bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expansion of Th17 cells and IL-17 are present only in a subset of patients with acute coronary syndrome (114.10)
Authors: Golino Paolo , Borriello Francesco , Barra Giusi , D'Aiuto Elena , Cirillo Plinio , Abbate Gianfranco , Cimmino Giovanni , De Palma Raffaele 
Published: January 2023

Abstract
T cells have a central role in atherosclerosis and Acute Coronary Syndromes (ACS). Th17 cells have a key role in chronic inflammation since they secrete a wide array of cytokines, including IL-17, having pro-inflammatory effects by recruiting other inflammatory cells and acting directly on target cells. So far, Th17 role in atherosclerosis is still a matter of debate. To study the role of Th17 cells in the pathophysiology of ACS, we studied 38 patients (ACS,n=23; Stable Angina,n=15. Cytokine production was measured by Luminex™ technology in sera obtained from the aorta(Ao)and the coronary sinus(CS)during diagnostic coronary angiography. Th17 cells were measured by flow cytometry after staining with MoAb for CD3,CD4,CCR6 and CD161. 5 out of 23 patients with ACS had a high number of Th17 cells (&gt;15% of total T cells) in the coronary sinus and high amounts of IL-17 (&gt;50pg/ml). No correlations were found with the presence of Th1 or Th2 or related cytokines. Only one patient with Stable Angina had a high number of Th17 cells in the coronary sinus. After a 18 months follow-up we found that patients with ACS having high number of Th17 presented a worse disease course, in terms of successive needs for hospitalization, stroke and/ or exitus. Further exploitation of these data could lead to a better understanding of processes leading to atherosclerosis and ACS, and to the identification of new prognostic biomarkers in atherosclerosis and to the set up of new therapeutic strategies.
Enhanced T cell proliferation, Th17 differentiation and unaltered IL-10 production lead to marginally enhanced development of experimental autoimmune encephalomyelitis in EBI3-deficient mice (114.12)
Authors: Bai Xue-Feng , Liu Jin-Qing , Carl, Jr. Joseph , Liu Zhenzhen , Zhang Xuejun , Talebian Fatemeh , Shi Fu-Dong , Whitacre Caroline , Trgovcich Joanne 
Published: January 2023

Abstract
Epstein-Barr virus-induced gene 3 (EBI3) encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity through inhibiting Th17 differentiation, and facilitating the inhibitory roles of Foxp3+ Treg cells, repectively. In this study we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that MOG peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR transgenic mice. EBI3-deficiency resulted in significantly increased proliferation and Th17 differentiation of MOG-specific CD4 T cells in the peripheral lymphoid organs and in the central nervous system (CNS). However, IL-10 production was not affected or even enhanced in the peripheral lymphoid organs or the CNS of EBI3-deficient mice. Treg cells from EBI3-deficient 2D2 mice had reduced capacity of inhibiting proliferation of 2D2 T cells. Taken together, we have found that EBI3-deficiency results in marginally enhanced EAE severity, which is associated with enhanced T cell proliferation and Th17 differentiation. However, the relatively milder EAE enhancement and lack of impact on IL-10 production by EBI3-deficiency suggest that alternative signaling pathways (presumably IL27P28-related) can partially compensate for EBI3-deficiency in EBI3-/- mice.
JAK2 is overexpressed in human multiple sclerosis Th17 cells and stabilizes cell surface expression of IFN-γR2 (114.14)
Authors: Novelli Francesco , De Palma Raffaele , Rolla Simona , Conti Laura , Clerico Marinella , Cintessa Giulia , Silveinnonen Olli , Durelli Luca 
Published: January 2023

Abstract
IFN-β inhibits the expansion of T helper 17 (Th17) cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. Here we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells from patients with AMS compared with those with inactive MS (IMS) or healthy subjects (HS). Anti-CD3 mAb stimulation and IFN-γ decreased the frequency of Th17 cells in peripheral blood mononuclear cells (PBMC) from AMS patients. Stimulation of PBMC from HS in Th17-polarizing conditions resulted in enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in MS and possibly other inflammatory diseases.
Th17 is involved in the pathogenesis of Beçhet’s disease (114.15)
Authors: Yasuoka Hidekata , Chen Zhu , Takeuchi Tsutomu , Kuwana Masataka 
Published: January 2023

