bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic markers of inflammation and neuronal injury in patients with epilepsy
Authors: Kunda Shailaja , LaFrance-Corey Reghann G. , Khadjevand Fatemah , Worrell Gregory A , Howe Charles L 
Published: January 2023

Abstract
Epilepsy is a chronic neurologic disorder characterized by recurrent seizures and variable cognitive and neurodevelopmental issues. In many individuals the underlying pathogenesis is unknown, but burgeoning evidence indicates a link between neuroinflammation and seizure development. Therapeutically targeting inflammation in epilepsy is of particular interest for patients that do not respond to the current standard of care. Likewise, identifying changes in peripheral immune status may provide a unique biomarker for seizure prediction. Using high-resolution repeated measures temporal profiling of serum cytokine levels and flow cytometric analysis of the activation status of circulating neutrophils and monocytes, we established an immune profile for patients undergoing multi-day continuous video-EEG monitoring. We identified an apparent temporal correlation between clinical seizure events and increased levels of serum CCL2, as well as evidence of acute peri-ictal changes in the status of inflammatory monocytes (CD14++CD16+ and CD14+CD16++) in 4 patients. We also measured acute peri-ictal changes in a marker of neuronal injury in these patients. Ongoing studies will correlate patient immune status with neuronal injury markers and attempt to incorporate analysis of sub-clinical EEG changes with the immunophenotype.
Multispecific recognition of developmental neuronal antigens and neurite outgrowth inhibition by an anti-myelin proteolipid protein (PLP) peptide monoclonal antibody (mAb)
Authors: Sobel Raymond A , Hinojoza Julian R , Eaton Mary Jane 
Published: January 2023

Abstract
CNS injury results in the generation of antibodies to self-antigens, including epitopes of PLP, the most abundant CNS myelin protein. We previously found that despite similar recognition of CNS vertebrate myelin, anti-PLP50–69 mAbs F4.4C2 (IgG1κ) and F3.6E9 (IgG2aκ) differ in their recognition of neurons (Greenfield et al, 2006). To identify the neuronal mAb targets and determine the potential pathobiological significance of this finding, we used rat hippocampal precursor cells (RHPC) and PC12 cells, a nerve growth factor (NGF)-responsive neuronal cell line that does not express PLP. Both mAbs bound RHPC and PC12 cells and inhibited their in vitro neurite outgrowth; they differed in recognition of extracted PC12 cell proteins on Western blot and in extent of their recognition of human CNS neurons of different ages and in adult neural stem cell niches (NSCN). Thus, epitope sequence alone did not predict mAb neuronal reactivity. We immunoprecipitated proteins from NGF-treated and -untreated PC12 cell extracts using F4.4C2- and F3.9E9-coated magnetic beads; SDS-PAGE-separated bands of eluates from the beads were cut from gels and analyzed by GeLC-MS/MS. mAb F4.4C2 consistently captured the proteolipid gene family M6 neuronal protein. M6b and PLP50–69 have 45% sequence identity. M6b is required for neurite outgrowth and axon guidance and is expressed in developing human CNS neurons and NSCN. F4.4C2 also immunoprecipitated EphA family proteins and other cell surface growth and differentiation molecules expressed in human NSCN. Thus, certain anti-PLP autoantibodies generated after myelin injury may inhibit neuronal repair in the developing and adult human CNS by multispecific binding to neuronal growth and differentiation molecules.
Immune response in Parkinson’s disease driven by HLA display of α-synuclein peptides
Authors: Arlehamn Cecilia S Lindestam , Alcalay Roy N. , Garretti Francesca , Cote Lucien , Kanter Ellen , Agin-Liebes Julian , Liong Christopher , McMurtrey Curtis , Hildebrand William H , Mao Xiabo , Dawson Valina , Dawson Ted M , Oseroff Carla , Pham John , Sidney John , Dillon Myles , Carpenter Chelsea , Weiskopf Daniela , Phillips Elizabeth J , Mallal Simon Alexander , Peters Bjoern , Frazier April , Sulzer David , Sette Alessandro 
Published: January 2023

