bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCL6 Is Up-regulated in Th17 cells and Is Required to Repress GATA3 Activity During Th17 Differentiation (47.27)
Authors: Dent Alexander Lloyd , Mondal Arpita , Sawant Deepali 
Published: January 2023

Abstract
One important goal for immunology is a complete understanding of the regulatory mechanisms controlling the differentiation of CD4 T helper cells. The BCL6 gene, originally identified as an oncogene for B cell lymphoma, encodes a transcriptional repressor protein. We have shown previously that BCL6 is a potent inhibitor of Th2 cell differentiation, and BCL6-deficient mice develop greatly exaggerated Th2 responses and Th2-type inflammation. We have recently found that BCL6-deficient T cells are severely impaired in their ability to undergo Th17 differentiation, indicating that BCL6 function is required for normal Th17 differentiation. The cytokine IL-6 can promote Th17 differentiation, but the Th2 cytokine IL-4 strongly blocks Th17 differentiation by promoting Th2 differentiation. We have found that BCL6 is necessary to repress GATA3-mediated Th2 differentiation induced by IL-6 during Th17 differentiation. Further, we have found that BCL6 is significantly up-regulated in T cells stimulated under Th17 conditions, indicating a unique requirement for BCL6 in Th17 differentiation. These data show a novel, critical role for BCL6 in promoting Th17 responses.
Insulin reactive Type B T cells escape negative selection and are diabetogenic (48.11)
Authors: Mohan James F , Herzog Jeremy , Levisetti Matteo , Unanue Emil R 
Published: January 2023

Abstract
Several autoantigens thought to play a role in type 1 diabetes pathogenesis have been implicated, one of which, insulin, has been extensively associated with onset of disease. In particular, the peptide spanning the residues 9-23 of the insulin beta chain bound to the MHC class II allele, I-Ag7, has been characterized as the dominant epitope in NOD mice for islet infiltrating insulin specific CD4+ T cells. Intriguingly, the majority but not all of autoreactive T cells that recognize insulin are deleted during development in the thymus. In an effort to figure out why certain autoreactive T cells escape selection we have a found a unique population of insulin reactive T cells that recognize the peptide fragment 9-23 given exogenously (type B) but are unable to recognize processed native protein (type A). These type B insulin reactive T cells escape negative selection during development and can be elicited by peptide immunization. Primary lines derived from these T cells proliferated when cocultured with ex vivo isolated beta cells suggesting that dendritic cells present in islets constituitively present the type B conformer of the 9-23 epitope of insulin. Finally, primary lines were capable of inducing diabetes when adoptively transferred into NOD.scid recipients. These results suggest T cells that recognize type B conformers of self proteins escape negative selection and have the capacity to induce autoimmunity.
Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) regulates the expression of human T cell receptor CD3ζ chain (48.8)
Authors: Moulton Vaishali R , Perl Marcel A , Tsokos George C 
Published: January 2023

Abstract
T cells in patients with systemic lupus erythematosus (SLE) fail to control the aberrant autoimmune response and also infiltrate target organs. SLE T cells express low levels of the T cell receptor (TCR) CD3ζ chain, the main intracellular signal transducer upon antigen encounter. This deficiency is partially due to altered splicing of the CD3ζ mRNA. SLE T cells express a short alternatively spliced (AS) isoform of CD3ζ which is missing 562 nucleotides within its 3` untranslated region (UTR). This transcript is unstable and leads to reduced CD3ζ protein expression. We hypothesized that proteins binding to the splice-deleted region of the 3`UTR of CD3ζ play a role in regulating post transcriptional processing. Using an RNA oligonucleotide pulldown assay and mass spectrometry, we identified the serine/arginine-rich (SR) protein alternative splicing factor/ splicing factor 2 (ASF/SF2) as a putative protein binding to the CD3ζ 3`UTR. Specific knockdown of ASF/SF2 in Jurkat T cells led to a significant reduction in CD3ζ protein expression. Blocking of ASF/SF2 in human T cells with di-erythro-C6-ceramide enhanced the alternative splicing of CD3ζ, while overexpression of ASF/SF2 repressed this splicing. ASF/SF2 did not alter the RNA stability of CD3ζ. These data reveal a novel factor in the regulation of the post transcriptional processing of CD3ζ that may lead to altered CD3ζ chain expression in SLE.
Investigation of MICA*A5.1 Allele in Ankylosing Spondylitis (49.23)
Authors: huo zhi , Zou Yizhou , Hu Fengping , Yu Ping 
Published: January 2023