Abstract
Behçet’s disease (BD) is an autoinflammatory disease with a unique distribution characterized by uveitis, and mucosal and skin lesions. To examine a role of Th17 response in the pathogenic process of BD, peripheral blood samples from 20 patients with BD and 13 controls were used to evaluate phenotypic and functional properties relevant to the Th17 response. Expression levels of RORC mRNA in peripheral blood mononuclear cells by RT-PCR and proportion of CD4+ cells expressing intracellular IL-17 by flow cytometry were increased in BD patients than in controls (P &lt; 0.05 in both comparisons). Expression of chemokine receptor CCR6 was detected in nearly all IL-17-expressing cells. The proportion of CD4+CCR6+ was higher in BD patients in remission compared those with active disease (P &lt; 0.05), suggesting that these cells are migrated to the lesions at active disease phase. In addition, CD4+ T cells from BD patients had an enhanced migration capacity induced by CCL20, than did those from controls. Finally, plasma CCL20 level was higher in BD patients than in controls (P &lt; 0.05). These results together suggest that Th17 cells are involved in the pathogenesis of BD by migrating into skin and mucosa through the CCL20-CCR6 axis.
The role of Stat4 in IL-23-dependent IL-17 production (114.2)
Authors: Glosson Nicole , Stritesky Gretta , Kaplan Mark 
Published: January 2023

Abstract
Signal transducers and activators of transcription (STAT) proteins are induced upon cytokine and growth factor stimulation and play a pivotal role in immune and inflammatory responses. Stat4 is a critical mediator of inflammatory immunity and is required for all known IL-12 biological responses, including the induction of IFN-γ and development of Th1 cells. IL-23, an IL-12-related cytokine, also induces Stat4 activation, which may be important for optimal IL-17 secretion from CD4+ T cells. We further characterized the requirement for Stat4 in IL-23-mediated cytokine production using cells from Stat4-deficient mice. Stat4-deficient CD4+ T cells display reduced cytokine-induced IL-17 production in comparison to control cells, and this phenotype is most prominent in IL-23-primed memory CD4+ T cells. Furthermore, innate IL-17-producing cells, such as γδ T cells, natural killer T (NKT) cells and natural killer (NK) cells display distinct dependence on Stat4 activation for IL-17 production following antigen receptor or cytokine stimulation. Taken together, these data demonstrate a restricted requirement for Stat4 in the responses of innate and adaptive IL-17-secreting cells and define candidates for further defining the role of Stat4 in inflammatory immunity.
Interleukin-2 independent expansion of Helios-expressing T-cells contributes to autoimmunity in regulatory T-cell deficient mice (115.13)
Authors: Sharma Rahul , Abaya Christian , Ju Chiao-Ying , Ju Shyr-Te 
Published: January 2023

Abstract
The CD4+Foxp3+ T regulatory cells (Treg) are important for peripheral tolerance. Expression of the transcription factor Helios (Hel) was recently identified as a marker for thymus-derived Treg (tTreg), and was not expressed on the induced Treg. A minor population of CD4+Foxp3negHel+ T-cells is present in normal B6 mice. We hypothesized that this population may be related to tTreg in lineage and may contribute to autoimmunity during lack of Foxp3 expression. Indeed, in Treg deficient Il2-/- and Scurfy (Sf) mice, the CD4+Foxp3negHel+ T-cells expanded in the periphery. These cells produced high levels of inflammatory cytokines and were present at high numbers in the inflamed organs. The peripheral maintenance of the CD4+Foxp3negHel+ cells was independent of interleukin (IL)-2 because they expanded in the periphery of Il2-/- and IL-2 deficient Sf mice (Sf.Il2-/- mice). In this respect, the majority of the peripheral Treg in the Il2-/- mice are Hel+, suggesting that they are also relatively IL-2 independent. Importantly, abnormal Foxp3 mRNA could be detected in the Sf CD4+ T-cells that contain high percentage of Hel+ T-cells. The data strongly suggest that abnormal tTreg contribute significantly to the CD4+Foxp3negHel+ T-cell -mediated autoimmunity in Sf mice. In contrast to Treg, the expansion of CD4+Foxp3negHel+ T-cells becomes IL-2 independent
Regulatory T cells (Treg) from B cell deficient (B-/-) mice are more effective at suppressing spontaneous autoimmune thyroiditis than WT Treg (115.15)
Authors: Ellis Jason , Braley-Mullen Helen 
Published: January 2023

