scholarly journals Ikaros-Associated Diseases: From Mice to Humans and Back Again

2021 ◽  
Vol 9 ◽  
Author(s):  
Brigette Boast ◽  
Cristiane de Jesus Nunes-Santos ◽  
Hye Sun Kuehn ◽  
Sergio D. Rosenzweig
Keyword(s):  
Immune System ◽  
Immune Dysregulation ◽  
Single Amino Acid ◽  
Human Immune System ◽  
Immune Systems ◽  
Associated Diseases ◽  
Normal Expression ◽  
Extreme Phenotypes ◽  
Human Immune ◽  
Entire Gene

The normal expression of Ikaros (IKZF1) is important for the proper functioning of both the human and murine immune systems. Whilst our understanding of IKZF1 in the immune system has been greatly enhanced by the study of mice carrying mutations in Ikzf1, analyses of human patients carrying germline IKZF1 mutations have been instrumental in understanding its biological role within the human immune system and its effect on human disease. A myriad of different mutations in IKZF1 have been identified, spanning across the entire gene causing differential clinical outcomes in patients including immunodeficiency, immune dysregulation, and cancer. The majority of mutations in humans leading to IKAROS-associated diseases are single amino acid heterozygous substitutions that affect the overall function of the protein. The majority of mutations studied in mice however, affect the expression of the protein rather than its function. Murine studies would suggest that the complete absence of IKZF1 expression leads to severe and sometimes catastrophic outcomes, yet these extreme phenotypes are not commonly observed in patients carrying IKZF1 heterozygous mutations. It is unknown whether this discrepancy is simply due to differences in zygosity, the role and regulation of IKZF1 in the murine and human immune systems, or simply due to a lack of similar controls across both groups. This review will focus its analysis on the current literature surrounding what is known about germline IKZF1 defects in both the human and the murine immune systems, and whether existing mice models are indeed accurate tools to study the effects of IKZF1-associated diseases.

scholarly journals Gene Expression Analysis Reveals Age and Ethnicity Signatures Between Young and Old Adults in Human PBMC

2021 ◽  
Author(s):  
Yang Hu ◽  
Yudai Xu ◽  
Lipeng Mao ◽  
Wen Lei ◽  
Jan Jian Xiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Human Immune System ◽  
Immune Systems ◽  
Network Analyses ◽  
Age Related ◽  
Human Immune

Abstract Background: Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Therefore, the aim of this study is to exploit a large-scale population-based strategy to systematically identify genes and pathways differentially expressed as a function of chronological age. Despite the importance of age and race in shaping immune cell numbers and functions, it is unclear whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated variations are shared among ethnicities. Results: Here, we characterize peripheral blood mononuclear cells transcriptome from 19 healthy adults of RNA-seq data and 153 healthy subjects of micoarray data with 21~90 years of age using the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Conclusion: Overall, our findings reveal how age and race differentially affect the immune systems between Asian and Caucasian, as well as discovered a common genetic variant that greatly impacts normal PBMC aging between Asian and Caucasian.

scholarly journals Increasing Hematopoietic Stem Cell Yield to Develop Mice with Human Immune Systems

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Juan-Carlos Biancotti ◽  
Terrence Town
Keyword(s):  
Immune System ◽  
Culture Media ◽  
Ex Vivo ◽  
Trophic Factors ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Human Immune System ◽  
Hematopoietic Stem ◽  
Immune Systems ◽  
Human Immune

Hematopoietic stem cells (HSCs) are unique in their capacity to give rise to all mature cells of the immune system. For years, HSC transplantation has been used for treatment of genetic and neoplastic diseases of the hematopoietic and immune systems. The sourcing of HSCs from human umbilical cord blood has salient advantages over isolation from mobilized peripheral blood. However, poor sample yield has prompted development of methodologies to expand HSCsex vivo. Cytokines, trophic factors, and small molecules have been variously used to promote survival and proliferation of HSCs in culture, whilst strategies to lower the concentration of inhibitors in the culture media have recently been applied to promote HSC expansion. In this paper, we outline strategies to expand HSCsin vitro, and to improve engraftment and reconstitution of human immune systems in immunocompromised mice. To the extent that these “humanized” mice are representative of the endogenous human immune system, they will be invaluable tools for both basic science and translational medicine.

Should we Try to Alleviate Immunosenescence and Inflammaging - Why, How and to What Extent?

2019 ◽  
Vol 25 (39) ◽  
pp. 4154-4162 ◽  
Author(s):  
Jacek M. Witkowski ◽  
Ewa Bryl ◽  
Tamas Fulop
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Immune Cells ◽  
Malignant Neoplasm ◽  
Human Beings ◽  
Therapeutic Approaches ◽  
Human Immune System ◽  
Immune Systems ◽  
Human Immune

With advancing age, immune responses of human beings to external pathogens, i.e., bacteria, viruses, fungi and parasites, and to internal pathogens - malignant neoplasm cells - become less effective. Two major features in the process of aging of the human immune system are immunosenescence and inflammaging. The immune systems of our predecessors co-evolved with pathogens, which led to the occurrence of effective immunity. However, the otherwise beneficial activity may pose problems to the organism of the host and so it has builtin brakes (regulatory immune cells) and - with age - it undergoes adaptations and modifications, examples of which are the mentioned inflammaging and immunosenescence. Here we describe the mechanisms that first created our immune systems, then the consequences of their changes associated with aging, and the mechanisms of inflammaging and immunosenescence. Finally, we discuss to what extent both processes are detrimental and to what extent they might be beneficial and propose some therapeutic approaches for their wise control.