Abstract
MICA (major histocompatibility complex class I chain-related genes A) is known to be associated with susceptibility to various autoimmune diseases. Recent studies have also demonstrated that MICA*A5.1, one allele of MICA, contributed to the resistance of microorganism infection. The aim of this study was to investigate the association between MICA*A5.1 allele and ankylosing spondylitis (AS). A total of 144 AS patients selected from south China and 110 ethnically matched unrelated healthy controls were typed for MICA*A5.1 polymorphism in addition to HLA-B27 typing by polymerase chain reaction using sequence-specific primers. Statistical analysis revealed: (1) a significantly higher frequency of HLA-B27 in the patient group (96.5%) than in the control group (8.2%) (P &lt; 0.0001); (2) the distribution of MICA*A5.1 genotype was significantly different between the patients and controls (P = 0.029), the frequency of MICA*A5.1 homozygote was significantly decreased in the patient group (2.1%) as compared with the controls (8.9%) (P = 0.023); (3) the association between MICA*A5.1 genotype and AS is not independent of HLA-B27 status (P = 0.94). These results suggest that MICA*A5.1 allele may play a potential role in the protection against AS.
Unique antibody gene signature in Multiple Sclerosis (49.25)
Authors: Monson Nancy L , Cameron Elizabeth , Spencer Sade , Lazarini Jonathan , Harp Christopher , Ward E. Sally , Burgoon Mark , Owens Gregory P. , Racke Michael K , Bennett Jeffrey L. , Frohman Elliot M. 
Published: January 2023

Abstract
Patients with multiple sclerosis (MS), an inflammatory, demyelinating disease of the Central Nervous System (CNS), derive the most benefit from disease modifying pharmacotherapies the earlier they are treated. Patients who have had a single episode of demyelination are at greater risk to develop clinically definite MS, but are not treated for MS, even though diagnosis of clinically definite MS could be significantly delayed if currently approved treatments are initiated immediately after the first attack. Defining biomarkers that identify patients with one demyelinating event who will convert to MS may provide a tool to allow earlier treatment of this "at risk" patient group. We have discovered a unique pattern of somatic mutations in the antibody genes of B cells isolated from the cerebrospinal fluid of patients with MS that can accurately and independently predict patients that subsequently develop definite MS after a single episode of demyelination. This antibody signature represents the first genetic biomarker candidate for MS outside of the MHC locus. If independently confirmed, our observations will have a major impact as a new diagnostic tool in patients with very early demyelinating disease of the CNS.
This work was supported by the National Institutes of Health (NIH) to NLM (RO1 NS 40993) and MKR (RO1 NS 37513, RO1 AI 47133, and K24 NS 44250), the National Multiple Sclerosis Society (NMSS) to NLM (RG3267) and JLB (RG3908), the Yellow Rose Foundation (NLM and MKR), the Wadsworth Foundation (to NLM) and Howson funds (to NLM).
n-3 PUFA ameliorates experimental autoimmune encephalomyelitis by modulating dendritic cell function (50.11)
Authors: Switzer Kirsten , Zheng Biao 
Published: January 2023

