scholarly journals Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Bert Malengier-Devlies ◽  
Mieke Metzemaekers ◽  
Carine Wouters ◽  
Paul Proost ◽  
Patrick Matthys
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Immune Responses ◽  
Defense Mechanisms ◽  
De Novo ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Hematopoietic Stem ◽  
Host Protection ◽  
Pass Through ◽  
Emergency Myelopoiesis

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, the de novo production of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease, i.e. systemic juvenile idiopathic arthritis.

scholarly journals Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guillaume Morelle ◽  
Martin Castelle ◽  
Graziella Pinto ◽  
Sylvain Breton ◽  
Matthieu Bendavid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Graft Versus Host Disease ◽  
Immune Thrombocytopenia ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Sustained Remission ◽  
Refractory Disease ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

scholarly journals Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis

2021 ◽  
Author(s):  
Guillaume Morelle ◽  
Martin Castelle ◽  
Graziella Pinto ◽  
Sylvain Breton ◽  
Matthieu Bendavid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Graft Versus Host Disease ◽  
Immune Thrombocytopenia ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Sustained Remission ◽  
Refractory Disease ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Background: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.Case report: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D+3 and +4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.Conclusion: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

scholarly journals Hematopoietic stem and progenitor cells are present in healthy gingiva tissue

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Siddharth Krishnan ◽  
Kelly Wemyss ◽  
Ian E. Prise ◽  
Flora A. McClure ◽  
Conor O’Boyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Myeloid Cell ◽  
Extramedullary Hematopoiesis ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Stem And Progenitor Cells

Hematopoietic stem cells reside in the bone marrow, where they generate the effector cells that drive immune responses. However, in response to inflammation, some hematopoietic stem and progenitor cells (HSPCs) are recruited to tissue sites and undergo extramedullary hematopoiesis. Contrasting with this paradigm, here we show residence and differentiation of HSPCs in healthy gingiva, a key oral barrier in the absence of overt inflammation. We initially defined a population of gingiva monocytes that could be locally maintained; we subsequently identified not only monocyte progenitors but also diverse HSPCs within the gingiva that could give rise to multiple myeloid lineages. Gingiva HSPCs possessed similar differentiation potentials, reconstitution capabilities, and heterogeneity to bone marrow HSPCs. However, gingival HSPCs responded differently to inflammatory insults, responding to oral but not systemic inflammation. Combined, we highlight a novel pathway of myeloid cell development at a healthy barrier, defining a gingiva-specific HSPC network that supports generation of a proportion of the innate immune cells that police this barrier.

An animal model of adult T-cell leukemia: humanized mice with HTLV-1–specific immunity

Blood ◽  
2014 ◽  
Vol 123 (3) ◽  
pp. 346-355 ◽  
Author(s):  
Kenta Tezuka ◽  
Runze Xun ◽  
Mami Tei ◽  
Takaharu Ueno ◽  
Masakazu Tanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Animal Model ◽  
Immune Responses ◽  
Humanized Mice ◽  
Cell Leukemia ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Adaptive Immune ◽  
Key Points

Key Points Humanized mice, IBMI-huNOG, were generated by intra–bone marrow injection of human CD133+ hematopoietic stem cells. HTLV-1–infected IBMI-huNOG mice recapitulated distinct ATL-like symptoms as well as HTLV-1–specific adaptive immune responses.

scholarly journals Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

2020 ◽  
Vol 21 (19) ◽  
pp. 6996
Author(s):  
Pablo Scharf ◽  
Milena Fronza Broering ◽  
Gustavo Henrique Oliveira da Rocha ◽  
Sandra Helena Poliselli Farsky
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Environmental Pollutants ◽  
Hematopoietic Stem ◽  
Vital Functions ◽  
Maturation Stages ◽  
And Function

Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow.

Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome

2020 ◽  
pp. annrheumdis-2020-217470
Author(s):  
Grant S Schulert ◽  
Alex V Pickering ◽  
Thuy Do ◽  
Sanjeev Dhakal ◽  
Ndate Fall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Idiopathic Arthritis ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Rna Seq ◽  
Bone Marrow Macrophage ◽  
Ifn Γ ◽  
Activation Syndrome

ObjectivesSystemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response.MethodsBulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling.ResultsBulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness.ConclusionsMacrophages with an ‘IFN-γ response’ phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.

