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NK cells missing hypothesis

Karl-Johan Malmberg, Ebba Sohlberg, Jodie P Goodridge, Hans-Gustaf Ljunggren
The ability of NK cells to specifically recognize cells lacking expression of self-MHC class I molecules was discovered over 30 years ago. It provided the foundation for the "missing self" hypothesis. Research in the two past decades has contributed to a detailed understanding of the molecular mechanisms that determine the specificity and strength of NK cell-mediated "missing self" responses to tumor cells. However, in light of the recent remarkable breakthroughs in clinical cancer immunotherapy, the cytolytic potential of NK cells still remains largely untapped in clinical settings...
August 2017: Immunogenetics
Daniele Kazue Sugioka, Carlos Eduardo Ibaldo Gonçalves, Maria da Graça Bicalho
BACKGROUND: Since the discovery of specific histocompatibility, literature has associated genes involved in the immune response, like the Human Leucocyte Antigen (HLA), with a better prognosis in transplantation. However, other non-HLA genes may also influence the immune process, such as the genes encoding the immunoglobulin-like receptors of natural killer cells (KIRs). The discovery that NK cell KIR receptors interact with conservative epitopes (C1, C2, Bw4) presented in HLA class I molecules that are genetically polymorphic, also observed in KIR genes, led to the investigation of the relevance of the KIR system to hematopoietic stem cell transplant...
2016: BMC Hematology
Md Ashik Ullah, Geoffrey R Hill, Siok-Keen Tey
Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are important in mediating immunity against both leukemia and pathogens. Although NK cell numbers generally reconstitute within a month, the acquisition of mature NK cell phenotype and full functional competency can take 6 months or more, and is influenced by graft composition, concurrent pharmacologic immunosuppression, graft-versus-host disease, and other clinical factors...
2016: Frontiers in Immunology
Samuel E Marsh, Edsel M Abud, Anita Lakatos, Alborz Karimzadeh, Stephen T Yeung, Hayk Davtyan, Gianna M Fote, Lydia Lau, Jason G Weinger, Thomas E Lane, Matthew A Inlay, Wayne W Poon, Mathew Blurton-Jones
The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology...
March 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
M Koch, A Lemke, C Lange
Application of mesenchymal stromal cells (MSC) has been proposed for solid organ transplantation based on their potent immunomodulatory effects. Since side effects from the injection of large cells cannot be excluded, the hypothesis rises that extracellular vesicles (EV) may cause immunomodulatory effects comparable to MSC without additional side effects. We used MSC-derived EV in a rat renal transplant model for acute rejection. We analysed peripheral blood leukocytes (PBL), kidney function, graft infiltrating cells, cytokines in the graft, and alloantibody development in animals without (allo) and with EV application (allo EV)...
2015: Stem Cells International
Shoko Kimura, Kikumi S Ozaki, Shinya Ueki, Matthew Zhang, Shinichiro Yokota, Donna B Stolz, David A Geller, Noriko Murase
Hepatic ischemia/reperfusion injury (IRI) remains a major clinical problem and involves the innate immune system's recognition of "nonself." Considering the efficient nonself recognition by natural killer (NK) cells, we hypothesize in this study that hepatic IRI associated with liver transplantation (LT) could be augmented in allogeneic rather than in syngeneic (Syn) grafts due to alloantigen recognition by innate immune cells, especially by NK cells. Using green fluorescent protein (GFP)/Sprague-Dawley rats, we tested our hypothesis in a rat LT model with 18 hours of cold storage in University of Wisconsin solution...
January 2016: Liver Transplantation
Bent Rolstad
In this review, I summarize some of the early research on NK cell biology and function that led to the discovery of a totally new receptor system for polymorphic MHC class I molecules. That NK cells both could recognize and kill tumor cells but also normal hematopoietic cells through expression of MHC class I molecules found a unifying explanation in the "missing self" hypothesis. This initiated a whole new area of leukocyte receptor research. The common underlying mechanism was that NK cells expressed receptors that were inhibited by recognition of unmodified "self" MHC-I molecules...