Abstract
NOD.H-2h4 mice given NaI in their water develop SAT with chronic inflammation of the thyroid by T and B cells. B-/- mice are resistant to SAT, but develop SAT after transient depletion of Treg by anti-CD25. After Treg depletion, Treg in B-/- mice take longer to repopulate than WT Treg. WT Treg have fewer FoxP3 low cells than B-/- Treg, suggesting they may have different suppressive capacities. B-/- mice have more FoxP3+ Treg, and a more activated phenotype than WT Treg with higher CD25, TGFβ, and CD44 expression, and lower CD62L and TNFR II p75. CD28-/-B-/- NOD.H2-4 mice have very few CD4+CD25+FoxP3+ Treg. We established a transfer model using splenocytes from CD28-/-B-/- mice (effector cells) cultured with or without sorted Treg from FoxP3GFP WT or B-/- mice. After transfer to mice lacking T cells, mice given Treg from B-/- mice developed significantly lower SAT severity than mice given Treg from WT mice. Although few Treg were detected at the end of culture, recipients given either WT or B-/- Treg had comparable numbers of splenic Treg 8 wks after transfer. The data herein suggests that despite being present in similar numbers both after culture and in vivo at the peak of disease, Treg that develop in B-/- mice are more effective at suppressing SAT than those in WT mice. In B-/- mice, a lack of B cells as APC during initiation of SAT may lead to preferential activation of Treg, resulting in reduced effector T cell activation and lack of SAT.
Tregs in autoimmunity to an inducible epidermal antigen (115.19)
Authors: Gratz Iris , Rosenblum Michael , Abbas Abul 
Published: January 2023

Abstract
The skin has unique immunological characteristics and it is known to be the most difficult organ to establish tolerance in a transplant-setting. The regulation of CD4+ T cell responses to epidermal self-antigen are largely undefined. Our goal was to establish a mouse model to study CD4+ T cell responses to epidermal neo-self-antigen. We established a mouse model that features tetracycline-inducible expression of chicken ovalbumin (Ova) in the epidermis under the control of the keratin K5 promoter. We analyzed the response of TCR-transgenic T cells (DO11.10) to Ova. Ova mRNA was inducibly expressed in the skin in a strictly tetracycline-dependent manner. In the thymus Ova was constitutively expressed in a tet-independent manner, leading to partial deletion of endogenous DO11 as well as induction of high percentages of natural Tregs. Interestingly, upon antigen-induction, mice developed an inflammatory dermatitis which was associated with IFN-γ and IL-17 production by DO11 T cells. This disease developed despite the presence of high starting numbers of natural DO11 Tregs, and, in fact, the Tregs proliferated in response to skin-Ag recognition. A remarkable feature of the skin disease was that it resolved spontaneously. This resolution correlated with changes in phenotype and, apparently, functional activity of Foxp3+ DO11 Tregs. We are currently using this inducible Ag-expression model to define the dependence of regulatory and effector T cells on persistent Ag recognition.
Anti inflammatory role of IFN gamma in a viral model of encephalitis (115.21)
Authors: Ramakrishna Chandran , Shen Yuewei , Cantin Edouard 
Published: January 2023