WT1-Specific Immune Responses in Patients with High-Risk Multiple Myeloma Undergoing Allogeneic T Cell-Depleted Hematopoietic Stem Cell Transplantation Followed by Donor Lymphocyte Infusions

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1993-1993 ◽  
Author(s):  
Eleanor Tyler ◽  
Achim A Jungbluth ◽  
Richard J. O'Reilly ◽  
Guenther Koehne
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Immune Responses ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Cell Responses

Abstract Abstract 1993 Wilm's tumor protein-1 (WT1) is over-expressed in a number of solid and hematologic malignancies including multiple myeloma (MM). The emergence of WT1-specific T cells has been shown to correlate with better relapse-free survival after allogeneic stem cell transplantation in patients (pts) with hematologic malignancies, such as leukemia. In MM, the expression of WT1 in the bone marrow has been shown to correlate with numerous negative prognostic factors, including disease stage and M protein ratio. Taken together, these findings suggest that immunotherapeutic augmentation of WT1-specific immune responses, such as adoptive transfer of WT1-specific T cells, may be capable of eradicating minimal residual disease and preventing relapse in MM. Thus, we examined the significance of WT1-specific cellular immune responses in pts with relapsed MM and high-risk cytogenetics who are undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation (TCD HSCT). In this study, pts were eligible to receive low doses of donor lymphocyte infusions (DLI, 5×105-1×106 CD3+/kg) no earlier than 5 months post TCD HSCT. WT1-specific T-cell frequencies were measured in freshly isolated peripheral blood and bone marrow specimens. Frequencies were detected by staining for intracellular IFN-γ production in response to WT1 peptides, and/or by tetramer analysis, where available. Of 17 pts evaluated, all pts exhibited low frequencies of WT1-specific T-cell responses pre TCD HSCT. Ten of these pts received DLI post TCD HSCT. All 10 pts developed WT1-specific T cell responses post DLI. These increments in WT1-specific T-cell frequencies were associated with reduction in circulating myeloma proteins in all pts. Long-term evaluation demonstrated fluctuations in persisting WT1-specific T-cell frequencies following DLI. In one representative patient, a peak of 3.5% (72/ml) WT1-specific CD8+ T cells were detected in the peripheral blood by staining with the tetramer HLA-A*0201 RMF. This peak T-cell response occurred post TCD HSCT and DLI, and coincided with disease regression. This patient has remained in complete remission for more than 3 years post transplant, with fluctuating levels of WT1-specific CD8+ T cells ranging from 0.3–1.5% still persisting. Findings from concurrent molecular chimerism studies conducted on isolated T cells post TCD HSCT suggest that the WT1-specific T cells are of donor origin. Immunohistochemical analyses of WT1 and CD138 staining in MM bone marrow specimens demonstrated consistent co-expression within malignant plasma cells. WT1 expression in the bone marrow of all 6 pts tested correlated with the extent of malignant plasma cell infiltration. In contrast, no WT1 expression was observed when disease was low or absent. Taken together, our findings suggest a correlation between the emergence of WT1-specific T cells post DLI, and disease regression in pts being treated for relapsed MM. The present data support the development of adoptive immunotherapeutic approaches utilizing WT1-specific T cells for pts with MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Application of Weighted Gene Coexpression Network Analysis to Identify Key Modules and Hub Genes in Systemic Juvenile Idiopathic Arthritis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Mi Zhou ◽  
Ruru Guo ◽  
Yong-Fei Wang ◽  
Wanling Yang ◽  
Rongxiu Li ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Network Analysis ◽  
Immune Responses ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Functional Enrichment ◽  
Coexpression Network ◽  
Gene Coexpression Network ◽  
Hub Genes ◽  
Gene Coexpression ◽  
Coexpression Network Analysis

Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disorder with a still not clearly defined molecular mechanism. To better understand the disease, we used scattered datasets from public domains and performed a weighted gene coexpression network analysis (WGCNA) to identify key modules and hub genes underlying sJIA pathogenesis. Two gene expression datasets, GSE7753 and GSE13501, were used to construct the WGCNA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to the genes and hub genes in the sJIA modules. Cytoscape was used to screen and visualize the hub genes. We further compared the hub genes with the genome-wide association study (GWAS) genes and used a consensus WGCNA to verify that our conclusions were conservative and reproducible across multiple independent datasets. A total of 5,414 genes were obtained for WGCNA, from which highly correlated genes were divided into 17 modules. The red module demonstrated the highest correlation with the sJIA module ( r = 0.8 , p = 3 e − 29 ), whereas the green-yellow module was found to be closely related to the non-sJIA module ( r = 0.62 , p = 1 e − 14 ). Functional enrichment analysis demonstrated that the red module was mostly enriched in the activation of immune responses, infection, nucleosomes, and erythrocytes, and the green-yellow module was mostly enriched in immune responses and inflammation. Additionally, the hub genes in the red module were highly enriched in erythrocyte differentiation, including ALAS2, AHSP, TRIM10, TRIM58, and KLF1. The hub genes from the green-yellow module were mainly associated with immune responses, as exemplified by the genes KLRB1, KLRF1, CD160, and KIRs. We identified sJIA-related modules and several hub genes that might be associated with the development of sJIA. Particularly, the modules may help understand the mechanisms of sJIA, and the hub genes may become biomarkers and therapeutic targets of sJIA in the future.

