bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drak2 contributes to type 1 diabetes by altering regulatory T cell development. (BA6P.128)
Authors: Harris Tarsha , Creasy Blaine , Wehenkel Marie , Lukens John , McGargill Maureen Ann 
Published: December 2022

Abstract
Mice deficient in the kinase, Drak2, are resistant to disease in mouse models of type 1 diabetes (T1D) and multiple sclerosis (MS) due to diminished survival of autoreactive T cells. Yet, Drak2-/- mice effectively eliminate infectious pathogens and retain the ability to combat tumors similar to wildtype mice. Thus, Drak2 is an ideal protein to target to treat autoimmune disorders without compromising immunity to infections or tumors. However, the molecular mechanisms and functions of Drak2 are unclear. It is important to discern how Drak2 contributes to T1D to further understand the etiology of this disease, as well as to validate Drak2 as a therapeutic target. We show here that the resistance to T1D in NOD.Drak2-/- mice was due to the absence of Drak2 in T cells rather than the pancreatic b-cells. Furthermore, the resistance to disease required regulatory T cells (Tregs). Interestingly, the development of thymic Tregs was increased in Drak2-/- mice due to augmented IL-2 signaling, which led to an increase in the proportion of Foxp3-expressing cells. These studies provide important insight into the etiology of T1D by showing that Drak2 contributes to autoimmune disease by reducing the proportion of Tregs through reduction of IL-2 signaling in T cells.
A novel B7 family member, B7-H3 is preferentially expressed on the cell surface of synovial monocytes in rheumatoid arthritis (RA) (BA7P.153)
Authors: Yoon Bo Ruem , Chung Yeon-Ho , Kim Dong Hyun , Kim Bonah , Yoo Su-Jin , Chung Doo Hyun , Kang Seong Wook , Lee Won-Woo 
Published: December 2022

Abstract
B7-H3, a newly identified B7 family member, has functional duality as a T-cell costimulator and coinhibitor that fine-tunes T-cell mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Monocytes also play crucial roles in the pathophysiology of various autoimmune diseases. However, the immunological role of B7-H3 in RA has not been defined. We aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments provide evidence that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, the expression level of 4Ig B7-H3 on synovial monocytes inversely correlates with clinical parameters such as CRP levels, ESR, and DAS28. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles thereby affecting the pathogenesis of RA.
Eosinophils and IL-4 are essential drivers of inflammatory dilated cardiomyopathy (BA7P.160)
Authors: Diny Nicola , Barin Jobert , Talor Monica , Ong SuFey , Wu Lei , Rose Noel , Cihakova Daniela 
Published: December 2022

Abstract
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults, and patients often require a heart transplant. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. In wildtype (WT) BALB/cJ mice, experimental autoimmune myocarditis (EAM) progresses to DCMi with heart failure. Surprisingly, eosinophil-deficient ΔGATA1 mice developed myocarditis similar to WT mice, but were completely protected from DCMi. This indicates that eosinophils are crucial for progression of myocarditis to DCMi. Moreover, the level of eosinophilia correlated with DCMi severity. We used two models of eosinophilic myocarditis: mice expressing IL-5 under the CD3 promoter and IFNγ-IL-17A-double knockout mice. Both strains developed massive eosinophil infiltration in the heart and even more severe DCMi than WT mice. Recently, eosinophils were shown to affect several physiological processes through their production of IL-4. We therefore assessed IL-4 producing cell types in myocarditis using IL-4 reporter mice. Indeed, eosinophils were the major IL-4 expressing cell type in EAM. Additionally, IL-4-deficient mice developed myocarditis but were completely protected from DCMi, matching the phenotype of ΔGATA1 mice. In conclusion, eosinophils are required for progression of myocarditis to DCMi, drive severe DCMi when present in large numbers, and likely mediate this process through IL-4.
Macrophage depletion attenuates skin and kidney disease in lupus mice (BA7P.143)
Authors: Chalmers Samantha , Doerner Jessica , Wen Jing , Putterman Chaim 
Published: December 2022