Abstract
HSV1 induced encephalitis in susceptible mice such as 129 and BALB/c mice is characterized by CNS inflammation associated with pathogenic Ly6Chigh macrophages and neutrophils. Mortality in this model correlates with degranulation by these cells rather than virus mediated cytopathology. IVIG, composed of pooled human IgG protects these mice by induction of regulatory CD4 T cells including IL-10 secreting Tregs and Tr1 cells secreting IL-10 and IFNγ. Surprisingly, IFNγ has an anti-inflammatory role in this model as infection of IFNγKO mice results in severe early morbidity and mortality associated with unabated CNS inflammation by neutrophils and Ly6Chigh monocytes suggesting that IFNγ is critical in the control of expansion of these cells. Interestingly, IVIG cannot protect IFNγKO mice despite control of infectious virus but not CNS inflammation typified by the inflammatory Ly6Chigh macrophages, indicating that IFNγ is crucial to IVIG’s anti-inflammatory activities. Adoptive transfer of T cells subsets from either WT or IFNγKO mice into Rag recipients reinforced the importance of IFNγ on CNS inflammation. Furthermore, IFNγ appears to have a role in the IVIG induced expansion of Tregs while in the absence of IFNγ, there was an increase in γδ T cells secreting IL-17, which may contribute to the early unmitigated expansion of the neutrophils and monocytes. IFNγ related effects on CEACAM1a and iNOS on monocytes, on Tregs, and the cell subset that secretes IFNγ will be discussed.
Emergence of polyclonal autoantibody responses to multiple platelet surface glycoproteins in regulatory T cell-deficient mice. (115.28)
Authors: Nishimoto Tetsuya , Satoh Takashi , Simpson Elisa , Ni Heyu , Takeuchi Tsutomu , Kuwana Masataka 
Published: January 2023

Abstract
Naturally occurring CD4+CD25+Foxp3+ regulatory T cells (Tregs) are known to play an important role in preventing pathogenic autoimmune responses. Recently, we have found that approximately one third of mice deficient of CD4+CD25+Foxp3+ Tregs spontaneously develop thrombocytopenia with increased platelet-associated IgG, analogous to patients with immune thrombocytopenia. To identify platelet autoantigens in Treg-deficient mice, plasma samples from thrombocytopenic and non-thrombocytopenic Treg-deficient mice were subjected to immunoblots using platelets as an antigen in reduced and non-reduced conditions. IgG antibodies to platelet surface glycoproteins, such as GPIb, GPIIb, and GPIIIa, were detected specifically in thrombocytopenic mice in various combinations. IgG antibodies to native platelets were further assessed by flow cytometry using platelet eluates and splenocyte culture supernatants. IgG antibodies capable of binding to native platelets were detected in thrombocytopenic, but not in non-thrombocytopenic mice. Antibody reactivity was cancelled in the majority of samples when platelets derived from GPIb-deficient or GPIIIa-deficient mice were used instead of wild-type platelets as an antigen. In summary, Treg deficiency alone leads to emergence of polyclonal IgG autoantibody responses to native and denatured platelet surface glycoproteins, supporting a critical role of CD4+CD25+Foxp3+ Tregs in suppressing induction of autoimmunity.
Dendritic cells initiate early autoimmunity in the absence of functional regulatory T cells (115.7)
Authors: Hoyer Katrina , Isakson Sara , Katzman Shoshana , Abbas Abul 
Published: January 2023

Abstract
BALB/c IL-2-KO mice develop systemic autoimmunity, dying within 4 wks from autoimmune hemolytic anemia. Disease in these mice is Th1-mediated, and IFNγ production is required for early autoimmunity. We asked whether APC are required for IFNγ production by T cells in the IL-2-KO mouse. Our data show that APC:T cell interactions through B7, but not via B cells, are necessary for IFNγ production in the absence of IL-2, suggesting that dendritic cells (DC) mediate this alteration. Disease is marked by DC accumulation, activation and elevated cytokine production, including IL-12 and type1-interferons. The depletion of either conventional (cDC) or plasmacytoid (pDC) significantly augmented the survival of IL-2-KO mice, demonstrating that DC contribute to the progression of autoimmunity. In the absence of IL-12, T cell activation and disease is only moderately altered, thus Th1 differentiation and IFNγ induction as a part of the underlying kinetics of autoimmunity is primarily IL-12-independent. Elimination of type 1 interferon signals in addition to IL-12 further augmented survival, indicating that cytokines derived from both pDC and cDC contribute to disease severity. Enhanced DC function is not dependent on T cell activation as DC in an environment without overt T cell activation are still functionally activated. Overall, our data suggest that DC activation can be an initiating event during the development of disease and thus DC are critical regulators of autoimmune development.
Characterization of antigen-specific CD4+CD25+ regulatory T-cells expanded with IL-2/IL-2mAb complexes in NOD mice (115.9)
Authors: MANIRARORA Jean , Wei Cheng-Hong 
Published: January 2023

