bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myelin specific regulatory T cells expand from naturally occurring regulatory T cells and accumulate in the CNS during EAE (128.8)
Authors: Oukka Mohamed , Bettelli Estelle , Korn Thomas , Gao Wenda , Sobel Ray , Strom Terry , Wucherpfennig Kai , Kuchroo Vijay 
Published: January 2023

Abstract
FoxP3 is a lineage specific marker for regulatory T cells (T-reg). We have generated FoxP3 knock-in mice by introducing a bicistronic GFP reporter into the endogenous FoxP3 locus, allowing us to faithfully track T-reg in vivo. We have also generated a MOG 35-55/IAb-tetramer. The combination of these two technologies enables us to study the in vivo behavior of myelin specific T-reg and effector T cells (T-eff) during EAE. Upon immunization with MOG 35-55, we identified a population of MOG-tetramer-reactive T-reg in the peripheral lymphoid compartment. T-reg trafficked to the CNS where they were readily detected as early as day 10 following immunization. At this stage and till the peak of the disease, an overwhelming number of T-eff also targeted the CNS. Thus, the ratio of T-reg and T-eff at the initiation of disease was 1:15. However at the onset of recovery, this ratio changed in favor of T-reg (T-reg/T-eff close to 1:1. During recovery, 50% of the CNS-derived T-reg were IL-10 producers compared to only 10% in the peripheral immune compartment. FOXP3+ T cells isolated from the CNS are effective in suppressing naive MOG-specific T cells, but fail to control CNS-derived T-eff that secrete IL-6 and TNF. Our data suggest that in order for CD4+FOXP3+ T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation
Phenotypes of TLR7-overexpressing B cells suggest a TLR7-mediated increase in antigen presentation (129.11)
Authors: Pisitkun Prapaporn , Deane Jonathan A. , Bolland Silvia 
Published: January 2023

Abstract
Autoantibodies against nuclear antigens secreted by autoreactive B cells are a hallmark of systemic autoimmunity. Failure to eliminate autoreactive B cells in the germinal center reaction has been reported in lupus disease. We have recently shown that TLR7 duplication in Yaa mice accelerates the onset of lupus disease. To better understand TLR7 roles in the pathogenesis of lupus disease, we created transgenic TLR7 (B6.Tg. TLR7) mice. We found an increase of spontaneous germinal center formation in both B6.Tg. TLR7 mice and B6. Yaa which is TLR7 dependent. We have carried out microarray analysis of gene expression profiles of follicular B cells (CD9-CD43-) from B6.Tg. TLR7 compared to B6. The upregulated genes in B6.Tg. TLR7 consist of interferon inducible genes, cell cycle regulators, MHC, and immunoglobulin genes. We have confirmed increased protein expression of phosphorylated stat1 (Ser727) by western blot and of H2-Ab1 by flow cytometry in B6.Tg. TLR7. These results suggest the possibility of increased antigen presentation by TLR7-overexpressing B cells in the high interferon environment.
Distinct subsets of dendritic cells drive tolerance in two models of CD4 T cell mediated autoimmunity (129.14)
Authors: Jain Renu , Divekar Rohit D , Nast Danielle M , Lee Hyun-Hee , Ellis Jason S , Hardaway John C , Haymaker Cara L , Hoeman Christine M , Zaghouani Habib 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen presenting cells that are capable of presenting both self and foreign antigens to T cells thereby inducing either tolerance or immunity respectively. What is still not clear is whether T cell tolerance requires a specific subset or any population of DCs can drive tolerance. To address this question different subsets of DCs were tested for suppression of autoimmunity in two major animal models- type I diabetes (T1D) and experimental allergic encephalomyelitis (EAE).
There are 3 major subsets of DCs in spleen- CD8α+, CD8α−CD4+ and CD8α−CD4−. In this study we investigated the ability of these subsets to induce tolerance in TID and EAE. Indeed the CD8α−CD4− DC subset mediated protection against diabetes in non-obese diabetic (NOD) mice. In fact, mice had reduced destructive infiltration within the islets and the antigen-specific lymphocytes showed reduced proliferation and an increase in IFNγ and IL-10 response. Surprisingly, in EAE it is the CD8α−CD4+ DC subset that supported protection against the disease. The lymphocytes from treated mice displayed more of a Th1 biased response. Both the protective subsets were mature and expressed significant levels of class II MHC and costimulatory molecules. However, the subsets trafficked differently to spleen and draining lymph nodes. Thus, distinct DC subsets drive tolerance in the two models of autoimmunity despite the fact that both diseases are mediated by CD4+ T cells.
Research supported by grants DK65748 and NS37406 from NIH.
Susceptibility to autoimmune myocarditis in mice: analysis of the Eam1 susceptibility locus (129.18)
Authors: Ligons Davinna LaChelle , Guler Mehmet L. , Li Haiyan S. , Rose Noel R. 
Published: January 2023