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of anti-nuclear autoantibodies and inflammatory damage in target organs, commonly the kidney and skin. Macrophages are thought to be important in the pathogenesis of lupus end organ disease, although studies to date have not been sufficiently conclusive. In this study, we investigated the role of macrophages in a spontaneous mouse model of SLE, the MRL/lpr mouse. PLX3397 (Plexxikon), a small molecule inhibitor of CSF1R, c-Kit, and FMS-like tyrosine kinase 3a, was administered in chow form to MRL/lpr mice starting at 9 weeks of age. Compared to matched control treated mice, PLX3397-treated MRL/lpr mice exhibited significantly less proteinuria and improved renal function. Furthermore, anti-dsDNA antibodies were significantly reduced at several time points. IBA-1 staining confirmed macrophage depletion within the kidneys of the PLX3397 treated mice. Interestingly, PLX3397-treated mice were also protected from the development of spontaneous skin lesions common to MRL/lpr mice, with control treated mice displaying significantly worse cutaneous disease macroscopically at 16 and 22 weeks of age. The improvement in skin lesions in PLX3397-treated mice was confirmed histologically in skin obtained at sacrifice. Our results indicate an important role for macrophages in the pathogenesis of skin and kidney disease in MRL/lpr mice, and implicate macrophages as a potential therapeutic target in SLE.
Batf3-dependent dendritic cells are essential for development of diabetes in the NOD strain of mouse (BA7P.145)
Authors: Ferris Stephen , Carrero Javier , Mohan James , Calderon Boris , Murphy Kenneth , Unanue Emil 
Published: December 2022

Abstract
Little is known about the early events that instigate autoimmune diabetogenesis. To understand these initiating events, we examined the early antigen presenting cells (APCs) within the islets of Langerhans in the NOD mouse. Islets contain a set of resident macrophages that are long lived and positioned next to blood vessels. We found, concurrent with T cell entry, a small subset of CD103+ dendritic cells (DCs) belonging to the Batf3-dependent lineage of DCs entering the islets during the early stages of diabetes. These DCs increase in the islets over the course of the disease paralleling the increase of T cells. In order to further investigate the function of these DCs during diabetes, we backcrossed the Batf3 deficient mouse to the NOD strain. These Batf3 deficient NOD mice displayed no diabetes when followed for over a year. No lymphocytic infiltration into the islets, innate or adaptive, was observed during their lifetime. Further examination showed that antigens presented to CD8+ T cells were absent, in conjunction with a reduction in antigen presentation to CD4+ T cells, in the draining lymph nodes. Finally, NOD.Rag1-/- bone marrow reconstitution rescued the CD103+ DCs and T cell infiltration to the islets. The reconstitution illustrates that Batf3 deficient T cells were intrinsically capable of being diabetic and confirms the necessity of the CD103+ DC lineage in diabetogensis. In sum, the CD103+DC controls the initiation of autoimmune diabetes.
IL-33 drives alum-induced cytokine production and provides a robust secondary antibody response independently of alum (CCR4P.211)
Authors: Rose William , Okragly Angela , Patel Chetan , Benschop Robert 
Published: December 2022

Abstract
For over 80 years, human vaccines have used aluminium-based adjuvants (alum) despite incomplete understanding of how alum enhances the immune response. One proposed mechanism is that alum induces cellular necrosis and release of endogenous danger signals. These signals induce inflammation-associated cytokines that lead to humoral immunity. IL-33 is proposed to be released from necrotic cells and can elicit TH2-biased cytokines. Therefore, we investigated a role for IL-33 in the adjuvant activity of alum. We show that alum induces cellular necrosis and elevates IL-33 levels shortly after intraperitoneal administration. Alum or IL-33 injection induces similar significant increases in IL-5, IL-6, KC, MCP-1 and MIP-1β. We establish that many of the alum-induced cytokines are dependent on IL-33 using IL-33 knockout mice or an IL-33-neutralizing recombinant ST2 receptor. Interestingly, IL-33 itself can function as an adjuvant. While IL-33 only induces a marginal primary response, it facilitates a secondary response comparable to alum and correlates with delayed splenic germinal center formation. Alum-induced antibody responses in IL-33 knockout mice are similar to those in wild-type mice, demonstrating that IL-33 is not absolutely required for the alum-induced humoral response. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.
Neuroprotective effects of IL-22 during CNS inflammation (CCR4P.203)
Authors: Caspi Rachel , Mattapallil Mary , Rigden Rachael , Zarate-Blades Carlos , Silver Phyllis , Luger Dror , Chan Chi Chao 
Published: December 2022