Abstract
Type-1 diabetes is an autoimmune disease caused by the destruction of insulin-producing pancreatic beta cells by auto-reactive T-cells. It results from a failure of the immune system to maintain tolerance to self-antigens. CD4+CD25+ regulatory T-cells represent one major mechanism by which auto-reactive T-cells are controlled in the periphery. Deficiency in this cell population number or function could tilt the regulatory cell-pathogenic cell balance and lead to type-1 diabetes development. In this study, we describe a new method to expand antigen-specific CD4+ CD25+ regulatory T-cells from autoimmune-prone non-obese diabetic mice. CD4+ CD25+ regulatory T-cells were expanded in vivo using a combination of IL-2, anti-IL-2 antibody, BDC 2.5 peptide, and rapamycin. The expanded CD4+ CD25+ regulatory T-cells expressed a classical phenotype, displayed suppressive functions in vivo, and preliminary data suggest that these cells can delay diabetes development in NOD mice. This new method of peripheral tolerance induction could be used in humans to promote tolerance to islet cell transplants without relying on immunosuppressive drugs.
BCAP negatively regulates TLR signaling in macrophages (116.13)
Authors: Ni Minjian , MacFarlane Alexander , Campbell Kerry , Lowell Clifford , Hamerman Jessica 
Published: January 2023

Abstract
B cell adaptor for phosphoinositide 3-kinase (BCAP) was originally identified as an adaptor molecule that binds to the p85 subunit of phosphatidylinositol 3-kinase (PI3K). BCAP-deficient mice have decreased numbers of mature B cells and attenuated B cell function due to defects in B cell receptor signaling. BCAP is also expressed in macrophages and activates PI3K downstream of Toll-like receptor (TLR) ligation. Here we investigated the responses of BCAP-deficient mice to stimulation through TLRs. BCAP-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli in vitro. Additionally, BCAP-deficient mice produced more IL-12 in response to LPS in vivo. The TLR mediated Akt activation is impaired in BCAP-deficient macrophages. Furthermore, the PI3K inhibitor wortmannin enhanced TLR mediated proinflammatory cytokine production in wild type but not in BCAP-deficient macrophages. In B cells, YXXM motifs of BCAP are required for BCR induced PI3K activation. Surprisingly, we found that YXXM motifs of BCAP are only partially responsible for the BCAP mediated negative regulation of TLR signaling in macrophages. BCAP is constitutively phosphorylated and associated with PI3K in resting macrophages, and, unlike in B cells, does not require Syk for its phosphorylation. Taken together, our findings show that BCAP negatively regulates TLR signaling in macrophages partly through regulation of TLR-mediated PI3K activation.
Induction of endotoxin tolerance in vivo inhibits LPS-inducible activation of IRAK4, p38 and NF-κB, decreases expression of pro-inflammatory cytokines and induces negative regulators of TLR4 signaling (116.14)
Authors: Xiong Yanbao , Medvedev Andrei 
Published: January 2023

Abstract
Toll-like receptors (TLRs) are conserved sensors of microbial pathogens and environmental or host-derived “danger” molecules. Development of TLR tolerance in septic patients re-programs monocyte responses to LPS, decreasing expression of pro-inflammatory cytokines without inhibiting anti-inflammatory and antimicrobial mediators, and increases a risk of secondary infections. To address the impact of endotoxin tolerization on activation of proximal TLR4 signaling pathways and expression of regulators of TLR4 signaling, we used an in vivo model of endotoxin tolerance. C57BL/6 mice were i.p. injected with LPS or PBC (used as a control), followed by in vitro challenge of isolated macrophages with medium or LPS and analyses of TLR4 signaling outputs and negative regulatory molecules. Compared to the control group, administration of LPS led to decreased TLR4-driven induction of IRAK4 kinase activity, degradation of IκB-α and phosphorylation of p38, and reduced expression of TNF-α, IL-6, and KC mRNA in peritoneal and splenic macrophages upon in vitro LPS challenge. In contrast, real-time PCR analyses revealed increased expression of IRAK-M, Tollip, SHIP, SARM, and SIKE in macrophages obtained from LPS-injected mice. We conclude that induction of endotoxin tolerance in vivo inhibits expression of pro-inflammatory cytokines and chemokines via impaired activation of IRAK4, p38 and NF-κB and up-regulation of negative regulators of MyD88- and TRIF-dependent pathways.