2014: Frontiers in Immunology
Megan M Tu, Ahmad Bakur Mahmoud, Andrew Wight, Amelia Mottashed, Simon Bélanger, Mir Munir A Rahim, Elias Abou-Samra, Andrew P Makrigiannis
According to the missing-self hypothesis, natural killer (NK) cells survey for target cells that lack MHC-I molecules. The Ly49 receptor family recognizes loss of MHC-I and is critical for educating NK cells, conferring the ability to eliminate transformed or infected cells. In this study, we evaluated their requirement in innate immune surveillance of cancer cells using genetically manipulated mice with attenuated expression of Ly49 receptors (NKC(KD)) in several models of carcinoma and metastasis. We found that NKC(KD) mice exhibited uncontrolled tumor growth and metastases...
July 15, 2014: Cancer Research
Martin A Ivarsson, Jakob Michaëlsson, Cyril Fauriat
Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed "licensing" or "education," and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells...
2014: Frontiers in Immunology
Bree Foley, Martin Felices, Frank Cichocki, Sarah Cooley, Michael R Verneris, Jeffrey S Miller
Natural killer (NK) cells were first identified for their capacity to reject bone marrow allografts in lethally irradiated mice without prior sensitization. Subsequently, human NK cells were detected and defined by their non-major histocompatibility complex (MHC)-restricted cytotoxicity toward transformed or virally infected target cells. Karre et al. later proposed 'the missing self hypothesis' to explain the mechanism by which self-tolerant cells could kill targets that had lost self MHC class I. Subsequently, the receptors that recognize MHC class I to mediate tolerance in the host were identified on NK cells...
March 2014: Immunological Reviews
Céline Baier, Aurore Fino, Carole Sanchez, Laure Farnault, Pascal Rihet, Brigitte Kahn-Perlès, Régis T Costello
Hematological malignancies (HM) treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed, due to remaining minimal residual disease. Therefore, sustainment of long-term remission is crucial, using either drug maintenance treatment or by boosting or prolonging an immune response. Immune system has a key role in tumor surveillance. Nonetheless, tumor-cells evade the specific T-lymphocyte mediated immune surveillance using many mechanisms but especially by the down-regulation of the expression of HLA class I antigens...
December 19, 2013: Frontiers in Immunology
Tsai-Hsia Hong, Shuenn-Wen Kuo, Fu-Chang Hu, Wen-Je Ko, Li-Ming Hsu, Shu-Chien Huang, Ya-Wen Yang, Sung-Liang Yu, Yih-Sharng Chen
Extracorporeal membrane oxygenation (ECMO) is used for cardiogenic shock rescue. It is hard to predict the outcome from this treatment by clinical observation in days soon after installation. We analyzed the plasma levels of interleukin (IL)-6, IL-8, IL-10, reactive oxygen species, and 8-OHdG, and the glutathione peroxidase activities from 23 cases at the time of ECMO installation before resuscitation. Generalized additive models (GAM) were performed to identify the death ranges of every variable, and the variables were further discretized...
January 1, 2014: Antioxidants & Redox Signaling
R J Boyton, C J Reynolds, K J Quigley, D M Altmann
Recent studies analysing immunogenetics and immune mechanisms controlling susceptibility to chronic bacterial infection in bronchiectasis implicate dysregulated immunity in conjunction with chronic bacterial infection. Bronchiectasis is a structural pathological end-point with many causes and disease associations. In about half of cases it is termed idiopathic, because it is of unknown aetiology. Bronchiectasis is proposed to result from a 'vicious cycle' of chronic bacterial infection and dysregulated inflammation...
February 2013: Clinical and Experimental Immunology
Katerina N Bambang, David G Lambert, Patricia M W Lam, Siobhan Quenby, Mauro Maccarrone, Justin C Konje
The success of pregnancy is dependent on a number of different cell types and signalling pathways, including immune cells which play a vital role in implantation. Immune cells express transcripts for all of the components of the endocannabinoid system, but the role of this system in the function of reproductive tract immune cells is still unclear. In this review, we present the hypothesis that the endocannabinoid signalling system is central to an endocannabinoid-immune-reproductive axis, and that it acts as the link via which immune cells exert their vital influence on implantation and foetal tolerance...