Abstract
H-2sA.SW and B10.S mice are susceptible and resistant to experimental autoimmune myocarditis (EAM), respectively. Our previous studies suggested that Eam1 on chromosome 1 is a non-MHC locus conferring susceptibility to cardiac myosin-induced (EAM) in A.SW mice. B10.A Eam1 congenic mice, carrying the Eam1 locus on the EAM-resistant B10.S background, develop EAM comparable to A.SW mice, suggesting that Eam1 plays a key role in the development of disease. We have previously reported that lymph node cells (LNC) of A.SW mice are more resistant to cyslophosphamide (Cy)-induced apoptosis in comparison to B10.S mice, and a similar apoptosis-resistant phenotype is found in NOD mice has been linked to the Idd5 locus overlapping with Eam1. Therefore, we hypothesized that the mechanisms by which Eam1 mediates the susceptibility to EAM could be due to its regulatory role in apoptosis. In the current study, we found that LNC from B10.A Eam1 congenic mice present an intermediate susceptibility to Cy-induced apoptosis, i.e. the percentage of apoptotic LNC with activated caspase 3, 8, 9 in congenic mice falls in between A.SW and B10.S mice. Interestingly, data suggest that A.SW mice have significantly lower levels of apoptotic LNC following immunization with cardiac myosin in CFA than B10.S mice. Our results therefore suggest that Eam1 partially down regulates LNC apoptosis and delays the removal of self-activated T cells, thereby providing an explanation for the role of Eam1 in the susceptibility to EAM.
Supported in part by NIH grant HL077611
Production of CCL2 by CNS resident cells regulates development of EAE through the recruitment of TNF-α and iNOS expressing macrophages (129.19)
Authors: Dogan Rukiye Nazan , Elhofy Adam , Karpus William J 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is demyelinating disease of the central nervous system (CNS), which serves as an animal model for Multiple Sclerosis (MS). Increased expression of CCL2, monocyte chemoattractant protein-1 has been detected in CNS inflammatory infiltrates, which consist of T cells, macrophages, and B cells. The critical role for CCL2 in MS-like diseases was identified in mice that lack this molecule and develop less severe EAE and impaired macrophages recruitment into the CNS. While CCL2 production is essential for macrophage infiltration into the CNS, it remains unclear which cell source is critical in disease induction. We constructed radiation bone marrow chimera to investigate the cell-specific source of CCL2 production in EAE. Mice lacking CCL2 production by resident CNS cells showed a delayed and diminished clinical disease as result of decreased macrophage infiltration into the CNS. Moreover, TNF-α and iNOS producing TipDC recruitment to CNS was reduced in mice devoid of CCL2 production by CNS resident cells. Mice lacking CCL2 production by infiltrating mononuclear cells developed EAE similar to controls. Our study demonstrates that CCL2 production by CNS resident cells is the major contributors to trafficking of macrophages into the CNS and subsequent disease progressions.
Supported by NIH NS034510
Possible mechanism of shedding of BAFF in human T cells (129.2)
Authors: Yoshimoto Keiko , Takahashi Yasue , Setoyama Yumiko , Suzuki Katsuya , Tsuzaka Kensei , Abe Tohru , Takeuchi Tsutomu 
Published: January 2023

Abstract
B cell activating factor of the TNF family, or BAFF, is a type II membrane-bound protein and the extracellular C-terminal fragment is released from the cells as soluble BAFF (sBAFF). BAFF is mainly produced in monocytes and dendritic cells, and regulates proliferation, differentiation, and survival of B cells. Our recent study has revealed that the expression of BAFF is abnormally elevated in peripheral T cells of SLE patients, suggesting that BAFF plays an important role in the pathogenesis of autoimmune diseases. In the present study, we investigated the expression of BAFF in T cells of Sjögren’s syndrome (SS), and found that the expression of BAFF was enhanced in peripheral T cells of SS patients upon stimulation. We further analyzed the mechanism of release of sBAFF from T cells, since this step may provide a therapeutic possibility to treat the diseases. Particularly, we focused on furin and matrix metalloproteinases, which are membrane bound proteases and responsible for shedding of several proteins. Investigation with specific inhibitors against these proteases revealed that at least furin and MMP9 was involved in the release of sBAFF.
Differential involvement of Th1 or Th17 cells in pathogenic autoimmune processes triggered by different TLR ligands (129.22)
Authors: Shi G. , Vistica B. P. , Yu C-R. , Cox C. A. , Montalvo V. , Wawrousek E. F. , Egwuagu C. E. , Gery I. 
Published: January 2023