Abstract
Abnormal processing of self-proteins can produce epitopes presented by major histocompatibility (MHC) proteins to be recognized by specific T cells that escaped central tolerance during thymic selection. Such actions by the acquired immune system are widely held to produce autoimmune disorders such as Type-1 diabetes. While not considered to possess autoimmune features, neurodegenerative diseases are characterized by the altered processing of specific proteins. One of the major pathological features of Parkinson’s disease are the presence of intraneuronal aggregrates known as Lewy bodies and neurites composed of α-synuclein. Genetic studies associate Parkinson’s disease with DRB5*01 and DRB1*15:01 MHC alleles. To address the hypothesis that Parkinson’s disease is associated with T cell recognition of epitopes derived from α-synuclein and presented by specific MHC alleles, we recruited 67 Parkinson’s disease patients and 36 age-matched non-Parkinson’s healthy controls. We found that a defined set of peptides derived from α-synuclein, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in Parkinson’s disease patients. We identified two antigenic regions in α-synuclein, the first near the N terminus (aa31-46), which was bound by DRB1*15:01 and DRB5*01:01, and the second near the C terminus, which required phosphorylation of an amino acid residue (S129). These α-synuclein epitopes were shown to arise from natural processing of both extracellular native α-synuclein and the fibrilized form associated with Parkinson’s disease pathogenesis. These responses may explain the association of Parkinson’s disease with alleles of the acquired immune system.
The transcription factor basic helix loop helix, member e40 is required for establishment of proper peritoneal macrophage identity
Authors: Jarjour Nicholas N , Lin Chih-Chung , Bradstreet Tara R , Schwarzkopf Elizabeth A , Huang Stanley C-C , Kim Ki-Wook , Taneja Reshma , Randolph Gwendalyn J , Edelson Brian T 
Published: January 2023

Abstract
Tissue-resident macrophages occupy key roles in immunity and physiology, both as sensors of and first responders to homeostatic perturbations. The majority of resident macrophages derive from embryonic progenitors and self-maintain locally as unique tissue-specific populations. The transcriptional basis for tissue-resident macrophage identity is poorly understood. We have observed that the transcription factor basic helix loop helix, member e40 (Bhlhe40) is highly expressed in a subset of hematopoietic cell types, including peritoneal macrophages. Based on these data, we hypothesized that Bhlhe40 is a key part of the peritoneal macrophage transcriptional network and adapts nascent macrophages to the functional demands of the peritoneal niche. We have found that peritoneal macrophages are selectively reduced in Bhlhe40−/− mice, in contrast to other resident macrophages. Furthermore, in the absence of Bhlhe40 the remaining large peritoneal macrophages (LPMs) are replaced by monocyte-derived cells to a greater extent than in wildtype mice. Bhlhe40-deficient peritoneal macrophages exhibit altered polarization and self-renewal. Mixed bone marrow chimeras and other approaches demonstrated a specific, intrinsic defect in mature Bhlhe40−/− LPMs. Using models of peritoneal immunity, we observed impaired responses of Bhlhe40-deficient peritoneal macrophages. Our preliminary findings demonstrate a role for Bhlhe40 in peritoneal macrophage biology and lead us to propose that Bhlhe40 transcriptionally controls a tissue-specific program in macrophages tailored to the peritoneal environment.
Preferential perinatal thymic generation of skin-homing CCR10+ NK1.1+ innate lymphocytes for establishment of skin homeostasis
Authors: Xu Ming , Yang Jie 
Published: January 2023

Abstract
Innate and innate-like lymphocytes have particularly important contribution to the establishment of local immune system in skin of newborn and infant stages, when adaptive immune cells are not fully established. However, the development pathway of the skin innate and innate-like lymphocytes is not well understood. Herein we report discovery of a novel process that generates skin-homing group 1 innate lymphoid cells (ILC1s) in fetal/neonatal thymi, which is important for regulation of commensal bacterial colonization in the skin. We found that fetal/neonatal but not adult thymus preferentially supports generation of a unique population of skin-homing CCR10+NK1.1+ ILC1s. The thymic stroma-associated Notch/ligand axis promotes the generation of CCR10+ NK1.1+ ILC1s, which is suppressed in adult thymi by developing abT cells. Infant mice that were depleted of NK1.1+ ILCs by in utero anti-NK1.1 antibody treatment had a significantly increased ratio of commensal bacteria in skin-draining lymph nodes relative to skin compared to untreated control mice. In addition, the skin of the NK1.1 antibody-treated mice had a profound alteration in composition of commensal bacteria. Our study suggests that the preferential generation of skin-homing ILCs in perinatal thymi is a developmentally programmed process to target immune cells to the skin to regulate the early colonization of commensal bacteria.
Secreted IL12p40 finds IL12p35 in the extracellular milieu to generate functional IL-12 cytokine
Authors: Gerber Allison N , Abdi Kaveh , Singh Nevil J 
Published: January 2023