December 2012: Journal of Reproductive Immunology
Regis T Costello, Cyril Fauriat, Daniel Olive
Extract: Under specific conditions, the immune response can eradicate tumors. The specific response against cancer requires the recognition of target molecules (antigens) by a subpopulation of white blood cells, the T lymphocytes. These antigens are exclusively or predominantly expressed by the tumor cells. Since many tumors fail to express specific antigens or express these antigens in a "wrong" way that impairs their recognition, cancer cells frequently escape from the specific immune response. Nonetheless, alternate effector cell populations have been described that are able to destroy tumor cells without any requirement for recognition of cancer-specific antigens...
October 2004: Discovery Medicine
Omodele Ashiru, Neil J Bennett, Louise H Boyle, Mair Thomas, John Trowsdale, Mark R Wills
Human cytomegalovirus (HCMV) evades T-cell recognition by down-regulating expression of major histocompatibility complex (MHC) class I and II molecules on the surfaces of infected cells. Contrary to the "missing-self" hypothesis, HCMV-infected cells are refractory to lysis by natural killer (NK) cells. Inhibition of NK cell function is mediated by a number of HCMV immune evasion molecules, which operate by delivering inhibitory signals to NK cells and preventing engagement of activating ligands. One such molecule is UL142, which is an MHC class I-related glycoprotein encoded by clinical isolates and low-passage-number strains of HCMV...
December 2009: Journal of Virology
Marianne J van den Heuvel, Kota Hatta, Crystal G Peralta, Victor K Han, David A Clark
PROBLEM: Uterine natural killer (uNK) cells are enriched in the post-ovulatory uterus and during pregnancy. Whether these cells arise from blood pre-cursors or from stem cells in the uterus is undefined. To support a hypothesis that precursors of uNK cells are recruited from blood, adhesive function of blood CD56+ subsets were assessed during one cycle and during pregnancy. METHOD OF STUDY: Fifteen women of proven fertility provided serial blood samples during one menstrual cycle and thirty women with a history of implantation failure or recurrent spontaneous abortion provided serial samples during infertility treatment...
February 2008: American Journal of Reproductive Immunology: AJRI
Ellen Kreijveld, Arnold van der Meer, Henk J Tijssen, Luuk B Hilbrands, Irma Joosten
BACKGROUND: The identification of transplant patients at high risk for rejection after reduction of immunosuppression would allow minimization of immunosuppression and avoidance of side effects in low-risk patients. Next to T cells, innate natural killer (NK) cells may contribute to graft rejection. NK cell activation depends on the balance between activating and inhibitory signals, delivered by self-human leukocyte antigens (HLA) through binding of killer-cell immunoglobulin receptors (KIR)...
October 27, 2007: Transplantation
Alessandro Poggi, Claudia Prevosto, Marta Zancolli, Paolo Canevali, Alessandra Musso, Maria Raffaella Zocchi
It is thought that human natural killer (NK) lymphocytes should not damage self-tissues due to the inhibiting signal initiated by the engagement of one or another inhibitory receptor superfamily (IRS) members with self-human histocompatibility antigen (HLA)-I. During viral infection, the low expression of self-HLA-I on infected-cells leads to a reduction of the inhibiting signal and thus NK cells kill self-cells (missing self-hypothesis). Here, we have analyzed human NK cell interaction with self-cells as antigen-presenting cells (APC) or stromal cells isolated from bone marrow or skin...
August 2007: Annals of the New York Academy of Sciences
Alessandro Poggi, Maria Raffaella Zocchi
Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of inhibitory receptor superfamily (IRS) members by HLA-I. Nevertheless, NK cells kill self cells expressing low levels or lacking HLA-I, as it may occur during viral infections (missing-self hypothesis). Herein, we show that human NK cells can be activated upon binding with self antigen presenting cells or stromal cells despite the expression of HLA-I. Indeed, NK cells can kill and produce pro-inflammatory and regulating cytokines as IFN-gamma, TNF-alpha and IL10 during interaction with autologous dendritic cells or bone marrow stromal cells or skin fibroblasts...
June 2006: Clinical & Developmental Immunology
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