Neonatal NOD/SCID/IL2rg-Null Mice Support the Functional Development of Human Hematopoietic and Immune Systems.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2781-2781 ◽  
Author(s):  
Fumihiko Ishikawa ◽  
Masaki Yasukawa ◽  
Bonnie Lyons ◽  
Shuro Yoshida ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Peripheral Blood ◽  
Human Immune System ◽  
Immune Systems ◽  
New Model ◽  
Cd34 Cells ◽  
Human Immune

Abstract (Purpose) We aimed to develop a new model for studying the development of a human hematopoietic and immune systems in vivo. (Methods) In order to establish a new model of xenogeneic transplantation, we establish an immune-compromised strain, NOD.Cg-PrkdcscidIL2rgtmlWjl/Sz (NOD/SCID/IL2rg-null) mice by backcrossing a complete null mutation of the IL2 receptor common gamma chain (IL2rg) onto the NOD/SCID background. 1 x 105 human CB-derived lineage antigen negative (Lin−) CD34+ cells were intravenously transplanted into newborn NOD/SCID/IL2rg-null mice following 100cGy irradiation. At 3 months post-transplantation, the engraftment of human cells was evaluated by flow cytometric analysis, immunostaining, and functional assays for production of human immunoglobulin and T-cell cytotoxicity against allogeneic cells. (Results) NOD/SCID/IL2rg-null mice showed extremely low activity of NK cells along with the complete lack of mature B cells and T cells. During post-natal development of the NOD/SCID/IL2rg-null mice, a human hematopoietic system was developed following injection of human CB-derived Lin-CD34+ cells. In BM of the recipient mice, human glycophorin A+ erythroid cells were present at 9.5 +/− 6.2% (n=5), and human CD41+ megakaryocytes were present at 1.64 +/− 0.42% (n=5). Human CB-derived Lin−CD34+ cells generated multi-lineage leukocytes, CD33+ myeloid cells, CD19+ B cells, and CD3+ T cells. The engraftment level of human CD45+ cells in peripheral blood was significantly higher (68.9 +/− 11.6%, n=5) in NOD/SCID/IL2rg-null mice than that in NOD/SCID/b2mnull mice (12.4 +/− 5.9%, n=4). Mature erythrocytes and platelets were identified in peripheral blood. The xenogeneic environment supported the systemic development of a human immune system, containing each stage of B cells and T cells in primary and secondary lymphoid tissues. CD34+CD19+ pro-B cells, CD10+CD19+ B cells, and CD19+CD20hi mature B cells were identified in the BM and spleen. Immature CD4+CD8+ double positive T cells were the major cell populations in the thymus, while spleen contained abundant single positive T cells at 1.39 +/− 0.61 (n=5) CD4/CD8 ratio, suggesting that human CB stem/progenitor-derived T cells underwent the maturation and proliferation similarly as identified in human body. Transplanted human stem cells reconstituted mucosal immunity in intestinal tracts as evidenced by human IgA+ B cells and CD3+ T cells. Adaptive human immune system cooperatively functioned in xenogeneic environment to produce antigen-specific human IgM and IgG antibodies, when engrafted mice were immunized with ovalbumin. Furthermore, human CD4+ T cells as well as CD8+ T cells generated in the xenogeneic host exerted cytotoxicity against allogeneic target cells. (Conclusion) The neonatal NOD/SCID/IL2rg-null model will facilitate studying post-natal development of the human hematopoietic and immune systems and for studying of human immune surveillance in vivo against exogenous antigens.

721 AT1412, a patient-derived CD9 antibody in preclinical development promoting tumor immune infiltration and inducing tumor rejection

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A763-A763
Author(s):  
Remko Schotte ◽  
Julien Villaudy ◽  
Martijn Kedde ◽  
Wouter Pos ◽  
Daniel Go ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Rejection ◽  
Human Immune System ◽  
Preclinical Development ◽  
High Affinity ◽  
Human Immune ◽  
A375 Melanoma