Abstract
We have previously shown that various TLR ligands are capable of converting naïve CD4 cells specific to hen egg lysozyme (HEL) to become effector cells that initiate inflammation in eyes of recipient mice expressing HEL in their lens. In addition, our data revealed that pertussis toxin (PTX) is superior to all other tested TLR ligands in this activity. Here, we examined the involvement of Th1 or Th17 cells in the pathogenic processes triggered by different TLR ligands. Using qPCR, we found that eyes of PTX-treated recipients expressed both IL-17 and IL-22 transcripts ~15, ~10 and ~6 fold higher than eyes from recipients treated with poly (I:C) (PIC), CpG oligodeoxynucleotide (CpG), or LPS, respectively. Although inflamed eyes from PTX-treated mice also expressed IFN-γ more than eyes of the other groups, the differences were markedly lower: ~5, ~ 4 and ~ 4 fold, respectively. Furthermore, intracellular staining of infiltrating cells collected from the inflamed eyes revealed that cells stained for IL-17 were ~5 fold higher than cells stained for IFN-γ in eyes of PTX-treated mice, ~2 fold higher in eyes of the LPS group, approximately equal in the PIC group, but ~2 fold lower in the CPG group.
IL13 induces IL17 by regulating dendritic cell maturation in autoimmune myocarditis (129.25)
Authors: Cihakova Daniela , Barin Jobert , Baldeviano G Christian , Kimura Miho , Talor Monica V , Rose Noel R 
Published: January 2023

Abstract
IL13 KO BALB/c mice developed severe myosin-induced experimental autoimmune myocarditis (EAM). This severe disease is characterized by increased inflammation, increased total intracardiac CD45+ leukocytes, and progression to dilated cardiomyopathy. Hearts of IL13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL1β, IL18, IFNγ, TGFβ1, IL4 and histamine. However, another proinflammatory cytokine, IL17 is significantly decreased in both hearts (p= 0.0005) and spleens of IL13 KO mice on day 21 of EAM. The decrease of IL17 is significantly correlated with decrease of another Th17 cytokine – TNF α in the hearts and spleens of IL13 KO mice. The substantial decrease of the Th17 population in the absence of IL13 is not due to the absence of cytokines required to induce Th17, since IL13 KO mice have increased levels of IL1β and TGFβ. This Th17 defect is also not caused by increased IL27, which is known to impair Th17 development, since IL27 is actually significantly decreased in IL13 KO mice. IL23, which is necessary for sustaining the Th17 population, is significantly decreased in IL13 KO mice. It has been shown that IL13 induces production of IL23 by dendritic cells. We have observed severely impaired DC maturation both in vivo as well as in vitro in IL13 KO mice. Thus, we hypothesize that IL13 is required for maturation and IL23 production by DCs; therefore, IL13 is required for Th17 differentiation.
(Supported by 2R01 HL67290).
IL-23 and IL-17 in pathogenesis of experimental ocular autoimmunity: requirement for IL–23 may extend beyond its role in sustaining the IL-17 effector response (129.26)
Authors: Caspi Rachel , Silver Phyllis , Cua Daniel , Chen Zoe , Chan Chi-Chao , Luger Dror 
Published: January 2023

Abstract
Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. Here we examined the role of the IL-23/IL-17 pathway in EAU. We immunized IL-23p19, IL-12p35, IL-12p40, IFN-γ and IL-17 KO mice with the uveitogenic Ag IRBP. Alternatively, we treated wild type mice immunized for EAU with Abs to IL-23p19 or to IL-17 throughout the disease course (prevention), or only during the effector phase (reversal). IL-23p19 KO were resistant to EAU, showing reduced Ag-specific DTH, IL-2, IFN-γ, IL-17, IL-1β, IL-6 and IL-5. In contrast, IL-12p35 and IFN-γ KO mice developed exacerbated EAU, DTH and IL-17 responses. Treatment with anti-IL-23p19 protected from EAU and reduced immunological responses, but was unable to reverse disease, indicating that EAU is dependent on early availability of IL-23. In contrast, anti-IL-17 prevented as well as reversed EAU. Interestingly, severe EAU could be induced with a Th1 cell line that does not produce IL-17. In vivo cytokine neutralization revealed requirement for IFN-γ and TNF-α, but not for IL-17, suggesting that under some conditions an antigen-specific Th1 effector is sufficient to induce EAU. In keeping with this, IL-17 KO mice were still susceptible to disease. These data raise the possibility that the nonredundant need for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and point to IL-23 and IL-17 as new therapeutic targets for uveitis.
Treg Development and Suppression of Experimental Allergic Encephalomyelitis (129.28)
Authors: Haymaker Cara , Yu Ping , Ellis Jason , Divekar Rohit D , Jain Renu , Tartar Danielle , Lee Hyun-Hee , Hardaway John , Hoeman Christine , Guloglu F. Betul , Zaghouani Habib 
Published: January 2023

