bluuebunny/crossref_metadata_2025_split huggingface dataset:
BTLA-HVEM interaction delivers bidirectional signals and modulates the severity of GVHD (169.48)
Authors: Tamada Koji , Sakoda Yukimi , Park JangJune , Zhao Yuming 
Published: January 2023

Abstract
B and T lymphocyte attenuator (BTLA), upon interaction with herpesvirus entry mediator (HVEM), delivers an inhibitory co-signal which regulates immune response in various diseases. In graft-versus-host disease (GVHD), unexpectedly, BTLA mediates positive effects on donor T cell survival, but immunological mechanisms of this function have yet to be fully explored. Our recent studies addressed a role of BTLA in GVHD by employing the newly established agonistic anti-BTLA mAb that stimulates BTLA signal without antagonizing BTLA-HVEM interaction. We revealed that BTLA signal inhibited donor anti-host T cell responses and ameliorated GVHD with a successful engraftment of donor hematopoietic cells. These effects were dependent on BTLA signal into donor T cells but neither donor non-T cells nor recipient cells. On the other hand, expression of BTLA mutant lacking an intracellular signaling domain restored impaired survival of BTLA-deficient T cells, suggesting that BTLA also serves as a ligand and delivers HVEM prosurvival co-signal in donor T cells. Thus, BTLA-HVEM interaction delivers positive and negative bidirectional co-signals to donor T cells via HVEM and BTLA, respectively, and modulates the severity of GVHD. Additional data obtained by recent studies will be also presented.
Survey of HPA and HLA class 1 antibodies in Nigerian antenatal women (169.5)
Authors: Jeremiah Zaccheaus , Atiegoba Anne , Mgbere Osaro 
Published: January 2023

Abstract
Background: The prevalence of antibodies to HPA and HLA class 1 antigens among Nigerian pregnant women has not been reported in our country. Aims: To screen for platelet specific and HLA class 1 antibody among pregnant women. Methods: One hundred and forty four (144) pregnant women attending the obstetric clinic of Military Hospital, Port Harcourt, participated in the study. Their sera were tested for antibodies to HPA and HLA class 1 antigens using GTI PakPlus solid phase ELISA Kit. Results: The total prevalence rate of antibody production was 60.5% (87 out of 144). Among the positive samples, 60 had platelet glycoprotein specific antibodies (41.7%) and 27 had HLA class 1 antibodies (18.8%). In 39.6% of the pregnant women, both platelet specific antibodies and HLA class 1 antibodies appeared. The prevalence of platelet specific glycoprotein antibodies were obtained as follows: GP IIb/IIIa 12 (8.3%), GP Ia/IIa 30 (20.8%), GP Ib/IX 18 (12.5%) and GP IV 9(6.3%). The prevalence of each platelet antibody subgroup was obtained as follows: anti-H PA-1a,-3a,-4a (4.2%), anti-H PA-1b,-3b,-4a (4.2%), anti-H PA- 5a and anti-GP Ib/IX (12.5% each), anti-HPA-5b (8.3%) and anti-GP IV (6.3%).). Conclusion: A high prevalence rate of human platelet and cytotoxic antibodies has been observed in our obstetric population.
Identification of novel immune factors regulating outcome to viral encephalitis. (170.12)
Authors: Taylor Katherine , Borisevich Vika , Kolokoltsova Olga , Smith Jennifer , Smith Jeanon , Estes Mark , Paessler Slobodan 
Published: January 2023

Abstract
Viewed as a public health and zoonotic threat, Venezuelan equine encephalitis virus (VEEV) causes morbidity and mortality in both human and equine populations during naturally occurring epizootic outbreaks. The specific immune factors contributing to lethality or survival following viral invasion of the brain remain largely unknown. Using intranasal infection of the vaccine strain of VEEV (TC83), we established three models of brain infection: (1) Lethal infection in C3H/HeN (C3H) mice (2) Non-lethal infection in C57BL/6 (C57) mice (3) Non-lethal infection followed by chronic viral persistence in α/β T cell-receptor deficient mice (TCR KO) on a C57 background. The three models display similar viral kinetics with each developing a high level viral load in the brain. While absence of a functional T-cell compartment contributes to persistent brain infection, profiling the host response using genomics and multiplex cytokine array identified natural killer (NK) cells and type I interferon (IFN) as potential prognosticators of outcome. The systemic depletion of NK cells enabled C3H mice to tolerate brain infection without developing lethal disease. The trend toward lower INF-β levels in the brains of lethally infected animals compared to surviving strains corroborates a protective role for IFN in the brain. The novel knowledge generated in this model system enabled identification of intervention points that influence a positive outcome to viral invasion of the brain.
Histocompatibility in an invertebrate is controlled by a complex of polymorphic IgSF-like genes. (170.4)
Authors: Nicotra Matthew , Dellaporta Stephen , Buss Leo 
Published: January 2023