BackgroundAdaptive immunity to cancer cells forms a crucial part of cancer immunotherapy. Recently, the importance of tumor B-cell signatures were shown to correlate with melanoma survival. We investigated whether tumor-targeting antibodies could be isolated from a patient that cured (now 13 years tumor-free) metastatic melanoma following adoptive transfer of ex vivo expanded autologous T cells.MethodsPatient‘s peripheral blood B cells were isolated and tested for the presence of tumor-reactive B cells using AIMM’s immmortalisation technology. Antibody AT1412 was identified by virtue of its differential binding to melanoma cells as compared to healthy melanocytes. AT1412 binds the tetraspanin CD9, a broadly expressed protein involved in multiple cellular activities in cancer and induces ADCC and ADCP by effector cells.ResultsSpontaneous immune rejection of tumors was observed in human immune system (HIS) mouse models implanted with CD9 genetically-disrupted A375 melanoma (A375-CD9KO) tumor cells, while A375wt cells were not cleared. Most notably, no tumor rejection of A375-CD9KO tumors was observed in NSG mice, indicating that blockade of CD9 makes tumor cells susceptible to immune rejection.CD9 has been described to regulate integrin signaling, e.g. LFA-1, VLA-4, VCAM-1 and ICAM-1. AT1412 was shown to modulate CD9 function by enhancing adhesion and transmigration of T cells to endothelial (HUVEC) cells. AT1412 was most potently enhancing transendothelial T-cell migration, in contrast to a high affinity version of AT1412 or other high affinity anti-CD9 reference antibodies (e.g. ALB6). Enhanced immune cell infiltration is also observed in immunodeficient mice harbouring a human immune system (HIS). AT1412 strongly enhanced CD8 T-cell and macrophage infiltration resulting in tumor rejection (A375 melanoma). PD-1 checkpoint blockade is further sustaining this effect. In a second melanoma model carrying a PD-1 resistant and highly aggressive tumor (SK-MEL5) AT1412 together with nivolumab was inducing full tumor rejection, while either one of the antibodies alone did not.ConclusionsThe safety of AT1412 has been assessed in preclinical development and is well tolerated up to 10 mg/kg (highest dose tested) by non human primates. AT1412 demonstrated a half-life of 8.5 days, supporting 2–3 weekly administration in humans. Besides transient thrombocytopenia no other pathological deviations were observed. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically. The thrombocytopenia is reversible, and its recovery accelerated in those animals developing anti-drug antibodies. First in Human clinical study is planned to start early 2021.Ethics ApprovalStudy protocols were approved by the Medical Ethical Committee of the Leiden University Medical Center (Leiden, Netherlands).ConsentBlood was obtained after written informed consent by the patient.

scholarly journals Transplacental priming of the human immune system with environmental allergens can occur early in gestation

2000 ◽  
Vol 106 (3) ◽  
pp. 530-536 ◽  
Author(s):  
Zsolt Szépfalusi ◽  
Josefa Pichler ◽  
Stefan Elsässer ◽  
Katalin van Duren ◽  
Christof Ebner ◽  
...  
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Human Immune

scholarly journals Antimicrobial peptides: The ancient arm of the human immune system

Virulence ◽  
2010 ◽  
Vol 1 (5) ◽  
pp. 440-464 ◽  
Author(s):  
Jochen Wiesner ◽  
Andreas Vilcinskas
Keyword(s):  
Immune System ◽  
Antimicrobial Peptides ◽  
Human Immune System ◽  
Human Immune

On the use of multiple heterogeneous devices to speedup the execution of a computational model of the Human Immune System

2015 ◽  
Vol 267 ◽  
pp. 304-313 ◽  
Author(s):  
T.M. do Nascimento ◽  
J.M. de Oliveira ◽  
M.P. Xavier ◽  
A.B. Pigozzo ◽  
R.W. dos Santos ◽  
...  
Keyword(s):  
Immune System ◽  
Computational Model ◽  
Human Immune System ◽  
Heterogeneous Devices ◽  
Human Immune

Al-Muddaththir of the Quran Linked to the Covid-19 and Spanish Flu Pandemics: Circumstantial Evidence

2021 ◽  
Vol 02 (02) ◽  
Author(s):  
Baback Khodadoost ◽  
Keyword(s):  
Immune System ◽  
Circumstantial Evidence ◽  
The Moon ◽  
Human Immune System ◽  
Main Emphasis ◽  
Spanish Flu ◽  
Human Immune

Recently there have been speculations concerning a possible link between the covid-19 pandemic and al-Muddaththir, the 74th chapter of the Quran. An examination of this chapter presented in this article shows further evidences in support of these speculations. It is shown that indications of not only the current Covid-19 pandemic, but also the horrific 1918 Spanish flu can be detected in chapter 74. The main emphasis of this article will be to demonstrate the timings of the pandemic events as they appear to have been encoded in four of the chapter verses. The concept of Translational-Coding and in particular, its use in decoding one of the time-informing verses will be explained. A remarkable scheme of al-Muddaththir to announce the exact occurring years of the two major pandemics, will also be exposed. Coincidences of the Super Moon occurrences with major events of both, Covid-19 and Spanish flu pandemics, will be shown as the possible reason for “by the moon” swearing in verse 74:32. In connection with these observed coincidences, possible effect of the moon’s differential gravity on suppression of the human immune system during a Super Moon occurrence will be addressed. Some other verses in al-Muddaththir with possible relevance to the pandemic perspective of this chapter will also be discussed.

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