bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological Parameters in Blood (NK, CD4+ numbers, CD4/CD8 ratios, Ig levels, etc.) change with treatment (XRT, Chemotherapy, Immunotherapy etc.): Results in Breast Cancer, Colorectal Cancer and other sites (H&N, Lung, et. al.)
Authors: Williams R Michael , Yunis Edmond J. 
Published: January 2023

Abstract
Our view of cancer and the immune system is that an immune deficiency/failure of immune surveillance results in immune dysregulation including a "hole" in the specificity repertoire that results in active tolerance (Tregs) to cancer antigens and common pathogens (Cell. Immunol. 1978). The genetic basis for cancer survival was described in the P815 mouse model for MHC linked IR-gene control (Williams, Dorf and Benacerraf, Ca. Res. 1974) and the method for application to man was described at AAI2012. At AAI2019 we described the Immunogenetic Theory of Cancer and Aging and defined the disease Acquired Immune Deficiency of Cancer. We described the fact that homozygosity at P2 of the leader peptide of HLA class I and at the NG2A NK cell receptor is associated with older age, longer survival after primary therapy for breast cancer and non-progression if HIV infection occurs. We showed that breast cancer survival is significantly longer among patients with higher numbers of NK cells at initial presentation for breast cancer treatment. Here we present data showing survival in colorectal cancer, just like in breast, is significantly better when NK cell numbers are higher at initial evaluation Presented also are data demonstrating that peripheral blood NK cell numbers decrease during radiation of the breast only to recover to baseline after XRT ends. There is little to no change in numbers of CD4+ cells and other immunological parameters. In colorectal cancer quantitative IgA are related to survival. This is not true in breast cancer. Quantitative IgM and IgG levels are not associated with survival in either breast or colorectal caner. We conclude that simple blood parameters can provide substantial insight about mechanisms of treatment in cancer survival.
Differential Activity of Key Super-Enhancers Drives Disease-Defining Oncogenes in B Cell Cancers
Authors: Payton Jacqueline , Andrews Jared , Pyfrom Sarah , Schmidt Jennifer , Marcy Hannah , Koues Olivia , Cashen Amanda F. , Oltz Eugene M. 
Published: January 2023

Abstract
Normal B cell development depends upon exquisitely timed and calibrated epigenetic and transcriptional changes. Significant perturbations should result in cell death, but rarely, cells escape this quality control system. We compared 3 types of B cell cancer and normal lymphocytes to identify common and distinct epigenetic perturbations that promote oncogenesis. Purified CD19+ B cells from 49 patients (18 Follicular, 12 Diffuse Large B Cell, 19 Chronic Lymphocytic Lymphomas) and 20 donor tonsils were subjected to chromatin immunoprecipitation (ChIP-) and sequencing for H3K4me1, H3K9/14ac, and H3K27ac; FAIRE-seq for open chromatin; RNA-seq for gene expression; and SNP arrays for genome mapping. These integrative studies identified 7,772 differentially bound regulatory regions (DBRs) between lymphoma subtypes and tonsillar B cells. Expression of nearby genes corresponded with ChIP/FAIRE-seq changes at these elements, particularly near DBRs in 1,367 identified super-enhancers. Several of the latter regulate known lymphoma oncogenes, including BCL6, BCL2, and IRF4. We also identified a novel super-enhancer connected to the aberrant expression of FCMR and PIGR. We confirmed enhancer activity using luciferase reporter assays and altered protein expression using immunofluorescence. FCMR regulates the surface expression of BCR; B cells deficient in FCMR have increased tonic BCR signaling and increased differentiation. We suggest that its overexpression may contribute to the chronic active BCR signaling that drives many B cell cancers. In sum, our studies defined distinct enhancer profiles among B cell cancer subtypes and identified a novel regulatory mechanism that may contribute to aberrant BCR signaling in lymphoma.
Epigenetic drivers of Cutaneous T Cell Lymphoma revealed at single cell resolution
Authors: Payton Jacqueline , Andrews Jared , Quinn Chaz , Schmidt Jennifer , Musiek Amy , Mehta-Shah Neha 
Published: January 2023