Abstract
n-3 polyunsaturated fatty acids (PUFA) have been shown to significantly attenuate T cell-mediated inflammatory diseases. Although evidence from epidemiological observations has long supported that dietary intake of n-3 PUFA may provide protection against multiple sclerosis (MS), available data about the effects of n-3 PUFA on the development and pathogenesis of MS or experimental autoimmune encephalomyelitis (EAE) remain very limited. We have found that treatment of mice with n-3 PUFA significantly prevented the development and severity of EAE. In addition, n-3 PUFA inhibited antigen-specific T cell proliferation and IFNγ production. Our preliminary studies suggest that n-3 PUFA exert their anti-encephalitogenic effects by interfering with multiple processes in the immunopathological cascade. Dendritic cells (DCs) are the most potent antigen-presenting cells, critical in the initiation of effective T cell immunity, therefore we investigated whether n-3 PUFA could interfere with DC function. We found that n-3 PUFA impaired DC migration from antigen entry sites to lymphoid tissue. In vitro treatment of BMDCs with docosahexanoic acid (DHA) resulted in suppression of DC maturation as assessed by reduced MHCII and CD86 expression. In addition, IL-12 cytokine production was decreased in a dose-dependant manner. Finally, pretreatment of DCs with DHA reduced their ability to present peptide for T cell activation. The findings from these projects may provide important information regarding therapeutic intervention for MS and other chronic inflammatory disorders.
Tolerization of BWF1 lupus mice with pConsensus peptide results in a distinct gene signature in WBC, CD4+ and CD8+T cells: Role of Foxp3 and IFI202b in suppression of SLE (50.22)
Authors: Singh Ram P , Dinesh Ravi , La Cava Antonio , Hahn Bevra H 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with autoantibodies, including IgG anti-DNA and immune complexes. Following tolerization with an artificial peptide (pCONSENSUS, pCons) that is based on anti-DNA IgG sequences containing MHC class I and class II T cell determinants, NZB/NZW F1 female (BWF1) mice develop CD4+CD25+ regulatory T cells and CD8+ Foxp3+ inhibitory T cells, both of which suppress anti-DNA Ig production. In this study, we analyzed 45,000 murine genes using Affymetrix Gene Chip 430, 2.0 arrays, in a comparison of total white blood cells (WBC), CD4, and CD8 spleen cell subsets from tolerized vs. non-tolerized mice. Results showed 448, 174 and 60 genes that were differentially expressed by at least two-fold in the two groups of mice. From the CD8+T cell arrays, we confirmed up regulation of several genes in cells from tolerized mice using real-time PCR. Increased expression (more than two-fold) in the CD8+Tcells from tolerized mice was repeatedly found for six genes: IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1. Silencing with siRNA of IFI202b and bcl2 abrogated the suppressive capacity of the tolerized CD8+T cells. In contrast, silencing of IFNar1 and CCR7 had no effect on the ability of the CD8+T cells to suppress autoantibody production. Further silencing of combination of multiple genes affected other genes in addition to silenced gene/genes in tolerized CD8+T cells. These data indicate the roles of IFI202b, Foxp3, bcl2, and further demonstrate that silencing of one gene or combinations may affect other genes and or their functions.
GM-CSF induces differentiation of bone marrow precursors into tolerogenic CD8a- dendritic cells (50.32)
Authors: Bhattacharya Palash , Gopisetty Anupama , Ganesh Balaji B , Prabhakar Bellur S 
Published: January 2023

Abstract
Experimental autoimmune thyroiditis, a murine model of Hashimoto's thyroiditis is characterized by the infiltration of the thyroid by self-reactive CD4+ T cells. Our earlier studies have shown that GM-CSF treatment of experimental animals can suppress ongoing thyroiditis through the induction of tolerogenic CD8a- dendritic cells (DCs) expressing low levels of pro-inflammatory cytokines. Antigen presentation by these tolerogenic CD8a- DCs resulted in an expansion of IL-10 secreting CD4+Foxp3+ regulatory T-cells (T-regs) which suppressed the effector T-cell function. To understand the underlying mechanism we studied the effect of GM-CSF on matured splenic DCs as well as on bone marrow (BM) DC precursors in vitro. In spite of increased surface expression of programmed death ligand 2 (PDL-2), a negative regulator of T-cell activation, and increased indole-deoxygenase (IDO) secretion, splenic DCs exposed to GM-CSF induced only a modest increase in Foxp3 expression in T-cells. In contrast, BM cells when cultured in the presence of GM-CSF gave rise to a population of CD11c+CD11bhigh DCs with lower levels of expression of pro-inflammatory cytokines IL-12 and IL-6 which induced Foxp3 expression in a very high percentage of T-cells in a contact dependent manner. Our studies strongly suggest that the tolerogenic effect of GM-CSF is mediated by a special class of CD8a- DCs that differentiate from BM precursors. NIH 1RO1AI058190
The VR1 ligand capsaicin confers protection from autoimmune diabetes by suppressing autoreactive T cells in an APC dependent manner (50.38)
Authors: Nevius Erin , Basu Sreyashi 
Published: January 2023

