bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative analysis of conventional natural killer cell responses to acute infection with Toxoplasma gondii strains of different virulence
Authors: Gigley Jason P. , Ivanova Daria 
Published: January 2023

Abstract
Toxoplasma gondii is an obligate intracellular parasitic protozoan present in 30% of humans and a significant health concern in immunocompromised people. Conventional Natural Killer Cells (cNK), members of group 1 innate lymphoid cells, are critical for early immunity to T. gondii via IFNγ production. However, little is understood about how cNK cell functionality, subpopulations, maturation and proliferation are affected by parasite infection and parasite virulence. Here we comprehensively performed this analysis with Type I virulent RH, Type II avirulent ME49 and fully attenuated Type I cps1-1 strains. In response to these three parasite strains, murine cNK cells produce IFNγ and become cytotoxic and polyfunctional (IFNγ+CD107a+) at the site of infection. In contrast to virulent RH and avirulent ME49 T. gondii strains, attenuated cps1-1 strain induced only local cNK cell responses. RH and ME49 infection significantly decreased cNK cell frequency and numbers in spleen compared with cps1-1 parasites. Responding cNK cell subsets expressing activating receptors and inhibitory receptors were similar regardless of parasite infection strain. 5 days post infection cNK cells did not proliferate, however, cellular maturation (CD27, CD11b and KLRG1) was impacted by parasite strain. cNK cell maturation was reduced after RH or ME49 infection compared with cps1-1 infection. Interestingly, KLRG1 was highly expressed on immature not mature cNK cells after RH infection. Results suggest increased parasite virulence differentially impacts cNK cell maturation during acute T. gondii infection. Different cNK cell responses could impact early immunity and susceptibility to these strains.
Human exposure to Angiostrongylus cantonensis on east Hawaii Island
Authors: Jarvi Susan Irene , Quarta Stefano , Eamsobhana Praphathip , Howe Kathleen , Jacquier Steven , McHugh Robert , Kramer Kuikei , Meyers McKayla 
Published: January 2023

Abstract
A study was completed to quantify exposure to Angiostrongylus cantonensis among 435 human volunteers from east Hawaii Island. Volunteers completed a questionnaire and provided blood samples (at Puna Community Medical Center and Clinical Labs of Hawaii). Serum was screened by indirect ELISA using crude antigen isolated from adult A. cantonensis harvested from wild Hawaiian rats, and 28% tested positive. Of volunteers who defined themselves as definitively diagnosed by a clinician (n = 15), 67% were positive by ELISA and reported being infected in 2004 and later. Of those self-reported as previously infected with A. cantonensis (n=105), 31% were positive; those who self-reported as uninfected (n=315), 25% tested positive by ELISA. All ELISA positives were further tested by ELISA dot-blot using the more definitive 31 kDa protein isolated from Thailand adult female A. cantonensis as antigen. Of the 186 tested by ELISA dot-blot, 30% were positive. Of the 15 definitively diagnosed, 47% were positive and reported being infected in 2007 and later, however antibodies were also detected in a volunteer infected in 1981, which may have been due to a more recent re-exposure. Of those self-reported as previously infected (n=45), 29% were positive and those who self-reported as uninfected (n=126), 29% were positive. The sensitivity of the ELISA dot-blot as compared with ELISA was 100%, but the specificity was only 25% due to the high number of false positives by crude antigen ELISA. No samples were dot blot positive and ELISA negative, thus the ELISA test appears to be an effective initial screening method and the ELISA dot-blot appears to have good efficacy as a diagnostic. Human exposure to A. cantonensis in east Hawaii is higher than previously thought.
Longitudinal analysis of Plasmodium falciparum-specific atypical and classical memory B cell responses to natural malaria infection in children and adults
Authors: Hopp Christine , Krishnamurty Akshay T , Portugal Silvia , Thouvenel Chris , Doumbo Ogobara K , Traore Boubacar , Pierce Susan K , Rawlings David J , Pepper Marion , Crompton Peter D 
Published: January 2023