Abstract
Cutaneous T-cell lymphomas (CTCL) are cancers of mature skin-homing T lymphocytes, but the molecular drivers remain poorly understood. We performed whole genome, exome, epigenome, bulk and single cell (sc) transcriptome analyses of serial peripheral blood, skin, and lymph node biopsies from 20 CTCL patients. Initial studies defined markers of therapy resistance and disease progression in pathways that mediate cell migration, cytokine signaling, and epigenetic regulation. Several were novel to CTCL, including BIRC5 (anti-apoptotic); RRM2 (cell cycle); CXCR4 and LAIR2 (migration). On average 7413 cells from 16 serial samples (&gt;100,000 cells total) passed quality thresholds for scRNA- + TCR-seq. We used Seurat, dittoSeq, and SingleR for quality control, dimensionality reduction (TSNE/UMAP), clustering, marker detection, cell type inference, and visualizations, and confirmed the therapy-resistant expression patterns we previously identified, including LAIR2. TCR clonotypes confirmed patient-specific malignant cell populations and defined clonal changes in serial samples. Pseudotime analysis of serial samples with Slingshot identified significant changes in expression related to changes in therapy, particularly in chemokine, TNF, and NFKB signaling. We identified mutations in STAT3&5 in 3/10 and in epigenetic modifiers (KMT2C/D and DNMT3A) in 6/10 patients. Loss of DNMT3A perturbs T cell differentiation and causes leukemia/lymphoma in mouse models. DNMT3A deficiency and additional epigenetic alterations may be previously unrecognized “drivers” of CTCL. These studies define mechanisms of therapy resistance, map clonal evolution, and reveal novel mechanisms of pathogenesis and progression in CTCL.
A Physiologically-Relevant Three-Dimensional In Vitro Model of Human Myeloma Bone Disease
Authors: Cottrell Jessica , Kolaja Kyel , Visconti Richard 
Published: January 2023

Abstract
Multiple myeloma (MM) is a hematologic cancer caused by mature B cell neoplasm that infiltrates the skeleton at several sites. The disease is characterized by uninhibited transformed plasma cell proliferation that disrupts skeletal homeostasis leading to increased bone resorption. Osteolytic lesions (OL) left in the bone, remain long after the treatment of the cancer and indicate disease progression to myeloma bone disease (MBD). Current combinatorial MM therapies inhibit malignant plasma cell proliferation, slow the progression towards MBD, and increase the mean five-year survival rate, but do little to improve osteoblastic function and restore skeletal homeostasis. Several novel MBD treatments have been developed to heal OLs but testing their efficacy against MBD is challenging. Therefore, we created a in vitro three-dimensional microphysiological human MM bone model to facilitate the identification of improved combinatorial treatments that suppress plasma cell proliferation while healing osteolytic lesions. Bone Marrow Stromal Cell derived osteoblasts and bone marrow macrophage derived osteoclasts were capable of bone formation and resorption in a homeostatic coculture as measured by gene expression profiling, alkaline phosphatase deposition, and alizarin red staining. The introduction of human plasmacytoma cell lines induced lesions in the mini-bones decreasing the cumulative hydroxyapatite (HA) content while increasing resorption markers and recapitulating physiological conditions of MBD. In the future, we hope to use this model of human MBD to evaluate the effectiveness of new combinatorial therapies that promise to restore skeletal homeostasis.
Differentiated immunoglobulins and neutrophil-related proteins in bronchoalveolar lavage fluid exosomes of acute respiratory distress syndrome
Authors: Ji Hong-Long , Samten Buka , Hadisurya Marco , Zhao Runzhen 
Published: January 2023

Abstract
Pulmonary immune response is a critical determining factor for acute respiratory distress syndrome (ARDS). Extracellular vesicles released from lung stem and immune cells may serve as inflammatory niches involved in immune response and lung injury repair. The role of exosomal immunoglobulins (Igs) and neutrophil-related proteins in bronchoalveolar lavage (BAL) in lung immunology is unknown. We aimed to examine the content and potential role of exosomal immune proteins of ARDS patients.
The abundance of exosomal proteins was quantified with a proteomic platform. Exosomal Igs and neutrophil-related proteins in BAL were analyzed with a combination of proteomic and bioinformatic software for functional enrichment, cell origin, and network analysis.
There were 4,458 proteins identified and approximately 400 exosomal proteins per stage were significantly altered in patients compared with healthy controls. The number of significantly reduced exosomal Igs was dependent on the severity: 19 for mild, 38 for moderate, and 51 for severe. Of them, 32 Igs were seen in at least two stages, while 19 Igs were occurred only in severe ARDS. Most of these downregulated Igs were either heavy or light chain variable regions, indicating their diverse cell origin. In contrast, no Igs were upregulated in ARDS patients. In addition, four neutrophil-related proteins (MPO, DEFA1, CXCL8, MME) were significantly upregulated in BAL exosomes of ARDS patients. Significant differences in functional enrichment, pathway, cell origin, and network were observed among three stages of ARDS patients.
Our proteomic data identified exosomal Igs and neutrophil-related proteins of ARDS that may serve as clinical biomarkers and the regulators of local immune response.
Gamma/delta (γδ) T-cell receptor (TCR)-expressing T cells are clonally expanded in aneurysmal lesions of patients with abdominal aortic aneurism (AAA)
Authors: Nwaneshiudu Ifeyinwa , White John V , Lu Song , Nwaneshiudu Adaobi , Solomides Charalambos , Gaughan John , Monos Dimitri , Oleszak Emilia L , Platsoucas Chris D 
Published: January 2023