Abstract
IL-22 has opposing effects in different tissues, from pro-inflammatory (skin, joints) to protective (liver, intestine) but little is known about its effects on neuronal tissue. We examined this using the induced models of experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE). During EAU, IL-22 was produced by CD4+ eye-infiltrating cells, most of which co-produced IL-17. IL-22-/- mice immunized for EAU or for EAE had exacerbated disease, as did wild type mice treated with anti-IL-22 systemically or intraocularly during the expression phase of EAU. Retinal glial Müller cells in uveitic eyes had upregulated IL-22rα1 expression. Furthermore, IL-22 upregulated IL-22rα1 on Müller cells in culture and enhanced their ability to suppress effector T cells. Finally, IL-22 injected concurrently with IL-1β into the eye inhibited IL-1-induced expression of multiple proinflammatory and proapoptotic genes in retinal tissue. Our results suggest that IL-22 can function locally within the CNS to ameliorate inflammatory damage and provide neuroprotection by affecting multiple molecular and cellular pathways.
Astrocytes express novel members of the IL-10 cytokine family in response to bacterial challenge (CCR4P.204)
Authors: Burmeister Amanda , Marriott Ian 
Published: December 2022

Abstract
We have previously demonstrated that resident cells of the central nervous system (CNS) express the anti-inflammatory cytokine IL-10 in a delayed manner following bacterial challenge. More recently, we have shown the ability of astrocytes to express the recently identified IL-10 family member IL-19 in a similar manner and demonstrated the ability of this cytokine to limit inflammatory mediator production by this cell type. In the present study we have further investigated the ability of astrocytes to express novel IL-10 family members. We show that primary murine astrocytes can express IL-24 in response to bacterial LPS as determined by mRNA expression and protein production. Interestingly, and in contrast to the delayed production of IL-10 and IL-19 by this cell type, IL-24 production by astrocytes is rapid and transient. Such kinetics is consistent with those previously reported in peripheral cell types, its reportedly pro-inflammatory effects, and its concomitant production with other inflammatory cytokines by astrocytes. Finally, we have determined that the production of these IL-10 family members can be modulated by soluble neuronal factors such as the neuropeptide substance P (SP). We show that SP significantly augments the production of IL-19 by astrocytes in response to LPS. These data suggest that microbe challenged astrocytes are a significant source of these novel immune mediators, and that their production is influenced by the CNS environment.
Identification of a human clonogenic monocyte/macrophage progenitor in fetal and adult hematopoiesis (HEM5P.232)
Authors: Seet Christopher , Miao Runfeng , Chin Chee Jia , He Chong Bin , Zhu Yuhua , Chan Rebecca , Crooks Gay 
Published: December 2022

Abstract
During steady-state hematopoiesis, the monocytic lineage, which includes macrophages, osteoclasts, monocytes, and monocyte-derived dendritic cells (moDCs), arises from a progenitor hierarchy in bone marrow. In humans, multipotent myeloid progenitors such as the granulocyte-monocyte progenitor (GMP) are proximal in this hierarchy, however the distal stages of monocytopoieis are unclear. We report here identification of a human clonogenic, monocytic-committed progenitor with a lineage negative, CD34+ CD38+ CD45RA+ CD123int CD115+ phenotype, which was developmentally conserved across bone marrow, cord blood, and fetal liver. Ex vivo analysis demonstrated a high cloning efficiency, and monocytic but not granulocytic CFU potential. Differentiation in the presence of M-CSF resulted in exclusive production of functional M2-like macrophages, whereas cultures modified with RANKL and GM-CSF/IL-4 resulted in highly enriched cultures of functional osteoclasts and moDCs, respectively. Transplantation into immunodeficient mice reconstituted bone marrow, splenic, pulmonary, and hepatic macrophage subsets, as well as circulating CD14+ monocytic cells. Of note, GMP depleted of CD115+ cells could regenerate the monocytic progenitor phenotype in vitro and in vivo, consistent with a step-wise program of lineage restriction during monocytopoiesis. Identification of the steady-state human monocytic progenitor offers opportunities for therapeutic expansion or modification of the monocytic lineage.
Rupture-type platelet biogenesis from bone marrow megakaryocytes is regulated by IL-1alpha in response to acute inflammatory or thrombocytopenic conditions (HEM5P.236)
Authors: Nishimura Satoshi 
Published: December 2022

