no positive cultures, normal IgG with low IgM and IgA. Lymphocyte subset analyses and antibodies titer to Pneumococcal and Tetanus were normal.
Chromosomal analysis revealed 46 XY normal male karyotype. However, pericentric breaks of chromosome 1 and 16 are observed in the majority of metaphasis, which is consistent with Immunodeficiency, centromeric instability and facial anomalies syndrome. Whole exome sequencing revealed a homozygous c2506G&gt;A mutation in DNMT3B gene. This mutation was previously reported in only one of the three patients reported from Saudi Arabia.
In conclusion, this patient had an unusual presentation for the ICF syndrome with colonic perforation which was previously not reported. In communities with high incidence of consanguinity, the possibility of ICF should be kept in mind is such cases.
The role of miR17-92 in regulating thymus fate during development
Authors: Mendoza Maria Gracia Garcia , Bain Virginia , Reeh Kaitlin A. , Manley Nancy , Martin James F. , Richie Ellen R 
Published: January 2023

Abstract
The thymus develops bilaterally from third pharyngeal pouch (3rd pp) endoderm, which is initially patterned into separate thymus and parathyroid specific domains. The transcription factors FOXN1 and GCM2 are expressed in 3rd pp thymus-fated or parathyroid-fated domains, respectively. They are required for organ development, but do not specify organ fate. We are investigating the molecular pathways required to generate a functional thymus from 3rd pp endodermal progenitors. We recently reported that Tbx1, which is required for parathyroid development, negatively regulates thymus development by suppressing Foxn1 expression. We are currently using gain-of-function and loss-of-function genetic models to test the hypothesis that Tbx1 expression in 3rd pp endoderm is regulated by microRNA (miR) 17-92. We find that TBX1 expression is expanded and FOXN1 expression is reduced in the 3rd pp endoderm of miR17-92nullembryos and that thymus organogenesis is severely impaired. We are currently targeting deletion of floxed miR17-92 to the endoderm using Sox17Cre to determine if the null phenotype is endoderm intrinsic. Similarly, Sox17Cre is being used to activate an R26miR17-92OE allele to determine the consequences of overexpressing miR17-92 in the 3rd pp endoderm. These studies will clarify the role of miR17-92 in regulating Tbx1 expression and provide insight into molecular mechanisms that regulate 3rd pp patterning and thymus organogenesis.
Deletion of ABCB7 arrests lymphocyte development
Authors: Lehrke Michael Jonathan , Wolf Natalie , Chung Ji Young , Arocha Sinibaldo Romero , Shapiro Michael , Shapiro Virginia Smith 
Published: January 2023

Abstract
Patients with iron overload disorders often develop lymphocyte deficiencies, indicating iron homeostasis is critical for lymphopoiesis. Loss of ABCB7, a mitochondrial iron transporter, leads to mitochondrial iron accumulation and rapid hematopoietic failure. We found that ABCB7 is required for lymphopoiesis, as CD2-icre ABCB7 cKO mice have a severe block in both T and B cell development. The block in T cell development occurs at the DN3 stage. This DN3 block is not due to aberrant β-selection, proliferation, or viability. The block in B cell development occurs at the Fr. C to Fr. C′ transition. Pre-BCR expression was reduced in developing B cells and they exhibited reduced proliferation compared to WT B cells. Because loss of ABCB7 causes mitochondrial iron accumulation, which is toxic to cells, we hypothesized that lymphoid cells increase heme synthesis in order to detoxify the accumulating iron. We found that HO-1, a surrogate marker for intracellular heme levels, was elevated in these lymphocytes. Currently, we are examining the mechanism responsible for the block in lymphocyte development upon loss of ABCB7.
Follistatin-like protein 1 modulates IL-17 signaling via IL-17RC regulation in stromal cells
Authors: Campfield Brian Thomas , Eddens Taylor John , Henkel Matthew , Majewski Martin , Horne William , Chaly Yury , Gaffen Sarah L , Hirsch Raphael , Kolls Jay K 
Published: January 2023

Abstract
Follistatin-like protein 1 (FSTL-1) possesses several newly identified roles in mammalian biology, including autoimmunity and IL-17 driven inflammation, though the mechanism underlying FSTL-1 influence on IL-17 mediated cytokine production is unknown. To examine the role of FSTL-1 in IL-17 signaling, we utilized parallel in vitro bone marrow stromal cell models of FSTL-1 attenuation. Microarray identified FSTL-1 regulated genes that could influence IL-17 dependent production of IL-6 and G-CSF, wherein we discovered that FSTL-1 modulates Il17rc gene expression. Specifically, FSTL-1 was necessary for Il17rc gene transcription, IL-17RC surface protein expression and IL-17-dependent cytokine production. In FSTL-1 KO BMSCs, ectopic Il17rc expression rescued IL-17 stimulated cytokine, and ectopic Fstl1 expression rescued Il17rc expression as well as IL-17 stimulated cytokines. Mechanisms influencing FSTL-1 dependent Il17rc transcript abundance were examined using Actinomycin D and nascent mRNA labeling approaches and identified that FSTL-1 regulates Il17rc gene transcription. Taken together, this work identifies a mechanism by which FSTL-1 influences IL-17 driven inflammation and reveals a novel function for FSTL-1 as a modulator of gene expression. Thus, enhanced understanding of the interplay between FSTL-1 and IL-17 mediated inflammation may provide insight into potential therapeutic targets of IL-17 mediated diseases.
Regulatory effects of immune system thyroid stimulating hormone β-subunit splice variant (TSHβv) on thyroid hormone secretion in mice.
Authors: Klein John R. 
Published: January 2023

Abstract
It has been known for over three decades that thyroid stimulating hormone (TSH) is made by cells of the immune system, yet little is known about the biological significance of that. Studies in my laboratory identified a novel splice variant of the TSH β-subunit (TSHβv) that is produced by bone marrow (BM) hematopoietic cells and peripheral leukocytes in humans and mice. As shown here, recombinant mouse TSHβ (rTSHβ) binds in a dose-dependent manner to the TSH receptor (TSHR) on the mouse AM macrophage cell line, and circulating T4 levels are suppressed 38% in mice 24 hrs after injection of rTSHβv. Moreover, TSHβ-producing leukocytes traffic to the thyroid during systemic L. monocytogenes infection. TSHβv is suppressed in mouse macrophages following transfection with short-hairpin RNA TSHβv (shRNA-TSHβv) expression plasmids, and is suppressed in BM cells transduced with shRNA-TSHβv lentivirus pseudoparticles. These findings collectively suggest that binding of immune system TSHβv to the TSHR on thyroid follicular cells may serve to modulate thyroid hormone output, thus providing a novel mechanism for regulating host metabolism during times of immune stress. Experiments are underway in mice to understand the in vivo involvement of immune system TSHβv in healthy conditions, and during chronic inflammation such as in autoimmune thyroiditis.