Abstract
IL-12 is a cytokine produced by dendritic cells (DCs) that critically regulates the differentiation of naïve T cells into IFNγ producing effectors. The canonical view is that IL-12 is secreted only after the 40 kDa (p40) and 35 kDa (p35) subunits form a heterodimer inside a DC. However, the p40 subunit is also released from DCs as a monomer whose function is unclear. We previously hypothesized that secreted p40 could bind p35 in the extracellular milieu to generate functional IL-12 cytokine. Indeed, in vitro experiments using lysates of CHO cells that overexpressed p40 and p35 showed that such a heterodimer could stably form outside the cell. In order to evaluate if such an extracellular assembly happens in vivo, mixed bone marrow chimeras were set up using p35−/− and p40−/− cells. In this model, since no cell can make both p40 and p35, any IL-12 activity would have to be generated by extracellular assembly of these subunits. Infection of such chimeric mice with Leishmania major showed IFNg production in the draining lymph nodes, suggesting that functional IL-12 may be able to assemble outside of DCs in vivo.
Interleukin-4 (IL-4) maintains lymphocyte-stromal cell axis in peripheral lymph nodes
Authors: Selva Diana Cortes , Ready Andrew L , Fairfax Keke C 
Published: January 2023

Abstract
Interleukin-4 (IL-4) is a critical cytokine in the differentiation of Th2 cells, B-cells, and antibody isotype switching. Despite the myriad of functions known to be mediated by IL-4, its role in the spatial organization of lymph node compartments is not well understood. Our studies demonstrate that IL-4 is vital for proper positioning of B cell, T cell and CD11c+ dendritic cells in lymph nodes in steady state, and that the lack of IL-4 and IL-4 receptor (IL-4Rα) correlates with a diminished immune response to Schistosoma mansoni antigens. The absence of IL4 and IL-4R resulted in decreased germinal center (GC) formation, T follicular helper (Tfh) and plasma cells expansion in peripheral lymph nodes in response to this Th2 polarizing antigen, but not to Th1 polarizing Toxoplasma gondii antigens. Stromal cell populations are known to support lymphocyte organization and function within secondary lymphoid tissues. Importantly, we observed a marked disorganization of follicular dendritic cells (FDCs), CD31+ lymphatic, and blood endothelial cells in mice lacking IL4R, suggesting that the lymphocyte-stromal cell axis is maintained by IL-4. Our study also shows that absence of IL-4Rα correlates with significant down-regulation of Lymphotoxin-beta (LTβ) and Lymphotoxin alpha (LTα) gene expression, which is vital for the development of specific stromal populations. Altogether, our results reveal a previously unexplored role of IL-4 in the maintenance of peripheral lymphoid organ microenvironments during an immune challenge as well as in homeostasis.
Hypoxia-inducible factor-1 mediated CX3CR1 expression correlates with progression and metastasis in ovarian cancer
Authors: Singh Santosh Kumar , Lillard James W. , Singh Rajesh 
Published: January 2023

Abstract
Chemokines mediate the important roles in organ-specific homing of various cancer cells, including ovarian cancer (OvCa) to distant organs that may favor or inhibit cancer progression and metastasis. Hypoxia, a common phenomenon in solid tumors, is associated with a malignant cancer phenotype. Here, we provided the evidence that hypoxia up-regulate CX3CR1 expression and lead to an increased chemotactic response to CX3CL1 in OvCa cells. Hypoxia- induced genes are widely involved in metastasis-associated functions; and also undergo epithelial-to-mesenchymal transition (EMT). In the present study, we found that CX3CR1 expression was significantly increased in OvCa cells (OVCAR-3, SW626 and TOV-112D) following exposure to hypoxia. Flow cytometry, RT-PCR, western blot, Immunohistochemistry and immunofluorescence techniques were used to quantify the expression of chemokine CX3CR1and CX3CL1 in OvCa. Moreover, a significant higher expression of CX3CR1 under hypoxia compared to the normoxic condition in OvCa. Furthermore, we demonstrated that OvCa cells display a marked increase in hypoxia-induced CX3CR1-dependent PI3K/Akt/mTOR and MAPK signaling molecules as well as EMT markers and matrix metalloproteinase (MMPs) which are involved in cancer progression and metastasis of OvCa cells in hypoxic condition. These data demonstrate hypoxia pathway regulate the expression of CX3CR1 that may contribute to progression and metastasis of OvCa.
Pro-inflammatory condition-induced tumor dormancy in pre-metastatic reservoir thymus
Authors: Sizova Olga , Kuriatnikov Denis , Su Dong-Ming 
Published: January 2023