Abstract
Several lines of evidence strongly suggest that AAA is a specific antigen-driven T-cell inflammatory disease with a strong genetic component. We tested the hypothesis that γ- and δ-chain TCR transcripts are clonally expanded in AAA lesions. Previously, we showed clonally expanded α-chain (PloS One 2019;14:e0218990) and β-chain (J Immunol. 2014; 192:4897) TCR transcripts in AAA lesions of patients with AAA. We employed two-sided VγI-, VγII-, Vδ1- and Vδ2-specific PCR followed by cloning and sequencing of amplified transcripts to examine whether VγI-, VγII-, Vδ1- and Vδ2-TCR transcripts, respectively, were clonally expanded in aneurysmal lesions of patients with AAA. Clonally expanded VγI-, VγII-, Vδ1- and Vδ2-TCR transcripts were identified in AAA aneurysmal lesions. We identified multiple identical copies of: (i) VγI-TCR transcripts in 16 of 18 patients (range of identical transcripts 30% to 80% in individual patients); (ii) VγII-TCR transcripts in 15 of 15 patients (range of identical transcripts 39% to 80%);.(iii) Vδ1-TCR transcripts in 12 of 12 patients (range of identical transcripts 29% to 94%); and (iv) Vδ2-TCR transcripts in 10 of 10 patients (range of identical transcripts 40% to 91%). These results were statistically significant. PBMC from normal donors (methodological controls) contained almost exclusively unique VγI-, VγII- and Vδ2-TCR transcripts. In contrast, Vδ1 transcripts from PBMC from certain normal donors contained clonally expanded T cells, in agreement with previous reports. In conclusion, clonally expanded γδ TCR-expressing T cells were found in aneurysmal lesions of patients with AAA. These T cells may play an important role in the pathogenesis of AAA. Supported in part by grant RO1 HL64340 from NIH.
Lung ILC2 responses to Alternaria alternata fungal allergen are blunted in “dirty” mice with physiologically transmitted murine microbes
Authors: Block Katharine E , Iijima Koji , Walsh Daniel A , Pierson Mark , Hamilton Sara E , Kita Hirohito , Jameson Stephen C 
Published: January 2023

Abstract
The objective of this study was to test the hypothesis that the increasing global incidence of allergy and atopy are due in part to improved hygiene and decreased microbial exposure. We have adopted a novel mouse model of normalized microbial exposure to test the impact of immune experience on subsequent responses to airway allergens. In this model, specific pathogen free (SPF) B6 mice are cohoused with mice from pet stores and become “dirty” – many commensals and pathogens are transmitted through cohousing and influence the immune cell populations systemically and in the lungs. We treated mice intranasally with a single dose of A. alternata fungal extract (Alt) and assessed production of type 2 cytokines. IL5 and IL13 levels in the lungs and bronchoalveolar lavage fluid were dramatically elevated by Alt in SPF mice but were not significantly increased by Alt in dirty mice. Type 2 innate lymphoid cells (ILC2) are the cells responsible for IL5 and IL13 after acute Alt treatment, and interestingly the number of lung ILC2 was unaltered by cohousing and their activation status appeared similar in both housing conditions. We treated mice with recombinant IL33, the alarmin released by lung epithelial cells in response to allergens, and the results suggest an impaired response to IL33 by dirty lung ILC2. In a repeated Alt exposure model, ILC2 cells expanded in SPF lungs and recruited eosinophils, neutrophils, and T cells. Most dirty mouse lungs contained these cell populations at steady state but were only modestly recruited with repeated Alt exposure. Lung function experiments are in progress. This study suggests that increased microbial exposure leads to more type-2 associated immune cells in the lungs, however responses to airway allergens are dampened.
Investigation of cytokine levels after dupilumb treatment in adults with acute atopic dermatitis
Authors: Chou Ya-Ling , Chou Chun-Jung , Guo Yong-Si , Li Ya-Chi , Lyu Sin-Yi , Chang Deh-Ming , Lu Chun-Chi 
Published: January 2023

Abstract

Objective
Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children, but also affects many adults. People with AD have high disease load and poor quality of life, without many treatment options. Dupilumab, a monoclonal antibody, approved for treatment inadequately controlled AD, of which the effect on serum cytokines remains unknown. The aim of this study was to compare serum levels of cytokines in adult patients with atopic dermatitis before and after dupilumab treatment and investigate the possible association between such cytokines and dupilumab.