Abstract
Animals have evolved sophisticated immune systems to distinguish self from infectious non-self. In addition, several groups of colonial marine invertebrates—animals such as sponges, corals, and sea squirts—have evolved allorecognition systems that allow them to distinguish between their own tissues and those other members of their species. Allorecognition phenomena occur when these animals, which live as encrustations on marine surfaces, grow into contact with each other. Compatible colonies fuse, while incompatible colonies reject and often compete for space. Although allorecognition phenomena have long been known to be under genetic control, the molecular basis of these phenomena remains largely unknown. One model system for the study of invertebrate allorecognition is Hydractinia, a cnidarian related to Hydra and reef corals. Using lines of Hydractinia inbred for &gt;8 generations, we have mapped allorecognition loci to a single genomic interval, called the allorecognition complex (ARC). The ARC contains at least two histocompatibility genes, alr1 and alr2, each of was identified by positional cloning. Both genes encode polymorphic transmembrane proteins similar to immunoglobulin superfamily (IgSF) molecules. Sequence variation between alleles of alr1 or alr2 is concentrated in the extracellular region and is predictive of allorecognition responses in inbred and wild-type colonies. Intriguingly, alr1 is located within a family of at least 10 other IgSF-like genes.
A complex family of diversified immunoglobulin domain-containing proteins (DICPs) includes inhibitory and activating forms and likely plays a role in zebrafish innate immunity (170.9)
Authors: Yoder Jeffrey , Haire Robert , Turner Poem , Mueller M. , O'Driscoll Marci , Litman Ronda , Cannon John , Litman Gary 
Published: January 2023

Abstract
One of the first lines of defense against pathogens and disease is the recognition of foreign or altered antigens by innate immune receptors. A large number of these receptors fall into the large immunoglobulin (Ig) super family of proteins. We have identified a multi-gene family of 29 diversified immunoglobulin domain-containing proteins (DICPs) encoded on zebrafish chromosomes 3, 14 and 16. DICPs typically encode two extracellular Ig domains: an amino terminal variable (V) Ig domain and an additional Ig-like domain. Certain DICPs possess a single Ig domain. DICP variants include membrane bound and secreted forms. Putative inhibitory forms have been identified which possess cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). Putative activating forms have been identified which possess a positively charged residue within their transmembrane domain and are predicted to associate with adaptor proteins that possess cytoplasmic activation motifs (e.g. Dap12, Dap10 etc). Database searches reveal that the Ig domains of DICPs are unlike any other Ig domains encoded by the zebrafish genome and are more (albeit very weakly) similar to the V domains of mammalian immunoglobulin genes, than to any other zebrafish or mammalian sequence. DICP annotation, transcript variants, tissue-specific expression and efforts to identify DICP ligands will be discussed.
IL-21/IL-21R interaction on both CD4 cells and B cells is required to promote autoimmune parameters in chronic graft versus host disease. (44.10)
Authors: Nguyen Vinh , Irina Luzina , Chen Qing , Rus Horea , Rus Violeta 
Published: January 2023

Abstract
IL-21 stimulates B cell proliferation, plasma cell (PC) differentiation and germinal center (GC) expansion and it exerts autocrine effects on T follicular B helper cells (TFH) and Th17 cells while downregulating Treg cells. We assessed the effect of IL-21/IL-21R signaling on B cells independent from the effect on CD4 T helper cells using IL-21R-/- or IL-21R+/+ mice as donor or hosts in the P-into-F1 and Bm12-into-B6 models of chronic Graft Versus Host Disease (cGVHD). cGVHD induced by injection of IL-21R-/- CD4 cells from B6 mice into B6D2F1 hosts was characterized by a significant decrease in the expansion of donor CD4, TFH and Th17 cells and an increase in Treg cells compared to IL-21R +/+ donor cells. Furthermore, the number and size of GC, GC B cells and levels of anti-ssDNA antibody (Ab) were significantly decreased. When cGVHD was induced by injecting Bm12 spleen cells into IL-21R+/+ or IL-21R-/- B6 mice, parameters of cGVHD including B cell activation, number and size of GC, percentage of GC B cells and plasmablasts, IgG anti-dsDNA Ab production were significantly decreased compared to IL-21+/+ hosts. Long-term studies showed decreased severity of lupus-like renal disease in the IL-21R-/- hosts. These results suggest that IL-21/IL-21R interaction enhances autoimmune features in lupus by promoting the expansion of TFH and Th17 cells and the downregulation of Treg cells and by promoting the differentiation of autoreactive B cells into autoAb producing cells.
Monocyte phenotypes in systemic juvenile idiopathic arthritis (44.13)
Authors: Macaubas Claudia , Nguyen Khoa , Peck Ariana , Wong Elizabeth , Buckingham Julia , Goertz Yael , Deshpande Chetan , Alexander Heather , Chang Sheng-Yung , Sun Yue , Park Jane , Lee Tzielan , Begovich Ann , Mellins Elizabeth 
Published: January 2023