Abstract
Antibodies play a key role in naturally acquired immunity to malaria; however, protective antibodies are only acquired after years of repeated Plasmodium falciparum (Pf) infections. We have shown in Mali that this inefficiency in humoral immunity to malaria is associated with an expansion of CD21loCD27− ‘atypical’ MBCs that are isotype-switched and somatically hypermutated, but that exhibit markedly reduced effector functions. A similar subset of ‘exhausted’ MBCs has been observed in patients with chronic viral infections. However, in the context of malaria, it remains unclear whether atypical MBC expansion is Pf-specific or represents a global expansion as a result of chronic immune activation from repeated Pf infections and/or co-infections common in malaria-endemic areas. Using PfMSP1/PfAMA1 B cell tetramer staining we recently identified an expanded population of Pf-specific MBCs in malaria-exposed individuals that were 60 fold more frequent as compared to healthy U.S. adults. Preliminary findings show that monoclonal antibodies expressed from PfMSP1-specific MBCs are indeed PfMSP1-specific by ELISA. Using this B cell tetramer approach, we are tracking Pf-specific classical and atypical MBCs in a longitudinal cohort study of children and adults in Mali. With tetramers specific for tetanus and influenza we will determine the relative role of Pf in driving atypical MBC expansion by comparing the Pf-, tetanus-and influenza-specific MBC responses from age 3 months to 25 years before, during and after an acute Pf infection. This analysis should provide new insights into the mechanisms underlying the delayed acquisition of immunity to malaria in children, and may aid in the development of an urgently needed malaria vaccine.
Viral, bacterial and host determinants converge on impairment of alveolar macrophage function to promote influenza and S. pneumoniae coinfection
Authors: Bansal Shruti , Yajjala Vijaya Kumar , Bauer Christopher , Sun Keer 
Published: January 2023

Abstract
Secondary bacterial pneumonia is a major cause of influenza-associated morbidity and mortality. The mechanism for this influenza-induced susceptibility to bacterial superinfection is incompletely understood. In this study, we examined the relative contribution of three central components in the virus-host-pneumococcus interaction, i.e., viral virulence, bacterial virulence, and host resistance to disease severity. Specifically, wild-type and interleukin-1 receptor type 1 deficient (Il1r1−/−) mice were infected with influenza virus X31 (H3N2) or highly virulent PR8 (H1N1), and then super-challenged with noninvasive pneumococcal serotype 19A or 14. The coinfections were followed by comparative analyses of animal survival, viral and bacterial loads, and inflammatory responses in the lungs. Several lines of our data indicate that lethal influenza and Streptococcus pneumoniae coinfection is primarily due to impairment of alveolar macrophage (AM)-mediated bacterial control. First, from a bacterial perspective, the requirement for AMs for bacterial killing increases the virulence of S. pneumoniae serotype 14 compared with 19A; from a viral perspective, the ability of PR8 to induce prominent IFN-γ production contributes to its enhanced virulence compared with X31; and finally from a host perspective, while IL-1 cytokines primarily enhance host resistance to coinfection by preventing AM depletion, IFN-γ impairs antibacterial defense by disrupting AM antibacterial function. Collectively, our data establish that dysregulation of alveolar macrophage function is the central pathogenic mechanism of influenza-induced susceptibility to secondary pneumococcal infection.
Murine models of Pneumocystis infection recapitulate human primary immune disorders
Authors: Elsegeiny Waleed Abdel Wahab , Zheng Mingquan , Eddens Taylor John , Alcorn John F , Chen Kong , Kolls Jay 
Published: January 2023