Abstract
Acute inflammatory conditions were frequently associated with increased platelet counts. However, their regulation and cellular mechanisms of acute thrombopoiesis from bone marrow megakaryocytes (MKs) were unclear. Herein, we determined the novel rupture type thrombopoiesis regulated by inflammatory cytokines, IL-1alpha, in response to acute platelet demands. The hematopoietic cytokine thrombopoietin (TPO) is believed to maintain thrombopoiesis via formation of proplatelets. However, proplatelet formation (PPF) is not the only path to platelet biogenesis. We elucidate that the IL-1alpha is a rapidly acting platelet releasing factor that induces an alternative MK rupture-type thrombopoietic pathway, characterized by cytoplasmic fragmentation with acute particle releases. During recovery after platelet depletion or under inflammatory conditions, serum IL-1alpha levels are acutely increased (within 24 h), whereas TPO is elevated only at later times (day 3 or later). In vivo, IL-1alpha administration rapidly induces rupture-type thrombopoiesis in MKs, mediating an increase in platelet counts. IL-1alpha/IL-1R1 signaling activates pERK, pAKT and caspase-3/-9, which reduces intracellular K+ concentrations, plasma membrane potential and membrane stability. Thus the balance between IL-1alpha and TPO dynamically determines MK fate, with IL-1alpha controlling rupture-type platelet release under inflammatory or acutely thrombocytopenic conditions.
Mir-34a promotes the development of dendritic cells and inhibits the function of DC on activating the CD4+ T cells by inducing high expression of IL-17 (HEM5P.237)
Authors: Zhang Jinping 
Published: December 2022

Abstract
Many evidence suggests that miRNAs are involved in the hematopoietic lineage commitment. Dendritic cells (DCs) play pivotal role in immune system. But the role of miRNAs in DC development is unclear. In this study, we first established mir-34a chimeric and transgenic mice. FACS analysis showed that both cDCs and pDCs were increased in miR-34a chimeric and TG mice. Brdu and annexin V staining experiments showed that miR-34a-induced increasing of cDCs and pDCs were not due to the alteration of proliferation and apoptosis of DCs. GMP\CMP\ProDC and PreDC were comparable between WT and mir-34a TG mice, but mir-34a TG PreDC could produced more DC in vitro compared to WT preDC. Luciferase report assay and Western blot demonstrated that WNT1 is the target of miR-34a. Overexpressing WNT1 could preserve the development of cDC and pDC in miR-34a TG mice. all above evidence suggests that WNT1 is the functional target of miR-34a in DC. To our surprise, cDCs from miR-34a TG mice produced large amount of IL-17a and these cDC could inhibit CD4+ T cell activation, but did not affect antigen-uptaking and maturation of cDC. Addition of IL-17a neutralizing antibody made this inhibition disappeared. Further experiments showed that mir-34a regulated Wnt1-TCF1-RORγT-IL-17a pathway. Taken together, miR-34a promotes preDC development into cDCs and pDCs by targeting WNT1, and inhibits the function of cDCs on the activation of CD4+ T cells by up-regulating IL-17a production in cDCs.
Agelasine D suppresses RANKL-induced osteoclastogenesis via down-regulation of c-Fos, NFATc1 and NF-κB (HEM5P.240)
Authors: Kang Jong Soon , Kang Moo Rim , Jo Sun Ah , Han Sang-Bae , Kim Youngsoo 
Published: December 2022