Abstract
Sensory nerve fibers innervating the pancreas play a critical role in the etiology of autoimmune diabetes. These sensory neurons express a nonselective cation channel vanilloid receptor 1 (VR1) which has been identified as a receptor for acid, temperatures &gt; 43°C and Capsaicin (CP), the principal pungent ingredient in chili peppers. We have reported that dendritic cells (DCs), a key cell type in immune responses, have the receptor for CP, and engagement of this receptor has powerful immune consequences. However very little is known about the function of VR1 expressing pancreas resident antigen presenting cells (APCs) including DCs in Type 1 diabetes. Here we have explored the immunomodulatory activity of CP in the non-obese diabetic (NOD) mouse and found that oral administration of CP delays the onset of diabetes and reduces the incidence of diabetes in NOD mice in a dose dependent manner. Moreover, splenocytes from CP treated mice are able to transfer protection in recipient NOD mice. CP administration attenuates the proliferation of pancreatic antigen-specific autoreactive T cells in pancreatic lymph nodes (PLN) both in vivo and in vitro in two distinct mouse models of diabetes, NOD and RIP-OVA. We have further found that this CP dependent modulation of autoimmunity requires both VR1 expression and a population of myeloid CD11b+ cells present in the PLN. These results reveal that CP is an immunologically potent ligand that when administered orally suppresses autoimmune diabetes by inhibiting the proliferation of autoreactive T cells in an APC dependent manner.
MR1 antigen presentation to mucosal-associated invariant T cells is highly conserved in mammals (78.7)
Authors: Huang Shouxiong , Martin Emmanuel , Kim Sojung , Yu Lawrence , Soudais Claire , Fremont Daved H , Lantz Olivier , Hansen Ted H 
Published: January 2023

Abstract
The development/expansion of mucosal associated invariant T cells or MAIT cells is dependent upon the class Ib molecule MR1, B cells and commensal flora. Additionally, MAIT cells express a canonical TCRα, a memory phenotype and rapidly secrete cytokines upon TCR ligation. Although these combined properties suggest that MAIT cells function as innate T cells in regulating mucosal immunity, this model has been difficult to test due to i) the paucity of MAIT cells that display MR1 specific activation in vitro, and ii) not knowing whether MR1 presents antigen. Here we show both mouse clones and human polyclonal MAIT cells display a high level of cross-reactivity on mammalian MR1 orthologs, but with differences consistent with limited ligand discrimination. Furthermore, acid eluates from recombinant or cellular MR1 proteins enhance MAIT cell activation in an MR1 specific and cross-species manner. Our combined findings demonstrate that the presentation pathway of MR1 to MAIT cells is highly physiologically conserved. These properties are reminiscent of pattern-like stimuli presented to previously described innate T cell populations and likely underlies the activated or memory phenotypes of MAIT cells.
This study was supported by grant AI046553 (Ted H. Hansen) from NIH, and in part by ANR MIME 2006 (Olivier Lantz) from the Inserm and ligue contre le cancer.
Aerosol allergen challenge results in airway hyperresponsiveness, inflammation, goblet cell metaplasia, and fibrosis in a murine model of fungal allergic airways disease (79.15)
Authors: Schuh Jane M. , Hoselton Scott A. 
Published: January 2023

Abstract
Allergic asthma is a chronic syndrome punctuated by acute respiratory distress that can result in irreversible remodeling of the airways. Experimental models that represent both acute and chronic dysfunction may provide insights into the pathology of asthma and a platform to test therapeutics. OBJECTIVE: To provide an allergic airway disease model that more closely reflects the human asthma syndrome. METHODS: BALB/c mice were sensitized with soluble Aspergillus fumigatus antigens over 5 weeks and were then challenged with a 10-min nose-only aerosol exposure to A. fumigatus spores. RESULTS: Airway hyperresponsiveness was observed through day 28 following allergen challenge. Goblet cell metaplasia and mucus hypersecretion peaked at day 7 after challenge. Eosinophil and lymphocyte recruitment peaked 7 and 14 days after allergen challenge, respectively, although persistent inflammation was still observed 35 days after challenge. Increased peribronchial and perivascular collagen deposition was first noted at day 14 after challenge in some animals and was consistently noted in lungs by day 35 post-challenge as compared to naïve animals. Visual evidence suggested that smooth muscle mass may also be increased at these time points. CONCLUSION: Aerosol delivery of fungal conidia provides a model that reflects both the acute and chronic outcomes of the allergic airways syndrome.
Soybean isoflavones regulate dendritic cell function: implications in food allergy (79.16)
Authors: Masilamani Madhan , Ruiter Bert , Shreffler Wayne G , Sampson Hugh A 
Published: January 2023