Abstract
Despite the discovery of key pattern recognition receptors and CD4+ T-cell subsets in laboratory mice, there is ongoing discussion of the value of murine models to reflect human disease. We recognize a strong parallel between human and mouse CD4+ T-cell immunity using the hallmark example of CD4+ T-cell dependent immunity, Pneumocystis pneumonia. Pneumocystis jirovecii infection was the first AIDS-defining illness and most closely tied with peripheral CD4+ T-cell counts. Due to successful control of HIV, the epidemiology of Pneumocystis infection in children is now primarily due to primary human immunodeficiencies and immunosuppressive therapies. To this end, we found that every human genetic immunodeficiency associated with Pneumocystis infection, recapitulated susceptibility in Pneumocystis infection in mice bearing similar mutations. Similar to human IL-21R deficiency, we found that IL-21R and CD4+ T-cell STAT3 signaling were required for both protective anti-fungal class-switched antibody responses and CD4+ effector T-cell mediated protection. Furthermore, we discerned that CD4+ T-cell intrinsic IL-21R/STAT3 signaling was required for inducing a Pneumocystis-specific IL-22 response, and that IL-22 inhibited trophozoite binding to alveolar epithelial cells. Moreover, recombinant IL-22 administration to Il21r−/− mice induced the expression of a fungicidal peptide, cathelicidin anti-microbial peptide which showed in vitro fungicidal activity. In conclusion, SPF laboratory mice faithfully replicate many aspects of human primary immunodeficiency and provide useful tools to understand the generation and nature of effector CD4+ T-cell immunity.
2,3,7,8-tetrachlorodibenzo-p-dioxin induced gut dysbiosis modulates delayed type hypersensitivity reaction
Authors: Abdulla Osama Azeldeen , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
Both gut microbiota and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been shown to have an impact on immune response and disease development. The present study investigates how TCDD alters gut microbiota, thereby inducing immunosuppression in delayed type hypersensitivity reaction (DTHR). C57BL/6 mice were sensitized with methylated bovine serum albumen (mBSA) and rechallenged after six days with mBSA. On day 5, one group received intraperitoneally TCDD (10μg/kg) and the other group received vehicle. On day 8, all groups were sacrificed. TCDD treated mice showed significant reduction in the DTHR in comparison with the vehicle group. Furthermore, we found an increase in the T regulatory cells (Tregs) in draining lymph nodes of TCDD-treated mice, and in the expression of TGFβ. Moreover, cecal flushes were collected and 16S rRNA sequencing was performed. We determined alpha and beta diversity. We found that at the level of phylum, there was a significant decrease in Bacteroidetes and a significant increase in Firmicutes in TCDD-treated mice in comparison with vehicle group. Interestingly, TCDD-treated group showed significant increase in members of the class Clostridia, which is known to maintain the immune homeostasis by inducing T-regs. Furthermore, we found a significant decrease in the species, Prevotella in TCDD-treated group in comparison with vehicle-treated group. It is known that decreased abundance of Prevotella in the gut correlates with reduction in inflammation in the joints. Together, TCDD treatment alters gut microbiota which may be responsible for amelioration from inflammatory diseases.
Inhaled silica induces autoimmunity in a strain-dependent manner
Authors: Clark Amy , Zhao Emma J. , Birukova Anastasiya , Buckley Elizabeth S. , Ord Jeffrey R. , Asfaw Yohannes G. , Tighe Robert M. , Foster Mary H. 
Published: January 2023

Abstract

Background
Respiratory exposure to crystalline silica in man is associated with autoimmunity that includes a prominent humoral component. We hypothesize that autoimmune B cell recruitment and regulation are altered in silica-exposed lungs in genetically susceptible individuals.

Methods
Wildtype and autoAb transgenic (Tg+) mice of B6 and lupus-prone NZB, MRL, and BXSB backgrounds were exposed to silica dust or vehicle by oropharyngeal aspiration. After 1–3 months, lung pathology and lymphocytic infiltrates were scored. Lupus and vasculitis autoAb levels were measured in bronchoalveolar lavage fluid (BALF), serum, and supernatants from cultured lung and spleen cells.

Results
All silica-exposed strains showed extensive lung pathology and focal B and T cell infiltrates consistent with ectopic lymphoid structures (ELS). In wildtype mice, % lung area containing ELS after silica exposure varied by strain (BXSB&gt;MRL&gt;B6&gt;NZB, p=0.03). Significant increases in autoAb production with silica exposure were observed in BALF, lung cell supernatants, and serum, and varied by genetic background. Among Tg+ mice, Tg+ Ig levels in BALF were higher in silica- vs vehicle-exposed mice in B6 and BXSB strains (p&lt;0.05).