Abstract
Many autoimmune disorders have been linked to a lack in T regulatory cells. As such, an understanding of how these cells develop and mature is critical. While thymic T cell selection has been described, this process remains largely undefined for Tregs. Since only the DM20 form of proteolipid protein (PLP) is expressed in the thymus during fetal and neonatal life, thymic selection against PLP139-151 which is missing in DM20 is not operative during those periods. PLP139-151 (designated PLP1) as well as PLP1 derived altered peptide with degenerate affinity to PLP1-specific T cells were expressed on immunoglobulin (Ig) and the resulting chimeras were used to cross the maternal placenta, deliver the peptides from mother to fetus, and restore peptide selection during the fetal and neonatal period. This model was then used to determine whether Tregs are subject to thymic selection and to gauge the affinity required for such selection. The findings indicate that selection of functional Tregs requires high affinity. Indeed, Ig chimeras harboring high avidity peptides facilitated development of Tregs that conferred protection against experimental allergic encephalomyelitis (EAE) while chimeras incorporating low affinity peptide did not drive selection of Tregs and the animals remained susceptible to EAE.
Role of MAPK signal pathway in the regulation of IL-23p19 expression in human microglia (129.29)
Authors: Li Yonghai , Chu Niansheng , Ju Jack , Gran Bruno , Rostami A.M. , Zhang Guang-Xian 
Published: January 2023

Abstract
Activated microglia can release a variety of proinflammatory cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). IL-23 is a novel proinflammatory cytokine that shares the p40 subunit with IL-12 and is required for the induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, IL-23 expression and regulation in human microglia is poorly understood. Here we detected IL-23p19 mRNA expression on human microglia by northern blot and protein level by double-fluorescence immunostaining analysis. When the intracellular signaling pathway for p19 regulation was determined, we found that IL-23p19 expression in human microglia was significantly reduced by blocking the p38 MAP kinase pathway with either neutralizing antibodies or dominant-negative p38 transduction. Thus, human microglia inducibly express p19, and the p38 MAP kinase signaling pathway plays a major role in regulation of p19 expression.
IFN-γ receptor signaling in the CNS, but not periphery, is critical for the induction of experimental autoimmune encephalomyelitis (129.33)
Authors: Elhofy Adam , Dogan Rukiye Nazan , Karpus William J 
Published: January 2023

Abstract
Activation of microglia and astrocytes in experimental autoimmune encephalitis (EAE) has been associated with chemokine induction in the CNS resulting in attraction of inflammatory infiltrate. The role of IL-17 in autoimmune disease has called into question the role of IFN-γ in EAE. In this report we investigate the necessity of IFN-γ receptor signaling in disease induction. To test this we made IFN-γR−/− radiation bone chimeras with animals expressing IFN-γR in the CNS, animals deficient for IFN-γR in the CNS but able to signal in the periphery and a wild-type control (WT). We found IFN-γR expression on astrocytes and microglia was critical for clinical disease symptoms in the adoptive transfer model of EAE. Without IFN-γ activation in the CNS there were no infiltrating leukocytes while in WT and in animals capable of signaling in the CNS there were CD4, CD8, and CD11b infiltrating cells. CCL2, CCL5 and CXCL10 were significantly decreased in CNS homogenates of animals devoid of IFN-γR on astrocytes and microglia compared to WT and mice expressing IFN-γR on peripheral leukocytes. These results argue that IFN-γ activation in the CNS is essential for clinical EAE disease induction.
Supported by NIH R01 NS034510.
Il-23 enhances diabetes induction in the wild type but not in INF-gamma −/− mice (129.36)
Authors: Lukic Miodrag L , Shahin Allen - , Mensah-Brown Eric - , Al-Hakim Ahmed - 
Published: January 2023