Abstract
Cancer patients suffering from metastatic relapse is the major cause of death. This is attributed to some undetectable minimal number of tumor cells, which are able to resist radio-chemotherapy, being in dormant state at some organs of the body. The largest T-lymphoid organ, thymus, has just recently been suggested as this kind of organ to be a pre-metastatic reservoir for tumor cell dormancy, and eventually relapse. We hypothesize that infection-, drug- and aging-resulted thymic atrophy induces inflammatory conditions to create this tumor premetastatic reservoir. Our observations in tumor-inoculated mouse model show that various cancer cells could be retained in the thymus. This retention ratio (in the thymus vs lymph nodes) was particularly high in the naturally-aging- or drug-caused atrophied thymus. We found that genotoxic chemotherapy (Doxorubicin) can lead to changes in thymic microenvironment, characterized by activation of p53 in thymic epithelial cells (TECs), induction of TEC senescence, and an increase of pro-inflammatory factors. These thymic conditions were able to confer tumor cell capacity to anti-apoptosis. We also found that dormant tumor cells in the thymus have a capacity to induce tumor recurrence in the distant organs. Our pilot experiments suggest that activation of p53 in TECs induced by DNA-damage upon Doxorubicin treatment promotes senescence, in which SASP (senescence-associated secretory phenotype) is activated, thereby leading to tumor cell dormancy/chemo-resistance. This work is clinically relevant because our findings may help to determine a new target to prevent tumor relapse after chemotherapy.
IRF8 deficiency in colonic epithelial cells promotes inflammation-mediated colon tumorigenesis and myeloid-derived suppressor cell differentiation.
Authors: Ibrahim Mohammed L. , Liu Kebin 
Published: January 2023

Abstract
IRF8 is a member of the nine IRF family proteins that was originally identified as a key transcription factor for myeloid cell lineage differentiation. IRF8 deficiency leads to deregulation of myelopoiesis and accumulation of CD11b+Gr1+ immature myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs). It has since been documented that IRF8 also plays important roles in other immune cells, including B, Natural Killer, Dendritic and T cells. IRF8 expression and function has recently been extended to non-hematopoietic cells, including epithelial cancer cells and heart cells. IRF8 is often silenced by its promoter DNA methylation in cancer cells. However, low level of IRF8 is expressed in cancer cells and IRF8 is IFNg inducible in cancer cells. IRF8 acts as an apoptosis inducer. To determine the function of IRF8 in spontaneous tumor development, we generate IRF8 deficient mice with IRF8 KO only in colonic epithelial cells (termed IRF8 CKO mice). Unlike conventional IRF8-deficient mice, IRF8 CKO mice phenotypically resemble WT mice. However, IRF8 CKO exhibited greater susceptibility to AOM-DSS-induced colon cancer formation as compared to WT mice. Although no differences were observed in MDSC profiles between WT and IRF8 CKO mice, tumor-bearing IRF8 CKO mice have significantly higher level of CD11b+Gr1+MDSCs than tumor-bearing WT mice. Our data determine that IRF8 functions in colonic epithelial cells as a spontaneous colon cancer suppressor and also functions in colon carcinoma cells to mediate MDSC differentiation in tumor-bearing host in vivo.
The Nrf2/Interleukin-17D axis as a novel target for cancer immune therapy
Authors: Seelige Ruth , Saddawi-Konefka Robert , Gross Emilie T.E. , Levy Eric , Searles Stephen C. , Washington Allen , Santosa Endi K. , Liu Beichen , O’Sullivan Timothy E. , Harismendy Olivier , Bui Jack D 
Published: January 2023

