scholarly journals Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 504-513
Author(s):  
Kelly Walkovich ◽  
James A. Connelly
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Immune Dysregulation ◽  
Inborn Errors ◽  
T Cell Therapy ◽  
Adaptive Immune

Abstract As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI—decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival—offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

scholarly journals Proteomic and metabolomic signatures associated with the immune response in healthy individuals immunized with an inactivated SARS-CoV-2 vaccine

2021 ◽  
Author(s):  
Yi Wang ◽  
Xiaoxia Wang ◽  
Laurence Don Wai Luu ◽  
Shaojin Chen ◽  
Jin Fu ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Systems Biology ◽  
Complement Activation ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Adaptive Immune Response ◽  
Humoral Response ◽  
Tca Cycle ◽  
Adaptive Immune

CoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results suggest that protective immunity against SARS-CoV-2 can be achieved via multiple mechanisms and highlights the utility of a systems biology approach in defining molecular correlates of protection to vaccination.

scholarly journals Mi-2β-targeted inhibition induces immunotherapy response in melanoma

2020 ◽  
Author(s):  
Bo Zhu ◽  
Zhengyu Wang ◽  
Licheng Yao ◽  
Xingyu Lin ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Underlying Mechanism ◽  
Adaptive Immune ◽  
Melanoma Patients ◽  
Ifn Γ ◽  
Targeted Inhibition

Abstract Recent development of some new immune checkpoint inhibitors has been particularly successfully in melanoma, but the majority of melanoma patients exhibit resistance. Understanding and targeting the potential underlying mechanism/targets, especially the tumor-intrinsic modulators to convert resistant melanomas to immunotherapy sensitivity will potentially provide a significant improvement in patient outcome. Here, Mi-2β, a chromatin remodeling enzyme was identified as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, targeting Mi-2β induced the adaptive immune response by transcriptionally enhancing expression of a set of IFN-γ-responsive genes including CXCL9, CXCL10 and IRF1. Finally, we developed a Mi-2β-targeted inhibitor Z36-MP5, which specifically and effectively induced a response to immune checkpoint blockades in otherwise resistant melanomas. Our work provides a new insight into the epigenetic regulation in adaptive immune response, and highlights a viable strategy to improve immunotherapies in melanoma.

scholarly journals Comprehensive Analysis of the Immune Microenvironment Reveals that CD52 is a Marker for Breast Cancer Treatment with Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Qiang Wang ◽  
Xuxu Liu ◽  
Pengfei Wang ◽  
Dankun Luo ◽  
Wenqi Gao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Adaptive Immune

Abstract Background:Breast cancer (BC) is one of the most common tumors in women. Recent years, immune checkpoint inhibitors (ICIs) have brought good news to BC patients. Although significant achievements have been made through treatment with ICIs, some people who experience serious immune-related adverse events (IrAEs) are still insensitive to this approach. The response to ICI treatment depends on the type of tumor microenvironment (TME). Methods:WGCNA (weighted gene co-expression network analysis), ESTIMATE algorithm, LASSO regression analysis, survival analysis, functional enrichment analysis are conducted to analyze the BC data in the TCGA database. Immunohistochemistry was used to verify the expression of CD52 in BC.Results:WGCNA and ESTIMATE algorithm found that the CD52 is closely related to the immune microenvironment. CD52 highly expressed in various breast cancer subtypes, and patients with high expression of CD52 have longer survival time. Compared with the low-CD52 group, the high-CD52 group had more immune cell infiltration. TIMER database verification results showed that CD8+ T cells, activated memory CD4 T cells, memory B cells, γδ T cells, and Tregs were positively correlated with CD52 expression, while M2 macrophages were negatively correlated. CD52 can change the trend of TIC (CD8+ T) and tumor-associated macrophage (TAM) infiltration with respect to the survival time of breast cancer patients. Based on the expression of CD52, we explored the relationship between CD52 and the adaptive immune response (AIR). CD52 is a marker of AIR stratification in breast cancer patients. We constructed a CD52-related adaptive immune response gene signature (CD52rAIRGsig) which is an independent prognostic factor for breast cancer and related to genome instability and the immune cells infiltration in the TME. CD52 and CD52rAIRGsig were associated with PD-1 signaling and immune checkpoint inhibitor markers, which proves that patients with high CD52 expression and low risk of CD52rAIRGsig are more suitable for ICI treatment. We then screened chemotherapeutics for personalized medicine based on CD52rAIRGsig. Conclusion:Therefore, we have discovered a new marker to guide the treatment and prognosis of breast cancer patients with ICIs. This provides a combined treatment strategy including different combinations of ICIs combined with chemotherapeutic drugs to treat breast cancer.

scholarly journals Activation of viral defense signaling in cancer

2018 ◽  
Vol 10 ◽  
pp. 175883591879310 ◽  
Author(s):  
Maria Gonzalez-Cao ◽  
Niki Karachaliou ◽  
Mariacarmela Santarpia ◽  
Santiago Viteri ◽  
Andreas Meyerhans ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Immune Responses ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Cancer Therapies ◽  
Microbial Infection ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

A coordinated action of innate and adaptive immune responses is required to efficiently combat a microbial infection. It has now become clear that cancer therapies also largely benefit when both arms of the immune response are engaged. In this review, we will briefly describe the current knowledge of innate immunity and how this can be utilized to prime tumors for a better response to immune checkpoint inhibitors. Comments on compounds in development and ongoing clinical trials will be provided.

scholarly journals CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ahmed Gaballa ◽  
Lucas C. M. Arruda ◽  
Emelie Rådestad ◽  
Michael Uhlin
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Gene Segment ◽  
Adaptive Immune Response ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Adaptive Immune

The role of gamma delta (γδ) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of γδ T cells in response to HCMV, shedding light on the adaptive immune response of γδ T cells. Nevertheless, most efforts have focused on Vδ2negγδ T cell subset while less attention has been given to investigate other less common γδ T cell subsets. In this regard, a distinct subpopulation of γδ T cells that expresses the CD8 coreceptor (CD8+γδ T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR γ-chain (TRG) to analyze in-depth bone marrow (BM) graft γδ T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8+γδ T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8+γδ T cells from CMV+ grafts express Vγ9- and preferentially differentiated from a naive to terminal effector memory phenotype (CD27low/-CD45RO-). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the Vγ9/JP gene segment in a CMV+ graft. Furthermore, CD8+γδ T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8-γδ T cells. We conclude that γδ T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8+γδ T cells in HCMV immune response.

scholarly journals Molecular mechanisms of macrophage Toll-like receptor–Fc receptor synergy

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 21 ◽  
Author(s):  
Michelle Lennartz ◽  
James Drake
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Recent Literature ◽  
Adaptive Immune Response ◽  
Toll Like Receptor ◽  
Toll Like Receptors ◽  
Cell Type ◽  
Fcγ Receptors ◽  
Adaptive Immune ◽  
Fine Tune

Macrophages (MØs) are a key cell type of both the innate and the adaptive immune response and can tailor their response to prevailing conditions. To sense the host’s status, MØs employ two classes of receptors: Toll-like receptors (TLRs), which are sensors for pathogen-derived material, and Fcγ receptors (FcγRs) that are detectors of the adaptive immune response. How MØs integrate the input from these various sensors is not understood and is the focus of active study. Here, we review the recent literature on the molecular mechanisms of TLR and FcgR crosstalk and synergy, and discuss the implications of these findings. This overview suggests a multilayered mechanism of receptor synergy that allows the MØ to fine-tune its response to prevailing conditions and provides ideas for future investigation.

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