Methods
We compared the profiles of cytokines in 5 adults with AD before and after one course of dupilumab treatment. Assessment of serum cytokine concentrations was performed via commercially-available Milliplex® assays.

Results
Milliplex analysis of cytokines revealed that interleukin 12p70 (IL-12p70), IL-13, IL-21, interferon r (IFN-r) and tumour necrosis factor a(TNF-a) levels were significantly decreased after dupilumab treatment, whereas IL-2, IL-4, IL-6 and IL-10 can not be detected.

Conclusions
These data indicate that serum interleukin 12p70 (IL-12p70), IL-13, IL-21, interferon r (IFN-r) and tumour necrosis factor a(TNF-a) levels were significantly decreased after dupilumab treatment. Further studies are needed to elucidate the role of cytokines and association with dupilumab in adults with AD.
HY209 ameliorates atopic dermatitis through NF-KB and P38 inhibition
Authors: Ghaderpour Aziz , Kim Youn-Hee , Lee Hai-Chon , Seong Seung-Yong 
Published: January 2023

Abstract
HY209 has been reported to be a ligand for the membrane G protein–coupled receptor, TGR5. HY209 could inhibit inflammatory responses in sepsis by increasing number of immunosuppressive myeloid-derived suppressor cells (MDSC), suggesting the potent role of HY209 in the treatment of atopic dermatitis (AD). Here HY209 was evaluated whether it controls inflammatory immune responses in AD. We employed mouse AD model using a topical treatment of dinitrochlorobenzene (DNCB) on the dorsal skin of Balb/c mice. HY209-treated mice showed significantly reduction in Th2 immune responses, shown as lower IgE serum, and inhibition of T cells mast cells, eosinophilia and neutrophil recruitment accompanied with reduced in epidermal and dermal thickness in skin of HY209 treated mice. Interestingly, regulatory T cells noticeably increased upon to HY209 treatment along with inhibition of type 2 cytokines production. Proteogenomic analyses of mouse skin demonstrated upregulated expression of molecules responsible for tissue regeneration and downregulated expression of proinflammatory molecules. Consistent with these findings, in vitro data indicated that HY209 decreased production of thymic stromal lymphopoietin (TSLP) and CCL17 (TARC) through inhibition of NF-KB and MAPK (P38) pathway. Taken together, HY209 ameliorates AD in mice by normalizing Th1/Th2 imbalance immune responses and inhibiting various pro-inflammatory responses via TGR5-cAMP-PKA axis, Suggesting HY209 could be a promising therapeutic candidate for AD.
COX inhibition enhances allergen-induced IL-33 release and ILC2 responses in mouse lungs
Authors: Zhou Weisong , Zhang Jian , Toki Shinji , Goleniewska Kasia , Norlander Allison E. , Newcomb Dawn C. , Boyd Kelli L. , Kita Hirohito , Peebles R. Stokes 
Published: January 2023

Abstract
The cyclooxygenase (COX) metabolic pathway has regulatory functions in immune responses and inflammation. However, the effect of the COX pathway on innate airway inflammation induced by protease-containing allergens such as Alternaria alternata is not fully defined. Here we show that COX inhibition augmented innate lung type 2 responses after repeated airway exposures to Alternaria extract in mice. We treated wild type BALB/c and IL-33 KO mice with either the COX inhibitor indomethacin or vehicle in drinking water and challenged mice intranasally with Alternaria extract for 4 consecutive days to induce innate lung inflammation. We found that indomethacin significantly increased the numbers of group 2 innate lymphoid cells (ILC2) and IL-5+IL-13+ ILC2 in the lung. Indomethacin also increased type 2 cytokine (IL-5 and IL-13) responses, the percentages of eosinophils, and mucus production in the lung. IL-33 is required for Alt-induced lung ILC2 responses, and indomethacin did not change IL-5 and IL-13 expression in IL-33 KO mice. Consistently, indomethacin increased the release of IL-33 in bronchoalveolar lavage fluid after Alternaria challenge, suggesting that more IL-33 was available for ILC2 activation. Indomethacin also increased reactive oxygen species (ROS) production in the lung, providing a possible mechanism for the increased IL-33 release. Although contrasting effects of PGD2 and PGE2/PGI2 on ILC2 responses have been previously reported, the overall effect of COX pathway on ILC2 function is inhibitory in Alternaria extract-induced airway innate type 2 responses.
Single-cell TCR analysis of mouse lung Vγ4 γδ T cells reveals a link between TCR clonotypes, SLAM family receptor expression, and effector function
Authors: Mistri Somen K , Hampel Kenneth J , Sidoropoulos Nikoletta , Dienz Oliver , Boyson Jonathan E 
Published: January 2023