Conclusions
Respiratory exposure to silica leads to pulmonary B and T cell accumulation with ELS formation and enhanced autoAb production. This occurs in a strain-dependent manner, highlighting the impact of genetic influences on silica-induced autoimmunity. Evidence of local autoAb secretion implicates dysregulated control of autoreactive B cells at the environment/lung interface, possibly through the intermediary of silica-induced ELS.
Exposure to bacterial Curli triggers antibody production and type I interferon activation in lupus patients
Authors: Pachucki Ryan J , Corradetti Chelsea , Kohler Lynne , Tursi Sarah , Gallucci Stefania , Kilpatrick Laurie , Tukel Cagla , Caricchio Roberto 
Published: January 2023

Abstract
Infections are a major contributor to lupus disease. We have previously demonstrated that bacterial amyloid curli, produced by E.coli, can accelerate disease in mouse models of lupus. Interestingly curli incorporates extracellular DNA, which in turn can be both adjuvant and a self-antigen in lupus. Finally, uropathogenic E. coli (UPEC) is responsible for the majority of urinary tract infections in SLE.
Based on our previous results, we hypothesize that exposure to UPEC triggers anti-curli antibodies, and that curli can also trigger the innate immune system.
We investigated 34 lupus patients who met at least 4 SLICC criteria. Results were compared to 17 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex for both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters, including anti-dsDNA antibodies and bacteriuria. Finally, we used curli/DNA complexes to stimulate PBMCs from lupus patients and controls and determined the levels by rt-PCR of IL-6 (bacterial response) and MX-1 (type I interferon (IFN I) activation). We found that lupus patients and healthy controls generated anti-curli antibodies of IgG and IgA subclasses. The levels of anti-curli antibodies significantly correlated with the levels of anti-dsDNA antibodies (p=0.029) and persistent bacteriuria (p=0.035) in lupus patients. Finally we found that curli/DNA complexes triggered production of IL-6 and MX-1 in both healthy and lupus PBMCs. Nevertheless, the expression of MX-1 was significantly higher in PBMCs from lupus patients (p=0.012). Our results show that bacterial curli/DNA is a trigger of systemic autoimmunity via activation of IFN I and production of autoantibodies.
Prostaglandin I2 -orchestrates regulatory and effector T cell–mediated autoimmunity
Authors: Bloodworth Melissa Harintho , Boyd Kelli L. , Rogers Lisa M. , Aronoff David M , Peebles R. Stokes 
Published: January 2023

Abstract
Tregs maintain tolerance and prevent autoimmune disease by inhibiting T cell activation. There is extensive interest in the application of Tregs in transplantation, autoimmune diseases, and allergy. Our group and others have shown that prostacyclin I2 (PGI2) signaling through the I prostanoid (IP) receptor inhibits allergic airway inflammation. However, it remains unknown whether PGI2 regulates Tregs and Treg-mediated inflammation. We hypothesized that PGI2 skews the immunological balance towards tolerance and away from inflammation. To determine whether PGI2 mediates systemic tolerance, we performed whole animal histopathology on aged WT and IP KO mice. PGI2 protected against autoimmune manifestations including splenomegaly, perivascular-bronchiolar lymphocytic cuffing, and epicarditis that developed in aged IP KO mice. Endogenous PGI2 also promoted Treg Foxp3 expression, suppressive function, and polarization. PGI2 concurrently decreased Teff proliferation and increased Teff susceptibility to Treg-mediated suppression. These studies are the first to show that PGI2 protects against autoimmunity and may represent a novel treatment strategy for Treg-mediated diseases.
Induction of antigen-specific tolerance with Hybrid Insulin Peptides in the NOD mouse model of autoimmune diabetes
Authors: Jamison Braxton , Neef Tobias , Miller Stephen D , Haskins Kathryn 
Published: January 2023

Abstract
In Type 1 Diabetes (T1D), autoreactive CD4 T cells are important contributors to the inflammatory infiltrate in the pancreatic islets which leads to the destruction of insulin-producing β-cells. We recently found that CD4 T cell lines and clones isolated from non-obese diabetic (NOD) mice and T1D patients are strongly activated by novel peptide ligands which are hybrid insulin peptides (HIPs) consisting of proinsulin fragments fused to other peptides present in β-cell secretory granules. Our data suggest that HIPs play a central role in the pathogenesis of T1D and we hypothesize that loss of tolerance to the pancreatic islets involves HIP-reactive T cells. In this project we have investigated whether HIPs can be used for the induction of antigen-specific tolerance in NOD mice. The specific objective is to determine whether HIP-loaded biodegradable nanoparticles can prevent disease transfer by diabetogenic T cells into NOD mice. Our experimental system involves HIPs coupled to or encapsulated within poly(lactide-co-glycolide) (PLG) nanoparticles which are administered to NOD mice following injection of BDC-2.5 TCR transgenic T cells to trigger disease. Preliminary data from these experiments indicates that a hybrid between an insulin C-peptide sequence and a peptide from ChgA can completely block transfer of BDC-2.5 diabetogenic T cells. Long-term goals of this project are (1) to test the ability of nanoparticles containing other HIPs in preventing transfer of diabetogenic T cells and (2) to determine whether HIP-loaded nanoparticles are capable of reversing spontaneous disease in NOD mice. Results from these studies could have significant implications for the development of antigen-specific therapy in T1D.
HYPERACTIVATION OF PI3 KINASE CAUSES DEFECTS IN HUMAN B-CELL DEVELOPMENT AND DIFFERENTIATION
Authors: Tangye Stuart 
Published: January 2023