Abstract
Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition of childhood, characterized by remitting fever, transient rash, and relapsing arthritis. The association of macrophage activation syndrome with SJIA and clinical evidence implicating monocyte-derived cytokines IL-1 and IL-6 suggest a key role for monocyte in SJIA pathogenesis. We have previously found monocyte expansion during disease activity (flare), and a normal distribution of the monocyte subsets CD14hiCD16- and CD14loCD16+. We also observed elevated expression of monocyte surface markers CD14 and CD16 in the respective CD14hiCD16- and CD14loCD16+ monocyte subpopulations during disease flare and inactivity (quiescence), suggesting phenotypic alteration of monocytes in SJIA, independent of clinical status. We further analyzed phenotypic and functional alterations of SJIA monocytes in relation to disease activity and in comparison to age- and ethnicity-matched controls, specifically regarding development towards a M1- or M2- polarized phenotype. Gene expression profile, flow-cytometry based analysis of surface markers, baseline and LPS-induced production of cytokines and phosphorylation patterns in response to cytokine stimulation indicate that SJIA monocytes have a mixed M1/M2 phenotype during disease flare. Disease quiescence is associated not with normalization, but with an M2 phenotype, suggesting the existence of a state of compensated inflammation that is broke during disease flare.
An altered peptide of Chromogranin A is a potent antigen for the diabetogenic T cell clone BDC-2.5 (44.21)
Authors: Delong Thomas , Barbour Gene , Bradley Brenda , Reisdorph Nichole , Haskins Kathryn 
Published: January 2023

Abstract
Pathogenesis of type 1 diabetes is mediated by autoreactive T cells directed toward antigens in islet beta cells. We have recently identified Chromogranin A (ChgA) as the antigen target for three diabetogenic CD4+ T cell clones that were derived from the non-obese diabetic mouse, including the clone BDC-2.5. These clones respond to WE14, a natural cleavage product of ChgA, but only at very high peptide concentrations, suggesting that WE14 may not be the natural T cell ligand. Our question in this study was to determine whether a post-translational modification (PTM) could be involved in the formation of the natural ligand for the T cell clones. Although WE14 is expressed in beta cells, we were not able to identify the complete peptide sequence in purified antigenic fractions from beta cell tumors. Mass spectrometric analysis revealed the presence of an amino acid sequence corresponding only to the C-terminal region of WE14. Glutamine, which is in the N-terminal region of WE14, is a potential target for the enzyme transglutaminase. We treated the peptide WE14 with transglutaminase and demonstrated that this treatment significantly increased the antigenicity. Transglutaminases are known to deamidate or covalently crosslink proteins and we are currently investigating whether those modifications can be found in the natural antigen from beta cells. If transglutaminase is required for the generation of autoantigenic T cell epitopes, it could be an attractive therapeutic target.
Requirement of antigen cross-presentation for lupus tissue injuries: essential role of endosomal trafficking and proteosomal degradation (44.24)
Authors: Tsumiyama Ken , Takimoto Mai , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: Our ‘self-organized criticality theory’ explaining the cause of SLE shows that full-matured CTL generated via antigen cross-presentation induces lupus tissue injuries. Here we examine the molecular details of antigen cross-presentation to clarify how effector CTL is generated. Methods: Bone marrow-derived DC (BMDC) from BALB/c mice was cultured with fluorescent-labeled OVA. EEA1, calnexin and Sec61 were detected by using immunofluorescent staining. MG132 or primaquine (PQ) was repeatedly co-immunized with OVA to inhibit proteasomal degradation or endosomal trafficking to cell surface, respectively. Proteinuria and IFNγ-producing CD8+ T cell in spleen were examined. Results: In BMDC, OVA co-localized with EEA1, an endosomal marker. However, OVA was gradually separated from EEA1. In contrast, OVA never co-localized with calnexin, a ER marker. Sec61, a translocon, was co-localized with OVA, which indicated that OVA was transported from endosome to cytoplasm via Sec61. MG132, which inhibits proteasomal degradation, and PQ, which inhibits endosomal trafficking to cell surface, abrogated generation of CTL and development of nephritis. Conclusion: Endosomal trafficking, bypassing ER, is important not only in antigen cross-presentation but also development of lupus nephritis. Export of antigen from endosome to cytoplasm via Sec61 seems to be the first step in antigen cross-presentation, and subsequent the generation of lupus nephritis.
Lupus psychosis in IFNα transgenic mice (44.26)
Authors: Honda Eriko , Akiyama Chieri , Uchimura Chiaki , Hashiramoto Akira , Shiozawa Shunichi 
Published: January 2023