Abstract
Peanuts and tree nuts are the most allergenic foods in children and adults in the U.S. Several allergens in peanut and soy share amino acid similarity by as much as 60%, yet soy allergy is less common and less severe compared to peanut allergy. Unlike peanuts, soybeans are rich in isoflavones such as genistein, daidzein and glycitein and are the most common source of isoflavones in the human food supply. Isoflavones are known to have anti-inflammatory and anti-oxidant properties. The maximum bioavailability of isoflavones is from the gut since they are quickly converted to inactive forms before entering the circulation. Therefore, we hypothesize that the active-isoflavones in the gut milieu are capable of modulating the initiation of immune responses to dietary-antigens by regulating DC function. In vitro, isoflavones inhibited lipopolysachharide (LPS) or cholera toxin (CT)-induced cell-surface expression of CD83, CD80 and CD86 in a dose dependent manner in human monocyte derived dendritic cells (MDDC). Isoflavone treatment augmented CT induced up-regulation of CXCR4 and CCR7. Isoflavone treated MDDC inhibited T cell proliferation in a mixed lymphocyte reaction and inhibited the secretion of Th2 cytokines. We hypothesize that these changes in DC function could induce tolerance to food allergens. Studies are underway to test this hypothesis in a peanut allergic mouse model.
Toll-like receptor 2 and 4 in cockroach antigen-induced asthma: a potential mechanism for establishing a Th1 phenotype (79.23)
Authors: Durham Carolyn G. , Lorenz Robin G. 
Published: January 2023

Abstract
According to the hygiene hypothesis, sensing bacteria in the gut is imperative to switching the immune system from Th2 to Th1, thus reducing potential for an asthma-like phenotype developing in the lungs. In the gut toll-like receptors 2 and 4 (TLR2, TLR4) are critical for sensing Gram positive and negative bacteria, respectively. Previous data indicate in the first two weeks of life when the immune system switch generally occurs and a microbial repertoire is established, these two receptors are significantly upregulated. This project's hypothesis is TLR2 and 4 are critical for microbial sensing in the gut, thus C57BL/6 mice deficient in TLR2, TLR4, or both (double knockout) should have a more asthmatic phenotype. Interestingly, after inducing asthma with cockroach antigen (CRA) in a specific pathogen-free environment, the TLR2-/-/4-/- treated with CRA had a significant increase in serum IgE compared to the C57BL/6 treated with CRA, while the TLR4-/- had increased IL-13 mRNA levels compared to the C57BL/6 treated with CRA. This indicates the lack of interplay of TLR2 and 4 may play a role in maintaining a Th2 phenotype in the lungs; consequently preventing the immune switch to a Th1 phenotype.
Research supported by the Strategic Program for Asthma Research
Human embryonic stem cells as a source of human mast cells for studies of allergies and inflammatory diseases (80.3)
Authors: Kovarova Martina , Latour Anne M , Koller Beverly H 
Published: January 2023

Abstract
Human mast cells are principal cells initiating allergic reaction and asthma exacerbations. They are isolated either as mature cells from human tissues including skin and lung or differentiated from hematopoietic progenitors isolated from peripheral or cord blood. Isolation is accompanied with several disadvantages and difficulties including necessity of continuous access to human samples, low proliferation capacity and low efficiency in genetic modifications of isolated mast cells. In order to overcome these problems we developed a new strategy for differentiation of human mast cells from human embryonic stem (hES) cells. First, we differentiated hES cells to hematopoietic progenitors (CD34+ CD43+ cells) by co-culture of hES cells with stromal cells or by direct differentiation from embryonic bodies. Mast cells were subsequently differentiated in mast cell medium. Both approaches result in population of cells stained for mast cell specific proteins tryptase and chymase. They express a broad range of receptors and are able to be activated by their ligands. However, only mast cells differentiated directly from embryonic bodies express functional FcεRI. Together with techniques for genetic manipulation of hES cells, human ES cell-derived mast cells represent a unique model to analyze the effects of specific genetic alterations on human mast cell development, phenotype, and function.
T cell-intrinsic B7-homolog-1 (B7-H1) regulates effector CD8 T cell survival and memory cell generation (83.13)
Authors: Dong Haidong , Pulko Vesna , Liu Xin , Harris Kimberley 
Published: January 2023

Abstract
B7 homolog-1 ( B7-H1) expressed by antigen-presenting cells or tumor cells is a negative regulator of T cell responses, however its function on T cells is not clear. Here we show that B7-H1 was upregulated in CD8 T cells during immunization and its expression was maintained on memory CD8 T cells. Although B7-H1 deficient naïve CD8 T cells responded normally to antigen stimulation and underwent normal antigen-independent homeostatic proliferation, the maximal expansion of CD8 T cells was blocked due to their high susceptibility to apoptosis. B7-H1-deficient effector CD8 T cells showed weaker effector function and cytotoxicity against tumor cells compared to that of normal CD8 T cells. Once activated, B7-H1-deficient CD8 T cells generated less memory T cells. This effect was independent of the primary expansion of the antigen-specific CD8 T cell population. Our results revealed previously unknown function of B7-H1 on CD8 T cells in mediating survival and differentiation of effector CD8 T cells into memory T cells.