Abstract
γδ T cells are unusual T cells that are highly enriched in mucosal tissues where they constitute a prominent source of pro-inflammatory cytokines like IL-17 and IFN-γ. The TCR usage of tissue-specific γδ T cells is often associated with specific effector functions. We have recently found that IL-17- and IFN-γ-producing Vγ4 γδ T cells in the mouse lung are marked by the expression of SLAMF1 and SLAMF6 receptors, respectively. The objective of this study was to investigate a possible link between SLAM-associated effector function and γδ TCR usage. We first identified the major Vγ4 γδ TCR clonotypes in the mouse lung (n=13 mice). Vγ4 γδ T cells were single cell-sorted and paired TCR clonotypes were identified using next-gen sequencing of TCR amplicon libraries. The data revealed that TRDV5, TRDV2, and TRDV7 chains accounted for 51.18%, 29.61%, and 14.96% of the productive TCRδ chain rearrangements, respectively. While TRDV5 and TRDV2 CDR3 sequences were limited in diversity, TRDV7 CDR3 sequences were highly diverse. A significant fraction (30.46%) of the TRDV5 sequences were characterized by an invariant germline-encoded Vδ5Dδ2Jδ1 sequence. A comparison between sorted SLAMF1+ and SLAMF6+lung Vγ4 γδ T cells revealed that TRDV5 and TRDV2 chains were predominantly associated with SLAMF1+IL-17+ γδ T cells while the TRDV7 chain was predominantly associated with SLAMF6+IFN-γ+ γδ T cells. Moreover, the invariant germline-encoded TRDV5 sequence was primarily associated with SLAMF1+IL-17+ cells. These data indicate that the lung Vγ4 γδ TCR repertoire is limited in diversity and that specific lung Vγ4 γδ TCR clonotypes segregate with the expression of discrete SLAM family receptors.
STAT4 promotes critical neutrophil functions and is required for antimicrobial immunity in mice
Authors: Keeter W. Coles , Moriarty Alina , Mehrpouya-Baharami Pegah , Melo Paulo , Nadler Jerry , Serezani Carlos H , Kaplan Mark H , Galkina Elena 
Published: January 2023

Abstract
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly associated with Th1 development, yet its role in neutrophil biology is unknown. We are the first to demonstrate that in vitro murine neutrophils stimulated with IL-12 directly activate STAT4 in a JAK2-dependent manner resulting in distinct transcriptional changes in antimicrobial response genes. STAT4-deficiency also impairs several neutrophil functions in vitro. Interestingly, IL-12 directly induces STAT4-dependent ROS formation at 14 hours, which is not due to cell death. Neutrophil extracellular trap (NET) formation in response to either LPS or heat-killed Pseudomonas aeruginosa results in decreased nuclear translocation of myeloperoxidase, decreased neutrophil elastase release, and decreased DNA release in STAT4-deficient neutrophils. In vivo neutrophil migration to the peritoneal cavity is blunted in Stat4−/− mice following either thioglycollate, CXCL1, or GM-CSF injections. Finally, we have generated Stat4floxLysMCre and Stat4floxS100A8Cre mice which are deficient in STAT4 in either myeloid cells or specifically neutrophils, respectively. Following in vivo infection with methicillin-resistant S. aureus, bacterial burden is increased in the blood and peritoneal cavity of Stat4floxLysMCre and Stat4floxS100A8Cre mice. Gene expression analysis of peritoneal exudate cells from infected mice show decreased expression of Ly6G/CD11b, further highlighting defective homing of Stat4−/− neutrophils in vivo. All together these data reveal an undiscovered role of STAT4 in neutrophil functions and a subsequent role of STAT4 in innate immunity and antimicrobial defense mechanisms.