Abstract
C57BL/6 male mice developed delayed progressive and sustained hyperglucemia, insulitis and loss of β cells when injected with 5 (40 μg/ kg b/w) daily doses of streptozotocin (STZ). C57BL/6 INF-γ −/− mice treated with same regimen develop the disease at the later stage (by day 28) but reach the same level of functional impairment by day 52 after disease induction. RT PCR analysis of the pancreatic lymph nodes revealed the presence of TNF, INF-γ, and IL-17 and in the “wild type” mice and only TNF-α and IL-17 in INF-γ −/− mice. Four injections of STZ did not induce hyperglycemia neither in the “wild type” nor INF-γ −/− mice. Concomitant treatment with IL-23 (10 x 40 mg/daily) dramatically enhanced the effect of this subdiabetogenic treatment in “wild type” mice, accompanied with the expression of TNF, INF-γ and IL-17 in the pancreatic lymph node while INF-γ −/− mice did not develop disease. We assume that INF-γ is required for the initial activation of antigen presenting cells in suboptimal conditions for diabetes induction but not for the expansion and activation of effector cells in this model of toxin induce autoimmune diabetes which is IL-23-IL-17 dependent (European Journal of Immunology, 36: 216–23, 2006).
A novel H2A−E+ transgenic model susceptible to human but not mouse thyroglobulin in autoimmune thyroiditis: identification of a mouse pathogenic epitope (129.37)
Authors: Brown Nicholas Korten , McCormick Daniel J. , Brusic Vladimir , David Chella S. , Kong Yi-chi M. 
Published: January 2023

Abstract
Experimental autoimmune thyroiditis (EAT) is a model for Hashimoto’s thyroiditis which is characterized by mononuclear cell infiltration and follicular destruction. We previously reported on an Eα-transgenic strain (H2A−E+) that is highly susceptible to human (h) thyroglobulin (Tg)-induced EAT, but strongly tolerant to mouse (m)Tg. After mTg and adjuvant, traditional, resistant strains do not develop thyroiditis, nor detectable primed T cell proliferation, but do make anti-mTg Abs. By contrast, this H2Eb+ strain does not even produce mTg Abs. To identify what epitopes in the mouse thyroid hTg-primed, thyroiditogenic T cells recognize to evoke EAT, we first confirmed that hTg-primed cells do not respond to mTg, nor to other thyroid Ags. We next selected the three immunogenic epitopes on hTg known to be processed and presented by H2Eb, as the basis for synthesizing potential mTg epitopes. One 15-mer peptide, mTg409, did prime T cells, elicit Ab, and generate moderate thyroiditis. Thyroiditis incidence was increased after adoptive transfer of in vitro activated, mTg409-primed cells. Moreover, cells primed to hTg410, the corresponding, pathogenic hTg peptide, cross-reacted with mTg409, and vice versa. This mTg autoepitope, identified by using thyroiditogenic hTg epitopes, helps to explain the severe thyroiditis seen in this novel H2E+ transgenic model.
(Supported by NIH grant DK45960)
Collagen-specific T cells are not downregulated following treatment with 17β-estradiol in CIA (129.39)
Authors: Latham Kary , Whittington Karen , Rosloniec Edward 
Published: January 2023

Abstract
Increases in estrogen levels in rheumatoid arthritis (RA) patients result in amelioration of RA symptoms. Similarly, administration of estrogen (17β-estradiol, or E2) decreases incidence of collagen-induced arthritis (CIA), a well-established murine model for RA. Our laboratory established that this decrease was associated with a change in the isotype of antibodies produced to type II collagen (CII) following immunization with CII from predominantly IgG2a to IgG1. In order to determine if E2-driven changes in the T cell response regulate this isotype switch, we focused on E2’s effect on the function of CD4+ CII-specific T cells. After immunization with CII, analysis of CII-specific T cells using MHC class II tetramers showed that their numbers increased slightly in E2-treated mice at 10 days post-immunization compared to controls. There were no significant differences in expression of activation markers (CD69, CD44, or CD62L) by CII-specific T cells between groups. Surprisingly, analysis of cytokine expression by qPCR following cell sorting of the tetramer+ cells indicated that the CII-T cells from E2-treated mice expressed higher levels of IL-17 mRNA than did CII-T cells from controls. Levels of other proinflammatory cytokines such as IL-2, IFN-γ, and IL-6 were similar to those found in tetramer+ cells from controls. These results suggest that CII-T cells do not directly mediate E2’s protective effect in CIA.