Abstract
Objective: We have shown that sole increase of interferon alpha (IFNα) in tetracycline-inducible transgenic (IFNα Tg) mice induces production of anti-dsDNA antibody and renal disease akin to human SLE. It has also been reported that IFNα is highly expressed in the brain and cerebrospinal fluids in patients with lupus psychosis. In this study, we have studied the contribution of IFNα to neuropsychiatric disease. Method: We made C57BL6/FVBN TetOp-mIFNα/EμSR-tTA transgenic female mice in which IFNα was expressed after cessation of doxycycline (Dox-off). Lupus psychosis was evaluated by behavioral test battery. Open field test (OFT), forced swim test (FST) and tail suspension test (TST) were performed in IFNα Tg mice 30 weeks after up-regulation of IFNα. Normal littermates (TetOp-mIFNα/EμSR-tTA: -/+) or IFNα Tg mice given doxycycline were used as control. Results: The locomotion score in OFT, which reflects exploratory activity, was lower in IFNα Tg mice than littermates (P&lt;0.005). The activity counts in TST, which express depression and anxiety, were significantly lower in Dox-off IFNα Tg mice compared with Dox-on IFNα Tg mice (P=0.001). Increase of serum IFNα and up-regulated expression of IFNα in brain were confirmed by ELISA and immunohistochemistry, respectively. Further, we found that alopecia typical for SLE also developed at 24 weeks on up-regulation of IFNα in IFNα Tg mice. Conclusion: IFNα causes lupus psychosis and alopecia, important manifestations of SLE.
Impaired CD1d downregulation on B cells limits the cGVH response in Mertk-/- mice (44.28)
Authors: Shao Wen-Hai , Zhen Yuxuan , Finkelman Fred , Eisenberg Robert , Cohen Philip 
Published: January 2023

Abstract
The splenic marginal zone (MZ) contains specialized macrophages and B cells. Activation and migration of MZB into follicular (FO) regions of the spleen has been proposed as one of the mechanisms that regulate the development of autoreactive B cells. The Mer receptor tyrosine kinase (Mertk) mediates apoptotic cell clearance and regulates cytokine production. Although Mertk was previously not believed to be expressed on B cells, we recently reported unresponsiveness of Mertk-/- B cells to class II-alloactivation in a chronic GVH model. In the present study, we show that B cells from Mertk-/- mice but not WT B6 mice exhibited a decreased but more sustained calcium influx when stimulated by MHC-II cross-linking, indicating an intrinsic B-cell defect. In addition, in cGVH induced with CD4+ T cells from bm12 mice into Rag-/- mice reconstituted with mixed chimeras with bone marrows from Mertk-/- mice and C20 mice, autoantibodies came only from wild type (a allotype) and not from Mertk-deficient (b allotype) B cells. Compared to wild type, MZB cells from Mertk-/- mice were unable to down regulate surface CD1d expression and subsequent inclusion in the MZ, correlating with significant lower germinal center (GC) responses assessed by absolute GC numbers and PNA staining. Taken together, these data show that Mertk is needed for class II-activation of B cells, and that Mertk plays a role in CD1d down-regulation on MZ B cells, a potential mechanism limiting B-cell activation in cGVH.
Specific effects of Fli1 levels on T cells in the MRL/lpr lupus prone model (44.30)
Authors: Nowling Tamara , Morris Richard Erin , Harrell Maria , Basher Fahmin , Zhang John 
Published: January 2023