Abstract
The oxidative stress-sensing transcription factor Nrf2 has been studied by cancer researchers as a double-edged sword that can either promote or inhibit cancer. Previous findings have shown that Nrf2 can act as a tumor suppressor by detoxifying carcinogens. Paradoxically, when cancer cells express Nrf2, they are protected from oxidative stress and certain chemotherapies, thus explaining why some cancer cells constitutively activate Nrf2 as a tumor promoter. We recently found that the cytokine Interleukin (IL)-17D mediates the recruitment of natural killer (NK) cells to tumor sites, thereby leading to tumor rejection. Here, we show that Nrf2 induced IL-17D in primary tumors and tumor cell lines. Moreover, the known Nrf2-activator tBHQ induced Nrf2 and IL-17D simultaneously, without creating harmful oxidative stress. Applying a tBHQ-containing skin cream to established tumors led to NK cell-mediated tumor regression, and this depended on IL-17D and Nrf2. We propose that the use of tBHQ or other Nrf2 activators can intiate a tumor surveillance pathway involving IL-17D and NK cells, thus mediating cancer regression and bearing potential for cancer immune therapy.
Co-localization of vimentin with a tumor associated antigen identified by the monoclonal antibody H5 in 9L gliosarcoma cells and normal glial cells from Fischer 344 rats
Authors: Davis Nancy A , Redd Joan M 
Published: January 2023

Abstract
Previously, we used a monoclonal antibody, designated H5, to isolate a tumor-associated antigen (TAA) expressed by 9L, a gliosarcoma line isolated from Fischer 344 (F344) rats. This TAA was tentatively identified as vimentin via mass spectrometry. In this project, we identified the location of this TAA and vimentin on 9L gliosarcoma and normal rat glial cells using confocal fluorescent microscopy. Vimentin and the TAA always co-localized which suggests that the TAA bound by H5 is a moiety on the vimentin protein. In addition, 9L expressed an increased level of vimentin compared to normal rat glial cells. Glial cells were examined from neonatal, 6 week, and adult rats. The glial cells expressed less vimentin than 9L gliosarcoma tumor cells at all ages. These results suggest that vimentin is upregulated as part of the tumor phenotype giving a possible mechanism for detecting transformed cells of this tumor type.
Targeting IL-17 for cancer-associated inflammation and immunity
Authors: Wang Kepeng 
Published: January 2023

Abstract
Interleukin-17A (IL-17A) is a proinflammatory cytokine whose expression has been linked to rapid malignant progression of colorectal cancer (CRC) and resistance to therapy. Ablation of IL-17A or its type A receptor (IL-17RA) in mouse models of colonic tumorigenesis confirmed their tumor-promoting function. IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes who just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. Consistent with the notion that IL-17 promotes tumor-associated inflammation and inhibits anti-tumor immunity, ablation of IL-17RA resulted in reduced infiltration of CD11b+ cells and elevated numbers and activity of cytotoxic T lymphocytes in colorectal tumors. Using anti-IL-17 as an adjuvant therapy may improve the efficacy and safety of current cancer immunotherapeutic schemes.
Dual role of SIRPα in macrophage activation: inhibiting M1 while promoting M2 polarization via selectively activating SHP-1 and SHP-2 signal
Authors: Shi Lei , Bian Zhen , Liu Yuan 
Published: January 2023

Abstract
Macrophages polarization into proinflammatory M1 or alternative M2 states, which plays a central role in inflammation and host defense, is tightly controlled by multiple regulatory molecules. Here we examined the role of signal regulatory protein α (SIRPα), which negatively regulates leukocyte responses, in regulating macrophage polarization and function. Compared to WT macrophages, macrophage obtained from SIRPα deficient (SIRPα−/−) mice demonstrated an enhanced response to M1 induction but were refractory to M2 induction, as indicated by the increased expression of M1-related markers CD86, MHC-II, iNOS, IL-1β, IL-12 and TNF-α under M1-skewed LPS/IFNγ treatment but the defective expression of anti-inflammatory mediators CD206, Arg1, IL-10 and TGFβ during IL-4 induced M2 activation. Furthermore, ligating SIRPα by CD47 extracellular domain (mCD47-AP) suppressed M1 polarization but enhanced M2 polarization in WT macrophages, whereas had no effect on SIRPα−/− macrophage polarization. Interestingly, under M1 and M2 activation, macrophage SIRPα was found to be tyrosine-phosphorylated and selectively associated with SHP-1 and SHP-2, respectively. Mechanistic studies indicated that SIRPα deficiency promoted M1 but attenuated M2 polarization of macrophages by enhancing the PI3k/Akt2 signaling pathway. Overall, our findings demonstrated for the first time that SIRPα plays an important role in modulating macrophage polarization, inhibiting M1 while promoting M2 phenotypic polarization through selectively activating SHP-1 and SHP-2 signaling.