Abstract
Gain of function (GOF) mutations in PIK3CD, encoding the p110δ subunit of PI3-kinase, cause immune dysregulation characterized by recurrent respiratory infections, increased susceptibility to herpesvirus infection, lymphoma, organomegaly and autoimmunity. Affected individuals display poor Ab responses to protein and polysaccharide Ags suggesting defective humoral immune responses. To better understand humoral immune defects due to hyperactive PI3K, we analysed B cells in these individuals. In peripheral blood, transitional B cells were markedly increased while memory B cells were reduced. The phenotype of naïve B cells with PIK3CD GOF mutations resembled that of normal transitional B cells, indicating an aberrant arrest of developing B cells. Analysis of bone marrow revealed increased proportions of pro/pre-B cells and reduced recirculating mature B cells patients with PIK3CD GOF mutations. Within the memory B cell population there was a reduction in IgG+ cells. Consistent with this, there was a selective impairment in IgG production by transitional of naive B cells following in vitro stimulation. To extend these studies in vivo, we generated a mouse model using CRISPR/Cas9 to introduce the common disease-causing mutation (E1021K) into Pik3cd. Analysis of bone marrow from these mice revealed disrupted B-cell development. Investigation of Ag-specific T-dependent B cell responses using mice expressing a transgenic HEL-specific BCR combined with Pik3cd GOF allowed us to dissect defects in specific Ab generation that are seen in human PIK3CD GOF mutations. These results indicate that intrinsic defects in B-cell development and differentiation underlie poor humoral immune responses in individuals with PIK3CD GOF mutations.
Phenotypic Characterization of ILC2s in an EoE Mouse Model
Authors: Kinard Jessica L. , Laky Karen , Guerrerio Anthony , Frischmeyer-Guerrerio Pamela 
Published: January 2023

Abstract
Loeys-Dietz Syndrome (LDS) is a genetic disorder caused by mutations in genes essential to TGFβ signaling including TGFBRI, which encodes a TGFβ receptor subunit. LDS patients exhibit a high prevalence of allergic disease. A mouse model of LDS Type I (TGFBR1M318R+/−) has been developed to further study this disease and its associated allergic conditions including eosinophilic esophagitis (EoE). EoE is characterized by the abnormal influx of eosinophils into esophageal tissue, basal cell hyperplasia, and smooth muscle dysfunction. The molecular mechanisms underlying this disease are not well understood, but Th2 cytokines are thought to play an essential role. TGFBR1M318R+/− mice spontaneously develop EoE with 100% penetrance, thereby providing an ideal model to study this allergic condition. Remarkably, TGFBR1M318R+/− mice continue to develop EoE in the absence of lymphocytes, suggesting that Th2 effector cells are not essential for driving EoE development. Further investigation has revealed increased numbers of type two innate lymphoid cells (ILC2s) in the esophagus of TGFBR1M318R+/− mice compared to wild type (WT) littermates. These cells are lineage negative, ST2+, GATA3+, and produce large amounts of IL-5 and IL-13, and to a lesser extent IL-4, following in vitro stimulation. The differences in ILC2 frequency between TGFBR1M318R+/− and WT mice appears around 10 days of age, while striking differences start to occur around 19 days, concurrently when ILC2 numbers peak in the normal esophagus. These large differences are sustained throughout the mouse’s lifespan, indicating that these cells may play a critical role in perpetuation of this disease. These findings support a novel role for ILC2s in driving EoE pathogenesis.