Abstract
The Ets factor Fli1 is implicated as a key modulator of lupus disease expression. Lowering the global levels of Fli1 in lupus mouse models or lowering the levels of Fli1 in hematopoietic cells in MRL/lpr lupus mice significantly improved kidney disease and prolonged survival. In this study, we analyzed the effects of reduced Fli1 levels on T cells in MRL/lpr lupus prone mice. Flow cytometry analyses of kidneys from MRL/lpr Fli1+/+ and Fli1+/- mice demonstrated a significant 35% decrease in total T cell numbers present in the kidney of 14 week old Fli1+/- mice, as well as significant changes in CD8+ (20% increase), CD4+ (40% decrease) and activated (30% decrease) T cells. We performed an adoptive transfer experiment with splenic T cells and B cells from 15-17 week old MRL/lpr Fli1+/+ and Fli1+/- mice. The cells were mixed in all combinations and transferred into Rag-1 deficient mice, which lack mature T and B cells. The Rag-1 deficient recipients receiving Fli1+/- T cells, regardless of the Fli1 levels in co-transferred B cells, expressed significantly lower levels of serum IgG and IgM. Mechanistically, the role of Fli1 in T cells has yet to be fully explored. However, these results suggest that Fli1 may play a role in T cell proliferation, apoptosis, or migration and/or T cell-B cell interactions. Importantly, the adoptive transfer results demonstrate that reducing Fli1 levels in T cells alone may have a positive therapeutic impact on the progression of lupus.
Activated natural killer cells enhance passive experimental autoimmune myasthenia gravis (44.35)
Authors: Wall Katherine , Saric Petar , Brown Paul 
Published: January 2023

Abstract
Myasthenia gravis (MG) is characterized by autoantibody-mediated loss of nicotinic acetylcholine receptors (AChR). However, antibody titers alone do not determine the severity of disease. Interleukin-12 (IL-12), a major inducer of interferon-gamma (IFN-γ) production, enhances experimental autoimmune MG (EAMG) in mice independently of the level of antibody and complement bound to AChR. IFN-γ is produced by various cell types, including CD8+ T cells, natural killer (NK) cells, and NK1.1+ T (NKT) cells. To investigate the roles of these cell types in disease enhancement, NK and NKT cells were depleted using anti-NK1.1 antibody prior to administration of IL-12 and passive transfer of monoclonal anti-AChR antibody D6 in B6 mice. For comparison, IL-12 treatment and passive transfer of mAb D6 was performed using TCRβ/TCRδ dual knock-out mice, which possess B cells and NK cells but lack functional T cells and NKT cells. IL-12 treatment worsened passive disease in wild-type B6 and TCR dual knock-out mice, but not in NK depleted B6 mice. Serum IFN-γ correlated with disease. These findings suggest that innate NK cells are the main source of disease-enhancing IFN-γ upon administration of IL-12. This provides a mechanism by which the innate immune response can enhance MG even when antibody levels remain unchanged.
Effects of Fli1 on T cell function in systemic lupus erythematosus (44.44)
Authors: Basher Fahmin , Harrell Maria , Richard Erin , Nowling Tamara 
Published: January 2023

Abstract
SLE, or lupus, is an autoimmune disease characterized by abnormal activation of T and B cells, resulting in autoantibody production and immune complex deposition in target tissues. T cells are one of the primary cell types infiltrating the kidney in lupus nephritis. Fli1 is a transcription factor implicated in the pathogenesis of lupus. Reduction of Fli1 expression resulted in decreased renal pathology and inflammation and increased survival in lupus-prone mice with specific effects on T cells observed. To determine the effects of Fli1 on T cell function, proliferation and apoptosis were measured in non-autoimmune prone (C57BL/6) and lupus prone (MRL/lpr) T cells stimulated with PMA and ionomycin. T cells isolated from C57BL/6 mice proliferated 170% more than MRL/lpr T cells regardless of Fli1 levels; however, no differences were observed in the rate of proliferation in Fli1+/- compared to Fli1+/+ T cells in either strain. Significantly more MRL/lpr T cells compared to C57BL/6 T cells, regardless of Fli1 levels, were undergoing apoptosis or dead. Interestingly, Fli1+/- T cells had a 26-35% increase in the percent of cells undergoing early apoptosis compared to Fli1+/+ cells in both strains. A chromatin immunoprecipitation array was scanned following IP with the Fli1 antibody of crosslinked T cell DNA. Highly enriched genes included IL-17F, IL-13, TNF, C3 and CEBPB. These results indicate that Fli1 may be involved in early apoptosis and inflammatory responses of T cells.