Abstract
Osteoclasts are considered as innate immune cells of a bone and involved in the regulation of hematopoiesis as well. In the present study, we investigated the effect of agelasine D (AD) on osteoclastogenesis. Treatment of bone marrow macrophages (BMMs) with receptor activator of nuclear factor κB ligand (RANKL) resulted in a differentiation of BMMs into osteoclasts. However, RANKL-induced osteoclastogenesis was significantly suppressed by AD treatment. We also confirmed the increased mRNA and protein expression of osteoclastic markers during RANKL-induced osteoclast differentiation and this was down-regulated by AD treatment. Moreover, AD treatment significantly suppressed RANKL-induced mRNA expression of DC-STAMP and OC-STAMP and cell fusion of TRAP-positive mononuclear osteoclast precursors. In addition, AD suppressed RANKL-induced expression of transcription factors, c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important transcription factors involved in differentiation of BMMs into osteoclasts. Furthermore, RANKL-induced phosphorylation of extracellular signal-related kinase (ERK) and activation of NF-κB were also inhibited by AD treatment. Collectively, these results suggest that AD inhibits RANKL-induced osteoclastogenesis by down-regulation of multiple signaling pathways involving c-Fos, NFATc1, NF-κB and ERK. Our results also suggest that AD might be a potential therapeutic agent for prevention and treatment of osteoporosis.
Immunological Evidence on the Role of the Lymphocyte in Antibody Formation
Authors: Habel Karl , Endicott Kenneth M. , Bell J. Frederick , Spear Frances 
Published: December 2022

Summary
In summary, it seems from the evidence here presented that the relatively high antibody content of lymph may be accounted for, at least in part, by physical transfer from blood. The ratio of lymph antibody to serum antibody increases when the node has been stimulated by an irritant such as a heterologous antigen. There is very little significant evidence in these experiments to indicate that the lymphocytes or lymph node cells per se carry large amounts of antibody. Until more critical immunological technics and better controlled experiments are employed, the immunological evidence for lymphocyte production of antibodies must be considered incomplete.
Flagellar Antigens of Escherichia Coli
Authors: Stuart C. A. , Carpenter Philip L. 
Published: December 2022

Abstract
Kauffmann (1947) has reviewed the extensive work of himself and several colleagues on the serology of the Escherichia coli group. According to this report, cultures from pathologic and normal sources could be typed serologically by a system patterned after that used with the genus Salmonella. Three kinds of antigens were used: the usual H and O antigens, and K antigens, which were either thermolabile (L and B) or thermostable (A) envelope or capsular substances.
This work is important in that it helps to clarify the serological picture of a puzzling group of organisms. It will be especially valuable from the phylogenetic point of view when it has been extended to show the interrelationships of Escherichia coli with other genera and species of the Enterobacteriaceae.
Kauffmann experienced great difficulty in determining the H antigens of the coli-group because of inability to obtain actively motile cultures. Only by use of U-tubes with 0.1 per cent agar were suitable antigens secured.
Blood Groups and Subgroups of the Newborn
Authors: Witebsky Ernest , Engasser Lillian M. 
Published: December 2022

Summary
Adult blood cells of subgroups A1 and A2 as well as cord blood cells of group A are agglutinated by native immune anti-A sera of human origin almost to the same extent, provided saline solution is used as the diluent. If saline solution is replaced as a diluent by normal adult serum of group A or AB, immune anti-A sera of human origin allow the differentiation of adult A1 and adult A2 cells. Under these conditions, cord blood cells of group A frequently resemble adult cells of subgroup A2 more than adult cells of subgroup A1. The addition of a solution of purified A substance to human immune anti-A sera results in the neutralization of the antibody content against all subgroups of A when saline solution is used as the diluent. Neutralized anti-A sera frequently agglutinate A1 cells up to the original titer, without agglutinating A2 cells at all, if saline solution is replaced as a diluent by normal adult serum. Cord blood cells of 34 babies belonging to the blood group A revealed wide variations of agglutinability when tested with this type of reagent, exhibiting differences corresponding to the subgroups of adult A bloods, though on a lower level of agglutinability. About half of the babies' cells reacted like adult A2 cells or even weaker. The other half could be placed between adult A2 and adult A1 cells, rarely reaching the agglutinability of adult A1 cells. Hirszfeld's theory of “pleiades” is discussed in its relation to the experimental results described in this paper.