Identification of Thymus Settling Progenitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2677-2677
Author(s):  
Benjamin A. Schwarz ◽  
Avinash Bhandoola
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Adult Life ◽  
Hematopoietic Stem ◽  
Adult Mice ◽  
Multipotent Progenitors ◽  
Pass Through ◽  
Adult Thymus

Abstract T cells develop in the thymus, but are ultimately derived from hematopoietic stem cells (HSCs) that reside in the bone marrow. In order to produce T cells throughout adult life, the thymus must be periodically seeded by bone marrow progenitors via the blood. The identity of progenitors that seed the adult thymus is unknown. To determine which bone marrow progenitors that have access to they thymus, we analyzed the blood of adult mice (Schwarz & Bhandoola, Nature Immunology 2004). We found that the only progenitors in blood with T lineage potential were lineage negative cells with high expression of Sca-1 and c-Kit (LSK). Such LSK cells in blood were potent T lineage progenitors, with the capacity to expand over a million fold in the thymus. Like the corresponding population in the bone marrow, the blood LSK population was heterogeneous, containing HSCs and downstream multipotent progenitors (MPPs) including RAG-expressing early lymphoid progenitors (ELPs) and CD62L+ cells. In order to determine which of these LSK subsets can settle in the thymus, we developed a quantitative assay for thymic seeding in normal adult mice. We find that the fraction of LSK cells that settle in the thymus from the blood is extremely small. Of the estimated 3,000 to 4,000 LSK cells that pass through the thymic circulation each day, less than 10 cells are able to settle in the thymus. Our data suggest that any decrease in thymic seeding, as may occur in aging, would lead to a decrease in total thymic output.

Activation of AKT1 in Hematopoietic Stem Cells Causes a Myeloproliferative Disease in a Tet-Inducible Mouse Model.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1356-1356
Author(s):  
Christian Brandts ◽  
Miriam Rode ◽  
Beate Lindtner ◽  
Gabriele Koehler ◽  
Steffen Koschmieder ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mouse Model ◽  
Hematopoietic Stem Cells ◽  
De Novo ◽  
Myeloproliferative Disorder ◽  
Myeloproliferative Disease ◽  
Hematopoietic Stem ◽  
Akt Phosphorylation

Abstract Activating mutations in Flt3, N- and K-Ras have been reported in all AML subtypes and represent common molecular defects in de novo AML. We have previously shown that these mutations lead to constitutive AKT phosphorylation and activation. As a consequence, Akt phosphorylation is found in myeloid blasts of the majority of AML patients. We reasoned that constitutively active AKT may contribute to leukemia development, and therefore we assessed the contribution of AKT in oncogenic transformation in vivo. For this purpose, we established an inducible mouse model expressing myristylated AKT1 under the control of the scl-3′ enhancer (MyrAKT1). This system restricts activated AKT1 to endothelium, hematopoietic stem cells and myeloid lineage cells at a low but detectable level. About 40% of induced mice developed a myeloproliferative disorder after latencies of 7 to 22 months. Onset of disease was frequently associated with hemangioma formation, due to endothelial MyrAKT1 expression. The myeloproliferative disorder was associated with splenomegaly with increased extramedullary hematopoiesis, while the peripheral blood contained mature granulocytes. Furthermore, the stem cell and progenitor cell compartment in spleens and bone marrow of these mice was altered compared to control mice. Colony formation assays with MyrAKT1-expressing bone marrow suggested that overactivation of AKT1 enhanced proliferation. The AKT1-induced disease was transplantable by both bone marrow and spleen cells. These findings highlight the oncogenic capacity of constitutively activated AKT1 in vivo and indicate that AKT is an attractive target for therapeutic intervention in AML.

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